Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist.
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1. We designed and synthesized several novel cyclic MSH analogues and tested their affinities for cells expressing the MC1, MC3, MC4 and MC5 receptors. 2. One of the substances HS028 (cyclic [AcCys11, dichloro-D-phenylalanine14, Cys18, Asp-NH2(22)]-beta-MSH11-22) showed high affinity (Ki of 0.95nM) and high (80 fold) MC4 receptor selectivity over the MC3 receptor. HS028 thus shows both higher affinity and higher selectivity for the MC4 receptor compared to the earlier first described MC4 receptor selective substance HS014. 3. HS028 antagonised a alpha-MSH induced increase in cyclic AMP production in transfected cells expressing the MC3 and MC4 receptors, whereas it seemed to be a partial agonist for the MC1 and MC5 receptors. 4. Chronic intracerebroventricularly (i.c.v.) administration of HS028 by osmotic minipumps significantly increased both food intake and body weight in a dose dependent manner without tachyphylaxis for a period of 7 days. 5. This is the first report demonstrating that an MC4 receptor antagonist can increase food intake and body weight during chronic administration providing further evidence that the MC4 receptor is an important mediator of long term weight homeostasis. (+info)
Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia.
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1. We examined whether endogenous inhibitors of NO synthesis are involved in the augmentation of intimal hyperplasia in rabbits with hyperglycaemia induced by alloxan. 2. Four weeks after the endothelial denudation of carotid artery which had been performed 12 weeks after alloxan, the intimal hyperplasia was greatly augmented with hyperglycaemia. The degree of hyperplasia was assessed using three different parameters of histopathological findings as well as changes in luminal area and intima: media ratio. 3. There were positive and significant correlations between intima:media ratio, plasma glucose, and concentrations of N(G)-monomethyl-L-arginine (L-NMMA) and N(G), N(G)-dimethyl-L-arginine (ADMA) in endothelial cells, that is, the intima:media ratio became greater as plasma glucose and endothelial L-NMMA and ADMA were increased. Furthermore, endothelial L-NMMA and ADMA were increased in proportion to the increase in plasma glucose. 4. In contrast, there were inverse and significant correlations between cyclic GMP production by carotid artery strips with endothelium and plasma glucose, between cyclic GMP production and endothelial L-NMMA and ADMA, and between the intima:media ratio and cyclic GMP production. 5. Exogenously applied L-NMMA and ADMA inhibited cyclic GMP production in a concentration-dependent manner. IC50 values were determined to be 12.1 microM for the former and 26.2 microM for the latter. The cyclic GMP production was abolished after the deliberate removal of endothelium from the artery strips. 6. These results suggest that the augmentation of intimal hyperplasia with hyperglycaemia is closely related to increased accumulation of L-NMMA and ADMA with hyperglycaemia, which would result in an accelerated reduction in NO production/release by endothelial cells. (+info)
Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat.
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We eliminated type beta transforming growth factor (TGF-beta) signaling by adenovirus-mediated local expression of a dominant-negative type II TGF-beta receptor (AdCATbeta-TR) in the liver of rats treated with dimethylnitrosamine, a model of persistent liver fibrosis. In rats that received a single application of AdCATbeta-TR via the portal vein, liver fibrosis as assessed by histology and hydroxyproline content was markedly attenuated. All AdCATbeta-TR-treated rats remained alive, and their serum levels of hyaluronic acid and transaminases remained at low levels, whereas all the AdCATbeta-TR-untreated rats died of liver dysfunction. The results demonstrate that TGF-beta does play a central role in liver fibrogenesis and indicate clearly in a persistent fibrosis model that prevention of fibrosis by anti-TGF-beta intervention could be therapeutically useful. (+info)
The Janus-faced aspect of 'dry weight'.
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BACKGROUND: The goal of haemodialysis treatment in end-stage renal disease (ESRD) patients is to correct the complications of the uraemic condition. Among the main complications are fluid overload and subsequent hypertension that are corrected by achievement of 'dry weight'. We report in this study the evolution of post-dialysis body-weight and blood pressure in patients who began their HD treatment in our unit. METHODS: We studied the monthly evolution of post-dialysis body-weight (expressed as a percentage of pre-dialysis body-weight at the first HD treatment) and predialysis mean arterial pressure (MAP) over 24 months in 61 patients (21 females, mean age 59.8 years; 20% diabetic), treated with cellulosic membranes for 8 h, 3 times a week. RESULTS: The post-dialysis body-weight decreased between the onset of HD and month 2 (M2) (-4.40+/-0.52%). Then it went up, reaching -1.56+/-0.96% at M6, +0.3+/-1.27% at M12, +1.27+/-1.38% at M18 and +1.64+/-1.33% at M24. The post-dialysis body-weight increased by 6% between M2 and M24. The mean arterial pressure (MAP) decreased from 111.3+/-2.5 mmHg at M0 to 94.4+/-1.7 at M6, and then remained stable after M6. Between M2 and M6 the post-dialysis body-weight increased, whereas the predialysis MAP continued to decline. The incidence of hypotension episodes was maximal during the first 4 months of HD treatment. CONCLUSIONS: After the second month of dialysis treatment, the simultaneous increase of post-dialysis body-weight and decrease of pre-dialysis MAP are related to the effects of two processes, i.e. increased weight as the result of anabolism induced by the HD treatment on the one hand and normalization of blood pressure by fluid removal on the other. Continuous clinical assessment of the patient is necessary to provide adequate prescription of post-dialysis body-weight. During the first months of HD treatment, the nephrologist, like Janus, is a double-faced gatekeeper: he must be willing to decrease post-dialysis weight to achieve 'dry weight' and to normalize blood pressure, but he must also be prepared to increase it to compensate for anabolism and to avoid episodes of hypotension. (+info)
Relationship between glycosylated hemoglobin and the prevalence of proteinuria in Japanese men.
