Tobacco product litter as a form of postconsumption marketing: an observational study in India.

BACKGROUND: Tobacco product litter may be a form of postconsumption marketing if the littered items are branded. We conducted an observational study in India to assess the presence of tobacco product litter and determine the proportion that included branding. METHODS: During November-December 2022, we identified tobacco product litter (cigarette/bidi butts and packaging; smokeless tobacco packaging) in nine Indian cities: Bengaluru, Bhubaneswar, Chennai, Delhi, Guwahati, Hyderabad, Lucknow, Mumbai and Patna. In each city, we conducted observations along 15 different routes, each approximately 250 m in distance, for a total of 135 observational routes. Data collectors classified each piece of tobacco litter (product/packaging) and recorded if the litter had visible branding, such as brand names and/or logos. RESULTS: The study identified 17 261 pieces of tobacco product litter; SLT packaging comprised the largest proportion of the sample (62%), followed by cigarette butts (26%), bidi butts (8%), cigarette packaging (3%) and bidi packaging (1%). Across the sample, 81% (n=13 924) of the litter was branded. A brand was visible on most packaging for cigarettes (98%), bidis (97%) and SLT (86%), and present on 82% of cigarette butts and 26% of bidi butts. CONCLUSION: This study found that the majority of tobacco product litter in India is branded, which could function as a form of postconsumption marketing. Plain and standardised packaging and banning branding features on filters would reduce tobacco litter branding.

Spectrum of Rare and Novel Indel Mutations Responsible for ß Thalassemia in Eastern India.

There is limited data available regarding the clinical utility of routine molecular diagnosis of ß Thalassaemia in addition to HPLC-based screening in low resource settings. The current study highlights the caveats of an HPLC-based screening compared to the inclusion of genetic confirmation as a second-tier test and its implications in terms of genotype-phenotype correlation. A prospective, institution-based, observational study was conducted at the Department of Paediatric Medicine, including 103 children aged up to 12 years. Five common mutations for ß Thalassemia and the HbE mutation in the HBB gene were tested by a two-tiered approach using multiplex ARMS PCR and PCR RFLP methods respectively. Sanger sequencing of all three exons of the HBB gene was performed in all negative cases. Sequencing revealed many rare pathogenic mutations like c.316-106 C > G (dbSNP: 34,690,599); Hb Kairouan (c.92G > C); c.33 C > A (dbSNP rs35799536); c.47G > A (dbSNP rs63750783); c.51delC (HbVar ID 799); c.[93-2 A > C] and c.118 C > T (HbVar ID 845). We detected a novel Pathogenic M_000518.5(HBB):c.164_168delinsGGCATCA (p.Val55fs) mutation in a heterozygous state which was reported in the ClinVar database with accession ID VCV000590977.2. We also encountered several cases of silent carrier on HPLC and de novo occurrence of mutation. We conclude that the multiplex touchdown ARMS PCR methodology employed in the present study provides a low-cost solution for molecular diagnostics of Β Thalassaemia. The problem of silent carriers in HPLC is significant enough to rethink if we need supplemental genetic testing in the couple when one of the partners is a carrier. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01098-w.

Innovative numerical modeling for predicting soil relaxation in the design of twin circular culverts.

This study presents a finite difference model for analyzing ground stability and settlement of twin circular culverts in undrained clay. The model is verified through simulations of soil movement and relaxation around a tunnel-boring machine's shield. Stability numbers and ground settlement are evaluated across various culvert geometries and soil ratios and compared to rigorous solutions and previous models. The settlement data obtained is used to determine inflection point parameters for practical culvert design, considering dimensionless ratios. The findings highlight the importance of precise design methodologies that consider soil properties and geometry. The finite difference model proves to be a valuable tool in culvert design, providing accurate analysis of stability and settlement characteristics. The presented design figures and regression equations serve as practical tools for engineers in designing stable twin circular culverts in undrained clay. The study emphasizes the need to carefully consider soil properties and geometry for successful culvert design. In conclusion, the finite difference model offers insights into ground stability and settlement of twin circular culverts. The presented design figures and regression equations support engineers in making informed design decisions, ensuring the stability and long-term performance of culverts in undrained clay conditions.

