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https://www.readbyqxmd.com/read/28529147/norursodeoxycholic-acid-improves-cholestasis-in-primary-sclerosing-cholangitis
#1
Peter Fickert, Gideon M Hirschfield, Gerald Denk, Hanns-Ulrich Marschall, Istvan Altorjay, Martti Färkkilä, Christoph Schramm, Ulrich Spengler, Roger Chapman, Annika Bergquist, Erik Schrumpf, Frederik Nevens, Palak Trivedi, Florian P Reiter, Istvan Tornai, Emina Halilbasic, Roland Greinwald, Markus Pröls, Michael P Manns, Michael Trauner
Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. AIM: To evaluate the safety and efficacy of 3 doses of oral norUDCA (500mg/d, 1000mg/d or 1500 mg/d) compared with placebo in PSC in a RCT including 38centers from 12European countries...
May 18, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28468019/preface
#2
Gideon Hirschfield
No abstract text is available yet for this article.
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28428344/vascular-adhesion-protein-1-is-elevated-in-primary-sclerosing-cholangitis-is-predictive-of-clinical-outcome-and-facilitates-recruitment-of-gut-tropic-lymphocytes-to-liver-in-a-substrate-dependent-manner
#3
Palak J Trivedi, Joseph Tickle, Mette Nåmdal Vesterhus, Peter J Eddowes, Tony Bruns, Jani Vainio, Richard Parker, David Smith, Evaggelia Liaskou, Liv Wenche Thorbjørnsen, Gideon M Hirschfield, Kaisa Auvinen, Stefan G Hubscher, Marko Salmi, David H Adams, Chris J Weston
OBJECTIVE: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC. DESIGN: We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium...
April 20, 2017: Gut
https://www.readbyqxmd.com/read/28427765/easl-clinical-practice-guidelines-the-diagnosis-and-management-of-patients-with-primary-biliary-cholangitis
#4
(no author information available yet)
Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in end-stage biliary cirrhosis. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse and risk stratification is important to ensure all patients receive a personalised approach to their care. The goals of treatment and management are the prevention of end-stage liver disease, and the amelioration of associated symptoms...
April 18, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28420030/role-of-endoscopy-in-primary-sclerosing-cholangitis-european-society-of-gastrointestinal-endoscopy-esge-and-european-association-for-the-study-of-the-liver-easl-clinical-guideline
#5
Lars Aabakken, Tom H Karlsen, Jörg Albert, Marianna Arvanitakis, Olivier Chazouilleres, Jean-Marc Dumonceau, Martti Färkkilä, Peter Fickert, Gideon M Hirschfield, Andrea Laghi, Marco Marzioni, Michael Fernandez, Stephen P Pereira, Jürgen Pohl, Jan-Werner Poley, Cyriel Y Ponsioen, Christoph Schramm, Fredrik Swahn, Andrea Tringali, Cesare Hassan
1 ESGE/EASL recommend that, as the primary diagnostic modality for PSC, magnetic resonance cholangiography (MRC) should be preferred over endoscopic retrograde cholangiopancreatography (ERCP).Moderate quality evidence, strong recommendation. 2 ESGE/EASL suggest that ERCP can be considered if MRC plus liver biopsy is equivocal or contraindicated in patients with persisting clinical suspicion of PSC. The risks of ERCP have to be weighed against the potential benefit with regard to surveillance and treatment recommendations...
