Biomedical subjects
Publications and source records attributed to J Dupuis.
A polar bear (Ursus maritimus) cub, delivered by a cesarean section, was diagnosed with congenital agenesis of the radius on the basis of clinical presentation and radiology. A specific etiology could not be ascertained. Agenesis of the radius has not been previously reported in any nondomestic species.
Orally active nonpeptide antagonists of endothelin (ET) receptors may prove beneficial in the treatment of cardiovascular and renal disease. The pharmacodynamics and pharmacokinetics of these drugs are not sufficiently known, and practical methods for their analysis have not been developed. We describe a simple, sensitive, and reproducible radioreceptor assay (RRA) for LU135252, a selective antagonist of the ETA receptor, using porcine aortic smooth muscle membranes as the acceptor and 125I-endothelin-1 as the ligand. With methanol extraction of plasma and urine samples, recovery of LU135252 ranged from 79% to 91% at 60-1000 nmol/L. The logit-log transformed calibration curves constructed with LU135252 added to plasma or to urine were linear (r = 0.993 +/- 0.005, n = 11) in the range from 18.7 to 2400 nmol/L. The detection limit with plasma- and urine-based calibration curves was 19 nmol/L. The interassay coefficient of variation was 12.6% at 70 nmol/L (n = 9) and 6.5% at 590 nmol/L (n = 9). Endothelin-1 did not interfere in the RRA at pathophysiologically and clinically relevant concentrations [up to 15 pmol/L (40 pg/ mL)]. When LU135252 was added to plasma, the signal was completely stable after storage for 1 week at 4 degrees C, although there was a modest loss of the signal after 24 h at room temperature. The practical performance of this RRA was then tested in plasma samples obtained from (a) rats after a single oral administration of LU135252, (b) from coronary-ligated rats chronically treated with LU135252, and (c) in plasma and urine samples obtained from dogs during intrarenal infusion of LU135252.
BACKGROUND: Central venous catheters are a principal source of nosocomial bloodstream infections, which are difficult to control. OBJECTIVE: To determine the efficacy of catheters coated with minocycline and rifampin in preventing catheter-related colonization and bloodstream infections. DESIGN: Multicenter, randomized clinical trial. SETTING: Five university-based medical centers. PATIENTS: 281 hospitalized patients who required 298 triple-lumen, polyurethane venous catheters. INTERVENTION: 147 catheters were pretreated with tridodecylmethyl-ammonium chloride and coated with minocycline and rifampin. Untreated, uncoated catheters (n = 151) were used as controls. MEASUREMENTS: Quantitative catheter cultures, blood cultures, and molecular typing of organisms to determine catheter-related colonization and bloodstream infections. RESULTS: The group with coated catheters and the group with uncoated catheters were similar with respect to age, sex, underlying diseases, degree of immunosuppression, therapeutic interventions, and risk factors for catheter infections. Colonization occurred in 36 (26%) uncoated catheters and 11 (8%) coated catheters (P < 0.001). Catheter-related bloodstream infection developed in 7 patients (5%) with uncoated catheters and no patients with coated catheters (P < 0.01). Multivariate logistic regression analysis showed that coating catheters with minocycline and rifampin was an independent protective factor against catheter-related colonization (P < 0.05). No adverse effects related to the coated catheters or antimicrobial resistance were seen. An estimate showed that the use of coated catheters could save costs. CONCLUSIONS: Central venous catheters coated with minocycline and rifampin can significantly reduce the risk for catheter-related colonization and bloodstream infections. The use of these catheters may save costs.
