Lucky Singh

Gene expression profile and mutational analysis of DNA mismatch repair genes in carcinoma prostate in Indian population.

DNA mismatch repair (MMR) plays a role in promoting genetic stability by repairing DNA replication errors, inhibiting recombination between nonidentical DNA sequences, and participating in responses to DNA damage. Although the role of MMR in prostate carcinogenesis remains unclear, MMR deficiency in Carcinoma Prostate (Pca) could prove to be clinically significant. Thus, the present study investigated the gene expression profile of six major MMR genes, viz. hMLH1, hMSH2, hPMS1, hPMS2, hMSH3, and hMSH6, and polymorphism in hMLH1 and hMSH2 in Pca in Indian population. Further, correlation with clinicopathological parameters was evaluated to establish their role as a potential prognostic marker. A significant downregulation of hMLH1, hMSH2, and hPMS2 expression was observed in Pca compared to benign prostatic hyperplasia (BPH). A greater loss of hPMS2 protein in poorly differentiated tumors was demonstrated, which was in concordance with a significant inverse correlation of hPMS2 gene expression with the Gleason score indicating its significance as a marker for Pca progression. An important association of hMLH1-93G>A polymorphism with the risk of Pca was also identified. The results of the present study suggest that an altered MMR has important biological and clinical significance in Pca in Indian population.

Changes in cause-specific neonatal and 1–59-month child mortality in India from 2000 to 2015: a nationally representative survey

Summary Background Documentation of the demographic and geographical details of changes in cause-specific neonatal (younger than 1 month) and 1–59-month mortality in India can guide further progress in reduction of child mortality. In this study we report the changes in cause-specific child mortality between 2000 and 2015 in India. Methods Since 2001, the Registrar General of India has implemented the Million Death Study (MDS) in 1·3 million homes in more than 7000 randomly selected areas of India. About 900 non-medical surveyors do structured verbal autopsies for deaths recorded in these homes. Each field report is assigned randomly to two of 404 trained physicians to classify the cause of death, with a standard process for resolution of disagreements. We combined the proportions of child deaths according to the MDS for 2001–13 with annual UN estimates of national births and deaths (partitioned across Indias states and rural or urban areas) for 2000–15. We calculated the annual percentage change in sex-specific and cause-specific mortality between 2000 and 2015 for neonates and 1–59-month-old children. Findings The MDS captured 52 252 deaths in neonates and 42 057 deaths at 1–59 months. Examining specific causes, the neonatal mortality rate from infection fell by 66% from 11·9 per 1000 livebirths in 2000 to 4·0 per 1000 livebirths in 2015 and the rate from birth asphyxia or trauma fell by 76% from 9·0 per 1000 livebirths in 2000 to 2·2 per 1000 livebirths in 2015. At 1–59 months, the mortality rate from pneumonia fell by 63% from 11·2 per 1000 livebirths in 2000 to 4·2 per 1000 livebirths in 2015 and the rate from diarrhoea fell by 66% from 9·4 per 1000 livebirths in 2000 to 3·2 per 1000 livebirths in 2015 (with narrowing girl–boy gaps). The neonatal tetanus mortality rate fell from 1·6 per 1000 livebirths in 2000 to less than 0·1 per 1000 livebirths in 2015 and the 1–59-month measles mortality rate fell from 3·3 per 1000 livebirths in 2000 to 0·3 per 1000 livebirths in 2015. By contrast, mortality rates for prematurity or low birthweight rose from 12·3 per 1000 livebirths in 2000 to 14·3 per 1000 livebirths in 2015, driven mostly by increases in term births with low birthweight in poorer states and rural areas. 29 million cumulative child deaths occurred from 2000 to 2015. The average annual decline in mortality rates from 2000 to 2015 was 3·3% for neonates and 5·4% for children aged 1–59 months. Annual declines from 2005 to 2015 (3·4% decline for neonatal mortality and 5·9% decline in 1–59-month mortality) were faster than were annual declines from 2000 to 2005 (3·2% decline for neonatal mortality and 4·5% decline in 1–59-month mortality). These faster declines indicate that India avoided about 1 million child deaths compared with continuation of the 2000–05 declines. Interpretation To meet the 2030 Sustainable Development Goals for child mortality, India will need to maintain the current trajectory of 1–59-month mortality and accelerate declines in neonatal mortality (to >5% annually) from 2015 onwards. Continued progress in reduction of child mortality due to pneumonia, diarrhoea, malaria, and measles at 1–59 months is feasible. Additional attention to low birthweight is required. Funding National Institutes of Health, Disease Control Priorities Network, Maternal and Child Epidemiology Estimation Group, and University of Toronto.BACKGROUND Documentation of the demographic and geographical details of changes in cause-specific neonatal (younger than 1 month) and 1-59-month mortality in India can guide further progress in reduction of child mortality. In this study we report the changes in cause-specific child mortality between 2000 and 2015 in India. METHODS Since 2001, the Registrar General of India has implemented the Million Death Study (MDS) in 1·3 million homes in more than 7000 randomly selected areas of India. About 900 non-medical surveyors do structured verbal autopsies for deaths recorded in these homes. Each field report is assigned randomly to two of 404 trained physicians to classify the cause of death, with a standard process for resolution of disagreements. We combined the proportions of child deaths according to the MDS for 2001-13 with annual UN estimates of national births and deaths (partitioned across Indias states and rural or urban areas) for 2000-15. We calculated the annual percentage change in sex-specific and cause-specific mortality between 2000 and 2015 for neonates and 1-59-month-old children. FINDINGS The MDS captured 52 252 deaths in neonates and 42 057 deaths at 1-59 months. Examining specific causes, the neonatal mortality rate from infection fell by 66% from 11·9 per 1000 livebirths in 2000 to 4·0 per 1000 livebirths in 2015 and the rate from birth asphyxia or trauma fell by 76% from 9·0 per 1000 livebirths in 2000 to 2·2 per 1000 livebirths in 2015. At 1-59 months, the mortality rate from pneumonia fell by 63% from 11·2 per 1000 livebirths in 2000 to 4·2 per 1000 livebirths in 2015 and the rate from diarrhoea fell by 66% from 9·4 per 1000 livebirths in 2000 to 3·2 per 1000 livebirths in 2015 (with narrowing girl-boy gaps). The neonatal tetanus mortality rate fell from 1·6 per 1000 livebirths in 2000 to less than 0·1 per 1000 livebirths in 2015 and the 1-59-month measles mortality rate fell from 3·3 per 1000 livebirths in 2000 to 0·3 per 1000 livebirths in 2015. By contrast, mortality rates for prematurity or low birthweight rose from 12·3 per 1000 livebirths in 2000 to 14·3 per 1000 livebirths in 2015, driven mostly by increases in term births with low birthweight in poorer states and rural areas. 29 million cumulative child deaths occurred from 2000 to 2015. The average annual decline in mortality rates from 2000 to 2015 was 3·3% for neonates and 5·4% for children aged 1-59 months. Annual declines from 2005 to 2015 (3·4% decline for neonatal mortality and 5·9% decline in 1-59-month mortality) were faster than were annual declines from 2000 to 2005 (3·2% decline for neonatal mortality and 4·5% decline in 1-59-month mortality). These faster declines indicate that India avoided about 1 million child deaths compared with continuation of the 2000-05 declines. INTERPRETATION To meet the 2030 Sustainable Development Goals for child mortality, India will need to maintain the current trajectory of 1-59-month mortality and accelerate declines in neonatal mortality (to >5% annually) from 2015 onwards. Continued progress in reduction of child mortality due to pneumonia, diarrhoea, malaria, and measles at 1-59 months is feasible. Additional attention to low birthweight is required. FUNDING National Institutes of Health, Disease Control Priorities Network, Maternal and Child Epidemiology Estimation Group, and University of Toronto.

