King Edward Memorial Hospital Research Centre

We have studied 477 8-year-old Indian children to define the relationship between birth weight and cardiovascular risk factors, including insulin resistance syndrome (IRS) variables and plasma total and LDL cholesterol concentrations. All risk factors were strongly related to current weight. After adjustment for current weight, age, and sex, lower birth weight was associated with higher systolic blood pressure (P = 0.008), fasting plasma insulin and 32-33 split proinsulin concentrations (P = 0.08 and 0.02), glucose and insulin concentrations 30 min postglucose (P = 0.06 and 0.04), subscapular/triceps skinfold ratio (P = 0.003), and plasma total and LDL cholesterol concentrations (P = 0.002 and 0.001). Lower birth weight was associated with increased calculated insulin resistance (homeostasis model assessment [HOMA], P = 0.03), but was not related to the HOMA index of beta-cell function. The highest levels of IRS variables and total and LDL cholesterol were in children of low birth weight but high fat mass at 8 years. Taller height at 8 years predicted higher fasting plasma insulin concentrations, insulin resistance, and plasma total and LDL cholesterol concentrations. The most insulin-resistant children were those who had short parents but had themselves grown tall. Although the implications of our findings in relation to height are unclear, interventions to improve fetal growth and to control obesity in childhood are likely to be important factors in the prevention of cardiovascular disease and IRS in India.

Abstract Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often specific to cell type 3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance ( P < 5 × 10 −8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores 5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

We studied body size and cord blood leptin and insulin concentrations in newborn urban Indian (Pune, India) and white Caucasian (London, UK) babies to test the hypothesis that the adiposity and hyperinsulinemia of Indians are present at birth. Indian babies (n = 157) were lighter in weight compared with white Caucasian babies [n = 67; median weight, 2805 g vs. 3475 g, respectively; P < 0.001, adjusted for gestational age and sex; -1.52 SD score; confidence interval (CI), -1.66, -1.42] and had smaller abdominal (-2.39 SD score; CI, -2.52, -2.09), midarm (-1.47 SD score; CI, -1.58, -1.34), and head (-1.23 SD score; CI, -1.42, -1.13) circumferences. However, their skinfolds were relatively preserved: subscapular (central) skinfold (-0.32 SD score; CI, -0.43, -0.20) was better preserved than triceps (peripheral) skinfold (-0.86 SD score; CI, -0.97, -0.75). Cord plasma leptin (median, 6.2 ng/ml Pune and 6.4 ng/ml London) and insulin (median, 34.7 pmol/liter Pune and 20.8 pmol/liter London) concentrations were comparable in the two populations but were higher in Indians when adjusted for birth weight, confirming relative adiposity and hyperinsulinemia of Indian babies. Indian mothers were smaller in all respects, compared with white Caucasian mothers, except subscapular skinfold, which was similar in the two populations. Our results support the intrauterine origin of adiposity, central adiposity, and hyperinsulinemia in Indians. Further research should concentrate on elucidating genetic and environmental influences on fetal growth and body composition. Prevention of insulin resistance syndrome in Indians will need to address regulation of fetal growth in addition to prevention of obesity in later life.

Studies in Britain have shown that adults who had a low birthweight have high plasma glucose concentrations 30 and 120 min after an oral glucose load, and an increased risk of Type 2 diabetes and impaired glucose tolerance. Both Type 2 diabetes and low birthweight are common in India. To determine whether low birthweight is associated with reduced glucose tolerance in Indian children, glucose tolerance tests were carried out on 379 4-year-old children, whose birthweights were recorded, in Pune, India. Among 201 children who had been looked after on the routine postnatal wards at birth, those with lower birthweights had higher plasma glucose and insulin concentrations 30 min after an oral glucose load, independently of their current size (p = 0.01 and 0.04, respectively). Mean glucose and insulin concentrations were 8.1 mmol l-1 and 321 pmol l-1 in children whose birthweight had been 2.4 kg or less, compared with 7.5 mmol l-1 and 289 pmol l-1 in those who weighted more than 3.0 kg. Among 178 children who had been looked after in the Special Care Baby Unit, those with lower birthweights also had higher plasma insulin concentrations at 30 min but there were no trends with plasma glucose. Our findings suggest that Indian children with reduced intra-uterine growth have reduced glucose homeostasis after a glucose challenge. This is consistent with the hypothesis that Type 2 diabetes mellitus in India may be programmed in fetal life.

