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Goldfine A.B.,Joslin Diabetes Center | Goldfine A.B.,Brigham and Womens Hospital | Stewart Buck J.,Brigham and Womens Hospital | Stewart Buck J.,Emory University | And 8 more authors.
Diabetes Care | Year: 2013

Objective-To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D). Research design and methods-We conducted an ancillary study to the National Institutes of Health-sponsored, multicenter, randomized, double-masked, placebocontrolled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g/day or placebo. The primary end point was change in FMD at 6 months. Results-A total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg/m2), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol/mol; P < 0.001), fasting glucose by 16.1 mg/dL (P < 0.001), and white blood cell count by 430 cells/μL (P < 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI -0.86 to 2.25%]; P = 0.38) or NMD (-0.59% [95% CI -2.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg/dL higher, respectively, and urinary albumin was 2.0 μg/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P < 0.009). Conclusions-Salsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function. © 2013 by the American Diabetes Association. Source

Marshall L.,Touro College | Obaidullah M.,Touro College | Fuchs T.,Touro College | Fineberg N.S.,University of Alabama at Birmingham | And 4 more authors.
Immunogenetics | Year: 2014

CASPASE-12 (CASP12) has a downregulatory function during infection and thus may protect against inflammatory disease. We investigated the distribution of CASP12 alleles (#rs497116) in African-Americans (AA) with rheumatoid arthritis (RA). CASP12 alleles were genotyped in 953 RA patients and 342 controls. Statistical analyses comparing genotype groups were performed using Kruskal-Wallis non-parametric ANOVA with Mann-Whitney U tests and chi-square tests. There was no significant difference in the overall distribution of CASP12 genotypes within AA with RA, but CASP12 homozygous patients had lower baseline joint-narrowing scores. CASP12 homozygosity appears to be a subtle protective factor for some aspects of RA in AA patients. © 2014 Springer-Verlag Berlin Heidelberg. Source

Thiele G.M.,University of Nebraska Medical Center | Thiele G.M.,Omaha Veterans Administration Medical Center | Duryee M.J.,University of Nebraska Medical Center | Duryee M.J.,Omaha Veterans Administration Medical Center | And 9 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2010

Background and aims: Aldehydes that are produced following the breakdown of ethanol (acetaldehyde) and lipid peroxidation of membranes (malondialdehyde) have been shown to bind (adduct) proteins. Additionally, these two aldehydes can combine (MAA) on nonsyngeneic and syngeneic proteins to initiate numerous immune responses to the unmodified part of the protein in the absence of an adjuvant. Therefore, these studies provide a potential mechanism for the development of antigen-specific immune responses resulting in liver damage should syngeneic liver proteins be adducted with MAA. Methods: This study sought to test whether MAA-modified syngeneic liver cytosolic proteins administered daily in the absence of adjuvant into C57BL/6 mice abrogates tolerance to initiate a MAA-induced autoimmune-like hepatitis. Results: In mice immunized with MAA-modified cytosols, there was an increase in liver damage as assessed by aspartate aminotransferase/alanine aminotransferase levels that correlated with liver pathology scores and the presence of the pro-fibrotic factors, smooth muscle actin, TGF-β, and collagen. IgG antibodies and T-cell proliferative responses specific for cytosolic proteins were also detected. Pro-inflammatory cytokines were produced in the livers of animals exposed to MAA-modified cytosols. Finally, transfer of immunized T cells to naïve animals caused biochemical and histological evidence of liver damage. Conclusions: These data demonstrate that a disease with an autoimmune-like pathophysiology can be generated in this animal model using soluble MAA-modified syngeneic liver cytosols as the immunogen. These studies provide insight into potential mechanism(s) that the metabolites of alcohol may play in contributing to the onset of an autoimmune-like disease in patients with alcoholic liver disease. © 2010 by the Research Society on Alcoholism. No claim to original U.S. government works. Source

Harting J.R.,Omaha Veterans Administration Medical Center | Harting J.R.,University of Nebraska Medical Center | Gleason A.,Omaha Veterans Administration Medical Center | Gleason A.,University of Nebraska Medical Center | And 7 more authors.
Journal of Toxicology and Environmental Health - Part A: Current Issues | Year: 2012

