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Galveston, TX, United States

Singal A.K.,University of Medical Branch | Fontana R.J.,University of Michigan
Alimentary Pharmacology and Therapeutics | Year: 2012

Background The optimal oral anti-viral agent to use in patients with decompensated HBV cirrhosis remains unclear. Aim We performed a meta-analysis of the oral nucleos(t)ide analogues in patients with decompensated HBV cirrhosis. Methods One year efficacy and safety outcomes in 22 studies published in English between95 and 2010 were analysed. Results Substantial heterogeneity was noted in the inclusion/exclusion criteria, controls, and sensitivity of the HBV DNA assay used. Pooled 1-year data showed benefit favouring lamivudine (LAM) vs. untreated controls for Child-Turcotte-Pugh (CTP) score improvement by ≥2 (OR: 117 (15 921), P ≤ 0.0001) and transplant-free survival (OR: 3.2 (1.2, 9), P = 0.022). Adefovir (ADV) led to undetectable HBV DNA at 1-year in 41% compared to 83% with LAM and 80% with entecavir (ETV). Overall, 1-year transplant-free survival rates varied from 78% with LAM to 95% and 94% with Tenofovir (TDF) and Telbivudine (TBV), respectively. The 1-year incidence of drug resistant HBV was 0% with ADV, ETV and TDF and 11% with LAM although TBV was associated with a 29% incidence at 2 years. Drug-related adverse events were infrequently reported. Conclusions All the oral anti-viral agents were associated with improved virological, biochemical and clinical parameters at 1-year. However, the efficacy of lamivudine and telbivudine is limited by drug resistance, and adefovir is limited by its potency and slower onset of action. Additional studies of tenofovir and entecavir are needed to determine the optimal agent(s) for treatment nave patients and in those with drug-resistant decompensated HBV cirrhosis. © 2012 Blackwell Publishing Ltd. Source

Gregory A.E.,University of Exeter | Judy B.M.,University of Medical Branch | Qazi O.,University of at Austin | Blumentritt C.A.,University of Texas Medical Branch | And 6 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2015

Burkholderia mallei are Gram-negative bacteria, responsible for the disease glanders. B. mallei has recently been classified as a Tier 1 agent owing to the fact that this bacterial species can be weaponised for aerosol release, has a high mortality rate and demonstrates multi-drug resistance. Furthermore, there is no licensed vaccine available against this pathogen. Lipopolysaccharide (LPS) has previously been identified as playing an important role in generating host protection against Burkholderia infection. In this study, we present gold nanoparticles (AuNPs) functionalised with a glycoconjugate vaccine against glanders. AuNPs were covalently coupled with one of three different protein carriers (TetHc, Hcp1 and FliC) followed by conjugation to LPS purified from a non-virulent clonal relative, B. thailandensis. Glycoconjugated LPS generated significantly higher antibody titres compared with LPS alone. Further, they improved protection against a lethal inhalation challenge of B. mallei in the murine model of infection. © 2015 Elsevier Inc. Source

Brooks N.C.,University of Medical Branch | Marshall A.H.,Sunnybrook Research Institute | Qa'aty N.,Sunnybrook Research Institute | Hiyama Y.,Sunnybrook Research Institute | And 4 more authors.
Molecular Medicine | Year: 2013

The first 24 h following burn injury is known as the ebb phase and is characterized by a depressed metabolic rate. While the postburn ebb phase has been well described, the molecular mechanisms underlying this response are poorly understood. The endoplasmic reticulum (ER) regulates metabolic rate by maintaining glucose homeostasis through the hepatic ER stress response. We have shown that burn injury leads to ER stress in the liver during the first 24 h following thermal injury. However, whether ER stress is linked to the metabolic responses during the ebb phase of burn injury is poorly understood. Here, we show in an animal model that burn induces activation of activating transcription factor 6 (ATF6) and inositol requiring enzyme-1 (IRE-1) and this leads to increased expression of spliced X-box binding protein-1 (XBP-1s) messenger ribonucleic acid (mRNA) during the ebb phase. This is associated with increased expression of XBP-1 target genes and downregulation of the key gluconeogenic enzyme glucose-6--phosphatase (G6Pase). We conclude that upregulation of the ER stress response after burn injury is linked to attenuated gluconeogenesis and sustained glucose tolerance in the postburn ebb phase. Source

Jampana S.C.,University of Medical Branch | Khan R.,University of Medical Branch
World Journal of Hepatology | Year: 2011

Inflammatory signaling and oxidative stress are two major components in the pathogenesis of alcoholic hepatitis. Alcohol consumption results in translocation of gut bacteria into the portal system along with lipopolysaccharides that interact with toll-like receptors and results in the production of inflammatory and immunogenic mediators such as tumor necrosis factor-alpha (TNF-α) and interferons. Chronic consumption of alcohol causes priming of this process in which there is enhanced production of cytokines, interferon, interleukins, and TNF-α. Oxidative stress, genetic predisposition, and the unfolded protein response are other contributory mechanisms. Novel therapies aimed at these pathways may prevent, decrease, or delay the complications of alcoholic hepatitis. © 2010 Baishideng. Source

Singal A.K.,Mayo Medical School | Guturu P.,University of Medical Branch | Hmoud B.,University of Medical Branch | Kuo Y.-F.,University of Medical Branch | And 2 more authors.
Transplantation | Year: 2013

Background. In the background of availability of better treatments for specific liver diseases and listing of nonalcoholic steatohepatitis (NASH) as an etiology for liver transplantation (LT), data are unclear on the impact of disease etiology on the frequency of LT and liver posttransplantation outcomes. Methods. The United Network for Organ Sharing database (1994-2009) was queried for adults receiving first LT for primary biliary cirrhosis (PBC; n=3052), primary sclerosing cholangitis (PSC; n=3854), hepatitis C virus (HCV; n=15,147), alcoholic cirrhosis (AC; n=8940), HCV+alcohol (n=6066), NASH (n=1368), cryptogenic cirrhosis (CC; n=5856), hepatitis B virus (HBV; n=1816), and hepatocellular carcinoma (HCC; n=8588). Graft and patient survival were compared and Cox models were built to determine independent prediction of outcomes by disease etiology. Results. The frequency of LT increased for NASH, HCC, and HCV+alcohol, remained stable for AC, and decreased for PBC, PSC, HCV, CC, and HBV. The proportion of simultaneous liver-kidney transplants increased from approximately 3% in 2001 to 10% in 2009. Compared with PBC, 5-year graft and patient survival were (a) similar for PSC, NASH, and HBV (80-85%), (b) poorer for AC and CC (hazard ratio, 1-1.5), and (c) worst for HCV, HCV+ alcohol, and HCC (hazard ratio, 1.5-2.4). Five-year outcomes for HCV-associated HCC were poorer compared with HCC due to other etiologies. Conclusions. LT performed for NASH and HCC are increasing. Potent treatment options resulted in a decrease in number of transplants for HBV, HCV, and PBC. Better treatment modalities for HCV are expected to further reduce the number of LT for HCV. Excellent posttransplantation outcomes for NASH and AC are encouraging, resulting in wider acceptance of transplants for these etiologies. Copyright © 2013 by Lippincott Williams & Wilkins. Source

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