OBJECTIVE: The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recently proposed new criteria for diagnosing gestational diabetes mellitus (GDM). We compared prevalence rates, risk factors, and the effect of ethnicity using the World Health Organization (WHO) and modified IADPSG criteria. METHODS: This was a population-based cohort study of 823 (74% of eligible) healthy pregnant women, of whom 59% were from ethnic minorities. Universal screening was performed at 28±2 weeks of gestation with the 75 g oral glucose tolerance test (OGTT). Venous plasma glucose (PG) was measured on site. GDM was diagnosed as per the definition of WHO criteria as fasting PG (FPG) ≥7.0 or 2-h PG ≥7.8 mmol/l; and as per the modified IADPSG criteria as FPG ≥5.1 or 2-h PG ≥8.5 mmol/l. RESULTS: OGTT was performed in 759 women. Crude GDM prevalence was 13.0% with WHO (Western Europeans 11%, ethnic minorities 15%, P=0.14) and 31.5% with modified IADPSG criteria (Western Europeans 24%, ethnic minorities 37%, P< 0.001). Using the WHO criteria, ethnic minority origin was an independent predictor (South Asians, odds ratio (OR) 2.24 (95% confidence interval (CI) 1.26-3.97); Middle Easterners, OR 2.13 (1.12-4.08)) after adjustments for age, parity, and prepregnant body mass index (BMI). This increased OR was unapparent after further adjustments for body height (proxy for early life socioeconomic status), education and family history of diabetes. Using the modified IADPSG criteria, prepregnant BMI (1.09 (1.05-1.13)) and ethnic minority origin (South Asians, 2.54 (1.56-4.13)) were independent predictors, while education, body height and family history had little impact. CONCLUSION: GDM prevalence was overall 2.4-times higher with the modified IADPSG criteria compared with the WHO criteria. The new criteria identified many subjects with a relatively mild increase in FPG, strongly associated with South Asian origin and prepregnant overweight.

The 'fetal origins' hypothesis (Barker, 1995) would predict that the rising epidemic of diabetes and CHD in India would be due to poor intrauterine growth of the Indian babies. While this explanation may be valid to an extent, the higher prevalence of these disorders in urban compared with rural India (where birth weights are lower) would suggest a significant role for postnatal factors. In a cohort of 477 children born in the King Edward Memorial Hospital, Pune, we found that at 8 years of age current obesity strongly predicted insulin resistance. When this effect was allowed for, low birth weight was significantly associated with insulin-resistance variables and other cardiovascular risk factors. Children who were born small but had grown heavy (or tall) were the most insulin resistant and had the highest levels of cardiovascular risk factors. Accelerated growth in relation to mid parental height was similarly predictive. Poor intrauterine growth also predicted higher central adiposity at 8 years of age. We have also studied maternal nutrition and fetal growth in six villages near Pune. A newborn Indian baby is small (2650 g, SD score (SDS) -1.6 compared with an average white Caucasian baby born in the UK) and 'thin' (ponderal index 2.45 kg/m3, SDS -1.2), but has preserved its subcutaneous fat (subscapular skinfold thickness SDS -0.6). The thinness of the Indian babies is due to poor muscle and small abdominal viscera. We have proposed this composition as the 'thrifty phenotype' (Hales & Barker, 1992) of Indian babies. Maternal size and intake of certain food groups during pregnancy were important determinants of the baby's phenotype. Thus, the small Indian babies are programmed to deposit fat from their intrauterine life. Exaggeration of this tendency in later life is associated with insulin-resistance syndrome. Control of the insulin-resistance epidemic in India might depend on improved intrauterine development and prevention of childhood obesity.