Cost-effectiveness of newborn screening for sickle cell disease: a systematic review protocol.

OBJECTIVE: The purpose of this systematic review is to assess the cost-effectiveness of targeted/selective newborn screening compared with universal screening for sickle cell disease across various countries and settings. INTRODUCTION: The incidence of sickle cell disease is a widespread and potentially fatal hematologic disorder that affects thousands of newborns worldwide. The cost of newborn screening creates a burden on households and the economy. INCLUSION CRITERIA: Studies will be eligible for inclusion in the review if they focus on the cost-effectiveness of newborn screening for sickle cell disease, comparing targeted/selective screening with universal screening. METHODS: A preliminary search of MEDLINE (PubMed) was undertaken using MeSH terms, such as sickle cell disease, newborn , and economic evaluations . Two reviewers will screen the titles, abstracts, and full text independently against the inclusion criteria. Disagreements will be resolved by discussion or with a third reviewer. To assess methodological quality, the JBI checklist for economic evaluation will be used. Data will be extracted by 2 reviewers using a modified JBI data extraction form. The JBI dominance ranking matrix for economic evaluations will be used to summarize and compare the results. Cost-effectiveness will be measured on the basis of cost per test/case detected, quality-adjusted life years gained, or disability-adjusted life years averted. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment will be conducted to evaluate the certainty of economic evidence, such as use of resources and expenditures, and to incorporate the results into the decision-making process. REVIEW REGISTRATION: PROSPERO CRD42017057963.

Morbidity among the tribal populations of West Bengal: A study based on data collected from the Mobile Medical Clinic.

Background: Tribes are the most socially excluded group in the nation due to their restricted access to healthcare. There are little data on the real burden and distribution of illnesses among tribes. The present study determines the types and patterns of sickness among tribal populations in West Bengal. Methods: Five blocks from five districts in West Bengal were used for this cross-sectional study. Between the years 2018 and 2019, 52,189 patients visited these mobile medical clinics (MMCs), but only 36,128 were included in our study. Data were analyzed using the SPSS software (ver. 27.0). Results: Younger age groups (1-25 years) show higher primary registration compared to other age categories; older age groups (>60 years) show higher repeat registration. High prevalence in infectious diseases (44.5% of the total primary registration) and high repeated cases in NCDs (11.5% to 33.2%), which are nearly three times higher than primary cases (Cramer's V test = 0.29; P = .001) are observed. Among the studied MMCs, Binpur II and Matiali MMC have more than two times the risk of gastrointestinal problems, while Madarihat MMC has more than one time the risk. Garbeta II MMC shows more than three times the risk of NCDs (adjusted odds ratio = 3.97; 95% confidence interval: 3.05-5.17) than the other diseases. Conclusion: The present study shows high prevalence of infectious diseases, injury and pain, NCDs, gastrointestinal problems, and vertigo in tribal populations of West Bengal.

Cost-effectiveness of a decentralized care model for managing multi-drug-resistant tuberculosis in low- and middle-income countries: a systematic review protocol.

