The discovery and structure-activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ET(B) receptor

The systematic modification of the ETA selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ETB selective antagonists is reported. The reversal in selectivity was brought about by substitution of the 4-position with aryl and substituted aryl groups. Of all the aromatic substituents studied, the para-tolyl group gave rise to the most active and selective ETB antagonist. Larger substituents caused a decrease in both ETB activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ETA receptor antagonists. The para-tolyl group was again found to be optimal for the ETB activity and selectivity. The structural features that were found to be favorable for binding to the ETB receptor, that is, the presence of a linear, conjugated pi-system of definite shape and size, have been successfully incorporated into the design of ETB selective polycyclic aromatic sulfonamides antagonists.     

Long-term test-retest reliability of personality disorder diagnoses in opiate dependent patients

Continuous wave Doppler methods have been widely used clinically for evaluating the severity of aortic regurgitation; however, there have been no studies comparing these continuous wave Doppler methods with a strictly quantifiable reference for regurgitant severity. The purpose of this study was to test the applicability of continuous wave Doppler methods (deceleration slope and pressure half-time) for evaluation of chronic aortic regurgitation in an animal model. Eight sheep were studied 8 to 20 weeks after surgery to create chronic aortic regurgitation. Twenty-nine hemodynamically different states were obtained pharmacologically. A Vingmed 775 system was used for recording continuous wave Doppler traces with a 5 MHz annular array transducer directly placed on the heart near the apex. The aortic regurgitation was quantified as peak and mean regurgitant flow rates, regurgitant stroke volumes and regurgitant fractions determined with pulmonary and aortic electromagnetic flow probes and meters balanced against each other. Peak regurgitant flow rates varied from 1.8 to 13.6 L/min (6.3 +/- 3.2 L/min) (mean +/- SD), mean regurgitant flow rates varied from 0.7 to 4.9 L/min (2.7 +/- 1.3 L/min), regurgitant stroke volume varied from 7.0 to 48.0 ml/beat (26.9 +/- 12.2 ml/beat), and regurgitant fraction varied from 23% to 78% (53% +/- 16%). Only marginal correlations were obtained between reference indexes and continuous wave Doppler deceleration slope and pressure half-time (r = 0.55 to 0.74). A deceleration slope greater than 3 m/sec2 and pressure half-time less than 400 msec did, however, provide 100% specificity for detecting severe AR (regurgitant fraction > 50%). Our study shows that the continuous wave Doppler deceleration slope and pressure half-time methods have limited use for quantifying aortic regurgitation.     

The lives of female physicians

Survey data from 113 female physicians, 634 male physicians, and 41 female dentists were compared. Instruments designed to assess work satisfaction, work stress, marital satisfaction, family competence, and psychiatric symptoms and treatment were used, thereby exploring important life domains concurrently. The results suggest that female physicians are much more like both male physicians and female dentists than anticipated. Generally, female physicians describe high levels of work satisfaction, moderate levels of work stress, average-to-high levels of marital satisfaction, and relatively low levels of psychiatric distress. Their lower levels of practice income remain something of an enigma as gender remains the most powerful predictor of income and is not replaced in statistical analyses by specialty, hours worked, or other significant variables. Finally, female physicians who find higher levels of satisfaction in work also report higher levels of marital satisfaction and fewer psychiatric symptoms. For these women, a highly satisfying medical career does not apparently need to be experienced at the cost of marital or personal distress.     

Fluoridation in Anglesey 1993: a clinical study of dental caries in 5-year-old children who had experienced sub-optimal fluoridation

Several studies since the commencement of fluoridation in 1955 have demonstrated over 50% reduction in mean dmft for 5-year-old Anglesey children in comparison with local control groups. From 1987 fluoridation became intermittent and in 1991 it was terminated. In the present study, carried out in 1993, the total number of children examined was 725 (88.4% of the entire population of 5-year-old school children), of whom 498 had continually resided in specific water distribution zones. The mean dmft for the entire number examined was 2.01 (SD = 3.27). For those who had experienced fluoridation during approximately 35% of their lives (n = 230) it was 1.81 (SD = 2.86) and for those who had experienced fluoridation for less than 10% of their lives (n = 268) it was 2.28 (SD = 3.48). In 1987/88, the last year of optimal fluoridation, the mean dmft of Anglesey 5-year-old children was 0.80 (SD = 1.43) and for those resident on the non-fluoridated Gwynedd mainland it was 2.26 (SD = 3.17). The study demonstrates the serious consequences for dental health when fluoridation is withdrawn and how difficult it will be to reach dental health targets in North Wales without fluoridation.     

Intraoperative echocardiography is indicated in high-risk coronary artery bypass grafting

BACKGROUND: Intraoperative echocardiography is a valuable monitoring and diagnostic technology used in cardiac surgery. This reports our clinical study of the usefulness of intraoperative echocardiography to both surgeons and anesthesiologists for high-risk coronary artery bypass grafting. METHODS: From March to November 1995, 82 consecutive high-risk patients undergoing coronary artery bypass grafting were studied in a four-stage protocol to determine the efficacy of intraoperative echocardiography in management planning. Alterations in surgical and anesthetic/hemodynamic management initiated by intraoperative echocardiography findings were documented in addition to perioperative morbidity and mortality. RESULTS: Intraoperative echocardiography initiated at least one major surgical management alteration in 27 patients (33%) and at least one major anesthetic/hemodynamic change in 42 (51%). Mortality and the rate of myocardial infarction in this consecutive high-risk study population using intraoperative echocardiography and in a similar group of patients without the use of intraoperative echocardiography was 1.2% versus 3.8% (not significant) and 1.2% versus 3.5% (not significant), respectively. CONCLUSIONS: We conclude that when all of the isolated diagnostic and monitoring applications of perioperative echocardiography are routinely and systematically performed together, it is a safe and viable tool that significantly affects the decision-making process in the intraoperative care of high-risk patients undergoing primary isolated coronary artery bypass grafting and may contribute to the optimal care of these patients.     

Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients

To determine whether matrix metalloproteinase (MMP)-9 is a potential mediator involved in the frequently detected blood-brain barrier leakage in human immunodeficiency virus (HIV)-infected patients, zymography was used to detect MMP-9 activity in cerebrospinal fluid (CSF) samples of 80 HIV-infected patients and of 10 control patients. CSF MMP-9 activity was detected in 40% of HIV-infected patients (but not in controls) and was significantly more frequent in HIV-infected patients than in those without neurologic deficits (50% vs. 13.6%). The frequency of CSF MMP-9 activity did not significantly differ between neurologically symptomatic HIV-infected patients with or without opportunistic central nervous system disease (51.6% vs. 48.1%). Additionally, the presence of CSF MMP-9 activity in HIV-infected patients was associated with an increased CSF white blood cell count and an elevated CSF-to-serum albumin ratio, suggesting that it may play a role in blood-brain/CSF barrier leakage in HIV-infected patients.