Chronic obstructive pulmonary disease (COPD) is characterized by an airway and systemic inflammatory response. Bioaerosols/organic dusts are important agricultural pollutants that may lead to COPD. These environments are complex, containing a rich source of various microbial components. The objective of this study was to determine whether individuals with COPD have enhanced systemic responsiveness to settled swine facility organic dust extract (ODE) or its main pathogenic components (peptidoglycan [PGN], lipopolysaccharide [LPS]) versus healthy volunteers. A modified whole blood assay (WBA) that included occupational levels of ODE and concentrations of LPS and PGN found in ODE was used to determine systemic responsiveness (mediator release), and sputum inflammatory markers were measured to explore for systemic and airway associations. Sputum samples were evaluated for cell counts, and tumor necrosis factor (TNF)-, interleukin (IL)-8/CXCL8, IL-6, and IL-10. Ex vivo whole blood stimulation with ODE, LPS, and PGN each resulted in significant mediator release in all subjects, with the highest occurring with ODE; PGN resulted in significantly enhanced TNF- and IL-8 as compared to LPS. COPD subjects demonstrated greater systemic responsiveness using the modified WBA versus healthy controls. Within COPD subjects, blood baseline TNF-, IL-8, and IL-10 and ODE-, PGN-, and LPS-stimulated IL-8 levels significantly correlated with lung function. In conclusion, dust-induced mediator release was robust, and PGN, in part, resembled dust-induced mediator release. Subjects with COPD demonstrated increased mediator release following ex vivo whole blood stimulation with bioaerosol components, suggesting that circulating blood cells in COPD subjects may be primed to respond greater to microbial/inflammatory insult. © 2012 Copyright Taylor and Francis Group, LLC. Source

Poole J.A.,Omaha Veterans Administration Medical Center | Poole J.A.,University of Nebraska Medical Center | Dooley G.P.,Colorado State University | Saito R.,Colorado State University | And 7 more authors.
Journal of Toxicology and Environmental Health - Part A: Current Issues | Year: 2010

In agricultural and other environments, inhalation of airborne microorganisms is linked to respiratory disease development. Bacterial endotoxins, peptidoglycans, and fungi are potential causative agents, but relative microbial characterization and inflammatory comparisons amongst agricultural dusts are not well described. The aim of this study was to determine the distribution of microbial endotoxin, 3-hydroxy fatty acids (3-OHFA), muramic acid, and ergosterol and evaluate inflammatory responses in human monocytes and bronchial epithelial cells with various dust samples. Settled surface dust was obtained from five environments: swine facility, dairy barn, grain elevator, domestic home (no pets), and domestic home with dog. Endotoxin concentration was determined by recombinant factor C (rFC). 3-OHFA, muramic acid, and ergosterol were measured using gas chromatography-mass spectrometry. Dust-induced inflammatory cytokine secretion in human monocytes and bronchial epithelial cells was evaluated. Endotoxin-independent dust-induced inflammatory responses were evaluated. Endotoxin and 3-OHFA levels were highest in agricultural dusts. Muramic acid, endotoxin, 3-OHFA, and ergosterol were detected in dusts samples. Muramic acid was highest in animal farming dusts. Ergosterol was most significant in grain elevator dust. Agricultural dusts induced monocyte tumor necrosis factor (TNF)α , interleukin (IL)-6, IL-8, and epithelial cell IL-6 and IL-8 secretion. Monocyte and epithelial IL-6 and IL-8 secretion was not dependent on endotoxin. House dust(s) induced monocyte TNFα, IL-6, and IL-8 secretion. Swine facility dust generally produced elevated responses compared to other dusts. Agricultural dusts are complex with significant microbial component contribution. Large animal farming dust(s)-induced inflammation is not entirely dependent on endotoxin. Addition of muramic acid to endotoxin in large animal farming environment monitoring is warranted. Copyright © Taylor & Francis Group, LLC. Source

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