Medicine and Health Sciences Commons^™

Interferon Alpha For Chronic Hepatitis D, Zaigham Abbas, Muhammad Arsalan Khan, Mohammad Salih, Wasim Jafri

Department of Medicine

Background:

Hepatitis D virus is a small defective RNA virus that requires the presence of hepatitis B virus infection to infect a person. Hepatitis D is a difficult-to-treat infection. Several clinical trials have been published on the efficacy of interferon alpha for hepatitis D virus (HDV) infection. However, there are few randomised trials evaluating the effects of interferon alpha, and it is difficult to judge any benefit of this intervention from the individual trials.

Objectives:

To evaluate the beneficial and harmful effects of interferon alpha for Patients with chronic hepatitis D.

Search methods:

We identified relevant for the review randomised …

Disparate Degrees Of Hypervariable Loop Flexibility Control T Cell Receptor Cross-Reactivity, Specificity, And Binding Mechanism, Daniel R. Scott, Oleg Y. Borbulevych, Kurt H. Piepenbrink, Steven A. Corcelli, Brian M. Baker

Food for Health: Publications

αβ T cell receptors recognize multiple antigenic peptides bound and presented by major histocompatibility complex molecules. TCR cross-reactivity has been attributed in part to flexibility of the complementarity-determining region loops, yet there have been limited direct studies of loop dynamics to determine the extent of its role. Here we studied the flexibility of the binding loops of the αβ TCR A6 utilizing crystallographic, spectroscopic, and computational methods. A significant role for flexibility in binding and cross-reactivity was indicated only for the CDR3α and CDR3β hypervariable loops. Examination of the energy landscapes of these two loops indicated that CDR3β possesses a …

Haemobilia: A Rare Cause Of Gastrointestinal Bleeding, L. Kamani, S. M. Faisal Mosharraf, Tanveer-Ul-Haq, Hasnain Ali Shah

Section of Gastroenterology

Iatrogenic injury to hepatic duct leading to pseudoaneurysm and haemobilia can occur following laparoscopic cholecystectomy. We report a case of a 60 years old man presenting with haematemesis found to have pseudoaneurysm of accessory hepatic artery 4 months after laparoscopic cholecystectomy. Diagnosis was made by computed tomography (CT) scan followed by celiac and mesenteric artery angiogram. The bleeding was successfully treated with coil embolization.

Autoimmune Enteropathy With A Cd8+ Cd7- T-Cell Small Bowel Intraepithelial Lymphocytosis: Case Report And Literature Review, Shrinivas Bishu, Violeta Arsenescu, Eun Y. Lee, H. David Vargas, Willem J. S. De Villiers, Razvan Arsenescu

Surgery Faculty Publications

Background

Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, …

Efficacy Of L-Ornithine-L-Aspartate As An Adjuvant Therapy In Cirrhotic Patients With Hepatic Encephalopathy, Shahab Abid, Wasim Jafri, Khalid Mumtaz, Muhammad Islam, Zaigham Abbas, Hasnain Ali Shah, Saeed Hamid

Section of Gastroenterology

OBJECTIVE: To evaluate the efficacy of L-ornithine-L-aspartate (LOLA) as an adjuvant therapy in cirrhotic patients with hepatic encephalopathy (HE).

STUDY DESIGN: Randomized placebo controlled study.

PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi in the year 2003-2004.

METHODOLOGY: Patients with HE were randomized to receive LOLA or placebo medicine as an adjuvant to treatment of HE. Number connection test-A (NCT-A), ammonia level, clinical grade of HE and duration of hospitalization were assessed.

RESULTS: Out of 120 patients, there were 62 males with mean age of 57 11 years. Improvement in HE was higher (n=40, 66.7%) in LOLA …

Small Intestinal Bacterial Overgrowth And Lactose Intolerance Contribute To Irritable Bowel Syndrome Symptomatology In Pakistan, Javed Yakoob, Zaigham Abbas, Rustam Khan, Saeed Hamid, Safia Awan, Wasim Jafri

Department of Medicine

Background /Aim: The symptoms of irritable bowel syndrome resemble those of small intestinal bacterial overgrowth (SIBO). The aim of this study was to determine the frequency of SIBO and lactose intolerance (LI) occurrence in Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) according to Rome III criteria.