OBJECTIVE: The purpose of this systematic review is to assess the available economic evidence of a decentralized care model compared to a centralized model for treating multi-drug-resistant tuberculosis (MDR-TB) in low- and middle-income countries (LMICs). INTRODUCTION: Diseases that affect physiological health create a burden on human livelihoods and the economy. There is a lack of studies examining the economic evaluation of MDR-TB across different countries. A preliminary search identified no published or ongoing reviews on MDR-TB in LMICs. INCLUSION CRITERIA: Studies will be eligible if they include both patients receiving centralized care (ie, care provided by specialist centers through inpatient or outpatient services) and patients receiving decentralized care (ie, care provided by grassroots community workers in peripheral facilities or in the patients' residence) for MDR-TB in LMICs. Eligible studies will report economic evaluations of treatment for MDR-TB. METHODS: A preliminary search of MEDLINE (PubMed) was undertaken using MeSH terms, such as MDR-TB, economic evaluation, therapeutics, LMICs . Two reviewers will independently screen the titles, abstracts, and full text against the inclusion criteria. Disagreements will be resolved through discussion or with a third reviewer. The JBI checklist for economic evaluations will be utilized to evaluate the methodological quality. Data will be extracted using a modified JBI data extraction form for economic evaluations. The Dominance Ranking Matrix, developed by JBI for economic evaluations, will be used to summarize and compare the results of different types of economic evaluations (cost-effectiveness, cost-benefit analysis, cost-utility analysis, or cost-minimization analysis). Cost per quality-adjusted life year gained and cost per disability-adjusted life year averted will be measures for economic evaluation. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be used to assess the certainty of economic evidence. REVIEW REGISTRATION: PROSPERO CRD42022368696.

Economic evaluations of neglected tropical diseases interventions in low- and middle-income countries: a systematic review protocol.

OBJECTIVE: The objective of this systematic review is to provide an overview of economic evaluation studies of interventions for neglected tropical diseases in low- and/or middle-income countries. INTRODUCTION: The majority of people most susceptible to neglected tropical diseases reside in low- and middle-income countries and suffer significant economic impact due to these diseases. The World Health Organization suggests utilizing a systematic and cross-cutting approach with multiple interventions to lessen the neglected tropical disease burden. INCLUSION CRITERIA: Studies will be eligible for inclusion if they include economic evaluations of interventions for neglected tropical diseases and are conducted in low- and/or middle-income country settings. METHODS: A preliminary search of MEDLINE (PubMed) was undertaken using MeSH terms, such as neglected tropical disease, economic evaluation, therapeutics, low- and/or middle-income countries. Two reviewers will screen titles and abstracts independently, followed by a full-text review against the inclusion criteria. Disagreements will be resolved by discussion or with a third reviewer. To assess methodological quality, the JBI checklist for economic evaluations will be used. For economic evaluations, data will be extracted using the standardized JBI data extraction form. The Dominance Ranking Matrix will be used to summarize and compare the results of different types of economic evaluations. Cost per quality adjusted life year gained and cost per disability adjusted life year averted will be measures for economic evaluation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to assess the certainty of economic evidence, such as resource use and costs. REVIEW REGISTRATION: PROSPERO CRD42017070386.

Hospitalisation expenditure on tuberculosis among tribal populations in India: A repeated cross-sectional analysis of national sample survey data, 2004 to 2018.

Objective: Tribal population in India (8.6% of the total population) have a greater prevalence of tuberculosis compared to the national average. The article aims to study out-of-pocket expenditure (OOPE), hardship financing, and impoverishment effects of TB hospitalisation treatment among tribal populations in India. Methods: Data of three rounds of National Sample Surveys (NSS) 60th (2004-05), 71st (2013-14) and 75th (2017-18) rounds were analyzed. Descriptive statistics, bivariate estimates and multivariate models were performed to calculate the OOPE, healthcare burden (HCB), catastrophic health expenditure (CHE), hardship financing and impoverishment effects using standard definitions at February 2023 price values. Propensity score matching (PSM) was used to examine the effect of health insurance coverage on catastrophic health expenditure, and impoverishment. Results: Over two-thirds of the TB cases are seen in the economically productive age group (14-59 years). Substantial OOPE and its impact on HCB, CHE, and poverty impact observed among 15-35 age group across all three rounds. Illiterate patients and those availing private hospitals for TB treatment had higher OOPE, HCB, hardship financing, CHE, and poverty impact. 38.5% (2014) and 33.2% (2018) are covered with any kind of public healthcare coverage, PSM analysis shows households with health insurance have lower incidence of CHE and impoverishment effects due to TB hospitalisation expenditure. Conclusions: The current study aids in comprehending the patterns in the financial burden of TB on tribal households during the previous 15 years and gives policy makers information for efficient resource allocation management for TB among Indian tribal communities.

