P. Raghupathy

Associations of variants in FTO and Near MC4R with obesity traits in South Asian Indians

Recent genome‐wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity‐related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity‐ and type 2 diabetes (T2DM)‐related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity‐related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist—hip ratio. Consistent associations were observed for adipose tissue‐specific measurements such as skinfold thickness reinforcing the association with obesity‐related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity‐related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity‐related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian “thin‐fat” phenotype.

Immune response of infants to fractional doses of intradermally administered inactivated poliovirus vaccine

Seventy eight infants aged 6-8 weeks received either two doses of 0.1 ml of inactivated poliovirus vaccine (IPV) intradermally 8 weeks apart (group A) or three doses 4 weeks apart (group B). Pre- and 4 weeks post-immunization serum samples were tested for the presence and titer of neutralizing antibody to poliovirus types 1, 2 and 3. The seroconversion rates to poliovirus types 1, 2 and 3 were 90, 70 and 97%, respectively, among infants in group A and 90, 80 and 98%, respectively, in group B; in children without pre-existing maternal antibody, seroconversion rates were 100% to all three poliovirus serotypes in both groups. These rates were comparable to those in children receiving five doses of OPV or two doses of intramuscular IPV. Intradermal administration of fractional doses of IPV may be a less expensive alternative for use in developing countries.

Nasopharyngeal colonization of infants in southern India with Streptococcus pneumoniae.

To investigate the dynamics of nasopharyngeal colonization with Streptococcus pneumoniae, and to determine the prevalent serogroups/types (SGT) and their antimicrobial susceptibility, we studied 100 infants attending our well-baby clinic. Nasopharyngeal swab specimens were obtained at 6, 10, 14, 18 and 22 weeks and at 9 and 18 months of age and submitted for culture, serotyping and antimicrobial susceptibility testing of S. pneumoniae. Colonization with pneumococcus was seen on at least one occasion in 81 infants. The median age of acquisition was 11 weeks and the median duration of carriage was 1 3 months. The common SGTs identified were 6, 19, 14 and 15. SGT 1, which was a common invasive isolate in children in our hospital during this period, was not isolated from these children. Sequential colonization by 2, 3 or 4 SGTs was observed in 18, 5 and 2 children, respectively. Resistance to penicillin, chloramphenicol, cotrimoxazole and erythromycin was observed in 0, 13 (6%) 11 (5 %) and 5 (3 %) isolates, respectively. There was a significant difference in susceptibility to cotrimoxazole between colonizing and invasive isolates (5 % vs. 40 %, P<0.0001).

Glucose tolerance, insulin resistance and insulin secretion in young south Indian adults: Relationships to parental size, neonatal size and childhood body mass index

OBJECTIVE To study the relationship of newborn size and post-natal growth to glucose intolerance in south Indian adults. RESEARCH DESIGN AND METHODS 2218 men and women (mean age 28 years) were studied from a population-based birth cohort born in a large town and adjacent rural villages. The prevalence of adult diabetes mellitus [DM] and impaired glucose tolerance [IGT], and insulin resistance and insulin secretion (calculated) were examined in relation to BMI and height at birth, and in infancy, childhood and adolescence and changes in BMI and height between these stages. RESULTS Sixty-two (2.8%) subjects had Type 2 diabetes (DM) and 362 (16.3%) had impaired glucose tolerance (IGT). IGT and DM combined (IGT/DM) and insulin resistance were associated with low childhood body mass index (BMI) (p<0.001 for both) and above-average BMI gain between childhood or adolescence and adult life (p<0.001 for both). There were no direct associations between birthweight or infant size and IGT/DM; however, after adjusting for adult BMI, lower birthweight was associated with an increased risk. CONCLUSIONS The occurrence of IGT and Type 2 DM is associated with thinness at birth and in childhood followed by accelerated BMI gain through adolescence.

Does 3-day course of oral amoxycillin benefit children of non-severe pneumonia with wheeze: a multicentric randomised controlled trial.

