A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

A case-control study on insulin resistance, metabolic co-variates & prediction score in non-alcoholic fatty liver disease.

BACKGROUND & OBJECTIVE: Asian Indians have a high prevalence of insulin resistance and the metabolic syndrome. Currently, non-alcoholic fatty liver disease (NAFLD) is considered to be an integral part of the metabolic syndrome with insulin resistance as a central pathogenic factor. We studied anthropometric parameters, insulin resistance and metabolic co-variates in subjects with NAFLD as compared to those without NAFLD, and also developed a prediction score for NAFLD. METHODS: Thirty nine subjects with NAFLD and 82 controls were selected for the study after ultrasonography of 121 consecutive apparently healthy subjects. Anthropometric profile [body mass index (BMI), waist circumference (WC) etc,], lipid profile, hepatic aminotransferases, fasting blood glucose (FBG), insulin were recorded and value of homeostasis model assessment of insulin resistance (HOMA-IR) was analysed. Step-wise logistic regression analysis and area under the receiver operator curve (aROC) were analysed to arrive at a prediction score. RESULTS: Overall, prevalence of NAFLD was 32.2 per cent and prevalence of metabolic syndrome was seen in 41 per cent among cases and 19.5 per cent in controls (P<0.01). Subjects with NAFLD had significantly higher values of BMI, WC, hip circumference, FBG, fasting insulin, total cholesterol and serum triglycerides. Step-wise logistic regression analysis showed odds ratio (OR) and 95 per cent confidence interval (CI) for BMI [ 4.3 (1.6, 11.3)], FBG [5.5 (1.5, 19.8)] and fasting insulin [ 2.4 (1.0, 5.8)] as independent predictors of NAFLD. The prediction score for NAFLD was; 1 (fasting insulin) +1.6 (BMI) + 1.9 (FBG) (sensitivity of 84.6%, specificity of 51.2% and aROC 76%). INTERPRETATION & CONCLUSION: In this study, presence of NAFLD indicated close relationship with multiple features of metabolic syndrome. The prediction score developed could be used as a screening tool to predict NAFLD among Asian Indians in north India.

Effect of tripod position on objective parameters of respiratory function in stable chronic obstructive pulmonary disease.

OBJECTIVE: To examine changes in respiratory dynamics in patients with chronic obstructive pulmonary disease (COPD) sitting leaning forward with hands supported on the knees (tripod position), a posture frequently assumed by patients in respiratory distress. METHODS: Spirometry, maximal inspiratory and expiratory pressures (MIP and MEP) generated at the mouth, and diaphragmatic excursion during tidal and vital capacity maneuver breathing measured by B-mode ultrasonography were studied in 13 patients with stable COPD in sitting, supine and tripod positions. RESULTS: Mean +/- SD age of patients was 52.2 +/- 6.8 years. Median disease duration was three years. There was no statistically significant difference in spirometry for sitting, supine and tripod positions (FEV1: 1.11 +/- 0.4L, 1.14 +/- 0.5L and 1.11 +/- 0.4L; p = 0.99), respectively, (FEV1/FVC: 49.2 +/- 11.0, 53.7 +/- 8.5 and 48.5 +/- 11.3, p = 0.37), mouth pressures (MIP: 102.9 +/- 28.9, 90.6 +/- 29.1 and 99.2 +/- 32.9 cm H2O, p = 0.61 and MEP: 100.8 +/- 29.9, 100.4 +/- 34.4 and 90.6 +/- 32.6 cm H2O, p = 0.74) and diaphragmatic movements during tidal (16.1 +/- 5.9, 20.1 +/- 6.8 and 16.6 +/- 6.2 mm, p = 0.22) and forced breathing (33.9 +/- 11.0, 43.1 +/- 19.6 and 37.4 +/- 17.1 mm, p = 0.35). CONCLUSION: Commonly measured indices of respiratory function were not different in the tripod compared to sitting and supine positions.

Derivation of a prognostic equation to predict in-hospital mortality and requirement of invasive mechanical ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: Predicting in-hospital mortality and formulating a scoring system derived from predictors of mortality may aid prognostication. METHODS: One hundred and fifty-one consecutive patients admitted with a diagnosis of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) were followed to discharge or death in hospital stay. Secondary variables studied were duration of hospital stay, and need for and duration of mechanical ventilation (MV). RESULTS: Mean (SD) age of patients was 60.5 (11.4) years; 65.6% were mechanically ventilated, and 25.2% died in hospital. Independent predictors of mortality at admission were serum creatinine (odds ratio [OR] 2.1, 95% Confidence intervals [CI] 1.03 to 4.30; p = 0.04), and serum sodium (OR 0.94, 95% CI 0.90 to 0.99; p = 0.03). An equation derived [Score = 8+ (0.74 x creatinine) = (0.015 x sodium)] to predict mortality, had an area under receiver operating characteristic (ROC) curve of 73%, with a cut-off of 6.74 having sensitivity, specificity, positive and negative predictive values for predicting death of 71%, 64%, 40% and 87%, respectively. Glasgow coma scale (GCS), partial pressure of oxygen in arterial blood (PaO2) and partial pressure of carbon dioxide in arterial blood (PaCO2) at admission independently predicted need for invasive ventilation. An equation derived [Score = 2.36+(0.02 x PaO2)+(0.05 x PaCO2)-(0.47 x GCS)] to predict need for MV, had an area under ROC curve of 85%, with a cut-off of 0.54 having sensitivity, specificity, positive and negative predictive values for predicting need for MV of 82%, 81%, 89% and 70%, respectively. CONCLUSIONS: Serum creatinine and sodium at admission are independent predictors of mortality for patients admitted with AECOPD. The equation derived from these two variables is a simple and useful method for predicting outcome.