Cost and cost-effectiveness of treatments for rheumatic heart disease in low- and middle-income countries: a systematic review protocol.

OBJECTIVE: This review will synthesize studies on costs, the impact of these costs, and the cost-effectiveness of treatments for rheumatic heart disease (RHD) in low- and middle-income countries. INTRODUCTION: RHD incurs high costs owing to its clinical complexity, surgical treatments, and prolonged hospital stays. Thus, the disease has a substantial economic impact on the health system, patients, and their families. No systematic review on economic evidence of treatments for RHD has been published to date. INCLUSION CRITERIA: This review will consider all cost and cost-effectiveness studies on RHD treatments for children and young adults (5─30 years), residing in low- and middle-income countries. METHODS: The review will follow the JBI methodology for systematic reviews of economic evaluation evidence. The search strategy will locate published and unpublished studies in English. Systematic searches will be conducted in MEDLINE (PubMed), MEDLINE (Ovid), Embase (Ovid), Scopus, CINAHL (EBSCOhost), National Health Service Economic Evaluation Databases, Pediatric Economic Database Evaluation, and Cost-Effectiveness Analysis Registry. Two independent reviewers will screen titles and abstracts, followed by a full-text review based on the inclusion criteria. Data will be extracted using a modified JBI data extraction form for economic evaluations. JBI's Dominance Ranking Matrix for economic evaluations will be used to summarize and compare the results of cost and cost-effectiveness studies. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be used to assess the certainty of economic evidence for outcomes related to resource use. REVIEW REGISTRATION NUMBER: PROSPERO CRD42023425850.

CpG methylation of half-CRE sequences creates C/EBPalpha binding sites that activate some tissue-specific genes.

DNA methylation of the cytosine in the CpG dinucleotide is typically associated with gene silencing. Genomic analyses have identified low CpG promoters that are both methylated and transcriptionally active, but the mechanism underlying the activation of these methylated promoters remains unclear. Here we show that CpG methylation of the CRE sequence (TGACGTCA) enhances the DNA binding of the C/EBPα transcription factor, a protein critical for activation of differentiation in various cell types. Transfection assays also show that C/EBPα activates the CRE sequence only when it is methylated. The biological significance of this observation was seen in differentiating primary keratinocyte cultures from newborn mice where certain methylated promoters are both bound by C/EBPα and activated upon differentiation. Experimental demethylation by either 5-azacytidine treatment or DNMT1 depletion diminished both C/EBPα binding and activation of the same methylated promoters upon differentiation suggesting that CpG methylation can localize C/EBPα. Transfection studies in cell cultures using methylated tissue-specific proximal promoters identified half-CRE (CGTCA) and half-C/EBP (CGCAA) sequences that need to be methylated for C/EBPα mediated activation. In primary dermal fibroblasts, C/EBPα activates a different set of methylated tissue-specific promoters upon differentiation into adipocytes. These data identify a new function for methyl CpGs: producing DNA binding sites at half-CRE and half-C/EBP sequences for C/EBPα that are needed to activate tissue-specific genes.

Estimation of non-health gross domestic product (NHGDP) loss due to COVID-19 deaths in West Bengal, India.

