Perspectives on folate with special reference to epigenetics and neural tube defects.

Folate is a micronutrient essential for DNA synthesis, cell division, fetal growth and development. Folate deficiency leads to genomic instability. Inadequate intake of folate during conception may lead to neural tube defects (NTDs) in the offspring. Folate influences the DNA methylation, histone methylation and homocysteine mediated gene methylation. DNA methylation influences the expression of microRNAs (miRNAs). Folate deficiency may be associated with miRNAs misregulation leading to NTDs. Mitochondrial epigenetics and folate metabolism has proved to be involved in embryogenesis and neural tube development. Folate related genetic variants also cause the occurrence of NTDs. Unmetabolized excessive folate may affect health adversely. Hence estimation of folate levels in the blood plays an important role in high-risk cases.

Glimpses from My Academic Journey : Based on the 15th Dr. K. C. Chaudhuri Lifetime Achievement Award Oration Delivered on 9th October 2022.

This article is based on the contents of 'Dr. K. C. Chaudhuri Lifetime Achievement Award Oration' delivered on the Indian Journal of Pediatrics Annual Day 2022. The author shares glimpses of his academic journey from a remote village to a central Institute. This includes his career as a medical teacher and developing the Department of Neonatology at JIPMER, Pondicherry. This article is primarily focused on some of the significant research conducted during his tenure, like perinatal asphyxia, therapeutic hypothermia, neonatal sepsis, intrauterine growth restriction, and human milk banking.

Genetics of atrial fibrillation-an update of recent findings.

Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. AF has a strong genetic predisposition. This review highlights the recent findings on the genetics of AF from genome-wide association studies (GWAS) and high-throughput sequencing studies. The consensus from GWAS implies that AF is both polygenic and pleiotropic in nature. With the advent of whole-genome sequencing and whole-exome sequencing, rare variants associated with AF pathogenesis have been identified. The recent studies have contributed towards better understanding of AF pathogenesis.

Effect of Therapeutic Hypothermia on the Outcome in Term Neonates with Hypoxic Ischemic Encephalopathy-A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of therapeutic hypothermia on the outcome in term neonates with hypoxic ischemic encephalopathy (HIE). METHODS: A randomized controlled trial was conducted in a tertiary care teaching hospital in south India. Term infants with moderate to severe HIE were randomized to be treated with normothermia or hypothermia. Mortality, neurological abnormality or normal outcome was recorded at hospital discharge or 28 days of age, whichever was earlier, and at 18 months of age. RESULTS: The baseline maternal and neonatal characteristics in the two groups were similar. The 78 infants in the hypothermia group had more normal survivors at discharge (38%) than the 84 infants in the normothermia group (30%), ratio 1.29 (95% confidence interval 0.84-1.99), and at 18 months of age (65% vs. 42%), ratio 1.54 (1.13-2.10). When these results were combined with those of a previous randomized trial in the same neonatal unit, there were significantly more normal survivors with hypothermia compared to normothermia at discharge, ratio 1.49 (1.18-1.88) and at 6-18 months of age, ratio 1.37 (1.17-1.60). CONCLUSION: In term infants with HIE, therapeutic hypothermia reduced mortality and neurological abnormalities, and resulted in more normal survivors. LAY SUMMARY: Babies who do not breathe immediately after they are born are likely to die or have brain damage. Previous studies have suggested that cooling these babies after birth might reduce the number who die or have brain damage. In this resource-limited setting, babies who were cooled were less likely to die or survive with brain damage.

Global DNA Methylation in Cord Blood and Neurodevelopmental Outcome at 18 Months of Age among Intrauterine Growth Restricted and Appropriate for Gestational Age Infants.

BACKGROUND: Intrauterine growth restriction (IUGR) is associated with faltered growth and development later in life. Alteration in DNA methylation may occur among IUGR babies and it can have bearing on the outcome. OBJECTIVES: To compare the DNA methylation in the cord blood among IUGR and appropriate for gestational age (AGA) babies and find it is association with their neurodevelopmental outcome at 18 months of age. METHODOLOGY: Genomic DNA methylation among 40 IUGR and equal number of AGA neonates was estimated by using 5-mC ELISA kit in the cord blood. Infants were assessed at birth and their anthropometric measurements were taken. They were regularly followed up and assessed for neurodevelopment outcome till 18 months of age using DASII (Developmental Assessment Scale for Indian Infants). DNA methylation was correlated with neurodevelopmental outcome. Numbers and percentages were used for categorical data. Mean and SD were used for continuous variables. The significant mean difference between IUGR and AGA was determined by independent Student t-test. To study the association between the DNA methylation and outcome, Spearman correlation was used. A p < 0.05 was considered as statistically significant. RESULTS: Significant difference in DNA methylation was observed between IUGR and AGA infants (IUGR: 3.12 ± 1.24; AGA: 4.40 ± 2.03; p < 0.001). Anthropometry (weight, length and head circumference) at birth was significantly decreased among IUGR infants. Hospital stay was significantly longer for IUGR infants. Motor (IUGR: 89.98 ± 18.77; AGA: 101.75 ± 9.62; p < 0.001), and mental (IUGR: 90.81 ± 11.13; AGA: 105.71 ± 7.20; p < 0.001) scores were significantly decreased among IUGR compared with AGA neonates at 18 months of follow-up. Global DNA methylation had a significant positive correlation with mental score but not with motor developmental score. CONCLUSION: IUGR babies had lower motor and mental score compared with AGA babies. Cord blood global DNA methylation significantly correlated with mental development score but not with motor development at 18 months of age.

