Familial pulmonary fibrosis is a heterogeneous group of interstitial lung diseases of unknown cause that is associated with multiple pathologic subsets. Mutations in the surfactant protein C (SP-C) gene (SFTPC) are associated with familial desquamative and nonspecific interstitial pneumonitis. Genetic studies in familial usual interstitial pneumonitis have been inconclusive. Using a candidate gene approach, we found a heterozygous exon 5 + 128 T-->A transversion of SFTPC in a large familial pulmonary fibrosis kindred, including adults with usual interstitial pneumonitis and children with cellular nonspecific interstitial pneumonitis. The mutation is predicted to substitute a glutamine for a conserved leucine residue and may hinder processing of SP-C precursor protein. SP-C precursor protein displayed aberrant subcellular localization by immunostaining. Electron microscopy of affected lung revealed alveolar type II cell atypia, with numerous abnormal lamellar bodies. Mouse lung epithelial cells transfected with the SFTPC mutation were notable for similar electron microscopy findings and for exaggerated cellular toxicity. We show that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred and may cause type II cellular injury. The presence of two different pathologic diagnoses in affected relatives sharing this mutation indicates that in this kindred, these diseases may represent pleiotropic manifestations of the same central pathogenesis.

Many cases of apparently sporadic primary pulmonary hypertension may be familial. Failure to detect familial primary pulmonary hypertension results from incomplete expression within families, skipped generations, and incomplete family pedigrees. The recent discovery of mutations in BMPR2 should make it possible to identify those with susceptibility to disease.

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BackgroundStudies in multiple organ systems have shown cross-talk between signaling through the bone morphogenetic protein receptor type 2 (BMPR2) and estrogen pathways. In humans, pulmonary arterial hypertension (PAH) has a female predominance, and is associated with decreased BMPR2 expression. The goal of this study was to determine if estrogens suppress BMPR2 expression.MethodsA variety of techniques were utilized across several model platforms to evaluate the relationship between estrogens and BMPR2 gene expression. We used quantitative RT-PCR, gel mobility shift, and luciferase activity assays in human samples, live mice, and cell culture.ResultsBMPR2 expression is reduced in lymphocytes from female patients compared with male patients, and in whole lungs from female mice compared with male mice. There is an evolutionarily conserved estrogen receptor binding site in the BMPR2 promoter, which binds estrogen receptor by gel-shift assay. Increased exogenous estrogen decreases BMPR2 expression in cell culture, particularly when induced to proliferate. Transfection of increasing quantities of estrogen receptor alpha correlates strongly with decreasing expression of BMPR2.ConclusionsBMPR2 gene expression is reduced in females compared to males in live humans and in mice, likely through direct estrogen receptor alpha binding to the BMPR2 promoter. This reduced BMPR2 expression may contribute to the increased prevalence of PAH in females.

The aim of the study was to examine the association of dietary carbohydrates and glycaemic load with the risk of type 2 diabetes among an urban adult Asian Indian population. Adult subjects aged .20 years (n 1843) were randomly selected from the Chennai Urban Rural Epidemiology Study, in Chennai city in southern India. Dietary carbohydrates, glycaemic load and food groups were assessed using FFQ. Oral glucose tolerance tests were performed using 75 g glucose in all subjects. Diagnosis of diabetes was based on WHO Consulting Group criteria. OR for newly detected diabetes were calculated for carbohydrates, glycaemic load and specific food groups comparing subjects in the highest with those in the lowest quartiles, after adjustment for potential confounders such as age, sex, BMI, family history of diabetes, physical activity, current smoking, alcohol consumption and relevant dietary factors. We identified 156 (8·5 %) newly diagnosed cases of type 2 diabetes. Refined grain intake was positively associated with the risk of type 2 diabetes (OR 5·31 (95 % CI 2·98, 9·45); P,0·001). In the multivariate model, after adjustment for potential confounders, total carbohydrate (OR 4·98 (95 % CI 2·69, 9·19), P,0·001), glycaemic load (OR 4·25 (95 % CI 2·33, 7·77); P, 0·001) and glycaemic index (OR 2·51 (95 % CI 1·42, 4·43); P¼ 0·006) were associated with type 2 diabetes. Dietary fibre intake was inversely associated with diabetes (OR 0·31 (95 % CI 0·15, 0·62); P, 0·001). In urban south Indians, total dietary carbohydrate and glycaemic load are associated with increased, and dietary fibre with decreased, risk of type 2 diabetes.

