Chronic treatment with polychlorinated biphenyls (PCB) during pregnancy and lactation in the rat: Part 1: Effects on somatic growth, growth hormone-axis activity and bone mass in the offspring

Polychlorinated biphenyls (PCBs) are pollutants detected in animal tissues and breast milk. The experiments described in the present paper were aimed at evaluating whether the four PCB congeners most abundant in animal tissues (PCB-138, -153, -180 and -126), administered since fetal life till weaning, can induce long-term alterations of GH-axis activity and bone mass in the adult rat. We measured PCB accumulation in rat brain and liver, somatic growth, pituitary GH expression and plasma hormone concentrations at different ages. Finally, we studied hypothalamic somatostatin expression and bone structure in adulthood, following long-term PCB exposure.Dams were treated during pregnancy from GD15 to GD19 and during breast-feeding. A constant reduction of the growth rate in both male and female offspring from weaning to adulthood was observed in exposed animals. Long-lasting alterations on hypothalamic-pituitary GH axis were indeed observed in PCB-exposed rats in adulthood: increased somatostatin expression in hypothalamic periventricular nucleus (both males and females) and lateral arcuate nucleus (males, only) and decreased GH mRNA levels in the pituitary of male rats. Plasma IGF-1 levels were higher in PCB-exposed male and female animals as compared with controls at weaning and tended to be higher at PN60. Plasma testosterone and thyroid hormone concentrations were not significantly affected by exposure to PCBs. In adulthood, PCBs caused a significant reduction of bone mineral content and cortical bone thickness of tibiae in male rat joint to increased width of the epiphyseal cartilage disk. In conclusion, the developmental exposure to the four selected PCB compounds used in the present study induced far-reaching effects in the adult offspring, the male rats appearing more sensitive than females.     

Caffeine drinking potentiates cannabinoid transmission in the striatum: Interaction with stress effects

Caffeine, the psychoactive ingredient of coffee and of many soft drinks, is frequently abused by humans especially during stressful live events. The endocannabinoid system is involved in the central effects of many psychoactive compounds and of stress. Whether caffeine alters the cannabinoid system and interferes with stress-induced synaptic alterations is however unknown. We have studied electrophysiologically the sensitivity of cannabinoid receptors modulating synaptic transmission in the striatum of mice exposed to caffeine in their drinking solution. Chronic caffeine assumption sensitized GABAergic synapses to the presynaptic effect of cannabinoid CB1 receptor stimulation by exo- and endocannabinoids. Caffeine was conversely unable to affect the sensitivity of cannabinoid receptors modulating glutamate transmission. The synaptic effects of caffeine were slowly reversible after its removal from the drinking solution. Furthermore, although exposure to caffeine for only 24 h did not produce measurable changes of the sensitivity of cannabinoid CB1 receptors, it was able to contrast the down-regulation of CB1 receptor-mediated responses after social defeat stress.Our data suggest that the cannabinoid system is implicated in the psychoactive properties of caffeine and in the ability of caffeine to reduce the pathological consequences of stress.     

High-performance liquid chromatographic/mass spectrometric studies on the susceptibility of heparin species to cleavage by heparanase

Heparanase is an endo-beta-D-glucuronidase that cleaves the heparan sulfate chains of heparan sulfate proteoglycans and is implicated in angiogenesis and metastasis. With the aim of establishing a simple and reliable method for studying the susceptibility of heparin/heparan sulfate oligosaccharides to be cleaved by heparanase, an on-line ion pair reversed-phase high-performance liquid chromatographic/electrospray ionization mass spectrometric method was set up. The method works in the micromolar range of concentration and does not require derivatization of the substrate or of the products. It is based on mass identification of oligosaccharide fragments generated by heparanase and their quantification with reference to an internal heparin disaccharide standard. Substrates were (1) the synthetic pentasaccharides GlcN (NS,6S) - GlcA - GlcN (NS,3S,6S) - IdoA (2S) - GlcN (NS,6S) - OMe (AGA*IA (M)) and GlcN (NS,6S) - GlcA - GlcN (NS,6S) - IdoA (2S) - GlcN (NS,6S) - OMe (AGAIA (M)), corresponding to the heparin/heparan sulfate active site for antithrombin, and to the same sequence devoid of the 3- O-sulfate group in the central glucosamine, respectively; and (2) two natural heparin octasaccharides containing the AGA*IA sequence in different locations along the chain. The two pentasaccharides exhibited a higher susceptibility to heparanase cleavage with respect to the octasaccharides. The commercial availability of AGA*IA (M) makes it an ideal substrate to determine the specific activity of heparanase preparations. The present method could also be used for rapid screening of potential heparanase inhibitors.     