OBJECTIVE: To compare analgesic effects of ketoprofen, oxymorphone hydrochloride, and butorphanol when used to control postoperative pain associated with elective orthopedic surgery in dogs. DESIGN: Prospective randomized clinical trial. ANIMALS: 70 dogs undergoing orthopedic surgery on a hind limb. PROCEDURE: Dogs were randomly assigned to 1 of 4 postoperative analgesic treatment groups: ketoprofen alone, oxymorphone alone, butorphanol alone, or ketoprofen-oxymorphone. Drugs were given IM at the end of anesthesia. Pain score, sedation score, arterial blood pressures, arterial blood gas partial pressures, and plasma cortisol concentration were measured for 12 hours after surgery. If the pain score was > or = 9, supplemental oxymorphone was administered IM. RESULTS: The proportion of dogs that did not require supplemental treatment with oxymorphone was significantly higher for the ketoprofen alone and ketoprofen-oxymorphone groups than for the oxymorphone alone group. During the first hour after surgery, pain score was lower for oxymorphone alone and ketoprofen-oxymorphone groups than for ketoprofen or butorphanol alone groups. Significant differences were not detected among groups in regard to pain score 2 and 3 hours after surgery or in regard to arterial blood pressures at any time. From 4 to 12 hours after surgery, pain score was significantly lower for the ketoprofen alone group than for other groups. Plasma cortisol concentration was significantly higher for the oxymorphone alone group 6 and 8 hours after surgery, compared with other groups. CLINICAL IMPLICATIONS: Except during the first hour after surgery, dogs given ketoprofen alone after elective orthopedic surgery had a greater level of, and longer-lasting, analgesia than did dogs given oxymorphone or butorphanol alone.
Two Shetland Sheepdogs that did not have a history of trauma were referred because of a gradual onset of lameness in the hind limbs. Bilateral slipped capital femoral epiphysis was diagnosed. Separation of the proximal femoral epiphysis that is not associated with trauma is recognized as a distinct clinical syndrome in adolescent human beings and swine, causing a condition called epiphysiolysis. The precise cause of this type of injury is unknown. Histologic lesions observed in the growth plates could have been the result of an abnormally high mechanical load imposed by obesity. It is not known whether cartilaginous lesions observed in the physis of 1 dog represented a preexisting cartilaginous defect (dyschondroplasia) or a late stage of repair after separation of the capital femoral epiphysis.
BACKGROUND: Cyclosporin A is known to alter endothelium-dependent responses to different agonists. Few data are available concerning the effect of cyclosporin A on the pulmonary vascular bed. METHODS: The endothelium-dependent responses to acetylcholine (20 micrograms), bradykinin (5 micrograms), and substance P (5 micrograms) were investigated in a dog model of left lung autoperfusion at constant flow. RESULTS: The vasodilator response to bradykinin and substance P was significantly decreased with cyclosporin A (20 mg) administration. The average decreases in pulmonary arterial pressure with bradykinin were 5.4 +/- 1.5 mm Hg and 2.4 +/- 0.4 mm Hg before and after cyclosporin A administration, respectively (p = 0.04). The average decreases in pulmonary arterial pressure with substance P were 4.4 +/- 1.0 mm Hg and 1.8 +/- 0.5 mm Hg before and after cyclosporin A administration, respectively (p = 0.04). The responses to acetylcholine and the endothelium-independent relaxing agent nitroglycerin were not significantly affected by cyclosporin A. The effects of cyclosporin A on endothelium-dependent responses to bradykinin and substance P were overcome by the administration of L-arginine (200 mg/kg intravenously). The decreased response to bradykinin and substance P after cyclosporin A administration was not significantly affected by indomethacin, a cyclooxygenase inhibitor. The pulmonary angiotensin-converting enzyme activity was also measured using [3H]benzoyl-phenylalanyl-glycyl-proline, an inactive angiotensin-converting enzyme substrate. There was an average [3H]benzoyl-phenylalanyl-glycyl-proline hydrolysis of 54% +/- 2% and 55% +/- 2% before and after cyclosporin A administration, respectively (not significant). CONCLUSIONS: The present study suggests that cyclosporin A selectively decreases endothelium-dependent responses to bradykinin and substance P without affecting the cyclic guanosine monophosphate-dependent pathway in the canine pulmonary vascular bed. The decreased endothelium-dependent responses to bradykinin and substance P are not related to increased angiotensin-converting enzyme activity. The toxic effect of cyclosporin A on endothelium-dependent responses is reversible by the administration of L-arginine, a source of substrate for nitric oxide.
The study of hepatic encephalopathy is limited by the lack of standardized experimental models to assess behavior. We have shown that rats continuously monitored while running on a wheel show abnormalities of the circadian rhythm of locomotor activity after portacaval anastomosis (PCA), such that entrainment of running activity to the light-dark cycle is severely impaired. To identify factors that affect postoperative circadian behavior, we have performed a multivariable analysis of 69 sham-operated controls and 107 rats after PCA. Our results indicate that shunt stenosis, as determined by the pressure gradient from the splenic pulp to the inferior vena cava, ameliorated the postoperative deterioration of the circadian rhythm. In addition, postoperative behavior was affected by preoperative performance, diet, and gender. Postoperative body weight gain, spleen weight, and liver atrophy did not impact this model. Because shunt stenosis is known to ameliorate hepatic encephalopathy in humans, our findings support the validity of this behavioral end point as a correlate of hepatic encephalopathy. Measurement of the pressure gradient across the anastomosis and achievement of sufficient preoperative entrainment appear critical for the standardization of the model.
