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Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca 2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca 2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca 2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP 3 R-mediated Ca 2+ transfer from ER to mitochondria and decreased mitochondrial Ca 2+ uptake. In turn, reduced mitochondrial Ca 2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD + ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca 2+ homeostasis, enhance mitochondrial function and improve neuronal health. Wolfram syndrome, caused by WFS1 or CISD2 gene mutations, disrupts ER Ca 2+ regulation in neurons. Here, the authors show how these mutations impair ER-mitochondria interactions, compromise Ca 2+ transfer and mitochondrial function, and lead to bioenergetic deficits and oxidative stress.

IntroductionAir pollution presents a major public health threat to India, affecting more than three quarters of the country’s population. In the current project, GEOHealth Health Effects of Selected Environmental Exposomes Across the Life CourSe–India, we aim to study the effect of environmental exposomes—fine particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3) and extremes of temperature—on multiple health outcomes using a modified life course approach. The associated training grant aims to build capacity in India to address the unique environmental health problems.Methods and analysisThe project aims to (A) Develop exposure assessments in seven cities, namely Delhi, Chennai, Sonipat, Vizag, Pune, Hyderabad and Bikaner, for: (1) A fine-scale spatiotemporal model for multiple pollutants (PM2.5, NO2, O3, temperature); (2) Combined ground monitoring and modelling for major chemical species of ambient PM2.5 at seven cities; and (3) Personal exposure assessment in a subsample from the six cities, except Pune, and (B) Conduct health association studies covering a range of chronic non-communicable diseases and their risk factors leveraging a unique approach using interdigitating cohorts. We have assembled existing pregnancy, child, adolescent, adult and older adult cohorts across India to explore health effects of exposomes using causal analyses. We propose to use Bayesian kernel machine regression to assess the effects of mixtures of all pollutants including species of PM2.5 on health while accounting for potential non-linearities and interactions between exposures. This builds on earlier work that constructed a fine spatiotemporal model for PM2.5 exposure to study health outcomes in two Indian cities.Ethics and disseminationEthical clearance for conduct of the study was obtained from the Institutional Ethics Committee (IEC) of the Centre for Chronic Disease Control, and all the participating institutes and organisations. National-level permission was provided by the Indian Council of Medical Research. The research findings will be disseminated through peer-reviewed publications, policy briefs, print and social media, and communicating with the participating communities and stakeholders. Training of Indian scientists will build the capacity to undertake research on selected adverse environmental exposures on population health in India.

Undernutrition during intrauterine life and early childhood is hypothesised to increase the risk of cardiovascular disease (Developmental Origins of Health and Disease Hypothesis), but experimental evidence from humans is limited. This hypothesis has major implications for control of the cardiovascular disease epidemic in South Asia (home to a quarter of world's population), where a quarter of newborns have low birth weight. We investigated whether, in an area with prevalent undernutrition, supplemental nutrition offered to pregnant women and their offspring below the age of 6 years was associated with a lower risk of cardiovascular disease in the offspring when they were young adults. The Hyderabad Nutrition Trial was a community-based nonrandomised controlled intervention trial conducted in 29 villages near Hyderabad, India (1987-1990). Protein-calorie food supplement was offered daily to pregnant and lactating women (2.09 MJ energy and 20-25 g protein) and their offspring (1.25 MJ energy and 8-10 g protein) until the age of six years in the 15 intervention villages, but not in the 14 control villages. A total of 1,826 participants (949 from the intervention villages and 877 from the control villages, representing 70% of the cohort) at a mean age of 21.6 years (62% males) were examined between 2009 and 2012. The mean body mass index (BMI) of the participants was 20 kg/m2 and the mean systolic blood pressure was 115 mm Hg. The age, sex, socioeconomic position, and urbanisation-adjusted effects of intervention (beta coefficients and 95% confidence intervals) on outcomes were as follows: carotid intima-media thickness, 0.01 mm (-0.01 to 0.03), p = 0.36; arterial stiffness (augmentation index), -1.1% (-2.5 to 0.3), p = 0.097; systolic blood pressure, 0.5 mm Hg (-0.6 to 1.6), p = 0.36; BMI, -0.13 kg/m2 (-0.75 to 0.09), p = 0.093; low-density lipoprotein (LDL) cholesterol, 0.06 mmol/L (-0.07 to 0.2), p = 0.37; and fasting insulin (log), -0.06 mU/L (-0.19 to 0.07), p = 0.43. The limitations of this study include nonrandomised allocation of intervention and lack of data on compliance, and potential for selection bias due to incomplete follow-up. Our results showed that in an area with prevalent undernutrition, protein-calorie food supplements offered to pregnant women and their offspring below the age of 6 years were not associated with lower levels of cardiovascular risk factors among offspring when they were young adults. Our findings, coupled with evidence from other intervention studies to date, suggest that policy makers should attach limited value to cardiovascular health benefits of maternal and child protein-calorie food supplementation programmes.