Background WHO-defined pneumonias, treated with antibiotics, are responsible for a significant proportion of childhood morbidity and mortality in the developing countries. Since substantial proportion pneumonias have a viral etiology, where children are more likely to present with wheeze, there is a concern that currently antibiotics are being over-prescribed for it. Hence the current trial was conducted with the objective to show the therapeutic equivalence of two treatments (placebo and amoxycillin) for children presenting with non-severe pneumonia with wheeze, who have persistent fast breathing after nebulisation with salbutamol, and have normal chest radiograph. Methodology This multi-centric, randomised placebo controlled double blind clinical trial intended to investigate equivalent efficacy of placebo and amoxicillin and was conducted in ambulatory care settings in eight government hospitals in India. Participants were children aged 2–59 months of age, who received either oral amoxycillin (31–54 mg/Kg/day, in three divided doses for three days) or placebo, and standard bronchodilator therapy. Primary outcome was clinical failure on or before day- 4. Principal Findings We randomized 836 cases in placebo and 835 in amoxycillin group. Clinical failures occurred in 201 (24.0%) on placebo and 166 (19.9%) on amoxycillin (risk difference 4.2% in favour of antibiotic, 95% CI: 0.2 to 8.1). Adherence for both placebo and amoxycillin was >96% and 98.9% subjects were followed up on day- 4. Clinical failure was associated with (i) placebo treatment (adjusted OR = 1.28, 95% CI: 1.01 to1.62), (ii) excess respiratory rate of >10 breaths per minute (adjusted OR = 1.51, 95% CI: 1.19, 1.92), (iii) vomiting at enrolment (adjusted OR = 1.49, 95% CI: 1.13, 1.96), (iv) history of use of broncho-dilators (adjusted OR = 1.71, 95% CI: 1.30, 2.24) and (v) non-adherence (adjusted OR = 8.06, 95% CI: 4.36, 14.92). Conclusions Treating children with non-severe pneumonia and wheeze with a placebo is not equivalent to treatment with oral amoxycillin. Trial Registration ClinicalTrials.gov NCT00407394

Cohort profile: The 1969-73 Vellore Birth Cohort Study in South India

This report summarizes a longitudinal study of maternal health and pregnancy outcomes including mothers from urban and rural areas of the North Arcot district in India. It describes the study sample the follow up attrition measurements the findings and the strengths and weaknesses of the study.

Effect of Vitamin A supplementation on the immune response to measles vaccination.

A randomized controlled trial was conducted in 395 infants aged 9-12 months to determine the effect of Vitamin A supplementation on concurrently administered measles vaccine. Antibody response was measured using the plaque reduction neutralization assay. No statistically significant differences were demonstrated between the immune response in Vitamin A supplemented and unsupplemented children. Unlike some recent studies, we were unable to demonstrate an immune enhancing effect of Vitamin A supplementation. On the contrary, among children who were given Vitamin A, a lower, but statistically non-significant, proportion had protective antibody levels 6 months after vaccination.

Modified latex agglutination test for rapid detection of Streptococcus pneumoniae and haemophilus influenzae in cerebrospinal fluid and direct serotyping of Streptococcus pneumoniae.

A modified latex agglutination test was designed and evaluated for the rapid detection ofStreptococcus pneumoniae andHaemophilus influenzae type b capsular antigens, and for direct serotyping ofStreptococcus pneumoniae in the cerebrospinal fluid. Reagents were prepared by sensitizing latex particles with Omniserum (against 83 capsular serotypes of pneumococci) andHaemophilus influenzae type b burro antiserum. For serotyping reagents, latex particles were similarly coated with nine pneumococcal pool (A to I) antisera and 46 individual pneumococcal serogroup/serotype specific antisera. The test was performed on cerebrospinal fluid from 298 patients with suspected meningitis. Serotyping was done directly on untreated cerebrospinal fluid samples showing positive reactions with the Omniserum reagent. Pneumococcal orHaemophilus influenzae type b antigens were detected in 41 patients; in 32 of these the etiology was established by culture and in 2 by smear examination. Five of the remaining seven cases were judged clinically and by cytological examination of cerebrospinal fluid to have partially treated bacterial meningitis. In two cases the test was false positive. The overall sensitivity and specificity of the latex agglutination test for the detection ofStreptococcus pneumoniae andHaemophilus influenzae type b antigens was 100% and 96.6% respectively. The commonest pneumococcal serotypes were type 1 (30%), types 6 and 19 (10% each). The latex agglutination test is rapid and simple to perform, yielding serotype data directly by testing of cerebrospinal fluid.