Myocardial metabolism of endothelin-1 (ET-1) and its effect on coronary microcirculatory exchanges were obtained in anesthetized dogs by combining the indicator-dilution technique with immunoreactive ET-1 measurements. The myocardium extracted 17.7 +/- 4.6% of tracer ET-1 (n = 12). Simultaneously measured ET-1 levels in the aorta (0.97 +/- 0.46 pg/ml) and coronary sinus (0.96 +/- 0.53 pg/ml) were not different, supporting a production of ET-1 by the heart that balances the amount extracted. Intracoronary infusion of ET-1 (5 ng.kg-1.min-1) increased coronary sinus ET-1 levels approximately 50-fold, decreased coronary blood flow per unit of interstitial space by approximately 30% (P = 0.006), and increased myocardial microcirculatory transit times (n = 6). Permeability to albumin was unaffected by ET-1, whereas the permeability-surface area product for sucrose decreased following derecruitment of myocardial capillaries. We conclude that there is a normal myocardial metabolic balance of ET-1 and that the heart marginally contributes to circulating ET-1. Pharmacological doses of ET-1 may adversely affect myocardial metabolism by reducing blood flow and the permeability-surface area product for small circulating substances.
Peptide growth factors (GFs), including epidermal GF (EGF) and transforming GF-alpha (TGF-alpha), are presumed to play an important role in the local regulation of breast cell proliferation. Breast fluid collected by nipple aspiration provides a potential means to assess the concentration of these factors in contact with the ductal epithelium. Although identification of immunoreactive EGF-like GFs in breast fluid has been reported previously, we performed this study to evaluate the sensitivity and reliability of newer RIA methods and to characterize the sources and amounts of both intra- and intersubject variability. We also evaluated the relationship of breast fluid EGF and TGF-alpha levels to each other and to plasma levels of estradiol and progesterone. Breast fluid and plasma samples were obtained two to four times at weekly intervals from 18 healthy, premenopausal women. EGF and TGF-alpha were measured by competitive binding RIA. Both GFs were detected with good precision in all breast fluid samples analyzed, using dilutions as low as 1:100 for EGF (1 microliter) and 1:25 for TGF-alpha (4 microliters). The correlations between the right and left breasts, sampled concurrently, were r = 0.78 (P = 0.003) for EGF and r = 0.89 (P = 0.0001) for TGF-alpha. For both GFs, the variation between women was substantially greater than the variation between breasts or over time in an individual woman, particularly for EGF, for which there were 100-fold differences between women in mean levels. When samples from multiple women were analyzed together, we found no apparent relationships between EGF and TGF-alpha levels or between either GF level and menstrual cycle phase or plasma hormone concentrations. However, in random effects analyses, EGF levels within an individual were significantly associated overall with both TGF-alpha (P = 0.02) and plasma estradiol levels (P = 0.01). These data, which are the first comprehensive results on the feasibility of measuring mitogenic GFs in breast fluid, support the conclusion that women secrete consistent and individually distinct levels of EGF and TGF-alpha and that, in at least some women, EGF secretion in vivo covaries with both TGF-alpha in breast fluid and circulating estradiol.
