Novel pyridyl ring C5 substituted analogues of epibatidine and 3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (A-84543) as highly selective agents for neuronal nicotinic acetylcholine receptors containing beta2 subunits

Introduction of a hydrophobic or hydrogen-bonding alkynyl group into the C5 position of the pyridyl ring of epibatidine and A-84543 significantly increased the selectivity for neuronal nicotinic acetylcholine receptors (nAChRs) containing beta2 subunits over nAChRs containing beta4 subunits (K(i) ratio up to 92000-fold). Our data indicate that the extracellular domains of the nAChRs are sufficiently different to allow for the design of novel ligands with high affinity and selectivity for the nAChR subtypes.     

Reproductive hormone levels in men exposed to persistent organohalogen pollutants: a study of inuit and three European cohorts

OBJECTIVE: Persistent organohalogen pollutant (POP) exposure may have a negative impact on reproductive function. The objective of this study was to assess the impact of POP exposure on the male hypothalamo-pituitary-gonadal axis. PARTICIPANTS: Participants included 184 Swedish fishermen and spouses of pregnant women from Greenland (n = 258), Warsaw, Poland (n = 113) , and Kharkiv, Ukraine (n = 194). EVALUATIONS/MEASUREMENTS: Serum levels of 2,2,4,4,5,5-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p -DDE) were determined in the four populations, showing different exposure patterns: Swedish fishermen, high CB-153/low p,p -DDE; Greenland, high CB-153/high p,p -DDE; Warsaw, low CB-153/moderate p,p -DDE; Kharkiv, low CB-153/high p,p -DDE. Serum was also analyzed for testosterone, estradiol, sex hormone-binding globulin (SHBG) , inhibin B, luteinizing hormone (LH) , and follicle-stimulating hormone (FSH) . Free testosterone levels were calculated based on testosterone and SHBG. RESULTS: We found significant center-to-center variations in the associations between exposure and the outcomes. The most pronounced effects were observed in Kharkiv, where statistically significant positive associations were found between the levels of both CB-153 and p,p -DDE and SHBG, as well as LH. In Greenland, there was a positive association between CB-153 exposure and LH. In the pooled data set from all four centers, there was positive association between p,p -DDE and FSH levels [beta = 1.1 IU/L; 95% confidence interval (CI), 1.0-1.1 IU/L]. The association between CB-153 levels and SHBG was of borderline statistical significance (beta = 0.90 nmol/L; 95% CI, -0.04 to 1.9 nmol/L). CONCLUSIONS: Gonadotropin levels and SHBG seem to be affected by POP exposure, but the pattern of endocrine response is the subject of considerable geographic variation.     

Modulating Effects of Rooibos and Honeybush Herbal Teas on the Development of Esophageal Papillomas in Rats

Widespread consumption of herbal teas has stimulated interest in their role as cancer preventive agents. The present investigation monitored the modulation of methylbenzylnitrosamine (MBN)-induced esophageal squamous cell carcinogenesis by rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) herbal and Camellia sinensis teas in male F344 rats. The tumor multiplicity was significantly (P < 0.05) inhibited by unfermented honeybush (45.5%), green (50%), and black (36%) teas, while the other teas exhibited weaker effects (<30% inhibition). The mean total papilloma size was reduced by unfermented rooibos (87%), unfermented honeybush (94%), and fermented honeybush (74%) due to the absence of large papillomas (>10 mm³). Reduction of the mean total papilloma number correlated with the total polyphenol (TPP) (r = 0.79; P < 0.02) and flavanol/proanthocyanidin (FLAVA) (r = 0.89; P < 0.008) intake (mg/100 g body weight) of the teas and the FLAVA (r = 0.89; P < 0.04) and flavonol/flavones/xanthones (r = 0.99; P < 0.002) intake when considering only the herbal teas. A daily TPP intake threshold of 7 mg/100 g body weight existed below where no inhibition of papilloma development was observed. Fermentation of herbal teas reduced the inhibitory effects on papilloma development associated with a reduction in the polyphenolic constituents. The inhibitory effect of herbal teas on papilloma development is associated with different flavonoid subgroups and/or combination thereof.     

Antidiabetic and cytotoxicity screening of five medicinal plants used by traditional African health practitioners in the Nelson Mandela Metropole, South Africa

Diabetes mellitus is a growing problem in South Africa and of concern to traditional African health practitioners in the Nelson Mandela Metropole, because they experience a high incidence of diabetic cases in their practices. A collaborative research project with these practitioners focused on the screening of Bulbine frutescens, Ornithogalum longibracteatum, Ruta graveolens, Tarchonanthus camphoratus and Tulbaghia violacea for antidiabetic and cytotoxic potential. In vitro glucose utilisation assays with Chang liver cells and C2C12 muscle cells, and growth inhibition assays with Chang liver cells were conducted. The aqueous extracts of Bulbine frutescens (143.5%), Ornithogalum longibracteatum (131.9%) and Tarchonanthus camphoratus (131.5%) showed significant increased glucose utilisation activity in Chang liver cells. The ethanol extracts of Ruta graveolens (136.9%) and Tulbaghia violacea (140.5%) produced the highest increase in glucose utilisation in C2C12 muscle cells. The ethanol extract of Bulbine frutescens produced the most pronounced growth inhibition (33.3%) on Chang liver cells. These findings highlight the potential for the use of traditional remedies in the future for the management of diabetes and it is recommended that combinations of these plants be tested in future.     

TrkB receptor controls striatal formation by regulating the number of newborn striatal neurons

In the peripheral nervous system, target tissues control the final size of innervating neuronal populations by producing limited amounts of survival-promoting neurotrophic factors during development. However, it remains largely unknown if the same principle works to regulate the size of neuronal populations in the developing brain. Here we show that neurotrophin signaling mediated by the TrkB receptor controls striatal size by promoting the survival of developing medium-sized spiny neurons (MSNs). Selective deletion of the gene for the TrkB receptor in striatal progenitors, using the Dlx5/6-Cre transgene, led to a hindpaw-clasping phenotype and a 50% loss of MSNs without affecting striatal interneurons. This loss resulted mainly from increased apoptosis of newborn MSNs within their birthplace, the lateral ganglionic eminence. Among MSNs, those expressing the dopamine receptor D2 (DRD2) were most affected, as indicated by a drastic loss of these neurons and specific down-regulation of the DRD2 and enkephalin. This specific phenotype of mutant animals is likely due to preferential TrkB expression in DRD2 MSNs. These findings suggest that neurotrophins can control the size of neuronal populations in the brain by promoting the survival of newborn neurons before they migrate to their final destinations.     

Seroincidence of 2009 H1N1 infection in HIV-infected and HIV-uninfected women prior to vaccine availability

The 2009 H1N1 pandemic was a unique opportunity to investigate differences in influenza infection using serology by HIV status. Using serial serum specimens collected from 1 April to 30 September 2009 and the prior 2 years from Women's Interagency HIV study participants, there was no difference in serologic evidence of 2009 H1N1 infection among HIV-infected women with a CD4 cell count at least 350 cells/μl compared with HIV-uninfected women. Owing to evidence showing a greater risk of influenza-related complications, HIV-infected individuals should continue to be a priority group for vaccination.