Dietary adequacy in Asian Indians with HIV.

Malnutrition is endemic in developing countries, which also bear the brunt of the human immunodeficiency virus (HIV) pandemic. HIV and its complications have a significant impact on nutritional status. Malnutrition and HIV have deleterious interactions. Dietary inadequacy is a major cause of malnutrition and few studies have been done to assess dietary adequacy in HIV-infected individuals and the factors affecting intake. Dietary intake of 71 consecutive patients was determined using 24-hour dietary recall, with the help of a questionnaire and a structured interview, and then compared with the recommended dietary allowances (RDA). The dietary intake of energy, total fat, fibre, vitamin C and iron were significantly less than the recommended RDA. There was no difference in protein intake. Only 5.7% of males and 16.7% of females reached the recommended energy allowance. The recommended protein allowance was reached by 43.4% males and 44.4% females and 41.5% males and 38.9% females consumed more than the upper limit of the recommended fat intake. Intake of major nutrients was also significantly less when compared to the national average intake. On bivariate analysis, the factors affecting these inadequacies were found to be annual per-capita income, dependency on another for livelihood, CD4 counts more than 200/cubic millimeter and absence of antiretroviral therapy. On multivariate analysis, only dependency on another was found to significantly influence energy intake. Dietary intake of many food constituents is significantly less in HIV patients than that recommended. Dietary counselling and efforts to improve food security are important in management of these patients.

Distribution and cutoff points of fasting insulin in Asian Indian adolescents and their association with metabolic syndrome.

AIM: To evaluate the levels and appropriate cutoff points of fasting insulin, and their association with the metabolic syndrome (MS) in Asian Indian adolescents. METHODS: This cross-sectional, population based study included 948 (527 males & 421 females) adolescent subjects aged 14-19 years selected randomly from New Delhi, India. Cutoff points of fasting insulin were defined using Receiver Operating Characteristics curve analysis against overweight, abdominal obesity and high subscapular skinfold thickness. The MS was defined according to NCEP, ATP III and IDF criteria using age-, gender- and ethnicity-specific cutoff points. RESULTS: Fasting insulin levels peaked at 16 y and reduced subsequently in both genders. The derived cutoff points for fasting insulin (pmol/L) were: 14-15 y- 128.5 and 164.8; 16-17 y- 126.1 and 152.8; 18-19 y- 121.2 and 162.4 in males and females, respectively. Prevalence of fasting hyperinsulinemia (39.1%) and MS (NCEP 2.2%, IDF 1.5%) was highest in age group 16-17 years. CONCLUSION: The data from this first study describing the distribution and cutoff points of fasting insulin in Asian Indian adolescents may be helpful for detection of and application of primary prevention strategies for fasting hyperinsulinemia and the metabolic syndrome in this population.

Peripheral vascular disease in systemic lupus erythematosus.

With increasing longevity of lupus patients, peripheral vascular disease (PVD) has become an important cause of morbidity. With no systematic study of PVD in systemic lupus erythematosus (SLE), this study was undertaken to define the frequency and spectrum of PVD in SLE and factors affecting such an occurrence. All medium-sized peripheral arteries of bilateral upper and lower extremities were studied in 50 SLE patients using Doppler ultrasonography. PVD was defined clinically as one or more of intermittent claudication, absent/unequal pulses, gangrene or ischemic ulcers and sub-clinically as asymptomatic patients with Doppler abnormalities, with > or =50% reduction in diameter considered hemodynamically significant. Mean (SD) age of the patients was 31.6 (10.1) years. Forty-one percent were hypertensive. Dyslipidemia was found in 62%. Fifteen (30%) had Raynaud's phenomenon. Fourteen (28%) patients had PVD, of whom three had positive markers for antiphospholipid antibody (aPL) and six were asymptomatic. Ischemic ulcers were seen in eight (16%), gangrene in three (6%), femoral artery plaques in two (4%), stenosis in four (8%) and intermittent claudication in none. Dyslipidemia was found to independently affect occurrence of PVD (OR = 5.37, [95% CI 1.05-27.5], P = 0.05). The causes of PVD overlap significantly and further studies are needed to ascertain the relative contribution of each.

Atherosclerosis in Asian Indians with systemic lupus erythematosus.

OBJECTIVES: Atherosclerosis has emerged as an important late complication of systemic lupus erythematosus (SLE). Asian Indians, as an ethnic group, are known to be metabolically predisposed to development of early atherosclerosis. No data on this aspect of SLE are available from Asia. This study was undertaken to find the frequency of atherosclerosis in Indian lupus patients and the factors affecting such an occurrence. METHODS: Carotid artery intimo-medial thickness (IMT) and plaque were used as markers of atherosclerosis. High-resolution B-mode ultrasonography was used to compare carotid IMT and plaque in 50 patients with SLE and 50 age- and sex-matched healthy controls. RESULTS: Patients with lupus (age 31.6+/-10.05, median 30.5 years; disease duration 52.3+/-36.7, median 46 months) exhibited a significantly greater IMT than controls (0.417+/-0.07 vs. 0.362+/-00.07 mm; p = 0.003). Carotid plaques were seen in seven (14%) cases. None of the control population had plaques (p = 0.006). On bivariate analysis, the IMT was significantly affected by age, systolic blood pressure (SBP), disease duration and menopausal status. On multivariate analysis, the only factor significantly affecting IMT was SBP. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) score was the sole factor found to significantly affect the occurrence of plaque. CONCLUSIONS: Asian Indian lupus patients in our study, despite being relatively young and with shorter disease duration, exhibited premature atherosclerosis in the form of significantly thicker intimo-media and plaque. The factors found to affect accelerated atherosclerosis in our cohort were age, SBP, disease duration, postmenopausal status and the SLICC/ACR score.