Afferent Visual Pathway Assessment in an Exploratory Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

There is a considerable need for treatments in MS for preventing progressive neurological disability. Assessment of the afferent visual pathway shows potential in investigating new therapies in MS. Mesenchymal Stem Cells exhibit properties of potential therapeutic relevance in progressive MS. A phase I/IIA trial of adult autologous mesenchymal stem cells as a potential therapy for Multiple Sclerosis [MSCIMS] was designed as an open label, pre (up to 20 months) vs. post treatment (up to 10 months) (single intravenous administration of autologous bone marrow derived mesenchymal stem cells) comparison study in ten secondary progressive MS patients. Primary end points were adverse events and secondary end points were efficacy measures. All 10 patients had previous history of clinical optic neuritis: this was in order to enable longitudinal structural and functional assessments of the disease-affected afferent visual pathway. Piecewise linear mixed models were used to assess the change in gradients over time at the point of intervention. All 10 patients tolerated the trial assessments and intervention. No significant or serious adverse events were seen. Improvement after treatment was seen in visual acuity and visual evoked response latency, along with an increase in optic nerve cross-sectional area. The results suggest that autologous mesenchymal stem cells are safe and could possibly promote endogenous repair mechanisms such as remyelination, although a definitive conclusion of this cannot be made from this small study. While MSCIMS was a proof of concept study only, based on the encouraging experience derived from it, there would seem to be potential value in future, larger placebo controlled, double-blinded, randomised therapeutic phase IIb/III trials that could (i) more definitively investigate stem cells as a therapy and (ii) use the visual pathway disease model for investigating the efficacy of potential neuroprotective and reparative therapeutic agents

Comparison of Tuberculin Reaction Sizes at 48 and 72 hours among children in Tiruvallur District, South India

Setting: A rural population in Tiruvallur district, south India. Objective: To study the variability of skin test reaction sizes between 48 and 72 hours. Methods: A tuberculin test survey was conducted among children aged less than 10 years. The reaction sizes were read by the same reader at 48 hours and 72 hours independently. The results of the tuberculin test were compared. Results: Of 957 children aged below 10 years were included in the study; the male and female ratio was 1:1.1. There were no significant differences between the readings of reaction size at 48 and 72 hours. Conclusion: The tuberculin test results can be read either at 48 hours or 72 hours without compromising the validity

Repeatability of nerve thickness assessment in the clinical examination for leprosy

The assessment of the thickness of the superficial peripheral nerve trunks to document nerve involvement is an important aspect of clinical examination in case finding for leprosy, and is usually done by trained paramedical workers (PMWs). This assessment is subject to variability and has implications on the outcome of the survey. The present study proposes to quantify this variability. In this study, 242 individuals, consisting of 50 neuritic cases, 143 nonneuritic cases of leprosy and 49 normal controls, selected from the records of the trial of BCG prophylaxis in leprosy in South India, were examined by a doctor and paramedical workers. Repeatability of nerve thickness assessment for ulnar aud popliteal nerves between the medical officer (MO) and the PMWs was quantified using Kappa statistics. The Kappa values for repeatability between the MO and the PMWs ranged from 0.45 to 0.54 and 0.52 to 0.69 for ulnar and popliteal nerves, respectively. The implications of the variability in nerve assessment are discussed

A window into the brain: an in vivo study of the retina in schizophrenia using optical coherence tomography.

Retinal nerve fibre layer (RNFL) thickness and macular volume (MV) can be measured in vivo using optical coherence tomography (OCT) providing a "window into the brain". RNFL and MV are promising biomarkers in neurological diseases. This study explores the potential of RNFL and MV to detect axonal abnormalities in vivo in schizophrenia and their correlations with clinical features. OCT was performed in 49 patients (38 schizophrenia, 11 schizoaffective disorder) and 40 healthy controls matched for age and gender. Group comparisons were made between whole retina and quadrant RNFL thickness and MV using multi-level analyses. In patients, associations were sought between RNFL and MV with symptom severity (positive/negative). Patients and controls had similar whole retina RNFL thickness (p=0.86) and MV (p=0.64), but RNFL in the right nasal quadrant of the schizoaffective group was thinner than in the schizophrenia group (p=0.02). In patients, positive symptom severity was associated with smaller MV (right β=-0.54, p=0.02; left β=-0.49, p=0.04). Normal MV and RNFL thickness suggests unmyelinated axons in patients with schizophrenia/schizoaffective disorder remain unaffected. Longitudinal studies using higher resolution OCT will clarify whether progressive RNFL and MV changes occur and whether they can be used as state or trait markers in schizophrenia

The Vibrio cholerae Minor Pilin TcpB Initiates Assembly and Retraction of the Toxin- Coregulated Pilus

