A Leishmania donovani dominant-negative mutant for eIF2α kinase LdeK1 elicits host-protective immune response.

Dominant-negative mutation of LdeK1 gene, an eIF2α kinase from Leishmania donovani, revealed its role in translation regulation in response to nutrient starvation earlier. However, whether the kinase influences the infectivity of the parasites which naturally encounters nutrient deprivation during its life cycle was interesting to investigate. Both in vitro and in vivo experiments resulted in decrease of the parasite burden in peritoneal macrophages and in splenic/ hepatic load, respectively. An insight into the immune response of mice infected with mutant parasite showed enhanced pro-inflammatory cytokines and nitric oxide levels but reduced TH 2 and Treg population. The significantly reduced loss of infectivity of the parasites lacking a functional LdeK1 by modulating the immune response towards host protection makes it a potential vaccine candidate against Leishmaniasis.

A national estimate of the birth prevalence of congenital anomalies in India: systematic review and meta-analysis.

BACKGROUND: A quarter of all global neonatal deaths occur in India. Congenital anomalies constitute the fifth largest cause of neonatal mortality in the country, but national estimates of the prevalence of these conditions are lacking. The objective of the study was to derive an estimate of the birth prevalence of congenital anomalies in India. METHODS: The search was carried out in PubMed and pooled prevalence was estimated using the inverse variance method. A random effects model was used due to high heterogeneity between the studies. Forest plots were generated using the Review Manager software. RESULTS: The PubMed search identified 878 articles from which 52 hospital based and three community based studies were included in the meta-analysis. The pooled prevalence of congenital anomaly affected births was 184.48 per 10,000 births (95% CI 164.74-204.21) among 802,658 births. Anomalies of the musculoskeletal system were highest among live births while the prevalence of central nervous system defects was highest when stillbirths were included in the analysis. Anencephaly and talipes were the most commonly reported anomalies. CONCLUSIONS: Data from this meta-analysis suggests that there may be as many as 472,177 (421,652 to 522,676) congenital anomaly affected births in India each year. Population based studies using standard definitions are needed to validate these estimates. The two most frequently reported anomalies were anencephaly that is potentially preventable through preconception folate supplementation, and talipes which can be corrected using relatively low cost interventions. Studies are needed to determine the impact of congenital anomalies on neonatal mortality in India.

Epidemiology & social costs of haemophilia in India.

India lacks a national policy on the prevention and control of genetic disorders. Although the haemoglobinopathies have received some attention, there are scarce data on the epidemiology of other genetic disorders in India. Haemophilia, an inherited single gene disorder with an incidence of 1 per 10,000 births, manifests as spontaneous or trauma-induced haemorrhagic episodes in patients, progressing to chronic disability and premature mortality in untreated patients or patients with sub-optimal treatment. Although the genetic basis of this disorder has been well studied in India, data on the number of patients, trends of the disorder in India, social costs of the condition and opportunities and competencies for offering genetic counselling through a public health programme have not been reported. This review article summarizes the available Indian data, which show that the country harbours the second highest number of global patients with haemophilia A. The reported number of patients with haemophilia A is 11,586 while the estimated prevalence could be around 50,000 patients. This review also identifies the need to immediately initiate a national programme for haemophilia, with components of prevention, care for patients, surveillance and education and support for families.

Systematic review of birth prevalence of neural tube defects in India.

BACKGROUND: Neural tube defects are one of the most prevalent congenital anomalies. Data on the total birth prevalence, live birth and stillbirth prevalence of neural tube defects in India are lacking. The objective of this study is to conduct a systematic review of birth prevalence of neural tube defects in India and compare it with existing estimates. METHODS: A PubMed search identified 463 articles, of which 19 articles were eligible for inclusion in the review. Meta-analysis was used to estimate the overall birth prevalence of neural tube defects and to investigate the variation among studies identified by this review. RESULTS: The 19 articles reported a total of 308,387 births, among which 1310 cases of neural tube defects were reported, giving an overall birth prevalence of 4.1 per 1000 (95% confidence interval [CI], 3.1-5.4). The live birth and stillbirth prevalence of neural tube defects was 1.3 per 1000 births (95% CI, 0.9-1.8) and 1.7 per 1000 births (95% CI, 0.7-4.0), respectively. Among the neural tube defects, the reported prevalence of anencephaly was highest at 2.1 per 1000 births (95% CI, 1.6-2.8) followed by spina bifida at 1.9 per 1000 births (95% CI, 1.4-2.7). CONCLUSION: The systematic review suggests that neural tube defects contribute to a significant number of live births and stillbirths in India, suggesting that preconception folic acid supplementation should be an essential element of reproductive health services.

A history of thalidomide in India.

