A high rate of recurrent tuberculosis in western Kenya independent of human immunodeficiency virus infection

Background: Previous studies have shown that recurrent TB develops in about 2-5% of the patients after curative treatment with short-course anti-TB chemotherapy. With the advent of HIV/AIDS, the rate TB recurrence is anticipated to rise. Objectives: To determine whether HIV infection and TB recurrence are associated with anti-TB drug resistance and the rates of ZN microscopy and culture positivity among the recurrent TB cases in western Kenya. Design and methods: A cross-sectional study was carried out between 2007 and 2009. Sputa from 872 tuberculosis suspects underwent mycobacteriologic evaluation using Ziehl Neelsen smear microscopy, LowensteinJensen and BACTEC MGIT 960 culturing, and Hain’s GenoType® Mycobacterium CM and GenoType® Mycobacterium AS molecular identification tests. Consenting participants were screened for HIV infection using Uni-Gold TM test and positives were confirmed with the enzyme linked immunosorbent assay. Results: In total, 361/872 (41%) of the suspects mycobacterial disease (346 TB, 4.2% non-tuberculous mycobacterial disease). HIV testing was accepted by 695 (79.7%) and 39.1% of these (272/695) were found positive. Recurrence of TB constituted 44.8% (155/346) of the TB cases, with 41.9% (65/155) of them co-infected with HIV. There was nosignificant difference in TB recurrence rates with HIV status [OR = 0.57; 95% CI: 0.29-1.13; P = 0.10]. Conclusions and recommendations: This study reports a much higher (44.8%) rate of recurrent TB, compared to that of National TB control Programme of 5% in 2008 and a combined retreatment rate of 14% in 2009. The HIV co-infection and TB recurrence were not associated with anti-TB drug resistance. The majority of TB recurrent cases were ZN smear negative (67.7%) and culture negative (80%). The high TB recurrence observed in this study calls for studies to determine the proportions of the disease attributable to endogenous re-activation (relapse) and exogenous re-infection. Keywords: Recurrent tuberculosis; HIV co-infectio

Brain monoamine oxidase A activity predicts trait aggression

The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression

Gene by Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

Chronic cocaine use has been associated with structural deficits in brain regions having dopamine receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. We therefore examined variations in gray matter volume (GMV) as a function of lifetime drug use and the monoamine oxidase A (MAOA) genotype in cocaine use disorders (CUD) and healthy controls

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation

Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders

There is a long-standing paradox that N-methyl-D-aspartate receptors (NMDARs) can both promote neuronal health and kill neurons. Recent studies show that NMDAR-induced responses depend on the receptor location: stimulation of synaptic NMDARs, acting primarily through nuclear Ca(2+) signaling, leads to the build-up of a neuroprotective ‘shield’, whereas stimulation of extrasynaptic NMDARs promotes cell death. These differences result from the activation of distinct genomic programmes and opposing actions on intracellular signalling pathways. Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington’s disease and could be a common theme in the aetiology of neurodegenerative diseases. Neuroprotective therapies should aim to both enhance the effect of synaptic activity and disrupt extrasynaptic NMDAR-dependent death signalling

Synthesis of N-(2-chloro-5-methylthiophenyl)-N'-(3-methyl-thiophenyl)-N'-[3H3] methylguanidine, l brace [3H3]CNS-5161 r brace

The preparation of the title compound, [{sup 3}H{sub 3}]CNS-5161, was accomplished in three steps starting with the production of [{sup 3}H{sub 3}]iodomethane (CT{sub 3}I). The intermediate N-[{sup 3}H{sub 3}]methyl-3-(thiomethylphenyl)cyanamide was prepared in 77% yield by the addition of CT{sub 3}I to 3-(thiomethylphenyl)cyanamide, previously treated with sodium hydride. Reaction of this tritiated intermediate with 2-chloro-5-thiomethylaniline hydrochloride formed the guanidine compound [{sup 3}H{sub 3}]CNS-5161. Purification by HPLC gave the desired labeled product in an overall yield of 9% with greater than 96% radiochemical purity and a final specific activity of 66 Ci mmol{sup -1}