Pulmonary hypertension is associated with endothelial dysfunction that may mediate or contribute to the disease process; among those abnormalities is an increase in circulating endothelin-1 levels. We investigated the effect of the orally active endothelin A receptor antagonist LU 135252 (LU) on the development of monocrotaline (MCT)-induced pulmonary hypertension and endothelial metabolic dysfunction. Rats were assigned to four groups by receiving a single dose of MCT or saline, followed by once-daily gavage with LU (50 mg/kg) or saline for 3 weeks. Plasma immunoreactive endothelin-1 levels doubled after MCT and were unaffected by LU therapy. The MCT-induced increase in right ventricular systolic pressure (72.5 +/- 15.9 mmHg) and hypertrophy (right ventricle/[left ventricle plus septum weight]; 0.58 +/- 0.08) were reduced by LU to 42.7 +/- 8.5 mmHg (P < .01) and 0.42 +/- 0.05 (P < .01), respectively. LU, however, did not modify MCT-induced pulmonary artery medial hypertrophy. Pulmonary vascular endothelial metabolic activity was evaluated in isolated lungs by measuring endothelium-bound angiotensin-converting enzyme activity using a synthetic angiotensin-converting enzyme substrate, 3H-benzoyl-phenylalanly-glycyl-proline. MCT reduced fractional 3H-benzoyl-phenylalanly-glycyl-proline hydrolysis (0.488 +/- 0.051, P < .01) which was normalized by LU therapy (0.563 +/- 0.050). LU treatment alone had no significant effect on any of these parameters. We conclude that the endothelin A antagonist LU reduces MCT-induced pulmonary hypertension and right ventricular hypertrophy and restores endothelial metabolic function. These results support the development of endothelin antagonists for the treatment of pulmonary hypertension and associated endothelial metabolic abnormalities.
BACKGROUND: Animal studies suggest a major role of the pulmonary circulation in the clearance of circulating endothelin-1 (ET-1). The contribution of the human pulmonary circulation to plasma ET-1 clearance, however, has never been quantified. The absence of an AV gradient in plasma ET-1 has previously been interpreted as evidence that the lungs do not have a role in modulating circulating ET-1 levels. This study was designed to quantify and discern between pulmonary ET-1 clearance and production in humans. METHODS AND RESULTS: We studied 13 subjects by combining the multiple indicator-dilution technique with the measurement of immunoreactive ET-1 (irET-1). All patients had normal left ventricular ejection fractions (61 +/- 7%, mean +/- SD) and baseline hemodynamics. Mean pulmonary ET-1 extraction was 47 +/- 7%. The ET-1 extracted does not return to circulation and can be characterized by a sequestration rate constant: Kseq = 0.048 +/- 0.019 s-1. There was no significant difference between irET-1 levels from the pulmonary artery and aorta (0.61 +/- 0.29 and 0.68 +/- 0.33 pg/mL, respectively; P = .22); the normal lung consequently produces an amount of ET-1 that is quantitatively similar to the amount that has been extracted. CONCLUSIONS: The human lung is an important site for both clearance and production of ET-1. There is a normal physiological balance of ET-1 across the pulmonary circulation, which explains the absence of difference in AV ET-1 levels despite a 47 +/- 7% clearance. Reduced pulmonary clearance or increased production of this peptide may contribute to the increase in circulating levels found in various cardiovascular conditions.
BACKGROUND: It has been postulated that different biologic characteristics of a tumor might account for at least a portion of the disparity in breast cancer survival for patients across racial and ethnic groups. The hormone receptor status of breast tumors is one characteristic with prognostic significance. Results of several studies indicate a higher proportion of estrogen receptor negative (ER-) breast tumors among black or Hispanic women compared with non-Hispanic whites. We investigated whether the association between race and ethnicity and the joint combination of ER and progesterone receptor (PR) status was independent of age and other tumor characteristics at diagnosis. METHODS: Relevant data were obtained from 13,239 breast cancer cases identified as part of the 1990 Patient Care Evaluation Study of Breast Cancer. RESULTS: In univariate analysis, the proportions of ER+PR+, ER+PR-, ER-PR+, and ER-PR- tumors among non-Hispanics whites were 59%, 15%, 6%, and 20%, respectively; among Hispanics the proportions were 58%, 12%, 8%, and 22%, respectively; and among blacks the proportions were 44%, 14%, 7%, and 35%, respectively. After controlling for age, tumor size, and histology, using polychotomous logistic regression, these was no difference in hormone-receptor status between Hispanic and non-Hispanic white women. However, ER-PR- tumors were more likely to occur in blacks than in non-Hispanic whites (odds ratio = 1.8, 95% confidence interval = 1.6, 2.1) CONCLUSIONS: The results of this study corroborate differences in hormone-receptor status between non-Hispanic white and black women, but not between Hispanics. Future studies of breast cancer should examine differences in epidemiologic risk factors between blacks and whites stratified on ER/PR status.
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In a randomized, double-blind trial, gamma radiation-sterilized, chlorhexidine-coated triple-lumen catheters were compared with uncoated control catheters for their ability to prevent catheter infection in 254 intensive care unit patients. The chlorhexidine coating was not efficacious, and a rabbit model demonstrated that reduction of chlorhexidine activity by gamma radiation sterilization was the likely explanation for the failure.