Mutation of NPM1 and FLT3 Genes in Acute Myeloid Leukemia and Their Association with Clinical and Immunophenotypic Features

Background. Mutations in NPM1 and FLT3 genes represent the most frequent genetic alterations and important diagnostic and prognostic indicators in patients with acute myeloid leukemia (AML). Objective. We investigated the prevalence and clinical characteristics of NPM1 and FLT3 mutations in 161 patients of de novo AML including adults and children. Results. NPM1 mutation was found in 21% and FLT3 mutation in 25% of the AML patients. Thirteen (8%) samples were positive for both NPM1 and FLT3/ITD mutations. Adult patients had significantly higher frequency of NPM1 mutation than children (25.8% versus 8.8%; P = 0.02). Further, NPM1 mutation was found to be more frequent in patients above 45 years of age (P = 0.02). NPM1 mutation was significantly associated with higher platelet count (P = 0.05) and absence of hepatosplenomegaly (P = 0.01), while FLT3/ITD mutation was associated with higher white blood count (P = 0.01). Immunophenotypically, NPM1 mutation was associated with the lack of CD34 (P < 0.001) and HLD-DR expression (P < 0.001), while FLT3/ITD mutation was positively associated with the expression of CD7 (P = 0.04). No correlation was found between NPM1 mutation and fusion gene. Interestingly, FLT3/ITD mutation was found to be inversely associated with AML/ETO fusion gene (P = 0.04). Conclusions. The results suggest that distinct clinical and immunophenotypic characteristics of NPM1 and FLT3/ITD mutations present further insight into the molecular mechanism of leukemogenesis.