In contrast to the well-known stories of the embryotoxic drug, thalidomide, in countries where it was responsible for large numbers of birth defects, there is limited information on its history in India. Its presence before 2002, when the country issued the first marketing licence for a thalidomide-containing preparation, is assumed to be negligible. This article challenges this view by showing that the drug entered the Indian subcontinent through the former Portuguese territory of Goa around 1960. We examine the subsequent development of its distribution, use and regulation in India from the mid-1960s up to the present situation. Colonial legacies are a crucial explanation for the early appearance of thalidomide on the Indian subcontinent. They also influenced its re-emergence as drug for treating leprosy reactions in India after 1965. We identify key actors in this process: the original German producer that delivered thalidomide free of charge, European doctors who worked for international non-governmental organizations, the World Health Organization (WHO), which supported clinical trials and later discouraged the use of the drug, and finally the Indian state institutions that limited its distribution and later quickly opened the way for the private sector to produce and market thalidomide and its analogues. Finally, we discuss the risk of thalidomide-induced birth defects by casting a critical look on the present state of regulatory provisions and the monitoring of birth defects in India.

"Fruits of our past karma": a qualitative study on knowledge and attitudes about congenital anomalies among women in Pune district, India.

Congenital anomalies are distressing events for future parents/parents when a foetal anomaly is detected during pregnancy or when the infant is born with a disability or a congenital disorder. Maternal health services in India do not provide information on these disorders as part of routine activities. The objective is to understand women's knowledge and attitude on causes, prevention, rights; attituted towards disability; and knowledge on medical care, rehabilitation, and welfare services in Pune district, India, with the goal of identifying the contents of birth defects education resources. The study used a qualitative descriptive design. Six focus group discussions were conducted with 24 women from Pune district. Qualitative content analysis was used to identify emergent themes. Three themes emerged. Firstly, women's knowledge on congenital anomalies was limited. These conditions were discussed generally with other adverse pregnancy experiences, and with reference to children with disabilities. Secondly, pregnancy termination for conditions considered untreatable was majorly advocated by most women. Directive counselling for pregnancy termination by doctors was common. Thirdly, stigmatizing attitudes were responsible for children with disabilities being considered a burden, for maternal blaming, and for the stigma and isolation of families. Knowledge on rehabilitation was limited. The study identified that participants. Three target groups and contents for birth defects education were identified. Women's resources should include knowledge on preconception and antenatal opportunities for reducing risks, available medical care, and legal rights. Parents' resources should provide information on treatment, rehabilitation, legal provisions, and rights of disabled children. Resources for the general community should additionally include disability sensitization messages to ensure the inclusion of children with congenital disabilities.

Birth defect mortality in India 1990-2017: estimates from the Global Burden of Disease data.

India is yet to establish a national surveillance for birth defects (congenital disorders). The objective of this study was to describe the epidemiology of birth defects in the neonatal, post-neonatal, and 1-4-year age groups, using modelled estimates from the Global Burden of Disease (GBD) database. We extracted age- and condition-specific birth defect mortality data and analysed the magnitude and trends of these conditions in India, and across Indian states. We compared these trends with other neonatal causes of mortality for the period 1990-2017. The results indicate that birth defects caused 37,104 (95%UI 31,825-43,134) deaths in the early neonatal period and 27,120 (95%UI 23,490-30,777) deaths in the post-neonatal period in 2017 in India. These rates were double and five times higher when compared with the whole group of middle- and high-income countries respectively. There was a small decline in birth defect mortality between 1990 and 2017. However, with the exception of orofacial clefts, the proportion of deaths caused by selected birth defects increased between 1990 and 2017, relative to other causes of child mortality. In 70% of states ranked in the high and middle Socio-demographic Index (SDI) category, birth defects were the third leading cause of neonatal mortality. The analysis identifies the need for establishing birth defects services in the country. It demonstrates that modelled estimates of the GBD could be used as the best available data for understanding the epidemiology of birth defects in low- and middle-income countries till surveillance systems are put in place.

Undiagnosed haemoglobinopathies among pregnant women attending antenatal care clinics in Pune, India.

Pregnant women with iron deficiency and those who are carriers of haemoglobinopathies present with anaemia of varying severity. There is no antenatal screening for haemoglobinopathies in India. The objective of this study was to determine the prevalence of undiagnosed haemoglobinopathy carriers in a random sample of pregnant women attending antenatal care clinics in Pune city, India. Biobanked DNA of 360 randomly selected pregnant women was genotyped for six common mutations and two common haemoglobin variants, HbS and HbE. Odds ratios (OR) with 95% confidence intervals were computed to determine association of carrier status with socio-demographic, haematological and clinical characteristics. The prevalence of undiagnosed haemoglobinopathy carriers was 6.3% (95% CI 4.2-9.4%) of which 3.3% (95% CI 1.9-5.7%) were beta thalassaemia carriers. There was an increased odds that beta thalassaemia carriers had moderate anaemia (OR 10.59, 95% CI 1.15-96.90). This study reveals the high prevalence of undiagnosed haemoglobinopathy carriers among pregnant women, indicating the need to immediately implement carrier screening and genetic counselling services across the country.

