Protective effects of endothelin receptor antagonists in dogs with aortic cross-clamping.

Endothelin (ET) may play an important role in the pathogenesis of vasoconstriction and acute renal failure after aortic cross-clamping (ACC). However, the relative contribution of the ET(A) and ET(B) receptors to the physiopathology of ischemic acute renal failure is poorly understood. This study was carried out to evaluate the potential protective effect of a selective ET(A) antagonist versus combined ET(A)/ET(B) antagonist on altered systemic, pulmonary, and renal hemodynamics induced by cross-clamping the suprarenal aorta for 1 h, followed by 2-h reperfusion. Studies were performed in three groups of anesthetized mongrel dogs. After baseline measurements, treatment (3 mg/kg i.v. bolus + 3 mg/kg/h infusion) with either a selective ET(A) antagonist, Ro 61-1790 (n = 5), or a combined ET(A)/ET(B) antagonist, bosentan (n = 5) or vehicle (n = 8) was initiated 5 min before ACC. There were marked increases in total peripheral (TPR), pulmonary (PVR), and renal (RVR) vascular resistances, and significant decreases in cardiac output (CO) and glomerular filtration rate (GFR) and tubular sodium reabsorption after ACC in the vehicle group. Both Ro 61-1790 and bosentan prevented the marked increases in TPR, PRV, and RVR, and attenuated the declines in CO, GFR, and tubular sodium reabsorption. We concluded that the profound systemic, pulmonary, and renal vasoconstriction, as well as the impairments in glomerular and tubular functions associated with ACC, is mostly ET mediated and that the ET(A) receptor activation makes a major contribution to the ET-mediated impairments of hemodynamics and renal function after ACC.     

Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which no effective treatment exists. In the present study, 12 IPF patients underwent analysis of gas exchange properties using the multiple inert gas elimination technique on day 1 before and after the administration of 125 mg bosentan, a dual endothelin antagonist. Following this, patients received chronic administration for 12 weeks (62.5 mg b.i.d. in week 1, 125 mg b.i.d. thereafter). The primary objective was to determine the effect of bosentan on gas exchange (day 1) and on oxygen saturation and minute ventilation (week 2). With one exception, where redistribution of total pulmonary blood flow from normal ventilation/perfusion (V'/Q') areas (93% before, 72% after bosentan) to low V'/Q' areas (0% before, 22.2% after) was encountered, no patient showed any change in gas exchange (mean+/-SD shunt flow (% of cardiac output) 8.5+/-3.4% before, 6.1+/-2.3% after bosentan; day 1) or oxygen saturation and minute ventilation (week 2). Similarly, none of the secondary parameters was significantly changed either at week 2 or at the end of the study period (week 12). Five patients developed respiratory infections and two died because of pneumonia; this was judged as being unrelated to bosentan intake. In conclusion, bosentan administration does not seem to induce clinically relevant gas exchange abnormalities in idiopathic pulmonary fibrosis patients.     

Individual smallest detectable difference in bone mineral density measurements.

Bone mineral density (BMD) measurement is a major outcome measure in osteoporosis. The BMD changes observed must exceed the variability inherent in the measurement process to be considered related to disease progression. The objective of the study was to estimate short-term variability of BMD measurement and to propose a cut-off value for the smallest detectable BMD changes for an individual. To estimate the short-term variability, 70 healthy postmenopausal women aged 53 +/- 4 years (group 1) and 57 elderly osteoporotic postmenopausal women aged 80 +/- 6 years (group 2) had two repeated BMD measurements of the lumbar spine (L2-L4) and the proximal femur with dual-energy X-ray absorptiometry, with complete repositioning within 1 h. Cut-offs derived from short-term variability were either estimated from the coefficient of variation (CV) (which is a function of the measured value) or from the standard deviation (SD), and applied to 330 postmenopausal women (group 3) who had BMD measurements at baseline and 2 years later. The short-term intrasubject variability was greater at the lumbar spine in group 2 versus group 1 (0.0123 vs. 0.0059 g/cm2, p < 10-4), whereas it was not at the femoral neck (0.0098 vs. 0.0076 g/cm2, p = 0.28). There was no statistically significant correlation between short-term intrasubject variability (SD) and BMD as demonstrated with an analysis of covariance (p values ranging from 0.17 to 0.90). Cut-offs estimated with SD and CV were individually applied to group 3 patients. Using these two cut-offs, discrepancies in assessment of progression were observed in 1.7-8.6% of cases. Short-term BMD variability is constant in a wide range of BMD values. Consequently, to determine cut-off values for the smallest detectable differences in BMD at the individual level, precision errors should be based on SD (expressed in absolute units) rather than on CV (expressed in percentage).     