OBJECTIVES: The state of West Bengal witnessed a significant surge of COVID-19 in all three waves. However, there is a gap in understanding the economic loss associated with COVID-19. This study estimates future non-health gross domestic product (NHGDP) losses associated with COVID-19 deaths in West Bengal, India. SETTING: Various open domains were used to gather data on COVID-19 deaths in West Bengal and the aforementioned estimates. PRIMARY AND SECONDARY OUTCOME MEASURES: The NHGDP losses were evaluated using the cost-of-illness approach. Future NHGDP losses were discounted at 3%. Excess death estimates by the WHO and Global Burden of Disease (GBD) were used. Sensitivity analysis was carried out by varying discount rates and average age of death (AAD). RESULTS: 21 532 deaths in West Bengal from 17 March 2020 to 31 December 2022 decreased the future NHGDP by $0.92 billion. Nearly 90% of loss was due to deaths occurring in the age group of 30 years and above. Majority of the NHGDP loss was borne by the 46-60 years age group. NHGDP loss/death was $55,171; however, the average loss/death declined with rise in age. Based on the GBD and WHO excess death estimates, the NHGDP loss increased to $9.38 billion and $9.42 billion, respectively. When the lower age interval is considered as AAD, the NHGDP loss increased to $1.3 billion. At 5% and 10% discount rates, the losses reduced to $0.767 billion and $0.549 billion, respectively. CONCLUSIONS: Results from the study suggest that COVID-19 contributed to a major economic loss in West Bengal. The mortality and morbidity caused by COVID-19, the substantial economic costs at individual and population levels in West Bengal, and probably across India and other countries, is another economic argument for better infection control strategies across the globe to minimise the impact of COVID-19.

Model-based estimation of burden of COVID-19 with disability-adjusted life years and value of statistical life in West Bengal, India.

OBJECTIVES: The COVID-19 pandemic has posed unprecedented challenges to health systems and populations, particularly in India. Comprehensive, population-level studies of the burden of disease could inform planning, preparedness and policy, but are lacking in India. In West Bengal, India, we conducted a detailed analysis of the burden caused by COVID-19 from its onset to 7 January 2022. SETTING: Open-access, population-level and administrative data sets for West Bengal were used. PRIMARY AND SECONDARY OUTCOME MEASURES: Disability-adjusted life years (DALYs), years of potential productive life lost (YPPLL), cost of productivity lost (CPL: premature mortality and absenteeism), years of potential life lost (YPLL), premature years of potential life lost, working years of potential life lost (WYPLL) and value of statistical life (VSL) were estimated across scenarios (21 for DALY and 3 each for YPLL and VSL) to evaluate the effects of different factors. RESULTS: COVID-19 had a higher impact on the elderly population with 90.2% of deaths arising from people aged above 45. In males and females, respectively, DALYs were 190 568.1 and 117 310.0 years, YPPLL of the productive population was 28 714.7 and 16 355.4 years, CPL due to premature mortality was INR3 198 259 615.6 and INR583 397 335.1 and CPL due to morbidity was INR2 505 568 048.4 and INR763 720 886.1. For males and females, YPLL ranged from 189 103.2 to 272 787.5 years and 117 925.5 to 169 712.0 years for lower to higher age limits, and WYPLL was 54 333.9 and 30 942.2 years. VSL (INR million) for the lower, midpoint and upper life expectancies was 883 330.8; 882 936.4; and 880 631.3, respectively. Vaccination was associated with reduced mortality. CONCLUSIONS: The losses incurred due to COVID-19 in terms of the computed estimates in West Bengal revealed a disproportionately higher impact on the elderly and males. Analysis of various age-gender subgroups enhances localised and targeted policymaking to minimise the losses for future pandemics.

Economic Burden of Mosquito-Borne Diseases in Low- and Middle-Income Countries: Protocol for a Systematic Review.