PatientS and Methods: In this retrospective case-control study, Patients over 18 years of age with altered bowel habit, bloating, and Patients who had lactose Hydrogen breath test (H 2 BT) done were included. The "cases" were defined as Patients who fulfill Rome III criteria for IBS-D, while "controls" were those having chronic nonspecific diarrhea …

Proliferation Of Acid-Secretory Cells In The Kidney During Adaptive Remodelling Of The Collecting Duct, Desa Welsh-Bacic, Marta Nowik, Brigitte Kaissling, Carsten A. Wagner

Desa Welsh

The renal collecting duct adapts to changes in acid-base metabolism by remodelling and altering the relative number of acid or alkali secreting cells, a phenomenon termed plasticity. Acid secretory A intercalated cells (A-IC) express apical H+-ATPases and basolateral bicarbonate exchanger AE1 whereas bicarbonate secretory B intercalated cells (B-IC) express basolateral (and apical) H+-ATPases and the apical bicarbonate exchanger pendrin. Intercalated cells were thought to be terminally differentiated and unable to proliferate. However, a recent report in mouse kidney suggested that intercalated cells may proliferate and that this process is in part dependent on GDF-15. Here we extend these observations to …

Mast Cell Activation And Clinical Outcome In Pediatric Cholelithiasis And Biliary Dyskinesia., Craig A. Friesen, Nancy Neilan, James F. Daniel, Kim Radford, Jennifer Verrill Schurman, Ding-You Li, Linda Andre, Shawn D. St Peter, G W. Holcomb Iii

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The current study was undertaken to determine the degree of activation of gallbladder mucosal mast cells, whether mast cell (MC) density or activation differ between patients with and without a positive clinical response to cholecystectomy, and whether either density or activation correlate with gallbladder emptying.

RESULTS: Fifteen biliary dyskinesia (BD) and 13 symptomatic cholelithiasis (CL) patients undergoing cholecystectomy were prospectively enrolled. Gallbladder wall MC density (by immunohistochemistry) and activation (by electron microscopy) were determined. Clinical response was evaluated 30 days post-cholecystectomy on a 5-point Likert-type scale. A complete or nearly complete clinical response was seen in 100% of CL …

Deletion Of Rb Accelerates Pancreatic Carcinogenesis By Oncogenic Kras And Impairs Senescence In Pre-Malignant Lesions, Catherine Carrière, A. Jesse Gore, Alixanna M. Norris, Jason R. Gunn, Alison Young, Daniel Longnecker, Murray Korc

Dartmouth Scholarship

Rb1 encodes a cell-cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of retinoblastoma (RB). To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras.We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis.

45 25 Gram Versus 50 Gram Of 25% Albumin In Preventing Renal Impairment After Large Volume Paracentesis In Cirrhosis.Khali, A. B. Khalid, Mumtaz J Khan, A Ghufran, Syed H Shah, Saeed Hamid, Wasim Jafri

Section of Gastroenterology

No abstract provided.

Early Complications After Biliary Enteric Anastomosis For Benign Diseases: A Retrospective Analysis, Syed Nabeel Zafar, M. R. Khan, Rushna Raza, Muhammad N. Khan, Mahwash Kasi, Ammar Rafiq, Omer H. Jamy

Department of Surgery

Background:Biliary-enteric anastomosis (BEA) is a common surgical procedure performed for the management of biliary obstruction or leakage that results from a variety of benign and malignant diseases. Complications following BEA are not rare. We aimed to determine the incidence and the factors associated with early complications occurring after BEA for benign diseases.

Methods:

We reviewed the medical records of all Patients who underwent BEA for benign diseases at our institution between January 1988 and December 2009. The primary outcome was early post operative complication. Logistic regression analysis was done to identify factors predicting the occurrence of complications.

Results:

Records …

A Conserved Tissue-Specific Homeodomain-Less Isoform Of Meis1 Is Downregulated In Colorectal Cancer., Richard C Crist, Jacquelyn J Roth, Scott A Waldman, Arthur M Buchberg

Department of Microbiology and Immunology Faculty Papers

Colorectal cancer is one of the most common cancers in developed nations and is the result of both environmental and genetic factors. Many of the genetic lesions observed in colorectal cancer alter expression of homeobox genes, which encode homeodomain transcription factors. The MEIS1 homeobox gene is known to be involved in several hematological malignancies and solid tumors and recent evidence suggests that expression of the MEIS1 transcript is altered in colorectal cancer. Despite this potential connection, little is known about the role of the gene in the intestines. We probed murine gastrointestinal tissue samples with an N-terminal Meis1 antibody, revealing …

Measures Of Socio-Demographic Factors For Child, Javed Yakoob, Safia Awan

Section of Gastroenterology

No abstract provided.