Prevalence and determinants of folate deficiency among urban Indian women in the periconception period.

Maternal folate insufficiency is of particular concern in developing countries due to its association with various adverse pregnancy outcomes. This study aimed to determine the prevalence of folate deficiency and its determinants among urban Indian women in the periconception period. Serum folate concentrations were measured in 584 women in early pregnancy (11 ± 3 weeks of gestation) using microbiological assay. Folate deficiency was detected in 24% women and possible deficiency was detected in 21% women. Multigravidity (aOR 1.84, 95% CI 1.16-2.92) and low education (aOR 1.67, 95% CI 1.06-2.62) emerged as determinants of folate deficiency while prenatal folic acid supplementation was favorable in decreasing the odds of folate deficiency (aOR 0.17, 95% CI 0.06-0.43). No association was observed between folate levels and adverse pregnancy outcomes including neural tube defects. The high prevalence of folate deficiency underlines the need for implementation of preconception folic acid supplementation as part of maternal health services in India.

Cold-induced alteration in the global structure of the male sex chromosome of In1BM2(reinverted) of Drosophila melanogaster is associated with increased acetylation of histone 4 at lysine 16.

In Drosophila melanogaster, dosage compensation occurs through hypertranscription of sex-linked genes in males. The hypertranscription involves acetylation of histone 4 at lysine 16 (H4K16) on amale X-chromosome, brought about by a histone acetyltransferase encoded by the dosage compensation gene, males absent on the first (mof). We report a phenomenon in the strain In(1)B(M2)(reinverted) of D. melanogaster where the global structure of the male X-chromosome can be altered at the third instar larval stage through a 4-h cold shock at 12+/-1 degrees C. We show that the cold shock results in a transient hyperacetylation of H4K16 and an increased expression of MOF. Control proteins H4 acetylated at lysine 5, and the dosage compensation gene msl-2, do not show any change in expression after cold shock. Cytology of the male X-chromosome at different time points during cold shock and recovery, suggests that the hyperacetylation of H4 at lysine 16 causes the X-chromosome to corkscrew into itself, thereby achieving the cold-induced change in the higher order structure of the male polytene X-chromosome. Our studies suggest a role for H4K16 in maintaining the structure of the male X-chromosome in Drosophila.

The Leishmania donovani IMPACT-like protein possesses non-specific nuclease activity.

IMPACT (Imprinted and Ancient)-like proteins are known to be regulators of GCN2 (General control non-derepressible 2) kinases involved in translation regulation. Here, we report on cloning and characterization of an IMPACT-like protein, LdIMPACT from Leishmania donovani which harbours two domains. 'RWD domain' at the N-terminal end that mediates GCN2 regulation, while a conserved 'ancient domain' lies at the C-terminal end whose function remains elusive. Interestingly, our observations indicated that LdIMPACT has a novel non-specific nuclease activity. In silico analysis further revealed the resemblance of ancient domain of LdIMPACT to RNase PH domain (known to bind to nucleic acids). The recombinant LdIMPACT exhibited a Mg2+-dependent nuclease activity. Moreover, thermostability and pH stability assays of the protein suggest it to be a stress-responsive protein. Circular dichroism studies elucidated the conformational transitions of the enzyme in response to various temperature and pH conditions which correlated well with the activity profiles. Thus, the current study highlights the structural and functional characteristics of LdIMPACT which interestingly also possesses a novel nuclease activity. With its physiological relevance unresolved, the multifaceted LdIMPACT might therefore lie in a hitherto unknown network, whose perturbation could be an attractive therapeutic approach for treating leishmaniasis.

A case-control study identifying the characteristics of patients providing incorrect contact information at registration for DOTS in Pune, India.

BACKGROUND: Provision of incorrect contact information by the patient at the time of registration for treatment is a deterrent to treatment adherence. OBJECTIVE: To determine the characteristics of patients providing incomplete contact information at the time of registration for Directly Observed Treatment Short course (DOTS) at the tuberculosis units (TUs) in Pune, India. METHODS: A nested case-control study was conducted where the characteristics of patients who had provided incorrect contact information (cases) were compared with the characteristics of patients who could be traced (controls). Cases and controls were identified from a cohort of 3802 tuberculosis patients registered at the DOTS centres in Pune. Correct or incorrect contact information was ascertained by visiting each address provided at the time of registration. Characteristics associated with providing incorrect contact information were determined through multinomial regression analysis. RESULTS: There were 406 (10.7%) patients who could not be traced due to incorrect address provided at the time of registration at the DOTS centres. Registration at the TUs in the peripheral areas of the city (odds ratio (OR)=3.57, 95% confidence interval (CI)=2.64-4.84) and engagement in migration prone occupation (OR=1.83, 95% CI=1.47-2.26) were associated with odds of providing incorrect information at the time of registration. CONCLUSION: Untraceable patients were more likely to be engaged in occupations with a potential for migration. DOTS centres located in developing areas of cities should reinforce validation of contact information of patients.

