Maternal separation alters nerve growth factor and corticosterone levels but not the DNA methylation status of the exon 17 glucocorticoid receptor promoter region

Separating rat pups from their mothers during the early stages of life is an animal model commonly used to study the development of psychiatric disorders such as anxiety and depression. The present study investigated how soon after the termination of the maternal separation period behavioural and neuroendocrine abnormalities relevant to above-mentioned illnesses would manifest. Sprague Dawley rat pups were subjected to maternal separation (3 h per day from postnatal day 2 through 14) and their behaviour and HPA axis activity determined 7 d later. We also measured nerve growth factor levels in their hippocampi and assessed the DNA methylation status of the promoter region of exon 17 of the glucocorticoid receptor in this brain region. As early as 7 d after the termination of the adverse event, a change in behaviour was observed that was associated with increased plasma corticosterone release and elevated nerve growth factor levels in the hippocampus. No alteration in the methylation status of the exon 17 glucocorticoid receptor promoter region was observed. Our data indicate that early life adversity may lead to the rapid development of abnormal behaviours and HPA axis dysregulation though no epigenetic changes to the exon 17 glucocorticoid receptor promoter region occurred. We further propose that the observed increased neurotrophin levels reflect compensatory mechanisms that attempt to combat the long-term deleterious effects of maternal separation. © 2009 Springer Science+Business Media, LLC.Articl

Designation of Major Mycobacterial Interspersed Repetitive-Unit Types within Mycobacterium tuberculosis Beijing Genotype, an Important Point

[No abstract available]Lette

Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux

Rationale: Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations. Objective: To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility. Methods: Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/ transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/cmice were infected with aMDR-TB strain and treated with first-line drugs with/without verapamil. Measurements and Main Findings: Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 mg/ml) for 7 days induced ofloxacin resistance (MIC > 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05). Conclusion: Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the secondline treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of antituberculosis drug treatment.Articl