Assessment Of Adherence To Guidelines For Hepatocellular Carcinoma Screening In Hiv/Hcv Coinfected Patients, Jonathan M. Fenkel, Md, Victor J. Navarro, Md

Division of Gastroenterology and Hepatology Faculty Papers

Conclusions:

1. Self-reported adherence with published guidelines for HCC screening is poor among primary providers for HIV/HCV coinfected patients, including HIV specialists and University-based providers.

2. Unnecessary imaging is also frequently ordered on non-cirrhotics, particularly by University-based providers.

3. Improved adherence to guidelines is needed among primary providers as over 50% of HCC's may be missed, and many patients many not be referred for subspecialty GI or Liver care, where screening practices may differ.

In-Vivo Ct Dosimetry During Virtual Colonoscopy, Jonathon W. Mueller

Dissertations & Theses (Open Access)

Virtual colonoscopy (VC) is a minimally invasive means for identifying colorectal polyps and colorectal lesions by insufflating a patient’s bowel, applying contrast agent via rectal catheter, and performing multi-detector computed tomography (MDCT) scans. The technique is recommended for colonic health screening by the American Cancer Society but not funded by the Centers for Medicare and Medicaid Services (CMS) partially because of potential risks from radiation exposure. To date, no in‐vivo organ dose measurements have been performed for MDCT scans; thus, the accuracy of any current dose estimates is currently unknown.

In this study, two TLDs were affixed to the inner …

Role Of Prostaglandin E2 In The Regulation Of Pancreatic Stellate Cells Hyper Activity Associated With Pancreatic Cancer, Chantale Charo

Dissertations & Theses (Open Access)

Pancreatic cancer is one of the most lethal type of cancer due to its high metastasis rate and resistance to chemotherapy. Pancreatic fibrosis is a constant pathological feature of chronic pancreatitis and the hyperactive stroma associated with pancreatic cancer. Strong evidence supports an important role of cyclooxygenase-2 (COX-2) and COX-2 generated prostaglandin E2 (PGE2) during pancreatic fibrosis. Pancreatic stellate cells (PSC) are the predominant source of extracellular matrix production (ECM), thus being the key players in both diseases. Given this background, the primary objective is to delineate the role of PGE2 on human pancreatic stellate cells (PSC) hyper activation associated …

Primary Provider Beliefs And Practice Patterns Contribute To The Lack Of Hiv/Hcv Coinfected Patients Undergoing Liver Transplantation In The United States, Jonathan M. Fenkel, Md, Victor J. Navarro, Md

Division of Gastroenterology and Hepatology Faculty Papers

Conclusions:

1. The majority of primary providers were ambivalent toward or against LT for HIV/HCV coninfected patients.

2. Half of all respondents were unlikely to refer cirrhotic coinfected patients for LT evaluation.

3. HIV specialists were significantly more likely to believe transplant should be offered, but reported no difference in likelihood of LT referral.

4. These findings suggest that primary provider beliefs and self-reported practice patterns may partially explain the paucity of coinfected US liver transplant recipients.

Factors Predicting The Recurrence Of Spontaneous Bacterial Peritonitis In Patients With Cirrhosis, Sajjad Jamil, Shahid Ahmed, Adil Memon, Sara Masood, Syed H Shah, Saeed Sadiq Hamid, Wasim Jafri

Department of Medicine

Objective: To evaluate the frequency of recurrence of spontaneous bacterial peritonitis (SBP) in patients with end stage liver disease and the factors responsible for it.

Study Design: Descriptive study.

Place and Duration of Study: The Aga Khan University Hospital, Karachi, from November 2008 till November 2009.

Methodology: Patients with cirrhosis who were admitted at AKUH with diagnosis of SBP during the study period were included. Any episode of SBP after resolution of the first index case of SBP within one year was considered as recurrence.

Results: Out of 238 cirrhotic patients, 157 (66%) had single, while 81 (34%) had recurrent …

Virological And Clinical Characteristics Of Hepatitis Delta Virus In South Asia, Khalid Mumtaz, Umair S. Ahmed, Sadik Memon, Ali Khawaja, Muhammad T. Usmani, Tariq Moatter, Saeed Hamid, Wasim Jafri

Section of Gastroenterology

Background & Aims:There is a paucity of data on the impact of hepatitis D virus (HDV) in Patients with hepatitis B virus (HBV) infection from South Asia. We studied the impact of HDV co-infection on virological and clinical characteristics.