Prevalence of Congenital Anomalies in an Indian Maternal Cohort: Healthcare, Prevention, and Surveillance Implications.

BACKGROUND: India lacks a national birth defects surveillance. Data on the prevalence of congenital anomalies are available mostly from hospital-based, cross-sectional studies. This is the first cohort study from India, where 2107 women were followed till pregnancy outcome, in order to measure the prevalence and types of congenital anomalies, their contribution to neonatal mortality, implications for surveillance, and the health service needs for prevention and management. METHODS: The study followed a cohort of 2107 pregnant women till outcome which was miscarriage, termination of pregnancy, live or stillbirth, neonatal and post-neonatal mortality. Case ascertainment of congenital anomalies was done through visual examination, followed by various investigations. Rates of congenital anomaly affected births were reported per 10 000 births. Health service needs were described through retrospective analysis of events surrounding the diagnosis of a congenital anomaly. RESULTS: Among 1822 births, the total prevalence of major congenital anomalies was 230.51 (170.99-310.11) per 10 000 births. Congenital heart defects were the most commonly reported anomalies in the cohort with a prevalence of 65.86 (37.72-114.77) per 10 000 births. Although neural tube defects were two and a half times less as compared to congenital heart defects, they were nevertheless significant at a prevalence of 27.44 (11.73-64.08) per 10 000 births. In this cohort, congenital anomalies were the second largest cause of neonatal deaths. The congenital anomaly prenatal diagnosis prevalence was 10.98 per 1000 births and the congenital anomaly termination of pregnancy rate was 4.39 per 1000 births. CONCLUSIONS: This first cohort study from India establishes that the congenital anomaly rates were high, affecting one in forty four births in the cohort. The prevalence of congenital anomalies was identical to the stillbirth prevalence in the cohort, highlighting their public health importance. The results of this study identify the need for a well defined national programme with components of prevention, care and surveillance.

Modification of family size in families reporting history of haemophilia from Maharashtra, India.

BACKGROUND: In India, genetic counselling services are largely unavailable. The question of whether awareness of the hereditary nature of the disorder leads to modified family size in affected families remains unanswered. The objective of this study was to determine whether family history of haemophilia resulted in modification of family size in families reporting haemophilia in the State of Maharashtra, India. METHODS: The study was a retrospective cohort analysis from pedigrees collected from an earlier survey on haemophilia in Maharashtra. Pedigree data were manually defined into families with or without experience of haemophilia. Family size was defined as the number of live births per woman as documented in the pedigree. The data were analysed using Microsoft Excel package (version 2000) and SPSS package (version 10). RESULTS: Family size of obligate carriers who were daughters of patients was significantly less than the family size of obligate carriers who reported haemophilia in a brother or maternal relative (z = 7.14, P < 0.001). As compared with parents from an older generation, a significant reduction in the number of children born to younger families with haemophilia was observed, irrespective of family history of the condition. In families with history of haemophilia, there was no significant reduction in the number of families with more than one affected son in between two generations of parents (chi(2) = 1.43). CONCLUSIONS: The results revealed a reduction in size of families with haemophilia over a generation, which possibly reflected the reducing fertility trends observed in the Indian population. Reduction in the number of children born to women with a haemophilic father suggested a comprehension of father to daughter transmission of haemophilia. This was not true when relatives other than the father were affected. The lack of significant reduction in the number of families with history of haemophilia of having more than one affected son may suggest a compensatory response to the high mortality associated with the disorder in India.

Population-based approach to study unintentional injury occurrences in Pune city, India.

Most injury-related studies in developing countries are hospital based. In India, where there is a high level of poverty, limited access to the health care, many unregistered slums and pavement dwellers, this study attempted to use an innovative sampling method to identify the magnitude of injuries in a population of an urban city in India. Totally, 9014 individuals (2100 households), representative of more than 3.5 million population were selected from 14 administrative wards of the city of Pune. Semi-structured questionnaires were used to elicit information. The annual incidence rate of unintentional injuries was 174 (95% CI 164-184) per 1000 individuals. There were 26 reported cases of death in a recall period of 5 years. Maximum number of unintentional injuries were due to road traffic accidents (49.5%) followed by falls (24.9%). These results showed the magnitude of unintentional injuries among the population. The study sampling method can be employed as a reference for similar studies in other developing countries.