BACKGROUND: Globally, among all the vector-borne diseases, mosquito-borne diseases are responsible for a substantial number of cases and deaths and amount to an economic cost of US $12 billion per year. However, there is a dearth of systematic research conducted on the economic burden of mosquito-borne diseases. To address the lack of comprehensive information on this topic, a systematic review will be conducted to synthesize evidence for informing targeted policies and strategies addressing this growing burden and for better financial protection of households. OBJECTIVE: The systematic review aims to review the economic burden of mosquito-borne diseases in low- and middle-income countries (LMICs). The review estimates the total cost, which is the compilation of both the direct costs and indirect costs. Additionally, it reports cost estimates per disease, country, and patient. The review outcome will also discuss the impact of the economic burden in terms of out-of-pocket expenditure, catastrophic health expenditure, impoverishment, and gross domestic product impact due to mosquito-borne diseases in LMICs. METHODS: Systematic searches will be conducted in PubMed (MEDLINE), Ovid Embase, Scopus, the cumulative index of nursing and allied health literacy, and Cochrane CENTRAL. Additionally, websites of the World Bank, World Health Organization, and Asian Development Bank as well as grey literature (eg, Malaria No More and the Ministry of Health websites) will be searched to gather comprehensive information on the topic and identify studies published in the English language. The titles and abstracts will be independently screened by 2 reviewers, followed by a full-text review against the inclusion criteria. Disagreements will be resolved through discussion with a third author. The methodological reporting quality of the studies will be evaluated using the Larg and Moss checklist, Cochrane risk-of-bias tool for randomized trials, and the Consensus on Health Economic Criteria. Data will be extracted using a standardized data extraction form. RESULTS: The protocol was registered in PROSPERO (CRD42023427111) prior to the initiation of the search strategy. The review is currently ongoing and will synthesize information from the identified studies through a process involving structured screening, data extraction, and critical appraisal in the form of tables and a narrative summary of studies reporting the economic burden incurred due to mosquito-borne diseases in LMICs. CONCLUSIONS: This review seeks to report the economic burden of mosquito-borne diseases. It will act as evidence for policymakers to prioritize their decisions regarding containing the prevalence of mosquito-borne diseases and the means to lowering the incidence of diseases spread by mosquitoes. TRIAL REGISTRATION: PROSPERO CRD42023427111; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=427111. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/50985.

Role of steroid on management of limb swelling and local pain in haematotoxic snake bite.

Introduction: Local Pain and swelling in the biting area of haematotoxic snake bite victims are very common symptoms. This study was conducted to retrospectively observe the effect of oral Tab Prednisolone on a short-term basis as an add-on therapy of haematotoxic snake bite management in respect of Local Pain and swelling recovery. Materials and Methods: This retrospective descriptive study was conducted in a tertiary care hospital in West Bengal among 36 haematotoxic snake bite victims, admitted from February 2020 to January 2021. After collection of the data from hospital records and screened by inclusion and exclusion criteria, 36 participants were included in two groups based on the treatment regimen. Group A (n: 24) received only conventional treatment and Group B (n: 12) received oral Tab Prednisolone on a short-term basis as an add-on therapy of conventional treatment. Swelling was measured as a distance from the site of the bite with measuring tape in centimeters and pain was measured by a numerical rating pain scale (NRS) between 0 and 10. Ethical permission has been waived from the Institutional Ethical Review Committee. Result: A total of 36 patients (32 male and 4 female) were included in the study. Age (Mean ± SD) of the snake victim persons in Group A and Group B were 35.79 ± 8.34 years and 31.33 ± 6.47 years, respectively. The local swelling length and pain score reduced significantly among group B patients on day 6 in comparison to day 2. However, in Group A, the pain score and local swelling increased significantly on day 6 in comparison to day 2. Conclusion: A short course of systemic steroids as an adjuvant with anti-venom serum (ASV) for the management of local pain and edema in case of haematotoxic snake bite may be beneficial if there is no contraindication.

Correlation of ATP7B gene mutations with clinical phenotype and radiological features in Indian Wilson disease patients.