A randomized study on Peg-interferon alfa-2a with or without ribavirin in liver transplant recipients with recurrent hepatitis C

BACKGROUND/AIMS: We performed a randomized trial on pegylated interferon alfa-2a (Peg-IFNalpha) monotherapy vs Peg-IFNalpha and ribavirin in non-cirrhotic liver transplant recipients with recurrent hepatitis C. METHODS: Forty-two patients transplanted for HCV-related cirrhosis 12-96 months earlier were randomized to Peg-IFNalpha monotherapy (180 microg weekly) or Peg-IFNalpha and ribavirin, up to the maximum tolerated dose, for 48 weeks. RESULTS: Early virological response (EVR, i.e., HCV-RNA2 log drop at week 12) occurred in 76% of the monotherapy and 71% of the combination groups, respectively (intention-to treat). Sustained virological response (SVR) occurred in 8 (38%) and 7 (33%) patients, respectively. EVR had a positive predictive value for SVR of 50% and 47%, respectively, and a 100% negative predictive value in both groups. Six drop-outs occurred in the monotherapy (including 3 rejections) and 7 in the combination groups (including one rejection). Peg-INFalpha dose was reduced in 7 and 8 patients, respectively. The average daily dose of ribavirin was 435 mg/day. CONCLUSIONS: Peg-IFNalpha-2a, with or without ribavirin, induces SVR in one-third of transplant recipients with recurrent hepatitis C. Treatment cessation is indicated in patients without EVR. The low SVR rate is mainly due to inability to sustain full doses of antivirals and lack of the booster effect of ribavirin.     

The use of the antifungal agent miconazole as an inhibitor of Blastocystis hominis growth in Entamoeba histolytica/E. dispar cultures

In regions with high prevalence, Blastocystis hominis is frequently found in association with Entamoeba histolytica/E. dispar in xenic cultures. Its exacerbated growth is often superimposed on the growth of amebas, thus impeding the continuation of the amebas in the culture, within a few generations. The present study reports on the excellent efficacy (100%) of the antifungal agent miconazole in eliminating B. hominis from cultures of E. histolytica/E. dispar, thereby maintaining the integrity of the trophozoites of the amebas. Nystatin presented low efficacy (33.3%).     

Acute pulmonary embolism is an independent predictor of adverse events in severe decompensated heart failure patients

BACKGROUND: Congestive heart failure (CHF) is a well-recognized risk factor for venous thromboembolism (VTE) and is associated with higher mortality in patients with an acute pulmonary embolism (PE). There are very few data on how acute PE affects the clinical course of patients with heart failure. The purpose of this study was to determine the impact of an acute PE on the short-term prognosis of patients hospitalized for decompensated CHF. METHODS: This was a prospective cohort study of 198 patients admitted to a coronary care unit between July 2001 and March 2003 with severe decompensated CHF. The primary outcome measure was death or rehospitalization at 3 months. RESULTS: PE was confirmed in 18 of 198 patients enrolled (9.1%). The groups with and without PE were comparable with regards to demographics, the prevalence of comorbid conditions, and severity of CHF (p > 0.05). The prevalence of cancer (p = 0.0001), previous VTE (p = 0.003), and right ventricular overload (p = 0.006) was higher in the PE group. The presence of PE was also associated with a longer hospital stay (37.5 +/- 71.6 days vs 15.4 +/- 15.0 days, p = 0.001) [mean +/- SD] and a higher incidence of death or rehospitalization at 3 months (72.2% vs 43.9%, p = 0.02). In a multiple logistic regression analysis, PE remained an independent predictor of death or rehospitalization at 3 months (odds ratio, 4.0; 95% confidence interval, 1.1 to 15.1; p = 0.038). CONCLUSIONS: Acute PE commonly complicates the hospital course of patients with severe CHF, increasing the length of hospital stay and the chance of death or rehospitalization at 3 months.