Levels, trends & predictors of infant & child mortality among Scheduled Tribes in rural India

Background & objectives: The level of infant and child mortality is high among Scheduled Tribes particularly those living in rural areas. This study examines levels, trends and socio-demographic factors associated with infant and child mortality among Scheduled Tribes in rural areas. Methods: Data from the three rounds of the National Family Health Survey (NFHS) of India from 1992 to 2006 were analysed to assess the levels and trends of infant and child mortality. Univariate and multivariate Cox proportional hazard model were used to understand the socio-economic and demographic factors associated with mortality during 1992–2006. Results: Significant change was observed in infant and child mortality over the time period from 1992-2006 among Scheduled Tribes in rural areas. After controlling for other factors, birth interval, household wealth, and region were found to be significantly associated with infant and child mortality. Hazard of infant mortality was highest among births to mothers aged 30 yr or more (HR=1.3, 95% CI=1.1-1.7) as compared with births to the mothers aged 20-29 yr. Hazard of under-five mortality was 42 per cent (95% CI=1.3-1.6) higher among four or more birth order compared with the first birth order. The risk of infant dying was higher among male children (HR = 1.2, 95% CI=1.1-1.4) than among female children while male children were at 30 per cent (HR=0.7, 95% CI=0.6-0.7) less hazard of child mortality than female children. Literate women were at 40 per cent (HR=0.6, 95% CI=0.50-0.76) less hazard of child death than illiterate women. Interpretation & conclusions: Mortality differentials by socio-demographic and economic factors were observed over the time period (1992-2006) among Scheduled Tribes (STs) in rural India. Findings support the need to focus on age at first birth and spacing between two births.

Socioeconomic disparities in coverage of full immunisation among children of adolescent mothers in India, 1990–2006: a repeated cross-sectional analysis

Objective Studies have highlighted that children of adolescent (aged 15–19 years) mothers are likely to receive relatively poor healthcare. With an unacceptably high adolescent birth rate, India houses the highest number of adolescent mothers globally, putting children at risk of inadequate vaccination. This paper assesses trends and extent of socioeconomic disparities in the coverage of full immunisation among children of adolescent mothers in India. Design Repeated cross-sectional analytical study. Data sources 3 consecutive rounds of the National Family Health Survey (NFHS) conducted during 1992–1993, 1998–1999 and 2005–2006 were used. Besides, the required information is also extracted from the 2011 Indian Census. Participants Children (aged 12–23 months) of adolescent (aged 15–19 years) mothers. Sample inclusion criteria involved the last child of the adolescent eligible to avail full immunisation. Setting Nationally representative sample. Data analysis The Cochran-Armitage test, χ2 test and binary logistic regression methods were applied to attain the study objective. Results Between 1990 and 2006, a non-significant increase of 4 percentage points in full immunisation of children of adolescent mothers was estimated. During the same period, a large difference between the probability of children of adolescent mothers receiving full immunisation belonging to the least (predicted probability (PP): 0.196 in 1990–1993, and PP: 0.213 in 2003–2006) and the most (PP: 0.589 in 1990–1993, and PP: 0.645 in 2003–2006) socioeconomically privileged group was estimated, and this disparity persisted over the survey period. Conclusions During 1990–2006, an insufficient improvement in provision of full immunisation to children born to adolescent mothers was recorded. The study underscored the suboptimum immunisation of rural, illiterate and poor children of adolescent women. The programme and policymakers could focus on district-wise concentration of adolescent women, especially those belonging to the underprivileged groups, to design a targeted intervention to elevate the level of immunisation of children of adolescent mothers.

Divergent trends in ischaemic heart disease and stroke mortality in India from 2000 to 2015: a nationally representative mortality study

