Tuberculosis Contact Screening and Isoniazid Preventive Therapy in a South Indian District: Operational Issues for Programmatic Consideration

BACKGROUND: Under India's Revised National Tuberculosis Control Programme (RNTCP), all household contacts of sputum smear positive Pulmonary Tuberculosis (PTB) patients are screened for TB. In the absence of active TB disease, household contacts aged <6 years are eligible for Isoniazid Preventive Therapy (IPT) (5 milligrams/kilogram body weight/day) for 6 months. OBJECTIVES: To estimate the number of household contacts aged <6 years, of sputum smear positive PTB patients registered for treatment under RNTCP from April to June'2008 in Krishna District, to assess the extent to which they are screened for TB disease and in its absence initiated on IPT. METHODS: A cross sectional study was conducted. Households of all smear positive PTB cases (n = 848) registered for treatment from April to June'2008 were included. Data on the number of household contacts aged <6 years, the extent to which they were screened for TB disease, and the status of initiation of IPT, was collected. RESULTS: Households of 825 (97%) patients were visited, and 172 household contacts aged <6 years were identified. Of them, 116 (67%) were evaluated for TB disease; none were found to be TB diseased and 97 (84%) contacts were initiated on IPT and 19 (16%) contacts were not initiated on IPT due to shortage of INH tablets in peripheral health centers. The reasons for non-evaluation of the remaining eligible children (n = 56, 33%) include no home visit by the health staff in 25 contacts, home visit done but not evaluated in 31 contacts. House-hold contacts in rural areas were less likely to be evaluated and initiated on IPT [risk ratio 6.65 (95% CI; 3.06-14.42)]. CONCLUSION: Contact screening and IPT implementation under routine programmatic conditions is sub-optimal. There is an urgent need to sensitize all concerned programme staff on its importance and establishment of mechanisms for rigorous monitoring

Clinical characteristics, etiology and antimicrobial susceptibility among overweight and obese individuals with diarrhea: observed at a large diarrheal disease hospital, Bangladesh

Background:The present study aimed to determine the clinical characteristics and etiology of overweight and obese (OO) individuals with diarrhea attending an urban Dhaka Hospital, International Centre for Diarrheal Disease Research (icddr,b), Bangladesh.Methods:Total of 508 under-5 children, 96 individuals of 5-19 years and 1331 of >19 years were identified as OO from the Diarrheal Disease Surveillance System (DDSS) between 1993-2011. Two comparison groups such as well-nourished and malnourished individuals from respective age stratums were selected.Results:Isolation rate of rotavirus was higher among OO under-5 children compared to malnourished group (46% vs. 28%). Rotavirus infection among OO individuals aged 5-19 years (9% vs. 3%) (9% vs. 3%) and >19 years (6% vs. 4%) (6% vs. 3%) was higher compared to well-nourished and malnourished children. Conversely, Vibrio cholerae was lower among all OO age groups compared to well-nourished and malnourished ones. Shigella (4% vs. 6%) (4% vs. 8%), and Campylobacter (3% vs. 5%) (3% vs. 5%) were lower only among OO in >19 years individuals compared to their counterparts of the same age stratum. Salmonella was similarly isolated in all age strata and nutritional groups. In multinomial logistic regression among under-5 children, significant association was observed only with use of antimicrobials at home [OR-1.97] and duration of hospital stay [OR-0.68]. For individuals aged 5-19 years, use of antimicrobials at home (OR-1.83), some or severe dehydration (OR-3.12), having received intravenous saline (OR-0.46) and rotavirus diarrhea (OR-2.96) were found to be associated with OO respectively. Moreover, significant associations were also found for duration of diarrhea before coming to hospital (>24 hours) (OR-1.24), Shigella (OR-0.46), and Campylobacter (OR-0.58) among >19 years OO individuals along with other associated co-variates in 5-19 years group (all

The use of watershed geomorphic data in flash flood susceptibility zoning: a case study of the Karnaphuli and Sangu river basins of Bangladesh