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A total of 5,174 Japanese men were included in a cross-sectional study to examine the relationship between the glycated hemoglobin (HbA1C) level and the prevalence of proteinuria as determined using a reagent strip. The prevalence of proteinuria rose significantly at HbA1C levels above 5.9%, whereas no relationship was observed at HbA1C levels below 5.9%. Multiple logistic regression analysis showed that blood pressure and a family history of diabetes were independent factors associated with proteinuria in subjects with a HbA1C below 5.9% who were not under medication for diabetes. In contrast, HbA1C, obesity and smoking were associated with proteinuria in subjects who were under medication for diabetes and/or have a HbA1C above 5.9%. These findings suggest that maintaining a HbA1C level below 5.9%, non-smoking and a standard body weight may reduce the prevalence of proteinuria in Japanese men. Healthy life-style and standard body weight are especially important for subjects with a family history of diabetes. (+info)
Variation in subglottic size in children.
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The incidence of variation in the subglottic size was investigated in 3304 infants and children. A mild degree of congenital subglottic stenosis was found in 0.91% and a moderate degree of stenosis in 0.06% of the patients. A mild degree of congenital subglottic enlargement was noted in 0.7% and moderate enlargement in 0.06% of the patients. (+info)
Pregnancy detection and the effects of age, body weight, and previous reproductive performance on pregnancy status and weaning rates of farmed fallow deer (Dama dama).
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Fallow does (n = 502) of different ages (mature, 2-yr-old, and yearling) were maintained with bucks for a 60-d breeding season to determine whether previous reproductive performance and changes in BW affect doe pregnancy rates and to compare the effectiveness of ultrasonography and serum pregnancy-specific protein B (PSPB) for the detection of pregnancy in fallow does. Ultrasonography was performed, blood samples collected, and BW recorded at buck removal (d 0) and at 30 and 90 d after buck removal. Lactational status (lactating = WET; nonlactating = DRY) were determined from farm records taken at weaning prior to each breeding season (autumn 1990 through autumn 1994). Ultrasonography and PSPB for determining pregnancy were in agreement 93% of the time. Overall pregnancy rates did not differ (P>.10) relative to age of the doe; the combined pregnancy rate was 92%. We also determined that 82.9% of does conceived early in the breeding season and that the incidence of embryonal-fetal mortality during the first 90 d after buck removal was 2.8%. In general, mature and 2-yr-old DRY does were heavier and had lower pregnancy rates than WET does. The overall weaning rate for all does was 77.9%. Loss in the number of fawns from pregnancy detection to weaning was equivalent to 14.8% for mature does, 24.7% for 2 yr old does, and 42.5% for yearling does. These data indicate that even though pregnancy rates were relatively high, further study is needed to determine the causes associated with subsequent fawn losses, particularly among yearling does. As a production tool, lactational WET/ DRY status testing was found to be an acceptable means for determining the reproductive potential of individual does within the herd. In addition, serum PSPB may be used in place of ultrasonography for pregnancy diagnosis in fallow deer as early as d 30 after buck removal. (+info)
Effects of twinning on gestation length, retained placenta, and dystocia.
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Constraints to maximal productivity from twinning in beef cattle include increased incidence of dystocia and retained placenta, longer postpartum interval, and lower conception rate. Incidence and cause(s) of the shorter gestation length and of the increased retained placenta and dystocia associated with twinning were evaluated for 3,370 single and 1,014 twin births produced in a population of cattle selected for natural twin births. Gestation length was shorter for twin than for single pregnancies (275.6 vs. 281.3 d, P<.01) and likely contributed to the higher incidence of retained placenta associated with twin births (27.9 vs. 1.9%; P<.01). Incidence of retained placenta was also higher in the spring (March-April) than in the fall (August-September) calving season (18.3 vs. 11.4%; P<.01). The higher incidence of dystocia with twins than with singles (46.9 vs. 20.6%, P<.01) was primarily due to abnormal presentation (37.0 vs. 4.5%, respectively) of one or both twin calves at parturition. First- (40.5%) and second- (22.7%) parity dams with a single birth had more (P<.01) dystocia than older dams (13.4%), whereas dystocia was not affected (P>.10) by parity with twin births. Because of the shorter gestation length and the increased incidence of retained placenta and(or) dystocia, achievement of increased productivity with twinning in cattle necessitates intensive management of twin-producing dams and their calves during the calving season. Management of the increased dystocia can be facilitated by preparturient diagnosis of twin pregnancies, enabling timely administration of obstetrical assistance to facilitate delivery of twin calves and to increase their neonatal survival. (+info)