Methods: We collected data of 480 Patients with HBsAg positive and a detectable HBV DNA PCR, who presented to the Aga Khan University, Karachi and Isra University in Hyderabad, Pakistan in the last 5 years. HDV co-infection was diagnosed on the basis of anti-HDV. ALT, HBeAg, HBeAb and HBV DNA PCR quantitative levels were checked in all Patients. We divided …

Regular Post Dinner Walk; Can Be A Useful Lifestyle Modification For Gastroesophageal Reflux, Shahid Karim, Wasim Jafri, Afsheen Faryal, Shahid Majid, Mohammad Salih, Fatima Jafri, Saeed Hamid, Hasnain Ali Shah, Zohaib Nawaz, Usman Tariq

Section of Gastroenterology

OBJECTIVES: To evaluate the correlation of gastroesophageal reflux disease (GERD) symptoms with routine post dinner physical activity and time interval before going to bed, in multiethnic South Asian population.

METHODS: Prospective, cross sectional analytical, multicenter study was conducted from February 2009 to March 2010. Patient's relative sitting in outpatient clinics with no comorbids, nonsmoker and non alcoholic were included. They were asked to fill a validated GERD questionnaire and were also inquired about routine post dinner physical activity (lying, sitting, walking) and dinner-bed time interval. Odds Ratios (OR) and their 95% Confidence Intervals (CI) were estimated using Logistic Regression, with …

Identification And Engineering Of Human Variable Regions That Allow Expression Of Stable Single-Chain T Cell Receptors, David H. Aggen, Adam S. Chervin, Francis K. Insaidoo, Kurt H. Piepenbrink, Brian M. Baker, David M. Kranz

Food for Health: Publications

Single-chain antibody fragments (scFv), consisting of two linked variable regions (V_H and V_L), are a versatile format for engineering and as potential antigen-specific therapeutics. Although the analogous format for T cell receptors (TCRs), consisting of two linked V regions (Vα and Vβ; referred to here as scTv), could provide similar opportunities, all wild-type scTv proteins examined to date are unstable. This obstacle has prevented scTv fragments from being widely used for engineering or therapeutics. To further explore whether some stable human scTv fragments could be expressed, we used a yeast system in which display of properly folded …

Risk Factors Associated With Helicobacter Pylori Infection Treatment Failure In A High Prevalence Area., Javed Yakoob, Wasim Jafri, Z Abbas, Shahab Abid, S Naz, Khan R, A. B. Khalid

Section of Gastroenterology

Triple therapy is commonly used for the treatment of Helicobacter pylori infection. We determined risk factors associated with its failure in compliant patients focusing on H. pylori density, virulence marker and 23S ribosomal RNA (rRNA) point mutations associated with clarithromycin resistance. H. pylori infection was diagnosed by 14C urea breath test (14C UBT) and rapid urease test or histology. Triple therapy with esomeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d. and clarithromycin 500 mg b.i.d. was prescribed for 10 days. 14C UBT was repeated 4 weeks after treatment. In total, 111 patients [69 (62%) males] with a mean age of …

Alcohol And Hepatitis C Virus--Interactions In Immune Dysfunctions And Liver Damage, Gyongyi Szabo, Jack Wands, Ahment Eken, Natalia Osna, Steven Weinman, Keigo Machida, Joe Wang

Gyongyi Szabo

Hepatitis C virus infection affects 170 million people worldwide, and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis, and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV-infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding …

Factors That Determine The Development And Progression Of Gastroesophageal Varices In Patients With Chronic Hepatitis C, Robert Fontana, Arun Sanyal, Marc Ghany, William Lee, Andrea Reid, Deepa Naishadham, Gregory Everson, Jeffrey Kahn, Adrian Di Bisceglie, Gyongyi Szabo, Timothy Morgan, James Everhart

Gyongyi Szabo

BACKGROUND and AIMS: We aimed to identify the incidence and predictors of de novo gastroesophageal variceal formation and progression in a large cohort of patients with chronic hepatitis C and advanced fibrosis. METHODS: All participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial were offered an endoscopy before treatment and again after 4 years. Patients with varices at baseline also had an endoscopy at 2 years. Baseline laboratory and clinical parameters were analyzed as predictors of de novo variceal formation and variceal progression. RESULTS: De novo varices developed in 157 of the 598 (26.2%) patients. Most of the …

