PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

BACKGROUND: PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. OBJECTIVE: We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. METHODS: We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. RESULTS: There was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (ß=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. CONCLUSIONS AND CLINICAL RELEVANCE: The decrease in the FEV1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation.

Lung spirometry parameters and diffusion capacity are decreased in patients with Type 2 diabetes.

AIMS: In cohort studies, Type 2 diabetes mellitus has been associated with decreased forced 1 s expiratory volume and forced vital capacity. We examined if forced vital capacity, forced 1 s expiratory volume and diffusion lung capacity correlate with diabetes mellitus across different races in a clinical setting. METHODS: We examined the medical records of 19,882 adults 18-97 years of age in our centre from 1 January 2000 to 1 May 2009. After excluding patients with diseases causing abnormal lung function, 4164 subjects were available for analysis. We used multiple linear regressions to examine cross-sectional differences in forced vital capacity, forced 1 s expiratory volume and carbon monoxide diffusing capacity between patients with and without diabetes mellitus, after adjustment for age, sex, race, height, smoking, BMI and heart failure. RESULTS: Patients with diabetes (n = 560) were older (62 ± 12 vs. 55 ± 16 years), more likely to be men (56 vs. 43%), overweight (BMI 31.7 ± 8.5 vs. 27.3 ± 6.7 kg/m2 ), have heart failure (33 vs. 14%) and less likely to be Caucasians (65 vs. 76%) and never smokers (66 vs. 72%) compared with patients without diabetes (n = 3604). The mean unadjusted values in patients with diabetes vs. those without were: forced vital capacity 2.78 ± 0.91 vs. 3.19 ± 1.03 l; forced 1 s expiratory volume 2.17 ± 0.74 vs. 2.49 ± 0.0.83; and carbon monoxide diffusing capacity 16.67 ± 5.53 vs. 19.18 ± 6.72 ml(-1) min(-1) mmHg, all P < 0.0001. These differences remained significant after adjustment for covariates. After race stratification, only Caucasians with diabetes had a significant decrease in all lung function measures. CONCLUSIONS: Patients with diabetes have decreased lung function compared with those without diabetes. Caucasians with diabetes have more global lung function impairment compared with African-Americans and Hispanics.

A mechanism of benefit of soy genistein in asthma: inhibition of eosinophil p38-dependent leukotriene synthesis.

BACKGROUND: Dietary intake of the soy isoflavone genistein is associated with reduced severity of asthma, but the mechanisms responsible for this effect are unknown. OBJECTIVE: To determine whether genistein blocks eosinophil leukotriene C(4) (LTC(4)) synthesis and to evaluate the mechanism of this effect, and to assess the impact of a 4-week period of soy isoflavone dietary supplementation on indices of eosinophilic inflammation in asthma patients. METHODS: Human peripheral blood eosinophils were stimulated in the absence and presence of genistein, and LTC(4) synthesis was measured. 5-lipoxygenase (5-LO) nuclear membrane translocation was assessed by confocal immunofluorescence microscopy. Mitogen-activated protein (MAP) kinase activation was determined by immunoblot. Human subjects with mild-to-moderate persistent asthma and minimal or no soy intake were given a soy isoflavone supplement (100 mg/day) for 4 weeks. The fraction of exhaled nitric oxide (FE(NO)) and ex vivo eosinophil LTC(4) production were assessed before and after the soy isoflavone treatment period. RESULTS: Genistein inhibited eosinophil LTC(4) synthesis (IC(50) 80 nm), blocked phosphorylation of p38 MAP kinase and its downstream target MAPKAP-2, and reduced translocation of 5-LO to the nuclear membrane. In patients with asthma, following 4 weeks of dietary soy isoflavone supplementation, ex vivo eosinophil LTC(4) synthesis decreased by 33% (N=11, P=0.02) and FE(NO) decreased by 18% (N=13, P=0.03). CONCLUSION: At physiologically relevant concentrations, genistein inhibits eosinophil LTC(4) synthesis in vitro, probably by blocking p38- and MAPKAP-2-dependent activation of 5-LO. In asthma patients, dietary soy isoflavone supplementation reduces eosinophil LTC(4) synthesis and eosinophilic airway inflammation. These results support a potential role for soy isoflavones in the treatment of asthma.

Altered lipid profile, leptin, insulin, and anthropometry in offspring of South Asian immigrants in the United States.

South Asians who immigrate to the United States have a propensity toward insulin resistance, central obesity, and elevated total cholesterol:high-density lipoprotein (HDL) ratio. To evaluate whether these alterations are apparent at a younger age, we studied 32 offspring of South Asian immigrants and compared them with 29 of European descent between 18 to 30 years of age. American-born South Asian males had significantly higher total cholesterol, low-density lipoprotein (TC:LDL) ratios, triglycerides, and fasting insulin levels (13.9 +/- 7.1 and 10.0 +/- 5.5 microU/mL, P <.01) than their European counterparts. The South Asian females only had increased plasma insulin levels (15.3 +/- 8.8 and 10.0 +/- 5.1 microU/mL, P =.05). The entire South Asian group had higher truncal skinfold thickness (40.1 +/- 18.1 and 30.3 +/- 12.6 mm, P = <.05) and lower insulin-like growth factor binding protein (IGFBP)-1 levels (46.8 +/- 33.4 and 56.0 +/- 33.4 microg/L, P =.05). Plasma leptin levels were also significantly higher in both males (4.3 +/- 2.5 v 2.8 +/- 1.3 ng/mL, P =.0001) and females (20.5 +/- 10.3 v 10.3 +/- 6.3 ng/mL, P =.002) South Asian subjects. A significant correlation between plasma leptin and insulin, triglycerides, TC, and body mass index (BMI) was seen in the South Asian males. South Asians born in the United States show evidence for an altered metabolic profile in young adulthood. The relative contributions of inheritance and nutritional practices early in life to this alteration remain unclear.

Rapid diagnosis of typhoid fever.

A Reverse Passive Haemagglutination Test (RPHA) was designed for the detection of Salmonella typhi antigen and rapid diagnosis of typhoid fever. Two per cent fresh sheep RBC's were coated with 32 micrograms/ml of immunoglobulin. The minimal detectable level of the antigen was 1250 micrograms/ml. Cross reactions were observed with the samples of patients suffering from Salmonella paratyphi A and pseudomonas infections. The RPHA established was used for the detection of S. typhi antigen in culture broths from 100 patients with clinically suspected typhoid fever with culture and/or widal positive, 50 patients with septicemia caused by bacteria other than S. typhi and 50 normal, afebrile healthy controls. It was found that the sensitivity and specificity of this assay was 70% and 92% respectively.