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Noureddin M.,University of California at San Diego | Yates K.P.,Johns Hopkins University | Vaughn I.A.,Johns Hopkins University | Neuschwander-Tetri B.A.,Washington University in St. Louis | And 8 more authors.
Hepatology | Year: 2013

The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P=0.02), and advanced fibrosis (25% versus 44%, P=0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P=0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P≤0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR]=1.12, P=0.007) and lower platelets (OR=0.98, P=0.02); and independent determinants of advanced fibrosis included higher AST (OR=1.08, P=0.007), lower alanine aminotransferase value (OR=0.91, P=0.002), and an increased odds of having low high-density lipoprotein (OR=8.35, P=0.02). Conclusion: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. © 2013 by the American Association for the Study of Liver Diseases.


Chiang C.,Illinois Institute of Technology | Karuri S.W.,National Cancer Institutes | Kshatriya P.P.,Illinois Institute of Technology | Schwartz J.,Princeton University | And 2 more authors.
Langmuir | Year: 2012

We report a robust strategy for conjugating mixtures of two or more protein domains to nonfouling polyurethane surfaces. In our strategy, the carbamate groups of polyurethane are reacted with zirconium alkoxide from the vapor phase to give a surface-bound oxide that serves as a chemical layer that can be used to bond organics to the polymer substrate. A hydroxyalkylphosphonate monolayer was synthesized on this layer, which was then used to covalently bind primary amine groups in protein domains using chloroformate-derived cross-linking. The effectiveness of this synthesis strategy was gauged by using an ELISA to measure competitive, covalent bonding of cell-binding (III 9-10) and fibronectin-binding (III 1-2) domains of the cell adhesion protein fibronectin. Cell adhesion, spreading, and fibronectin matrix assembly were examined on surfaces conjugated with single domains, a 1:1 surface mixture of III 1-2 and III 9-10, and a recombinant protein "duplex" containing both domains in one fusion protein. The mixture performed as well as or better than the other surfaces in these assays. Our surface activation strategy is amenable to a wide range of polymer substrates and free amino group-containing protein fragments. As such, this technique may be used to create biologically specific materials through the immobilization of specific protein groups or mixtures thereof on a substrate surface. © 2011 American Chemical Society.


Goubran H.A.,Cairo University | Sholkamy S.,Ain Shams University | El-Haddad A.,National Cancer Institutes | Mahmoud A.,Cairo University | And 2 more authors.
Thrombosis Journal | Year: 2012

Background: Venous thromboembolism (VTE) is a leading cause of hospital-related deaths worldwide. However, the proportion of patients at risk of VTE who receive appropriate prophylaxis in Egypt is unknown. The ENDORSE study in Egypt is part of a global initiative to uncover the incidence of high-risk surgical and medical patients and determine what proportion of these patients receive appropriate VTE prophylaxis.Methods: Ten Egyptian hospitals participated in this observational study, enrolling all surgical and medical patients that met the study criteria. This resulted in a cohort of 1,008 patients in acute care facilities who underwent a retrospective chart review. Each patient's VTE risk status and the presence or absence of appropriate prophylactic care was assessed according to the American College of Chest Physicians (ACCP) guidelines 2004.Results: Of the 1,008 patients enrolled, 395 (39.2%) were found to be at high-risk for VTE. Overall, 227 surgical patients were at high-risk, although only 80 (35.2%) received ACCP-recommended prophylaxis. Similarly, 55/268 (32.75%) of high-risk medical patients received appropriate VTE prophylaxis. Low molecular weight heparin was the most commonly used anticoagulant, while mechanical prophylactic use was quite low (1.5%) in high-risk patients.Conclusions: In Egypt, more than one-third of all patients hospitalized for surgery or acute medical conditions are at high risk for developing VTE. However, only a small fraction of these patients receive appropriate VTE prophylaxis. Corrective measures are necessary for preventing VTE morbidity and mortality in these high risk patients. © 2012 Goubran et al.; licensee BioMed Central Ltd.


Boutte A.M.,Vanderbilt University | Friedman D.B.,Vanderbilt University | Bogyo M.,Stanford University | Min Y.,National Cancer Institutes | And 2 more authors.
FASEB Journal | Year: 2011

Myeloid-derived suppressor cells (MDSCs) are significantly increased in cancer patients and tumor bearing-animals. MDSCs infiltrate into tumors and promote tumor invasion and metastasis. To identify the mediator responsible for the prometastatic property of MDSCs, we used proteomics. We found neutrophilic granule protein (NGP) was decreased >2-fold in MDSCs from metastatic 4T1 tumor-bearing Mice compared to nonmetastatic 67NR Controls. NGP mRNA levels were decreased in bone marrow and in tumor-infiltrating MDSCs by 45 and 66%, respectively, in 4T1 tumor-bearing mice compared to 67NR controls. Interestingly, 4T1-conditioned medium reduced myeloid cell NGP expression by ~40%, suggesting that a secreted factor mediates gene reduction. Sequence analysis shows a putative cystatin domain in NGP, and biochemical analysis confirms NGP a novel cathepsin inhibitor. It inhibited cathepsin B activity by nearly 40% in vitro. NGP expression in 4T1 tumor cells suppressed cell invasion, delayed primary tumor growth, and greatly reduced lung metastasis in vivo. A 2.8-fold reduction of cathepsin activity was found in tumors expressing NGP compared to controls. NGP significantly reduced tumor angiogenesis to 12.6 from 19.6 and lymphangiogenesis to 4.6 from 9.1 vessels/field. Necrosis was detectable only in NGP-expressing tumors, and the number of apoptotic cells increased to 22.4 from 8.3 in controls. Taken together, this study identifies a negative regulator of tumor metastasis in MDSCs, NGP, which is down-regulated in metastatic conditions. The finding suggests that malignant tumors promote invasion/metastasis not only through up-regulation of proteases but also down-regulation of protease inhibitors. © FASEB.


Kshatriya P.P.,Illinois Institute of Technology | Karuri S.W.,National Cancer Institutes | Chiang C.,Illinois Institute of Technology | Karuri N.W.,Illinois Institute of Technology
Biotechnology Progress | Year: 2012

Fibrillar fibronectin (FN) has the crucial role of attracting and attaching cells as well as molecules that mediate tissue repair during wound healing. A previous study demonstrated higher extracellular staining of FN fibrils in cells cultured on surfaces tethered with an equimolar mixture of a FN binding domain and FN's cell binding domain, III 1-2 and III 9-10 respectively, than on surfaces with III 9-10 alone. The effect of varying surface amounts of III 1-2 and III 9-10 on the quantity of FN fibrils formed by NIH-3T3 fibroblasts was examined. GST tagged III 1-2 and III 9-10 were conjugated to polyurethane surfaces and ELISAs were used to identify the experimental design space or the range of concentrations of GST-III 1-2 and GST-III 9-10 that demarcated the limits of protein loading on the surface. When GST-III 1-2 was fixed and GST-III 9-10 varied within the design space, the amount of FN fibrils measured by immunoblotting detergent insoluble cell lysates was dependent on the ratio of III 9-10 to III 1-2. When the total protein concentration was fixed and the mixture composition of GST-III 1-2 and GST-III 9-10 varied such that it optimally covered the design space, a parabolic relationship between FN fibril amount and the ratio of III 9-10 to III 1-2 was obtained. This relationship had a maximum value when the surface was bonded to equal amounts of III 1-2 and III 9-10 (P < 0.05). Thus the ratio of III 9-10 to III 1-2 can be utilized to direct the quantity of FN fibrils formed on surfaces. © 2012 American Institute of Chemical Engineers (AIChE).

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