Type I Interferons Protect From Toll-Like Receptor 9-Associated Liver Injury And Regulate Il-1 Receptor Antagonist In Mice, Jan Petrasek, Angela Dolganiuc, Timea Csak, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Liver inflammation and injury are mediated by the innate immune response, which is regulated by Toll-like receptors (TLR). Activation of TLR9 induces type I interferons (IFNs) via the interferon regulatory factor (IRF)-7. We investigated the roles of type I IFNs in TLR9-associated liver injury. METHODS: Wild-type (WT), IRF7-deficient, and IFN-alpha/beta receptor 1 (IFNAR1)-deficient mice were stimulated with TLR9 or TLR2 ligands. Findings from mice were verified in cultured hepatocytes and liver mononuclear cells (LMNCs) as well as in vivo experiments using recombinant type I IFN and interleukin-1 receptor antagonist (IL-1ra). RESULTS: Type I IFNs were up-regulated during …

Deficiency In Myeloid Differentiation Factor-2 And Toll-Like Receptor 4 Expression Attenuates Non-Alcoholic Steatohepatitis And Fibrosis In Mice, Timea Csak, Arumugam Velayudham, Istvan Hritz, Jan Petrasek, Ivan Levin, Dora Lippai, Donna Catalano, Pranoti Mandrekar, Angela Dolganiuc, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Toll-like receptor 4 (TLR4), and its co-receptor, Myeloid Differentiation Factor 2 (MD-2), are key in recognition of lipopolysaccharide (LPS) and activation of pro-inflammatory pathways. Here we tested the hypothesis that TLR4 and its co-receptor MD-2 play a central role in non-alcoholic steatohepatitis (NASH) and liver fibrosis in non-alcoholic fatty liver disease. Mice of control genotypes and those deficient in MD-2 or TLR4 (knock-out, KO) received methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet. In mice of control genotypes MCD diet resulted in non-alcoholic steatohepatitis, liver triglycerides accumulation and increased Thiobarbituric Acid Reactive Substances (TBARS), a marker of lipid peroxidation, compared to MCS …

Interferon Regulatory Factor 3 And Type I Interferons Are Protective In Alcoholic Liver Injury In Mice By Way Of Crosstalk Of Parenchymal And Myeloid Cells, Jan Petrasek, Angela Dolganiuc, Timea Csak, Bharath Nath, Istvan Hritz, Karen Kodys, Donna Catalano, Evelyn Kurt-Jones, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

Alcoholic liver disease (ALD) features increased hepatic exposure to bacterial lipopolysaccharide (LPS). Toll-like receptor-4 (TLR4) recognizes LPS and activates signaling pathways depending on MyD88 or TRIF adaptors. We previously showed that MyD88 is dispensable in ALD. TLR4 induces Type I interferons (IFNs) in an MyD88-independent manner that involves interferon regulatory factor-3 (IRF3). We fed alcohol or control diets to wild-type (WT) and IRF3 knock-out (KO) mice, and to mice with selective IRF3 deficiency in liver parenchymal and bone marrow-derived cells. Whole-body IRF3-KO mice were protected from alcohol-induced liver injury, steatosis, and inflammation. In contrast to WT or bone marrow-specific IRF3-KO …

The 40th Anniversary Of The National Institute On Alcoholism And Alcohol Abuse: The Impact On Liver Disease, Gyongyi Szabo

Gyongyi Szabo

No abstract provided.

Innate Immunity And Alcoholic Liver Disease, Bin Gao, Ekihiro Seki, Jessica Cohen, Laura Nagy, Gyongyi Szabo, Samir Zakhari

Gyongyi Szabo

Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, while activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates …

Alcohol Exposure As A Risk Factor For Adverse Outcomes In Elective Surgery, Bharath Nath, Youfu Li, James Carroll, Gyongyi Szabo, Jennifer Tseng, Shimul Shah

Gyongyi Szabo

BACKGROUND AND AIMS: Alcohol consumption is a well-documented determinant of adverse perioperative outcome. We sought to determine the effect of active alcohol consumption following elective surgery. METHODS: We queried discharge records from the American College of Surgeons' National Surgical Quality Improvement Program (NSQIP, 2005-2007) for all elective adult admissions. The 7,631 (2.5%) patients with documented alcohol use (active alcohol use of at least two drinks per day within 2 weeks of surgery; ETOH use) underwent elective surgery; 301,994 (97.5%) patients denied ETOH use. Multivariate analysis was performed with adjustments for demographic and comorbid factors. Primary outcome measures included length of …