BACKGROUND: Low vitamin B12 concentration in South Asian Indians is common, but the exact prevalence is not known. AIM: To investigate prevalence and associations of low vitamin B12 concentration and hyperhomocysteinemia in rural and urban Indian men living in and around Pune, Maharashtra. METHOD: We studied 441 middle-aged men (149 rural, 142 slum and 150 urban middle-class residents, mean age 39 y). Data on lifestyle, socio-economic status, nutrition and medical history were obtained. Circulating concentrations of vitamin B12, folate, ferritin, total homocysteine (tHcy), and haematological indices, and cardiovascular risk variables were measured. RESULTS: Median plasma B12 concentration was low (110 pmol/L): Overall, 67% of men had low vitamin B12 concentration (<150 pmol/L) and 58% had hyperhomocysteinemia (>15 micromol/L). Of the urban middle class, 81% had low vitamin B12 concentration and 79% had hyperhomocysteinemia. Low vitamin B12 concentration contributed 28% to the risk of hyperhomocysteinemia (population attributable risk) while low red cell folate contributed 2%. Vegetarians had 4.4 times (95% CI 2.1, 9.4) higher risk of low vitamin B12 concentrations and 3.0 times (95% CI 1.4, 6.5) higher risk of hyperhomocysteinemia compared to those who ate non-vegetarian foods frequently. Urban middle-class residence was an additional independent risk factor of hyperhomocysteinemia (odds ratio 7.6 (95% CI 2.5, 22.6), compared to rural men). Low vitamin B12 concentration was related to lower blood haemoglobin concentration and higher mean corpuscular volume, but macrocytic anemia was rare. CONCLUSION: Low vitamin B12 concentration and hyperhomocysteinemia are common in Indian men, particularly in vegetarians and urban middle class residents. Further studies are needed to confirm these findings in other parts of India.

Background: Vitamins B12 and folate participate in the one-carbon metabolism cycle and hence regulate fetal growth. Though vitamin B12 deficiency is widely prevalent, the current public health policy in India is to supplement only iron and folic acid for the prevention of anaemia. Prompted by our research findings of the importance of maternal vitamin B12 status for a healthy pregnancy, birth and offspring health outcomes, we evaluated available literature evidence using a systematic review approach, to inform policy. Methods: A systematic search was performed for relevant Indian studies in the MEDLINE/PubMed and IndMed databases. We selected studies reporting maternal vitamin B12 status (dietary intake or blood concentrations), and/or metabolic markers of vitamin B12 deficiency (homocysteine, methylmalonic acid) or haematological indices during pregnancy and their associations with outcomes of pregnancy, infancy or in later life. Intervention trials of vitamin B12 during pregnancy were also included. Quality of evidence was assessed on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Of the 635 articles identified, 46 studies met the inclusion criteria (cohort studies-26, case-control studies-13, RCT's -7). There is a high prevalence of vitamin B12 deficiency in Indian women during pregnancy (40-70%) (3 studies). Observational studies support associations (adjusted for potential sociodemographic confounders, maternal body size, postnatal factors) of lower maternal B12, higher homocysteine or an imbalance between vitamin B12-folate status with a higher risk of NTDs (6 studies), pregnancy complications (recurrent pregnancy losses, gestational diabetes, pre-eclampsia) (9 studies), lower birth weight (10 studies) and adverse longer-term health outcomes in the offspring (cognitive functions, adiposity, insulin resistance) (11 studies). Vitamin B12 supplementation (7 RCT's) in pregnancy showed a beneficial effect on offspring neurocognitive development and an effect on birth weight was inconclusive. There is a high quality evidence to support the role of low maternal vitamin B12 in higher risk for NTD and low birth weight and moderate-quality evidence for higher risk of gestational diabetes and later life adverse health outcomes (cognitive functions, risk for diabetes) in offspring. Conclusion: In the Indian population low maternal vitaminB12 status, is associated with adverse maternal and child health outcomes. The level of evidence supports adding vitamin B12 to existing nutritional programs in India for extended benefits on outcomes in pregnancy and offspring health besides control of anaemia. Systematic Review Registration: [website], identifier [registration number].

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

PURPOSE: To determine the efficacy of bronchial artery embolization in the control of massive hemoptysis due to pulmonary tuberculosis. MATERIALS AND METHODS: Between 1988 and 1994, 140 patients (125 men and 15 women; mean age, 31.5 years) who presented with massive hemoptysis (more than 300 mL of blood in 24 hours) underwent bronchial artery embolization. Fifty-one patients had received no antituberculosis drugs. Bronchial artery embolization was performed on the side with the greater abnormality on the chest radiograph. Catheters (4 F) and a gelatin sponge were used for embolization. Inflammatory hypervascularity was seen in all patients (five patients had contrast material extravasation and 10 patients had pseudoaneurysms). RESULTS: Almost complete control of hemoptysis was achieved in 102 patients. Of the remaining 38 patients with a notable amount of bleeding after the procedure, 29 were treated successfully with conservative measures and nine underwent re-embolization. Seven patients who underwent re-embolization had recurrent bleeding; four of these patients underwent successful surgery, and three died of aspiration. Two patients developed transient paraparesis 6 hours after the procedure. Nine patients reported transient referred pain to the ipsilateral orbit during injection of the gelatin sponge. One patient had transient dysphagia. CONCLUSION: Patients with massive hemoptysis due to pulmonary tuberculosis should first be treated with bronchial artery embolization.

