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Lo N.C.,Rice University | Turner N.A.,Rice University | Cruz M.A.,Baylor College of Medicine | Cruz M.A.,Center for Translational Research in Inflammatory Diseases | Moake J.,Rice University
Journal of Biological Chemistry | Year: 2013

Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli causes diarrhea-associated hemolytic-uremic syndrome (DHUS), a severe renal thrombotic microangiopathy. We investigated the interaction between Stx and von Willebrand Factor (VWF), a multimeric plasma glycoprotein that mediates platelet adhesion, activation, and aggregation. Stx bound to ultra-large VWF (ULVWF) secreted from and anchored to stimulated human umbilical vein endothelial cells, as well as to immobilized VWF-rich human umbilical vein endothelial cell supernatant. This Stx binding was localized to the A1 and A2 domain of VWF monomeric subunits and reduced the rate of ADAMTS- 13-mediated cleavage of the Tyr1605- Met1606 peptide bond in the A2 domain. Stx-VWF interaction and the associated delay in ADAMTS-13-mediated cleavage of VWF may contribute to the pathophysiology of DHUS. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Kanwal F.,Center for Innovations in Quality | Kanwal F.,Baylor College of Medicine | Kramer J.R.,Center for Innovations in Quality | Kramer J.R.,Baylor College of Medicine | And 8 more authors.
Clinical Gastroenterology and Hepatology | Year: 2016

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the United States. However, few data are available on recent trends in the incidence and prevalence of NAFLD in the U.S. Methods: We analyzed the national Veterans Administration databases from 2003 to 2011 and calculated the age-adjusted prevalence and incidence of NAFLD for the overall sample of patients and by demographic subgroups. We used a previously validated algorithm to define NAFLD, which was based on persistent increases in levels of liver enzymes in the absence of positive results from tests for hepatitis C or hepatitis B or evidence of excessive alcohol use. Results: Of the 9,784,541 patients with at least 1 visit to the Veterans Administration between 2003 and 2011, 1,330,600 patients (13.6%) had NAFLD. The annual incidence rates of NAFLD remained stable (from 2.2% to 3.2%) during the study duration. The prevalence of NAFLD increased from 6.3% in 2003 (95% confidence interval, 6.26%-6.3%) to 17.6% in 2011 (95% confidence interval, 17.58%-17.65%), a 2.8-fold increase. The incidence and prevalence increased at significantly greater rates in patients younger than 45 years vs older patients. Conclusions: In a U.S. population, the annual incidence of NAFLD ranges from 2% to 3%. The prevalence of NAFLD more than doubled from 2003 through 2011; it is likely to continue to increase because of a steady overall incidence coupled with a rising incidence in younger individuals. © 2016 AGA Institute.

Mandava P.,Michael bakey Va Medical Center | Mandava P.,Baylor College of Medicine | Shah S.D.,Baylor College of Medicine | Sarma A.K.,Baylor College of Medicine | And 3 more authors.
Translational Stroke Research | Year: 2015

Most early phase trials in stroke and brain trauma have failed in phase 3, including efforts to improve acute ischemic stroke outcomes beyond that achieved by intravenous recombinant tissue plasminogen activator (t-PA) (IVT). With the exception of more recent stent retriever trials, most subsequent phase 3 trials failed. We previously showed that baseline imbalances, non-linear relationships of these factors to outcome, and unrepresentative control populations invalidate traditional statistical analysis in early trials of heterogeneous diseases such as stroke. We developed an alternative approach using a pooled outcome model derived from control arms of randomized clinical trial (RCTs). This model then permits comparing treatment trials to an expected outcome of a pooled population. Here, we hypothesized we could develop such a model for IVT and tested it against outcomes without IVT. We surveyed literature for all trials involving one arm with IVT reporting baseline National Institute Stroke Scale (NIHSS), age, and outcome. A non-linear fit was performed including multi-dimensional statistical intervals (±95 %) permitting visual comparison of outcomes at their own baselines. We compared models derived from non-IVT control arms. Models from 24 IVT RCTs representing 3195 subjects were successfully generated for functional outcome, modified Rankin Scale (mRS) 0–2 (r2 = 0. 83, p < 0.001), and mortality (r2 = 0.54; p = 0.001). We confirmed better outcomes compared to no IVT and mixed use IVT models across the range of baseline factors. It was possible to generate an expected outcome model for IVT from existing literature. We confirmed benefit compared to placebo. This model should be useful to compare to new agents without the need for statistical manipulation. © 2015, Springer Science+Business Media New York (Outside the USA).

Samuel E.L.G.,Rice University | Duong M.T.,Rice University | Bitner B.R.,Baylor College of Medicine | Marcano D.C.,Rice University | And 4 more authors.
Trends in Biotechnology | Year: 2014

Oxidative stress reflects an excessive accumulation of reactive oxygen species (ROS) and is a hallmark of several acute and chronic human pathologies. Although many antioxidants have been investigated, most have demonstrated poor efficacy in clinical trials. Here we discuss the limitations of current antioxidants and describe a new class of nanoparticle antioxidants, poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs). PEG-HCCs show high capacity to annihilate ROS such as superoxide (O2•-) and the hydroxyl (HO•) radical, show no reactivity toward the nitric oxide radical (NO•), and can be functionalized with targeting moieties without loss of activity. Given these properties, we propose that PEG-HCCs offer an exciting new area of study for the treatment of numerous ROS-induced human pathologies. © 2014.

Samuel E.L.G.,Rice University | Marcano D.C.,Rice University | Berka V.,University of Houston | Wu G.,University of Houston | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Many diseases are associated with oxidative stress, which occurs when the production of reactive oxygen species (ROS) overwhelms the scavenging ability of an organism. Here, we evaluated the carbon nanoparticle antioxidant properties of poly(ethylene glycolated) hydrophilic carbon clusters (PEG-HCCs) by electron paramagnetic resonance (EPR) spectroscopy, oxygen electrode, and spectrophotometric assays. These carbon nanoparticles have 1 equivalent of stable radical and showed superoxide (O2 •-) dismu-tase-like properties yet were inert to nitric oxide (NO•) as well as peroxynitrite (ONOO-). Thus, PEG-HCCs can act as selective antioxidants that do not require regeneration by enzymes. Our steadystate kinetic assay using KO2 and direct freeze-trap EPR to follow its decay removed the rate-limiting substrate provision, thus enabling determination of the remarkable intrinsic turnover numbers of O2 •-to O2 by PEG-HCCs at >20,000 s-1 . Themajor products of this catalytic turnover are O2 and H 2 O 2, making the PEG-HCCs a biomimetic superoxide dismutase.

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