haemophilus influenzae disease in children in India: a hospital perspective

We review and summarize published information on diseases caused by Haemophilus influenzae in India and unpublished data from our center covering more than three decades. Since the mid-1950s H. influenzae has been the most common cause of pyogenic meningitis in children admitted to our hospital, accounting for one-third to one-half of cases. Information from other centers in India has been scanty; the lower frequency of isolation of Haemophilus in studies in some centers may be caused by unsatisfactory media and culture methods. The annual numbers of admissions for pyogenic meningitis in our hospital have been quite similar to the numbers of cases of poliomyelitis. Assuming that the similar numbers of children hospitalized with these two diseases indicate similar incidence rates in the community and taking into account the frequency of Haemophilus isolations in pyogenic meningitis, we estimate that there may be as many as 75 to 100 cases of meningitis caused by this organism per year per 100000 children <5 years of age. Although pneumonia caused by H. influenzae has been recognized in a few studies, information is too scanty to attempt the estimation of incidence. Pus-producing infections caused by Haemophilus are rare. Epiglottitis caused by Haemophilus does not seem to occur in India. In recent years we have found that most invasive Haemophilus infections are caused by H. influenzae type b (Hib); other types or untypable strains are infrequent. An increasing prevalence of resistance to chloramphenicol and ampicillin has been recognized in our center and elsewhere. Thus from a hospital perspective, primary prevention by using Hib vaccine seems to be a rational and beneficial intervention. Community-based studies to measure the disease burden of Hib are urgently needed for a more satisfactory assessment of the need for, and cost benefit of, Hib immunization of all infants.

Absence of birth-weight lowering effect of ADCY5 and near CCNL, but association of impaired glucose-insulin homeostasis with ADCY5 in Asian Indians.

Background A feature of the Asian Indian phenotype is low birth weight with increased adult type 2 diabetes risk. Most populations show consistent associations between low birth weight and adult type 2 diabetes. Recently, two birth weight-lowering loci on chromosome 3 (near CCNL1 and ADCY5) were identified in a genome-wide association study, the latter of which is also a type 2 diabetes locus. We therefore tested the impact of these genetic variants on birth weight and adult glucose/insulin homeostasis in a large Indian birth cohort. Methodology/Principal Findings Adults (n = 2,151) enrolled in a birth cohort (established 1969-73) were genotyped for rs900400 (near CCNL1) and rs9883204 (ADCY5). Associations were tested for birth weight, anthropometry from infancy to adulthood, and type 2 diabetes related glycemic traits. The average birth weight in this population was 2.79±0.47 kg and was not associated with genetic variation in CCNL1 (p = 0.87) or ADCY5 (p = 0.54). Allele frequencies for the ‘birth weight-lowering’ variants were similar compared with Western populations. There were no significant associations with growth or adult weight. However, the ‘birth weight-lowering’ variant of ADCY5 was associated with modest increase in fasting glucose (β 0.041, p = 0.027), 2-hours glucose (β 0.127, p = 0.019), and reduced insulinogenic index (β -0.106, p = 0.050) and 2-hour insulin (β -0.058, p = 0.010). Conclusions The low birth weight in Asian Indians is not even partly explained by genetic variants near CCNL1 and ADCY5 which implies that non-genetic factors may predominate. However, the ‘birth-weight-lowering’ variant of ADCY5 was associated with elevated glucose and decreased insulin response in early adulthood which argues for a common genetic cause of low birth weight and risk of type 2 diabetes.