India is experiencing an alarming rise in the burden of noncommunicable diseases, but data on the incidence of chronic kidney disease (CKD) are sparse. Using the Center for Cardiometabolic Risk Reduction in South Asia surveillance study (a population-based survey of Delhi and Chennai, India) we estimated overall, and age-, sex-, city-, and diabetes-specific prevalence of CKD, and defined the distribution of the study population by the Kidney Disease Improving Global Outcomes (KDIGO) classification scheme. The likelihood of cardiovascular events in participants with and without CKD was estimated by the Framingham and Interheart Modifiable Risk Scores. Of the 12,271 participants, 80% had complete data on serum creatinine and albuminuria. The prevalence of CKD and albuminuria, age standardized to the World Bank 2010 world population, was 8.7% (95% confidence interval: 7.9–9.4%) and 7.1% (6.4–7.7%), respectively. Nearly 80% of patients with CKD had an abnormally high hemoglobin A1c (5.7 and above). Based on KDIGO guidelines, 6.0, 1.0, and 0.5% of study participants are at moderate, high, or very high risk for experiencing CKD-associated adverse outcomes. The cardiovascular risk scores placed a greater proportion of patients with CKD in the high-risk categories for experiencing cardiovascular events when compared with participants without CKD. Thus, 1 in 12 individuals living in two of India’s largest cities have evidence of CKD, with features that put them at high risk for adverse outcomes.

Certain oral bacterial pathogens may play a role in oral carcinogenesis. We assessed the feasibility of conducting a population-based study in India to examine the distributions and levels of Porphyromonas gingivalis, Fusobacterium nucleatum and Prevotella intermedia in relation to oral leukoplakia (a potentially malignant disorder) and other participant characteristics. This exploratory case-control study was nested within a large urban Indian cohort and the data included 22 men and women with oral leukoplakia (cases) and 69 leukoplakia-free controls. Each participant provided a salivary rinse sample, and a subset of 34 participants (9 cases; 25 controls) also provided a gingival swab sample from keratinized gingival surface for quantitative polymerase chain reaction (qPCR). Neither the distribution nor the levels of pathogens were associated with oral leukoplakia; however, individual pathogen levels were more strongly correlated with each other in cases compared to controls. Among controls, the median level of total pathogens was the highest (7.55×104 copies/ng DNA) among persons of low socioeconomic status. Salivary rinse provided better DNA concentration than gingival swab for qPCR analysis (mean concentration: 1.8 ng/μl vs. 0.2 ng/μl). This study confirms the feasibility of population studies evaluating oral microbiome in low-resource settings and identifies promising leads for future research.