Type IV pilus (T4P) systems are complex molecular machines that polymerize major pilin proteins into thin filaments displayed on bacterial surfaces. Pilus functions require rapid extension and depolymerization of the pilus, powered by the assembly and retraction ATPases, respectively. A set of low abundance minor pilins influences pilus dynamics by unknown mechanisms. The Vibrio cholerae toxin-coregulated pilus (TCP) is among the simplest of the T4P systems, having a single minor pilin TcpB and lacking a retraction ATPase. Here we show that TcpB, like its homolog CofB, initiates pilus assembly. TcpB co-localizes with the pili but at extremely low levels, equivalent to one subunit per pilus. We used a micropillars assay to demonstrate that TCP are retractile despite the absence of a retraction ATPase, and that retraction relies on TcpB, as a V. cholerae tcpB Glu5Val mutant is fully piliated but does not induce micropillars movements. This mutant is impaired in TCP-mediated autoagglutination and TcpF secretion, consistent with retraction being required for these functions. We propose that TcpB initiates pilus retraction by incorporating into the growing pilus in a Glu5-dependent manner, which stalls assembly and triggers processive disassembly. These results provide a framework for understanding filament dynamics in more complex T4P systems and the closely related Type II secretion system

Risk factors for pulmonary tuberculosis: a clinic-based case control study in The Gambia

BACKGROUND: The tuberculosis (TB) epidemic in Africa is on the rise, even in low-HIV prevalence settings. Few studies have attempted to identify possible reasons for this. We aimed to identify risk factors for pulmonary tuberculosis in those attending a general outpatients clinic in The Gambia, a sub-Saharan African country with relatively low HIV prevalence in the community and in TB patients. METHODS: We conducted a case control study at the Medical Research Council Outpatients' clinic in The Gambia. Pulmonary TB cases were at least 15 years old, controls were age and sex matched clinic attendees. Participants were interviewed using a structured questionnaire. RESULTS: 100 sputum smear positive TB cases and 200 clinic controls were recruited. HIV prevalence was 6.1% in cases and 3.3% in controls. Multivariable assessment of host factors showed that risk of TB was increased among the Jola ethnic group and smokers, and decreased in those in a professional occupation. Assessment of environmental factors showed an increased risk with household crowding, history of household exposure to a known TB case, and absence of a ceiling in the house. In a combined multivariable host-environment model, the risk of TB increased with crowding, exposure to a known TB case, as well as amongst the Jola ethnic group. CONCLUSION: In The Gambia, household crowding and past household exposure to a known TB case are the standout risk factors for TB disease. Further research is needed to identify why risk of TB seems to differ according to ethnicity

Estrogenic regulation of skeletal muscle proteome : a study of premenopausal women and postmenopausal MZ cotwins discordant for hormonal therapy

Female middle age is characterized by a decline in skeletal muscle mass and performance, predisposing women to sarcopenia, functional limitations, and metabolic dysfunction as they age. Menopausal loss of ovarian function leading to low circulating level of 17-estradiol has been suggested as a contributing factor to aging-related muscle deterioration. However, the underlying molecular mechanisms remain largely unknown and thus far androgens have been considered as a major anabolic hormone for skeletal muscle. We utilized muscle samples from 24 pre- and postmenopausal women to establish proteome-wide profiles, associated with the difference in age (30-34 years old vs. 54-62 years old), menopausal status (premenopausal vs. postmenopausal), and use of hormone replacement therapy (HRT; user vs. nonuser). None of the premenopausal women used hormonal medication while the postmenopausal women were monozygotic (MZ) cotwin pairs of whom the other sister was current HRT user or the other had never used HRT. Label-free proteomic analyses resulted in the quantification of 797 muscle proteins of which 145 proteins were for the first time associated with female aging using proteomics. Furthermore, we identified 17-estradiol as a potential upstream regulator of the observed differences in muscle energy pathways. These findings pinpoint the underlying molecular mechanisms of the metabolic dysfunction accruing upon menopause, thus having implications for understanding the complex functional interactions between female reproductive hormones and health.Peer reviewe