Evaluation of Thyroid Function in Obese Dogs and in Dogs Undergoing a Weight Loss Protocol

Summary Obesity and weight loss have been shown to alter thyroid hormone homeostasis in humans. In dogs, obesity is the most common nutritional problem encountered and weight loss is the cornerstone of its treatment. Therefore, it is important to clarify how obesity and weight loss can affect thyroid function test results in that species. The objectives of this study were to compare thyroid function in obese dogs and in lean dogs and to explore the effects of caloric restriction and weight loss on thyroid hormone serum concentrations in obese dogs. In the first experiment, 12 healthy lean beagles and 12 obese beagles were compared. Thyroid function was evaluated by measuring serum concentrations of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), thyrotropin (TSH), and reverse triiodothyronine (rT3) as well as a TSH stimulation test using 75 μg IV of recombinant human TSH. In the second experiment, eight obese beagles were fed an energy‐restricted diet [average 63% maintenance energy requirement (MER)] until optimal weight was obtained. Blood samples for determination of TT4, FT4, TT3, TSH and rT3, were taken at the start and then weekly during weight loss. Only TT3 and TT4 serum concentrations were significantly higher in obese dogs as compared to lean dogs. In the second experiment, weight loss resulted in a significant decrease in TT3 and TSH serum concentrations. Thus obesity and energy restriction significantly alter thyroid homeostasis in dogs, but the observed changes are unlikely to affect interpretation of thyroid function test results in clinics.     

Deciphering the genetic and epigenetic landscape of pediatric bithalamic tumors

Pediatric bithalamic gliomas encompass several histomolecular tumoral types from benign to malignant and underlines the central role of a comprehensive neuropathological review, including immunohistochemistry, genetic, and epigenetic analyses, to achieve an accurate diagnosis.     

Hemodynamic effects of the early and long-term administration of propranolol in rats with intrahepatic portal hypertension

Background and aims The aims of this study were to evaluate a preventive effect on collateral venous circulation of long-term administration of propranolol in intrahepatic portal hypertensive rats. Methods Eighty-six Sprague–Dawley rats were allocated to two models of hepatic fibrosis, bile duct-ligated (BDL) induced and carbon tetrachloride (CCl₄) induced. Each model was divided into two groups: one receiving placebo and the other propranolol (75 mg kg⁻¹ d⁻¹). Mean arterial pressure (MAP), heart rate (HR), portal pressure (PP), cardiac index (CI), vascular systemic resistance, and splenorenal shunt blood flow (SRS-BF) were measured in anesthetized rats. Results In the BDL model, no significant hemodynamic changes were observed in the propranolol group compared with the placebo group. In CCl₄-induced rats, HR (390 ± 50 vs. 329 ± 51 beats/min, P = .001), CI (44 ± 11 vs. 34 ± 10 ml/min, P = .004), PP (15.4 ± 3.0 vs. 13.4 ± 1.9 mmHg, P = .045), and SRS-BF (1.4 ± 1.1 vs. 1.0 ± 1.0 ml/min, P = .047) were significantly lower in the propranolol group. Conclusions This study showed that propranolol has a significant hemodynamic effect only in the CCl₄ model and suggested a model-dependent effect of propranolol.