We comparatively assessed the performance of six simple obesity indices to identify adults with cardiovascular disease (CVD) risk factors in a diverse and contemporary South Asian population. 8,892 participants aged 20-60 years in 2010-2011 were analyzed. Six obesity indices were examined: body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), waist-hip ratio (WHR), log of the sum of triceps and subscapular skin fold thickness (LTS), and percent body fat derived from bioelectric impedance analysis (BIA). We estimated models with obesity indices specified as deciles and as continuous linear variables to predict prevalent hypertension, diabetes, and high cholesterol and report associations (prevalence ratios, PRs), discrimination (area-under-the-curve, AUCs), and calibration (index χ2). We also examined a composite unhealthy cardiovascular profile score summarizing glucose, lipids, and blood pressure. No single obesity index consistently performed statistically significantly better than the others across the outcome models. Based on point estimates, WHtR trended towards best performance in classifying diabetes (PR = 1.58 [1.45-1.72], AUC = 0.77, men; PR = 1.59 [1.47-1.71], AUC = 0.80, women) and hypertension (PR = 1.34 [1.26,1.42], AUC = 0.70, men; PR = 1.41 [1.33,1.50], AUC = 0.78, women). WC (mean difference = 0.24 SD [0.21-0.27]) and WHtR (mean difference = 0.24 SD [0.21,0.28]) had the strongest associations with the composite unhealthy cardiovascular profile score in women but not in men. WC and WHtR were the most useful indices for identifying South Asian adults with prevalent diabetes and hypertension. Collection of waist circumference data in South Asian health surveys will be informative for population-based CVD surveillance efforts.

This paper investigates how an electrostatic Langmuir wave having large amplitude affects the Weibel instability (WI) in the existence of ions and an electron beam. Two Langmuir side band waves are produced by coupling of EM perturbation to the Langmuir wave. The Langmuir wave (LW) increases the growth rate beyond its linear value. Here, we noticed that the growth rate Γ( sec −1 ) scales linearly with the electron beam velocity v be and 1/2 power of the electron beam density n be . As we increase the density of ions inside the plasma, the growth rate stabilizes. Additionally, we find that the growth rate is very sensitive to the plasma frequency of ions. Therefore, our work finds an application in space, galactic cosmic rays and supernovas. Also, our work covers a range of application from the development of fusion power to understand the various astrophysical phenomena.

While data from the latter part of the twentieth century consistently showed that immigrants to high-income countries faced higher cardio-metabolic risk than their counterparts in low- and middle-income countries, urbanization and associated lifestyle changes may be changing these patterns, even for conditions considered to be advanced manifestations of cardio-metabolic disease (e.g., chronic kidney disease [CKD]). Using cross-sectional data from the Center for cArdiometabolic Risk Reduction in South Asia (CARRS, n = 5294) and Mediators of Atherosclerosis in South Asians Living in America (MASALA, n = 748) studies, we investigated whether prevalence of CKD is similar among Indians living in Indian and U.S. cities. We compared crude, age-, waist-to-height ratio-, and diabetes- adjusted CKD prevalence difference. Among participants identified to have CKD, we compared management of risk factors for its progression. Overall age-adjusted prevalence of CKD was similar in MASALA (14.0% [95% CI 11.8-16.3]) compared with CARRS (10.8% [95% CI 10.0-11.6]). Among men the prevalence difference was low (prevalence difference 1.8 [95% CI -1.6,5.3]) and remained low after adjustment for age, waist-to-height ratio, and diabetes status (-0.4 [-3.2,2.5]). Adjusted prevalence difference was higher among women (prevalence difference 8.9 [4.8,12.9]), but driven entirely by a higher prevalence of albuminuria among women in MASALA. Severity of CKD--i.e., degree of albuminuria and proportion of participants with reduced glomerular filtration fraction--was higher in CARRS for both men and women. Fewer participants with CKD in CARRS were effectively treated. 4% of CARRS versus 51% of MASALA participants with CKD had A1c < 7%; and 7% of CARRS versus 59% of MASALA participants blood pressure < 140/90 mmHg. Our analysis applies only to urban populations. Demographic--particularly educational attainment--differences among participants in the two studies are a potential source of bias. Prevalence of CKD among Indians living in Indian and U.S. cities is similar. Persons with CKD living in Indian cities face higher likelihood of experiencing end-stage renal disease since they have more severe kidney disease and little evidence of risk factor management.