Structure and Reaction Mechanism of Basil Eugenol Synthase

Phenylpropenes, a large group of plant volatile compounds that serve in multiple roles in defense and pollinator attraction, contain a propenyl side chain. Eugenol synthase (EGS) catalyzes the reductive displacement of acetate from the propenyl side chain of the substrate coniferyl acetate to produce the allyl-phenylpropene eugenol. We report here the structure determination of EGS from basil (Ocimum basilicum) by protein x-ray crystallography. EGS is structurally related to the short-chain dehydrogenase/reductases (SDRs), and in particular, enzymes in the isoflavone-reductase-like subfamily. The structure of a ternary complex of EGS bound to the cofactor NADP(H) and a mixed competitive inhibitor EMDF ((7S,8S)-ethyl (7,8-methylene)-dihydroferulate) provides a detailed view of the binding interactions within the EGS active site and a starting point for mutagenic examination of the unusual reductive mechanism of EGS. The key interactions between EMDF and the EGS-holoenzyme include stacking of the phenyl ring of EMDF against the cofactor's nicotinamide ring and a water-mediated hydrogen-bonding interaction between the EMDF 4-hydroxy group and the side-chain amino moiety of a conserved lysine residue, Lys132. The C4 carbon of nicotinamide resides immediately adjacent to the site of hydride addition, the C7 carbon of cinnamyl acetate substrates. The inhibitor-bound EGS structure suggests a two-step reaction mechanism involving the formation of a quinone-methide prior to reduction. The formation of this intermediate is promoted by a hydrogen-bonding network that favors deprotonation of the substrate's 4-hydroxyl group and disfavors binding of the acetate moiety, akin to a push-pull catalytic mechanism. Notably, the catalytic involvement in EGS of the conserved Lys132 in preparing the phenolic substrate for quinone methide formation through the proton-relay network appears to be an adaptation of the analogous role in hydrogen bonding played by the equivalent lysine residue in other enzymes of the SDR family

Alcohol Use Disorders (AUD) among Tuberculosis Patients: A Study from Chennai, South India

BACKGROUND: Alcohol Use Disorders (AUDs) among tuberculosis (TB) patients are associated with nonadherence and poor treatment outcomes. Studies from Tuberculosis Research Centre (TRC), Chennai have reported that alcoholism has been one of the major reasons for default and mortality in under the DOTS programme in South India. Hence, it is planned to conduct a study to estimate prevalence of alcohol use and AUDs among TB patients attending the corporation health centres in Chennai, India. METHODOLOGY: This is a cross-sectional cohort study covering 10 corporation zones at Chennai and it included situational assessment followed by screening of TB patients by a WHO developed Alcohol Use Disorders Identification Test AUDIT scale. Four zones were randomly selected and all TB patients treated during July to September 2009 were screened with AUDIT scale for alcohol consumption. RESULTS: Out of 490 patients, 66% were males, 66% were 35 years and above, 57% were married, 58% were from the low monthly income group of <Rs 5000 per month. No females reported alcohol use. Overall, out of 490 TB pts, 29% (141) were found to consume alcohol. Among 141 current drinkers 52% (73) had an AUDIT score of >8. Age (>35 years), education (less educated), income (<Rs 5000 per month), marital status (separated/divorced) and treatment category (Category 2) were statistically significant for TB patients with alcohol use than those TB patients without alcohol use. CONCLUSIONS: AUD among TB patients needs to be addressed urgently and the findings suggest the importance of integrating alcohol treatment into TB care

Indoor solid fuel use and tuberculosis in China: a matched case-control study

<p>Abstract</p> <p>Background</p> <p>China ranks second among the 22 high burden countries for tuberculosis. A modeling exercise showed that reduction of indoor air pollution could help advance tuberculosis control in China. However, the association between indoor air pollution and tuberculosis is not yet well established. A case control study was conducted in Anhui, China to investigate whether use of solid fuel is associated with tuberculosis.</p> <p>Methods</p> <p>Cases were new sputum smear positive tuberculosis patients. Two controls were selected from the neighborhood of each case matched by age and sex using a pre-determined procedure. A questionnaire containing demographic information, smoking habits and use of solid fuel for cooking or heating was used for interview. Solid fuel (coal and biomass) included coal/lignite, charcoal, wood, straw/shrubs/grass, animal dung, and agricultural crop residue. A household that used solid fuel either for cooking and (/or) heating was classified as exposure to combustion of solid fuel (indoor air pollution). Odds ratios and their corresponding 95% confidence limits for categorical variables were determined by Mantel-Haenszel estimate and multivariate conditional logistic regression.</p> <p>Results</p> <p>There were 202 new smear positive tuberculosis cases and 404 neighborhood controls enrolled in this study. The proportion of participants who used solid fuels for cooking was high (73.8% among cases and 72.5% among controls). The majority reported using a griddle stove (85.2% among cases and 86.7% among controls), had smoke removed by a hood or chimney (92.0% among cases and 92.8% among controls), and cooked in a separate room (24.8% among cases and 28.0% among controls) or a separate building (67.8% among cases and 67.6% among controls). Neither using solid fuel for cooking (odds ratio (OR) 1.08, 95% CI 0.62-1.87) nor using solid fuel for heating (OR 1.04, 95% CI 0.54-2.02) was significantly associated with tuberculosis. Determinants significantly associated with tuberculosis were household tuberculosis contact (adjusted OR, 27.23, 95% CI 8.19-90.58) and ever smoking tobacco (adjusted OR 1.64, 96% CI 1.01-2.66).</p> <p>Conclusion</p> <p>In a population where the majority had proper ventilation in cooking places, the association between use of solid fuel for cooking or for heating and tuberculosis was not statistically significant.</p