Summary Introduction India accounts for about a fifth of cardiovascular deaths globally, but nationally representative data on mortality trends are not yet available. In this nationwide mortality study, we aimed to assess the trends in ischaemic heart disease and stroke mortality over 15 years using the Million Death Study. Methods We determined national and subnational cardiovascular mortality rates and trends by sex and birth cohort using cause of death ascertained by verbal autopsy from 2001 to 2013 among 2·4 million households. We derived mortality rates for ischaemic heart disease and stroke by applying mortality proportions to UN mortality estimates for India and projected the rates from 2000 to 2015. Findings Cardiovascular disease caused more than 2·1 million deaths in India in 2015 at all ages, or more than a quarter of all deaths. At ages 30–69 years, of 1·3 million cardiovascular deaths, 0·9 million (68·4%) were caused by ischaemic heart disease and 0·4 million (28·0%) by stroke. At these ages, the probability of dying from ischaemic heart disease increased during 2000–15, from 10·4% to 13·1% in men and 4·8% to 6·6% in women. Ischaemic heart disease mortality rates in rural areas increased rapidly and surpassed those in urban areas. By contrast, the probability of dying from stroke decreased from 5·7% to 5·0% in men and 5·0% to 3·9% in women. A third of premature stroke deaths occurred in the northeastern states, inhabited by a sixth of India’s population, where rates increased significantly and were three times higher than the national average. The increased mortality rates of ischaemic heart disease nationally and stroke in the northeastern states were higher in the cohorts of adults born in the 1970s onwards, than in earlier decades. A large and growing proportion of the ischaemic heart disease nationally and stroke deaths in high-burden states reported earlier diagnosis of cardiovascular disease, but low medication use. Interpretation The unexpectedly diverse patterns of cardiovascular mortality require investigation to identify the role of established and new cardiovascular risk factors. Secondary prevention with effective and inexpensive long-term treatment and adult smoking cessation could prevent substantial numbers of premature deaths. Without progress against the control of cardiovascular disease in India, global goals to reduce non-communicable diseases by 2030 will be difficult to achieve. Funding Fogarty International Center of the US National Institutes of Health, Dalla Lana School of Public Health, University of Toronto, Indian Council of Medical Research, and the Disease Control Priorities.

Sustained progress, but no room for complacency: Results of 2015 HIV estimations in India

Background & objectives: Evidence-based planning has been the cornerstone of Indias response to HIV/AIDS. Here we describe the process, method and tools used for generating the 2015 HIV estimates and provide a summary of the main results. Methods: Spectrum software supported by the UNAIDS was used to produce HIV estimates for India as a whole and its States/Union Territories. This tool takes into consideration the size and HIV prevalence of defined population groups and programme data to estimate HIV prevalence, incidence and mortality over time as well as treatment needs. Results: Indias national adult prevalence of HIV was 0.26 per cent in 2015. Of the 2.1 million people living with HIV/AIDS, the largest numbers were in Andhra Pradesh, Maharashtra and Karnataka. New HIV infections were an estimated 86,000 in 2015, reflecting a decline by around 32 per cent from 2007. The declining trend in incidence was mirrored in most States, though an increasing trend was detected in Assam, Chandigarh, Chhattisgarh, Gujarat, Sikkim, Tripura and Uttar Pradesh. AIDS-related deaths were estimated to be 67,600 in 2015, reflecting a 54 per cent decline from 2007. There were variations in the rate and trend of decline across India for this indicator also. Interpretation & conclusions: While key indicators measured through Spectrum modelling confirm success of the National AIDS Control Programme, there is no room for complacency as rising incidence trends in some geographical areas and population pockets remain the cause of concern. Progress achieved so far in responding to HIV/AIDS needs to be sustained to end the HIV epidemic.

Is CXCL10/CXCR3 axis overexpression a better indicator of leprosy type 1 reaction than inducible nitric oxide synthase?

Background & objectives: Leprosy type 1 reactions (T1R) are acute episodes of immune exacerbation that are a major cause of inflammation and nerve damage. T1R are diagnosed clinically and supported by histopathology. No laboratory marker is currently available that can accurately predict a T1R. Increased plasma and tissue expression of inducible nitric oxide synthase (i-NOS) and chemokine CXCL10 have been demonstrated in T1R. We studied the gene expression and immunoexpression of i-NOS, CXCL10 and its receptor CXCR3 in clinically and histopathologically confirmed patients with T1R and compared with non-reactional leprosy patients to understand which biomarker has better potential in distinguishing reaction from non-reaction. Methods: Gene expression of i-NOS, CXCL10 and CXCR3 was studied in 30 skin biopsies obtained from patients with borderline tuberculoid (BT), mid-borderline (BB) and borderline lepromatous (BL) leprosy with and without T1R by real-time PCR. Further validation was done by immunhistochemical expression on 60 borderline leprosy biopsies with and without T1R. Results: Of the 120 patients histopathological evaluation confirmed T1R in 65 (54.2%) patients. CXCR3 gene expression was significantly (P<0.05) higher in BT- and BB-T1R patients compared to those without T1R. The CXCL10 gene expression was significantly higher (P<0.05) in BB leprosy with T1R but the difference was not significant in patients with BT with or without T1R. Immunoexpression for CXCR3 was significant in both BB-T1R and BB (P<0.001) and BT and BT-T1R (P<0.001). Immunoexpression of CXL10 was significant only in differentiating BB from BB-T1R leprosy (P<0.01) and not the BT cases. i-NOS immunoexpression was not useful in differentiating reactional from non-reactional leprosy. Interpretation & conclusions: Both CXCL10 and CXCR3 appeared to be useful in differentiating T1R reaction in borderline leprosy while CXCR3 alone differentiated BT from BT-T1R. CXCR3 may be a potentially useful immunohistochemical marker to predict an impending T1R.