In India there is a rapidly escalating epidemic of insulin resistance syndrome (diabetes and coronary heart disease). Contribution of genes and environment is under debate. Small size at birth coupled with subsequent obesity increases risk for insulin resistance syndrome in later life. The tendency of Indians to have higher body fat and central adiposity compared with other races may be programmed in utero. The adipose tissue releases not only fatty acids but also a number of proinflammatory cytokines, which increase insulin resistance and cause endothelial dysfunction. Crowding, infections, and environmental pollution in Indian cities may increase cardiovascular risk by stimulating fat cells. Prevention of diabetes and coronary heart disease in India will have to be approached throughout the life cycle.

OBJECTIVE: Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case-control studies. RESEARCH DESIGN AND METHODS: We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEX-rs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects. RESULTS: We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 x 10(-3) to 4.6 x 10(-34)). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71-2.09], P = 4.6 x 10(-34)). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of beta-cell function (P = 6.9 x 10(-8) and 3 x 10(-4), respectively), which looked consistent with recessive and under-dominant models, respectively. CONCLUSIONS: Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.

Laparoscopic surgery provides patients with less painful surgery but is more demanding for the surgeon. The increased technological complexity and sometimes poorly adapted equipment have led to increased complaints of surgeon fatigue and discomfort during laparoscopic surgery. Ergonomic integration and suitable laparoscopic operating room environment are essential to improve efficiency, safety, and comfort for the operating team. Understanding ergonomics can not only make life of surgeon comfortable in the operating room but also reduce physical strains on surgeon.

In a casual perusal of papers on hypertension, one comes across well over a hundred so-called hypotensive remedies alleged to possess the property of lowering the blood pressure. In 1930, Ayman could collect over two hundred reports on the successful treatment of hyperplesia by various hypotensive remedies. In view of the persistently high mortality from hypertension in spite of the large number of measures recommended in the treatment of this disease one is forced to admit the futility or helplessness of the situation. In Ayman’s opinion, the “proper treatment is still unknown.” Evans and Loughnan, after a critical analysis and trial of thirty three different preparations in seventy cases of high blood pressure (essential hypertension), were forced to admit the uselessness of them all. In their opinion, simple sedative measures are often more effective than the much more expensive and fashionable products extensively displayed on the market. There is unfortunately, a great tendency on the part of both the medical profession and the laiety, to hail or applaud any new drug or measure introduced into the market, often on the basis of a few stray experiences or clinical impressions. In consequence of this attitude, many of the present day clinicians have learnt not to accept any claim for a new remedy unless and

Campylobacter pylori has been implicated as a causative factor in acid-peptic disease. Lactobacillus acidophilus is known to inhibit the growth of pathogens in the human gastrointestinal tract. We recovered C. pylori from gastric antral biopsies of seven patients with acid-peptic disease; the isolates were then cultured in brucella broth. The effect of L. acidophilus (cultured in DeMan-Rogosa-Sharpe broth) on the growth of C. pylori was tested by a mixed culture technique. L. acidophilus inhibited the growth of all seven isolates of C. pylori in vitro. All these isolates were also inhibited by the L. acidophilus culture supernatant (brucella blood agar cup technique) obtained at or after 48 h of incubation. Inhibition of C. pylori growth was also observed with 1 and 3% lactic acid but not with 0.5 and 1% hydrogen peroxide, the L. acidophilus sonic extract, or a citrate-phosphate buffer (pH 4.0). We conclude that the inhibitory action of L. acidophilus on C. pylori is dependent on an extracellular secretory product, probably lactic acid. This inhibitory effect may be of therapeutic relevance in patients with C. pylori-positive acid-peptic disease.

