Inhalation of 70 ppb O(3) for 6.6 hours, a concentration below the current 8-hour National Ambient Air Quality Standard of 75 ppb, is sufficient to induce statistically significant decrements in FEV(1) in healthy young adults.

Background: Paraoxonase 1 (PON1) phenotype is a better predictor of atherosclerosis risk than are PON1 genetic polymorphisms alone. Larger studies are required to determine the role of PON1 and there is a need for standardized PON1 assays between laboratories. Methods: We have adapted 5 enzyme kinetic assays for high-throughput automated analysis of PON1 activity. Using different substrates and reaction conditions, we measured PON1 activity and used activity ratios to identify the PON1 Q192R genetic polymorphisms and assessed the accuracy of the genotype assignments in 79 adult study participants by comparing them with genotypes determined by AlwI restriction enzyme digestion of a 176-bp PCR amplification product from genomic DNA. Imprecision was determined using pooled serum and purified enzyme preparations. Biological variability was estimated by analysis of serial samples from 17 individuals. Variability parameters were compared with total cholesterol as a point of reference to a recognized biomarker of coronary heart disease risk. Results: Salt stimulation and inhibition ratios were 97.4% and 94.7% correct in assigning Q192R genotype, respectively. Analytical imprecision (CV) was 1.0%-3.0% for phenylacetate and paraoxon substrate assays and 3.0%-8.0% for the para-nitrophenylacetate substrate assays. Combination of the 2 ratios into a double ratio resulted in 100% correct genotype classification.

OBJECTIVEThe purposes of this study were to investigate whether reduced lung function is associated with metabolic syndrome (MS) and diabetes (DM) in American Indians (AIs) and to determine whether lower pulmonary function presents before the development of DM or MS.RESEARCH DESIGN AND METHODSThe Strong Heart Study (SHS) is a multicenter, prospective study of cardiovascular disease (CVD) and its risk factors among AI adults. The present analysis used lung function assessment by standard spirometry at the SHS second examination (1993–1995) in 2,396 adults free of overt lung disease or CVD, with or without DM or MS. Among MS-free/DM-free participants, the development of MS/DM at the SHS third examination (1996–1999) was investigated.RESULTSSignificantly lower pulmonary function was observed for AIs with MS or DM. Impaired pulmonary function was associated with MS and DM after adjustment for age, sex, abdominal obesity, current smoking status, physical activity index, hypertension, and SHS field center. Both forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were negatively associated with insulin resistance or DM severity and with serum markers of inflammation (P < 0.05). FVC and FEV1-to-FVC ratio both predicted DM in unadjusted analyses but not when adjusted for covariates, including waist circumference. In the adjusted model, abdominal obesity predicted both MS and DM.CONCLUSIONSReduced lung function is independently associated with MS and with DM, and impaired lung function presents before the development of MS or DM; these associations may result from the effects of obesity and inflammation.

Bone marrow-derived mesenchymal stem cells (MSCs) are being explored for clinical applications, and genetic engineering represents a useful strategy for boosting the therapeutic potency of MSCs. Vascular endothelial growth factor (VEGF)-based gene therapy protocols have been used to treat tissue ischemia, and a combined VEGF/MSC therapeutics is appealing due to their synergistic paracrine actions. However, multiple VEGF splice variants exhibit differences in their mitogenicity, chemotactic efficacy, receptor interaction, and tissue distribution, and the differential regulatory effects of multiple VEGF isoforms on the function of MSCs have not been characterized. We expressed three rat VEGF-A splice variants VEGF120, 164, and 188 in MSCs using adenoviral vectors, and analyzed their effects on MSC proliferation, differentiation, survival, and trophic factor production. The three VEGF splice variants exert common and differential effects on MSCs. All three expressed VEGFs are potent in promoting MSC proliferation. VEGF120 and 188 are more effective in amplifying expression of multiple growth factor and cytokine genes. VEGF164 on the other hand is more potent in promoting expression of genes associated with MSC remodeling and endothelial differentiation. The longer isoform VEGF188, which is preferentially retained by proteoglycans, facilitates bone morphogenetic protein-7 (BMP7)-mediated MSC osteogenesis. Under serum starvation condition, virally expressed VEGF188 preferentially enhances serum withdrawal-mediated cell death involving nitric oxide production. This work indicates that seeking the best possible match of an optimal VEGF isoform to a given disease setting can generate maximum therapeutic benefits and minimize unwanted side effects in combined stem cell and gene therapy.

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