Goat lung surfactant for treatment of respiratory distress syndrome among preterm neonates: a multi-site randomized non-inferiority trial.

OBJECTIVE: To investigate the safety and efficacy of goat lung surfactant extract (GLSE) compared with bovine surfactant extract (beractant; Survanta®, AbbVie, USA) for the treatment of neonatal respiratory distress syndrome (RDS). STUDY DESIGN: We conducted a double-blind, non-inferiority, randomized trial in seven Indian centers between June 22, 2016 and January 11, 2018. Preterm neonates of 26 to 32 weeks gestation with clinical diagnosis of RDS were randomized to receive either GLSE or beractant. Repeat dose, if required, was open-label beractant in both the groups. The primary outcome was a composite of death or bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age (PMA). Interim analyses were done by an independent data and safety monitoring board (DSMB). RESULT: After the first interim analyses on 5% enrolment, the "need for repeat dose(s) of surfactant" was added as an additional primary outcome and enrolment restricted to intramural births at five of the seven participating centers. Following second interim analysis after 98 (10% of 900 planned) neonates were enroled, DSMB recommended closure of study in view of inferior efficacy of GLSE in comparison to beractant. There was no significant difference in the primary outcome of death or BPD between GLSE group (n = 52) and beractant group (n = 46) (50.0 vs. 39.1%; OR 1.5; 95% CI 0.7-3.5; p = 0.28). The need for repeat dose of surfactant was significantly higher in GLSE group (65.4 vs. 17.4%; OR 9.0; 95% CI 3.5-23.3; p < 0.001). CONCLUSIONS: Goat lung surfactant was less efficacious than beractant (Survanta®) for treatment of RDS in preterm infants. Reasons to ascertain inferior efficacy of goat lung surfactant requires investigation and possible mitigating strategies in order to develop a low-cost and effective surfactant.

Causes of death in preterm neonates (<33 weeks) born in tertiary care hospitals in India: analysis of three large prospective multicentric cohorts.

OBJECTIVE: To estimate the direct causes of mortality among preterm neonates <33 weeks' gestation by examining three large multisite, hospital-based datasets in India. METHOD: Three prospective hospital-based datasets: the National Neonatal Perinatal Database (NNPD) of India, the Delhi Neonatal Infection Study (DeNIS) cohort, and the Goat Lung Surfactant Extract (GLSE)-Plus cohort were analyzed to study the causes of death among preterm neonates of less than 33 weeks' gestation admitted to the participating tertiary care hospitals in India. RESULTS: A total of 8024 preterm neonates were admitted in the three cohorts with 2691 deaths. Prematurity-related complications and sepsis contributed to 53.5% and 19.8% of deaths in the NNPD cohort, 51.0% and 25.0% in the DeNIS cohort, and 39.7% and 40.9% in GLSE-Plus cohort, respectively. CONCLUSIONS: Nearly a quarter (20-40%) of preterm neonates less than 33 weeks' gestation admitted to Indian NICUs died of sepsis. The study results have implications for health policies targeted to reduce the neonatal mortality rate in India.

DNA Damage Analysis in Children with Non-syndromic Developmental Delay by Comet Assay.

INTRODUCTION: Majority of the developmental delays in children are non-syndromic and they are believed to have an underlying DNA damage, though not well substantiated. Hence the present study was carried out to find out if there is any increased DNA damage in children with non-syndromic developmental delay by using the comet assay. AIM: The present case-control study was undertaken to assess the level of DNA damage in children with non syndromic developmental delay and compare the same with that of age and sex matched controls using submarine gel electrophoresis (Comet Assay). MATERIALS AND METHODS: The blood from clinically diagnosed children with non syndromic developmental delay and controls were subjected for alkaline version of comet assay - Single cell gel electrophoresis using lymphocytes isolated from the peripheral blood. The comets were observed under a bright field microscope; photocaptured and scored using the Image J image quantification software. Comet parameters were compared between the cases and controls and statistical analysis and interpretation of results was done using the statistical software SPSS version 20. RESULTS: The mean comet tail length in cases and control was 20.77+7.659µm and 08.97+4.398µm respectively which was statistically significant (p<0.001). Other comet parameters like total comet length and % DNA in tail also showed a statistically significant difference (p < 0.001) between cases and controls. CONCLUSION: The current investigation unraveled increased levels of DNA damage in children with non syndromic developmental delay when compared to the controls.