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated. RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored. RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference. CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

India has rapidly become a "diabetes capital" of the world, despite maintaining high rates of under-nutrition. Indians develop diabetes at younger age and at lower body weights than other populations. Here, we interpret these characteristics in terms of a "capacity-load" model of glucose homeostasis. Specifically, we assume that glycemic control depends on whether the body's "metabolic capacity," referring to traits, such as pancreatic insulin production and muscle glucose clearance, is able to resolve the "metabolic load" generated by high levels of body fat, high dietary glycemic load, and sedentary behavior. We employ data from modern cohorts to support the model and the interpretation that elevated diabetic risk among Indian populations results from the high metabolic load imposed by westernized lifestyles acting on a baseline of low metabolic capacity. We attribute this low metabolic capacity to the low birth weight characteristic of Indian populations, which is associated with short stature and low lean mass in adult life. Using stature as a marker of metabolic capacity, we review archeological and historical evidence to highlight long-term declines in Indian stature associated with adaptation to several ecological stresses. Underlying causes may include increasing population density following the emergence of agriculture, the spread of vegetarian diets, regular famines induced by monsoon failure, and the undermining of agricultural security during the colonial period. The reduced growth and thin physique that characterize Indian populations elevate susceptibility to truncal obesity, and increase the metabolic penalties arising from sedentary behavior and high glycemic diets. Improving metabolic capacity may require multiple generations; in the meantime, efforts to reduce the metabolic load will help ameliorate the situation.

Systemic lupus erythematosus (SLE) is an inflammatory rheumatic disease characterized by production of autoantibodies and organ damage. Elevated levels of cytokines have been reported in SLE patients. In this study we have investigated the effect of proinflammatory cytokines (IL-6, TNF-α, and IL-1β) on clinical manifestations in 145 Indian SLE patients. One hundred and forty-five healthy controls of the same ethnicity served as a control group. Clinical disease activity was scored according to SLEDAI score. Accordingly, 110 patients had active disease and 35 patients had inactive disease. Mean levels of IL-6, TNF-α, and IL-1β were found to be significantly higher in SLE patients than healthy controls (P < 0.001). Mean level of IL-6 for patients with active disease (70.45±68.32 pg/mL) was significantly higher (P = 0.0430) than those of inactive disease patients (43.85±63.36 pg/mL). Mean level of TNF-α was 44.76±68.32 pg/mL for patients with active disease while it was 25.97±22.03 pg/mL for those with inactive disease and this difference was statistically significant (P = 0.0161). Similar results were obtained for IL-1β (P = 0.0002). Correlation between IL-6, TNF-α, and IL-1β serum levels and SLEDAI score was observed (r = 0.20, r = 0.27, and r = 0.38, resp.). This study supports the role of these proinflammatory cytokines as inflammatory mediators in active stage of disease.

OBJECTIVE: To follow-up children who had been resuscitated at birth with either 21% or 100% oxygen (O2). METHODS: A multicenter study with 10 participating centers recruited 609 infants to the Resair 2 study where resuscitation was performed with either 21% or 100% O2. A follow-up between ages 18 and 24 months was performed. However, during follow-up registration, it was found that 18 infants had been enrolled twice in the original Resair 2 study with different registration numbers, leaving 591 enrolled in the Resair 2 study and 410 enrolled in the 7 centers participating in the follow-up. Of these 410 infants, 79 died (76 in the neonatal and 3 in the postneonatal period). Furthermore, for 8 infants informed consent was not obtained, leaving 323 eligible for follow-up. Of these, 213 infants (66%) were followed-up: 91 (62%) had been resuscitated with 21% O2, and 122 (69%) with 100% O2. At a median age of 22 and 20 months (not significant) in the 21% and 100% groups, respectively, a simple questionnaire was filled out and neurologic assessment was performed in addition to measuring anthropometric data. RESULTS: There were no significant differences in weight, height, or head circumference between the 2 groups. Cerebral palsy developed in 10% and 7%, respectively, in the 2 groups (not significant). In total, 11 cases (12%) in the 21% versus 11 cases (9%) in the 100% O(2) group (odds ratio: 1.39, 95% confidence interval: 0.57-3.36) developed cerebral palsy and/or mental or other delay. Furthermore, it was concluded that 14 (15%) in the 21% group and 12 (10%) in the 100% group were not normal (odds ratio: 1.67, 95% confidence interval: 0.73-3.80). CONCLUSIONS: There were no significant differences in somatic growth or neurologic handicap at an age of 18 to 24 months in infants resuscitated with either 21% or 100% O2 at birth. Based on these data, resuscitation with ambient air seems to be safe, at least in most cases. More studies are needed to settle this issue.