PCR-positivity in harvested bone marrow predicts relapse after transplantation with autologous purged bone marrow in children in second remission of precursor B-cell acute leukaemia

Purging of autologous bone marrow (BM) grafts of children in second remission after a relapse of precursor B acute lymphoblastic leukaemia (ALL) in the BM has been carried out in our laboratory since 1987, initially by complement mediated cell lysis. This protocol was extended by performing an immunorosette depletion before lysis with complement. The aim of the present study was to assess by polymerase chain reaction the presence of residual leukaemic cells in the BM grafts before and after purging. The results were then correlated to clinical outcome. In 24/28 patients a PCR product was obtained by amplification of IgH and/or TcR junctional regions. BM before purging was available for analysis in 13 patients. We found that leukaemic cells could be detected in 8/13 (62%) of these grafts before purging . All these eight patients experienced a relapse, regardless of whether the purging procedure had been successful (defined as achievement of PCR-negativity) or not. In contrast, none of the five patients with PCR-negative grafts before purging relapsed ( P  = 0.0008). One patient died due to transplant-related toxicity. Of the remaining 23 patients, nine patients received a PCR-positive BM graft after purging. All these nine patients experienced a relapse as compared to 6/14 whose BM was PCR-negative after purging ( P  = 0.0072). Two of eight PCR-positive BM grafts could be purged to PCR-negativity. Thus, improvements both in treatment of leukaemia and in purging efficacy are still needed.     

Reverse engineering the (beta/alpha )8 barrel fold

The (beta/alpha)(8) barrel is the most commonly occurring fold among protein catalysts. To lay a groundwork for engineering novel barrel proteins, we investigated the amino acid sequence restrictions at 182 structural positions of the prototypical (beta/alpha)(8) barrel enzyme triosephosphate isomerase. Using combinatorial mutagenesis and functional selection, we find that turn sequences, alpha-helix capping and stop motifs, and residues that pack the interface between beta-strands and alpha-helices are highly mutable. Conversely, any mutation of residues in the central core of the beta-barrel, beta-strand stop motifs, and a single buried salt bridge between amino acids R189 and D227 substantially reduces catalytic activity. Four positions are effectively immutable: conservative single substitutions at these four positions prevent the mutant protein from complementing a triosephosphate isomerase knockout in Escherichia coli. At 142 of the 182 positions, mutation to at least one amino acid of a seven-letter amino acid alphabet produces a triosephosphate isomerase with wild-type activity. Consequently, it seems likely that (beta/alpha)(8) barrel structures can be encoded with a subset of the 20 amino acids. Such simplification would greatly decrease the computational burden of (beta/alpha)(8) barrel design.     

Dropout from care among HIV-infected patients enrolled in care at a tertiary HIV care center in Chennai,India

Long-term follow-up of persons infected with HIV infection is essential to optimize clinical outcomes. However, limited data exist on the rates of dropout (DO) from HIV care and factors associated with DO especially from resource-limited settings. We conducted a retrospective analysis of the data available at YRGCARE, a private HIV care provider in south India that has registered over 15,000 HIV-infected persons since its inception in 1993. We included 7995 patients who registered for care between 1 January 2004 and 31 December 2009. A dropout was defined as a person who registered for care during this period and had not been seen in the clinic for >1 year. Logistic regression was used to examine factors associated with DO from clinical care. The median age of the patients registered for care was 34 years; 66% were male and 83% were married. The overall DO rate was 38.1 per 100 person-years – the majority of the DOs occurred within 6 months from registration. In multivariate analyses, patients who were enrolled in clinical studies/projects entitling them to free medications and retention staff (Odds Ratio [OR]: 0.65) or were on antiretroviral therapy (ART; OR: 0.37) or had a CD4 > 350 at the last visit (OR: 0.20) were significantly less likely to DO from clinical care. We observed a high rate of DO from clinical care at this tertiary HIV clinic in Chennai, India. Making ART available free of charge in the private sector and providing incentives/benefits for attending clinic visits as is routinely done in clinical trials might help improve retention.     

Associations between Extreme Precipitation and Gastrointestinal-Related Hospital Admissions in Chennai,India

Background: Understanding the potential links between extreme weather events and human health in India is important in the context of vulnerability and adaptation to climate change. Research exploring such linkages in India is sparse.Objectives: We evaluated the association between extreme precipitation and gastrointestinal (GI) illness-related hospital admissions in Chennai, India, from 2004 to 2007.Methods: Daily hospital admissions were extracted from two government hospitals in Chennai, India, and meteorological data were retrieved from the Chennai International Airport. We evaluated the association between extreme precipitation (≥ 90th percentile) and hospital admissions using generalized additive models. Both single-day and distributed lag models were explored over a 15-day period, controlling for apparent temperature, day of week, and long-term time trends. We used a stratified analysis to explore the association across age and season.Results: Extreme precipitation was consistently associated with GI-related hospital admissions. The cumulative summary of risk ratios estimated for a 15-day period corresponding to an extreme event (relative to no precipitation) was 1.60 (95% CI: 1.29, 1.98) among all ages, 2.72 (95% CI: 1.25, 5.92) among the young (≤ 5 years of age), and 1.62 (95% CI: 0.97, 2.70) among the old (≥ 65 years of age). The association was stronger during the pre-monsoon season (March–May), with a cumulative risk ratio of 6.50 (95% CI: 2.22, 19.04) for all ages combined compared with other seasons.Conclusions: Hospital admissions related to GI illness were positively associated with extreme precipitation in Chennai, India, with positive cumulative risk ratios for a 15-day period following an extreme event in all age groups. Projected changes in precipitation and extreme weather events suggest that climate change will have important implications for human health in India, where health disparities already exist.Citation: Bush KF, O’Neill MS, Li S, Mukherjee B, Hu H, Ghosh S, Balakrishnan K. 2014. Associations between extreme precipitation and gastrointestinal-related hospital admissions in Chennai, India. Environ Health Perspect 122:249–254; http://dx.doi.org/10.1289/ehp.1306807     

2-Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against Mycobacterium tuberculosis

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Ribavirin inhibits Chandipura virus replication in Vero cells

Chandipura virus (CHPV) is an emerging tropical pathogen in India. The virus has been reported to be associated with an acute encephalitis syndrome in young children with a case fatality rate of 55% to 75%. Clinical management with symptomatic treatment is the only option available to treat infected patients. No vaccines are available for prophylaxis. In light of the prophylactic limitations, antiviral therapy would play an important role in control of CHPV infection. In the present study, ribavirin (RBV), an antiviral drug widely accepted for human use and having an antiviral effect on many RNA and DNA viruses, was tested against the CHPV. A screening assay that scores for the virus-mediated plaque formation in the cultured Vero cells was used. RBV exhibited 50% inhibitory concentration (IC₅₀) at 89.84 ± 1.8 µM. The drug was very effective when the cells were treated either within an hour postinfection or 4 to 6 hours before infection. The plaque morphology was different in RBV treated cells; the plaques were smaller in size as compared with the plaques in the virus infected cells. The study reports the antiviral activity of RBV against CHPV, and hence, suggests the possible utility of RBV in CHPV infected patients to mitigate the disease. A further clinical trial is needed before introducing the drug for human use against CHPV infection.