The occurrence of heavy rainfall in the south-eastern hilly region of Bangladesh makes this area highly susceptible to recurrent flash flooding. As the region is the commercial capital of Bangladesh, these flash floods pose a significant threat to the national economy. Predicting this type of flooding is a complex task which requires a detailed understanding of the river basin characteristics. This study evaluated the susceptibility of the region to flash floods emanating from within the Karnaphuli and Sangu river basins. Twenty-two morphometric parameters were used. The occurrence and impact of flash floods within these basins are mainly associated with the volume of runoff, runoff velocity, and the surface infiltration capacity of the various watersheds. Analysis showed that major parts of the basin were susceptible to flash flooding events of a ‘moderate’-to-‘very high’ level of severity. The degree of susceptibility of ten of the watersheds was rated as ‘high’, and one was ‘very high’. The flash flood susceptibility map drawn from the analysis was used at the sub-district level to identify populated areas at risk. More than 80% of the total area of the 16 sub-districts were determined to have a ‘high’-to-‘very-high’-level flood susceptibility. The analysis noted that around 3.4 million people reside in flash flood-prone areas, therefore indicating the potential for loss of life and property. The study identified significant flash flood potential zones within a region of national importance, and exposure of the population to these events. Detailed analysis and display of flash flood susceptibility data at the sub-district level can enable the relevant organizations to improve watershed management practices and, as a consequence, alleviate future flood risk

Mda-9/Syntenin Is Expressed in Uveal Melanoma and Correlates with Metastatic Progression

Uveal melanoma is an aggressive cancer that metastasizes to the liver in about half of the patients, with a high lethality rate. Identification of patients at high risk of metastases may provide indication for a frequent follow-up for early detection of metastases and treatment. The analysis of the gene expression profiles of primary human uveal melanomas showed high expression of SDCBP gene (encoding for syndecan-binding protein-1 or mda-9/syntenin), which appeared higher in patients with recurrence, whereas expression of syndecans was lower and unrelated to progression. Moreover, we found that high expression of SDCBP gene was related to metastatic progression in two additional independent datasets of uveal melanoma patients. More importantly, immunohistochemistry showed that high expression of mda-9/syntenin protein in primary tumors was significantly related to metastatic recurrence in our cohort of patients. Mda-9/syntenin expression was confirmed by RT-PCR, immunofluorescence and immunohistochemistry in cultured uveal melanoma cells or primary tumors. Interestingly, mda-9/syntenin showed both cytoplasmic and nuclear localization in cell lines and in a fraction of patients, suggesting its possible involvement in nuclear functions. A pseudo-metastatic model of uveal melanoma to the liver was developed in NOD/SCID/IL2Rγ null mice and the study of mda-9/syntenin expression in primary and metastatic lesions revealed higher mda-9/syntenin in metastases. The inhibition of SDCBP expression by siRNA impaired the ability of uveal melanoma cells to migrate in a wound–healing assay. Moreover, silencing of SDCBP in mda-9/syntenin-high uveal melanoma cells inhibited the hepatocyte growth factor (HGF)-triggered invasion of matrigel membranes and inhibited the activation of FAK, AKT and Src. Conversely syntenin overexpression in mda-9/syntenin-low uveal melanoma cells mediated opposite effects. These results suggest that mda-9/syntenin is involved in uveal melanoma progression and that it warrants further investigation as a candidate molecular marker of metastases and a potential therapeutic target

Exploitation of Herpesvirus Immune Evasion Strategies to Modify the Immunogenicity of Human Mesenchymal Stem Cell Transplants

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs) are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected. METHODOLOGY/PRINCIPAL FINDINGS: We aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC) class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID) mice could be attained provided that recipients' natural killer (NK) cells were depleted prior to cell transplantation. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs non-immunogenic and thereby universally transplantable

Genetic Signatures of Exceptional Longevity in Humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Complete genes may pass from food to human blood

Our bloodstream is considered to be an environment well separated from the outside world and the digestive tract. According to the standard paradigm large macromolecules consumed with food cannot pass directly to the circulatory system. During digestion proteins and DNA are thought to be degraded into small constituents, amino acids and nucleic acids, respectively, and then absorbed by a complex active process and distributed to various parts of the body through the circulation system. Here, based on the analysis of over 1000 human samples from four independent studies, we report evidence that meal-derived DNA fragments which are large enough to carry complete genes can avoid degradation and through an unknown mechanism enter the human circulation system. In one of the blood samples the relative concentration of plant DNA is higher than the human DNA. The plant DNA concentration shows a surprisingly precise log-normal distribution in the plasma samples while non-plasma (cord blood) control sample was found to be free of plant DNA