We report on the reproducibility and validity of a food frequency questionnaire (FFQ) developed for southern India. One hundred and two adult subjects aged > or =20 years drawn from the Chennai Urban Rural Epidemiology Study participated. The FFQ was developed based on local foods and habits, and was administered three times at 0, 6 and 12 month periods (called FFQ1, FFQ2 and FFQ3) to assess the reproducibility. To test the validity of the FFQ, multiple 24-h recalls collected at 2-monthly intervals for a period of 1 year and the estimated energy intake/basal metabolic rate (EI/BMR) ratio were used. The 'EpiNu' in-house food and nutrient database was used to compile dietary intakes, which were analyzed for statistical analysis. The intraclass correlation coefficient for all three FFQs ranged from 0.72 for carbohydrates to 0.45 for folate. The de-attenuated Pearson correlation for the energy adjusted nutrients between FFQ3 and 24-h recalls ranged from 0.73 for carbohydrates to 0.35 for calcium. Bland and Altman plots for energy intake between the two methods showed the limits of agreement ranged from 768 to -1358 calories/day (+/-2 standard deviations). Misclassification was low for most of the nutrients. Under-reporting of the energy intake (EI/BMR ratio<1.2) was higher in females than males. This FFQ appears to be a robust tool to measure dietary intakes in southern India.

The aim of this study was to ascertain whether international glycaemic index (GI) values, predominantly developed using peoples living in Europe, North America or Australia, are applicable to Asian Indians resident in their own country. Thirty-four Caucasian subjects were recruited in Oxford, UK and thirteen Asian Indian subjects in Chennai, India. Two types of sweet biscuits and three breakfast cereals were tested for glycaemic response in each group. Subjects were served equivalent available carbohydrate amounts (50 g) of test foods and a reference food (glucose), on separate occasions. Capillary blood glucose was measured from finger-prick samples in fasted subjects ( − 5 and 0 min) and at 15, 30, 45, 60, 90 and 120 min after starting to eat. For each test food, the incremental area under the curve (IAUC) and GI values were determined. Although the glycaemic response to the reference food was higher in Asian Indian subjects compared with UK Caucasian subjects (IAUC 219 mmol/min per litre v. 157 mmol/min per litre, respectively; P < 0·01), there was no significant difference in GI values of the five test foods between the two groups. This is the first study known to the authors to examine the role of ethnicity on GI when the subjects are resident in their own countries. The findings from this study have important implications for the use of the GI concept worldwide and support the application of international values to different ethnic groups. The higher glycaemic response to all foods in Asian Indians may represent another mechanism for increased diabetes susceptibility among Asian Indians.

The study examines the relationship between fruit and vegetable intake (g/d) and CVD risk factors in urban south Indians. The study population comprised of 983 individuals aged $ 20 years selected from the Chennai Urban Rural Epidemiological Study (CURES), a population-based crosssectional study on a representative population of Chennai in southern India. Fruit and vegetable intake (g/d) was measured using a validated semiquantitative FFQ. Linear regression analysis revealed that after adjusting for potential confounders such as age, sex, smoking, alcohol, BMI and total energy intake, the highest quartile of fruit and vegetable intake (g/d) showed a significant inverse association with systolic blood pressure (b ¼ 2 2·6 (95 % CI 2 5·92, 21·02) mmHg; P¼0·027), BMI (b ¼ 2 2·3 (95 % CI 2 2·96, 21·57) kg/m 2 ; P, 0·0001), waist circumference (b ¼ 2 2·6 (95 % CI 23·69, 2 1·46) cm; P, 0·0001), total cholesterol (b ¼ 250 (95 % CI 2 113·9, 213·6) mg/l; P¼0·017) and LDL-cholesterol concentration (b ¼ 2 55 (95 % CI 2 110·8, 2 11·1) mg/l; P¼0·039) when compared with the lowest quartile. A higher intake of fruit and vegetables explained 48 % of the protective effect against CVD risk factors. Increased intake of fruits and vegetables could play a protective role against CVD in Asian Indians who have high rates of premature coronary artery disease.