INTRODUCTION: Wilson disease (WD) is characterized by a wide variety of clinical manifestations. Our study aimed to correlate genotype with clinical and radiological features in Indian WD patients. METHODS: We conducted a descriptive observational study in a tertiary care neurology referral center of eastern India over a period of 2 years. Demographic data collection, clinical examination and relevant investigations were done for all WD patients meeting the inclusion criteria. Based on previous reports of mutation hotspots for WD in Eastern India, we performed PCR-Sanger sequencing of selected exons of ATP7B gene. To understand the role of each of these covariates on the occurrence of common mutation, we applied a logistic regression as well as random forest in a supervised learning framework. RESULTS: Fifty-two WD patients were included in the study. c.813C > A (p.C271X) was the commonest identified mutation. The statistical methods applied to our data-set reveal the most important features for predicting common mutation or its absence. We also found that the state-of-the-art classification algorithms are good at predicting the absence of common mutation (with true positive rates being 0.7647 and 0.8823 for logistic classifier and random forest, respectively), but predicting the occurrence remains a harder modeling challenge. CONCLUSIONS: WD patients in eastern India have significant genotypic and phenotypic diversity. Statistical methods for binary classification show some early promise of detecting common mutations and suggest important covariates, but further studies with larger samples and screening of remaining exons are warranted for understanding the full genetic landscape of Wilson disease.

Genetic variation and haplotype structures of innate immunity genes in eastern India.

This study reports results of an extensive and comprehensive study of genetic diversity in 12 genes of the innate immune system in a population of eastern India. Genomic variation was assayed in 171 individuals by resequencing approximately 75kb of DNA comprising these genes in each individual. Almost half of the 548 DNA variants discovered was novel. DNA sequence comparisons with human and chimpanzee reference sequences revealed evolutionary features indicative of natural selection operating among individuals, who are residents of an area with a high load of microbial and other pathogens. Significant differences in allele and haplotype frequencies of the study population were observed with the HapMap populations. Gene and haplotype diversities were observed to be high. The genetic positioning of the study population among the HapMap populations based on data of the innate immunity genes substantially differed from what has been observed for Indian populations based on data of other genes. The reported range of variation in SNP density in the human genome is one SNP per 1.19kb (chromosome 22) to one SNP per 2.18kb (chromosome 19). The SNP density in innate immunity genes observed in this study (>3SNPskb(-1)) exceeds the highest density observed for any autosomal chromosome in the human genome. The extensive genomic variation and the distinct haplotype structure of innate immunity genes observed among individuals have possibly resulted from the impact of natural selection.

Proline homozygosity in codon 72 of p53: a risk genotype for human papillomavirus related cervical cancer in Indian women.

The objective of the present study was to determine the codon 72 genotypic frequencies of p53 in Indian women and to analyze the association of this polymorphism with human papillomavirus (HPV) related cervical cancer (CaCx). We used tissues derived from 55 women diagnosed with squamous cell carcinoma of the cervix (of whom 46 were HPV types 16/18 positive) and cervical scrapes derived from 201 cytologically normal women (of whom 84 were HPV types 16/18 positive) as controls. The DNA isolated from these samples was genotyped for p53 polymorphism by polymerase chain reaction and restriction fragment length polymorphism method. The genotypic frequency of homozygous arginine among women with CaCx was 27% and this did not differ with the controls. But, proline homozygosity of 33% in the malignant samples was significantly higher than controls (OR=2.23; 95% CI: 1.14-4.35; P=0.02). The associated risk of this genotype towards CaCx was more prominent (OR=2.67; 95% CI: 1.16-6.15; P=0.02) when analysis was restricted to HPV 16/18 positive women. Thus, proline homozygosity at codon 72 of p53 and not arginine homozygosity, could be a risk factor for development of CaCx associated with high risk HPV among Indian women.

Combinatorial recruitment of CREB, C/EBPß and c-Jun determines activation of promoters upon keratinocyte differentiation.