The multiple indicator-dilution technique was employed in the exercising dog to evaluate the effect of increasing activity on the pulmonary extraction and kinetics of removal of tracer 3H-labeled serotonin (5-HT) and on the measured central blood volume and tracer-accessible extravascular lung water. 51Cr-labeled red blood cells, 125I-labeled albumin, and 14C-labeled 1,8-octanediol were injected with labeled 5-HT at rest and at two increasing levels of exercise (lower and higher in 9 dogs). Blood flow approximately tripled at the highest level of exercise, and the central blood volume increased linearly with increasing blood flow. The tracer-accessible extravascular lung water increased in the transition from rest to low-level exercise and stabilized at an average proportion of 0.85 of the gravimetric extravascular lung water at the higher values of blood flow. The average labeled 5-HT extraction at rest was 42 +/- 11%, and this slowly decreased with increase in flow. The calculated permeability-surface area product for 5-HT increased approximately directly with increasing blood flow. We conclude that exercise results in an increase in the central blood volume that is accompanied by an increase in the tracer-accessible extravascular lung water (lung tissue recruitment) over low exercise levels, with no change at higher levels of exercise, and that the pulmonary capillary surface area subserving 5-HT uptake increases almost linearly with flow over the range of flows attained.
The pulmonary circulation plays an important role in the removal of circulating endothelin-1 (ET-1). Plasma ET-1 levels are increased in pulmonary hypertensive states of various etiologies (e.g., idiopathic, heart failure, and congenital anomalies) in proportion to the severity of pulmonary hypertension. It is possible that reduced pulmonary clearance of this peptide contributes to the hyperendothelinemia of those pathologies. The ETA and ETB receptors are abundant in lung tissues: on the vascular endothelium, the ETB receptor is predominant and may contribute to ET-1 extraction through receptor-mediated endocytosis. We designed experiments to determine and quantify the importance of the ETA and ETB receptors in the pulmonary extraction of circulating ET-1 in anesthetized dogs. The single-pass cumulative tracer ET-1 extraction by the lung was measured with the indicator-dilution technique before and 5 min after intrapulmonary injection of the specific ETA antagonist BQ-123 (n = 5, 120-960 nmol) and the specific ETB antagonist BQ-788 (n = 6, 1,000 nmol). The inhibitors had no significant effect on pulmonary and systemic hemodynamics. Mean cumulative pulmonary ET-1 extraction was not modified by BQ-123 [control (C): 36 +/- 4%, antagonist (A): 34 +/- 6%] but was completely abolished by BQ-788 (C: 34 +/- 6%, A: 0 +/- 2%, P < 0.001). The pulmonary rate constant (K) for ET-1 removal was also unaffected by BQ-123 (C: 0.050 +/- 0.0085 s-1, A: 0.047 +/- 0.012 s-1) but significantly decreased and became close to zero after BQ-788 (C: 0.058 +/- 0.014 s-1, A: 0.009 +/- 0.007 s-1, P < 0.1). We conclude that the ETB receptor is completely and exclusively responsible for pulmonary ET-1 removal in vivo. Future studies are needed to show whether desensitization or downregulation of the ETB receptor may contribute to the increase in circulating ET-1 levels in conditions associated with pulmonary hypertension. This novel pulmonary endothelial cell function may play a protective role by modulating circulating ET-1 levels in the systemic circulation.
A multilocus model for complex traits is described that generalizes the additive and multiplicative models and hence allows simultaneously for both heterogeneity and gene interaction (epistasis). Statistical methods of linkage analysis are discussed under the assumption that identity by descent data from a dense set of polymorphic markers are available. Three methods, single locus search, simultaneous search and conditional search, are described and compared.
OBJECTIVE: The authors hypothesized that less research performed in the United States was reported in the five major general surgical journals in 1993 than in 1983. SUMMARY BACKGROUND DATA: Academic surgeons believe they have less time and fewer funds for research than previously. METHODS: Five journals were analyzed for the number of pages and articles devoted to basic and clinical research in 1983 and 1993 and for the country in which the research was performed. RESULTS: The number of U.S. research pages and articles decreased over the past decade, and the number of non-U.S. pages and articles increased. CONCLUSIONS: The reason(s) for the decrease in U.S. research reported in the general surgical journals should be studied, identified, and, if possible, rectified.