Chronic conditions cause notable health and economic burdens. While health insurance enables access to healthcare, its effects on chronic care outcomes remain under-explored. To examine the association between health insurance coverage and cardiometabolic risk factors among people with chronic conditions in India. Data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) and Solan studies, including 2,926 adults with chronic conditions were analyzed using propensity score weighting to evaluate the associations between health insurance and cardiometabolic risk factors (HbA1c, low-density lipoprotein cholesterol [LDLc], and blood pressure [BP]) and self-reported health status (measured using European Quality of Life Visual Analogue Scale [EQ-VAS]). Mediation analysis evaluated healthcare visits as a potential mediator. Among 2,926 respondents meeting criteria, mean (SD) age was 54.6 years (11.8), and 1630 (55.7%) were women. Health insurance coverage was low (6.5%) and more prevalent among men, higher-income groups, and rural vs urban residents. Insured participants had lower mean diastolic BP (84.8 vs 86.0 mmHg), mean LDLc (113.3 vs 117.2 mg/dl), mean HbA1c (6.9% vs 7.5%), and higher health status (EQ-VAS: 74.6 vs 69.1) than uninsured participants, respectively (  < 0.05). Mediation analysis showed healthcare visits strongly mediated the relationship between insurance and BP and partially mediated effects on LDLc, HbA1c, and self-rated health. Health insurance coverage was associated with better cardiometabolic risk profiles and health status, largely mediated by increased healthcare utilization. Expanding insurance coverage to include outpatient chronic care services should be prioritized to improve health outcomes in low- and middle-income countries.

Background Dietary patterns (DPs) in India are heterogenous. To date, data on association of indigenous DPs in India with risk factors of nutrition-related noncommunicable diseases (cardiovascular disease and diabetes), leading causes of premature death and disability, are limited. We aimed to evaluate the associations of empirically-derived DPs with blood lipids, fasting glucose and blood pressure levels in an adult Indian population recruited across four geographical regions of India. Methods We used cross-sectional data from the Indian Migration Study (2005–2007). Study participants included urban migrants, their rural siblings and urban residents and their urban siblings from Lucknow, Nagpur, Hyderabad and Bangalore ( n  = 7067, mean age 40.8 yrs). Information on diet (validated interviewer-administered, 184-item semi-quantitative food frequency questionnaire), tobacco consumption, alcohol intake, physical activity, medical history, as well as anthropometric measurements were collected. Fasting-blood samples were collected for estimation of blood lipids and glucose. Principal component analysis (PCA) was used to identify major DPs based on eigenvalue> 1 and component interpretability. Robust standard error multivariable linear regression models were used to investigate the association of DPs (tertiles) with total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides, fasting-blood glucose (FBG), systolic and diastolic blood pressure (SBP and DBP) levels. Results Three major DPs were identified: ‘cereal-savoury’ (cooked grains, rice/rice-based dishes, snacks, condiments, soups, nuts), ‘fruit-vegetable-sweets-snacks’ (Western cereals, vegetables, fruit, fruit juices, cooked milk products, snacks, sugars, sweets) and ‘animal food’ (red meat, poultry, fish/seafood, eggs) patterns. High intake of the ‘animal food’ pattern was positively associated with levels of TC (β = 0.10 mmol/L; 95% CI: 0.02, 0.17 mmol/L; p-trend = 0.013); LDL-C (β = 0.07 mmol/L; 95% CI: 0.004, 0.14 mmol/L; p-trend = 0.041); HDL-C (β = 0.02 mmol/L; 95% CI: 0.004, 0.04 mmol/L; p-trend = 0.016), FBG: (β = 0.09 mmol/L; 95% CI: 0.01, 0.16 mmol/L; p-trend = 0.021) SBP (β = 1.2 mm/Hg; 95% CI: 0.1, 2.3 mm/Hg; p-trend = 0.032); DBP: (β = 0.9 mm/Hg; 95% CI: 0.2, 1.5 mm/Hg; p-trend = 0.013). The ‘cereal-savoury’ and ‘fruit-vegetable-sweets-snacks’ patterns showed no association with any parameter except for a positive association with diastolic blood pressure for high intake of ‘fruits-vegetables-sweets-snacks’ pattern. Conclusion Our results indicate positive associations of the ‘animal food’ pattern with cardio-metabolic risk factors in India. Further longitudinal assessments of dietary patterns in India are required to validate the findings.