BACKGROUND: Transcription factors CREB, C/EBPß and Jun regulate genes involved in keratinocyte proliferation and differentiation. We questioned if specific combinations of CREB, C/EBPß and c-Jun bound to promoters correlate with RNA polymerase II binding, mRNA transcript levels and methylation of promoters in proliferating and differentiating keratinocytes. RESULTS: Induction of mRNA and RNA polymerase II by differentiation is highest when promoters are bound by C/EBP ß alone, C/EBPß together with c-Jun, or by CREB, C/EBPß and c-Jun, although in this case CREB binds with low affinity. In contrast, RNA polymerase II binding and mRNA levels change the least upon differentiation when promoters are bound by CREB either alone or in combination with C/EBPß or c-Jun. Notably, promoters bound by CREB have relatively high levels of RNA polymerase II binding irrespective of differentiation. Inhibition of C/EBPß or c-Jun preferentially represses mRNA when gene promoters are bound by corresponding transcription factors and not CREB. Methylated promoters have relatively low CREB binding and, accordingly, those which are bound by C/EBPß are induced by differentiation irrespective of CREB. Composite "Half and Half" consensus motifs and co localizing consensus DNA binding motifs are overrepresented in promoters bound by the combination of corresponding transcription factors. CONCLUSION: Correlational and functional data describes combinatorial mechanisms regulating the activation of promoters. Colocalization of C/EBPß and c-Jun on promoters without strong CREB binding determines high probability of activation upon keratinocyte differentiation.

A novel statistical algorithm for enhancing the utility of HapMap data to design genomic association studies in non-HapMap populations.

The HapMap database should be effectively used in designing disease association studies in non-HapMap populations. The efficiency of portability of tagSNPs from HapMap to non-HapMap populations is widely variable. A new algorithm is proposed for selecting SNPs from HapMap for use in non-HapMap populations by simultaneously considering and combining data on allele frequencies and linkage-disequilibrium values in the four HapMap populations. Empirical comparison and validation of the algorithm are provided by using Tagger, available HapMap data and data from an Indian population. The proposed method is shown to be efficient and effective. A software implementing this algorithm is freely available.

Suppression of the C/EBP family of transcription factors in adipose tissue causes lipodystrophy.

Adipose-specific inactivation of both AP-1 and CCAAT-enhancer-binding protein (C/EBP) families of B-ZIP transcription factors in transgenic mice causes severe lipoatrophy. To evaluate whether inactivation of only C/EBP members was critical for lipoatrophy, A-C/EBP, a dominant-negative protein that specifically inhibits the DNA binding of the C/EBP members, was expressed in adipose tissue. For the first 2 weeks after birth, aP2-A-C/EBP mice had no white adipose tissue (WAT), drastically reduced brown adipose tissue (BAT), and exhibited marked hepatic steatosis, hyperinsulinemia, and hyperlipidemia. However, WAT appeared during the third week, coinciding with significantly improved metabolic functioning. In adults, BAT remained reduced, causing cold intolerance. At 30 weeks, the aP2-A-C/EBP mice had only 35% reduced WAT, with clear morphological signs of lipodystrophy in subcutaneous fat. Circulating leptin and adiponectin levels were less than the wild-type levels, and these mice exhibited impaired triglyceride clearance. Insulin resistance, glucose intolerance, and reduced free fatty acid release in response to ß3-adrenergic agonist suggest improper functioning of the residual WAT. Gene expression analysis of inguinal WAT identified reduced mRNA levels of several enzymes involved in fatty acid synthesis and glucose metabolism that are known C/EBPα transcriptional targets. There were increased levels for genes involved in inflammation and muscle differentiation. However, when dermal fibroblasts from aP2-A-C/EBP mice were differentiated into adipocytes in tissue culture, muscle markers were elevated more than the inflammatory markers. These results demonstrate that the C/EBP family is essential for adipose tissue development during the early postnatal period, the regulation of glucose and lipid homeostasis in adults, and the suppression of the muscle lineage.