April 18, 2017: Endoscopy
https://www.readbyqxmd.com/read/28349484/in-vitro-and-ex-vivo-models-to-study-t-cell-migration-through-the-human-liver-parenchyma
#6
Benjamin G Wiggins, Konstantinos Aliazis, Scott P Davies, Gideon Hirschfield, Patricia F Lalor, Gary Reynolds, Zania Stamataki
The liver is the largest internal organ and filters around 3 pints of blood per minute. This continuous flux of blood should not be confused with rapid egress of lymphocytes through the liver; this organ has intricate corridors of specialized sinusoidal spaces, ensuring that immune cells decelerate to shear flow rates, and providing ample opportunities to interact with parenchymal cells. Migration has been intricately linked to T cell function; it is therefore important to study liver T cell biology into context within the liver microenvironment...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28274849/patient-age-sex-and-inflammatory-bowel-disease-phenotype-associate-with-course-of-primary-sclerosing-cholangitis
#7
Tobias J Weismüller, Palak J Trivedi, Annika Bergquist, Mohamad Imam, Henrike Lenzen, Cyriel Y Ponsioen, Kristian Holm, Daniel Gotthardt, Martti A Färkkilä, Hanns-Ulrich Marschall, Douglas Thorburn, Rinse K Weersma, Johan Fevery, Tobias Mueller, Olivier Chazouillères, Kornelius Schulze, Konstantinos N Lazaridis, Sven Almer, Stephen P Pereira, Cynthia Levy, Andrew Mason, Sigrid Naess, Christopher L Bowlus, Annarosa Floreani, Emina Halilbasic, Kidist K Yimam, Piotr Milkiewicz, Ulrich Beuers, Dep K Huynh, Albert Pares, Christine N Manser, George N Dalekos, Bertus Eksteen, Pietro Invernizzi, Christoph P Berg, Gabi I Kirchner, Christoph Sarrazin, Vincent Zimmer, Luca Fabris, Felix Braun, Marco Marzioni, Brian D Juran, Karouk Said, Christian Rupp, Kalle Jokelainen, Maria Benito de Valle, Francesca Saffioti, Angela Cheung, Michael Trauner, Christoph Schramm, Roger W Chapman, Tom H Karlsen, Erik Schrumpf, Christian P Strassburg, Michael P Manns, Keith D Lindor, Gideon M Hirschfield, Bettina E Hansen, Kirsten M Boberg
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries...
June 2017: Gastroenterology
https://www.readbyqxmd.com/read/28249258/apical-sodium-dependent-transporter-inhibitors-in-primary-biliary-cholangitis-and-primary-sclerosing-cholangitis
#8
REVIEW
Vinod S Hegade, David E J Jones, Gideon M Hirschfield
Bile acids (BAs) have gained mainstream attention since the discovery of their key role as signalling molecules in health and disease. The apical sodium-dependent transporter (ASBT) protein located in the terminal ileum plays an important physiological role in the enterohepatic circulation of BAs and therefore essential for the BA homeostasis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the 2 most common cholestatic liver diseases are characterised by altered BA flow and BA composition, which contribute to disease progression and symptom (pruritus) development...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28187915/effect-of-ileal-bile-acid-transporter-inhibitor-gsk2330672-on-pruritus-in-primary-biliary-cholangitis-a-double-blind-randomised-placebo-controlled-crossover-phase-2a-study
#9
Vinod S Hegade, Stuart F W Kendrick, Robert L Dobbins, Sam R Miller, Douglas Thompson, Duncan Richards, James Storey, George E Dukes, Margaret Corrigan, Ronald P J Oude Elferink, Ulrich Beuers, Gideon M Hirschfield, David E Jones
BACKGROUND: Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus...
March 18, 2017: Lancet
https://www.readbyqxmd.com/read/28176332/low-dose-interleukin-2-promotes-stat-5-phosphorylation-treg-survival-and-ctla-4-dependent-function-in-autoimmune-liver-diseases
#10
H C Jeffery, L E Jeffery, P Lutz, M Corrigan, G J Webb, G M Hirschfield, D H Adams, Y H Oo
CD4(+) CD25(high) CD127(low) forkhead box protein 3 (FoxP3(+) ) regulatory T cells (Treg ) are essential for the maintenance of peripheral tolerance. Impaired Treg function and an imbalance between effector and Tregs contribute to the pathogenesis of autoimmune diseases. We reported recently that the hepatic microenvironment is deficient in interleukin (IL)-2, a cytokine essential for Treg survival and function. Consequently, few liver-infiltrating Treg demonstrate signal transducer and activator of transcription-5 (STAT-5) phosphorylation...
June 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28146446/immunogenetics-in-primary-sclerosing-cholangitis
#11
Brian K Chung, Gideon M Hirschfield
PURPOSE OF REVIEW: Primary sclerosing cholangitis (PSC) is a progressive biliary liver disorder strongly associated with inflammatory bowel disease (PSC-IBD). We summarize the genetics of PSC-IBD and highlight recent findings that further differentiate PSC-IBD as a unique disease. RECENT FINDINGS: To date, genome-wide studies have uncovered 23 susceptibility loci for PSC-IBD, the majority of which have been previously reported as risk factors in other immune-mediated disorders...
March 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28074075/primary-biliary-cholangitis-in-2016-high-definition-pbc-biology-models-and-therapeutic-advances
#12
Gwilym J Webb, Gideon M Hirschfield
No abstract text is available yet for this article.
February 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28018103/portal-hypertension-in-polycystic-liver-disease-patients-does-not-affect-wait-list-or-immediate-post-liver-transplantation-outcomes
#13
Neil Rajoriya, Dhiraj Tripathi, Joanna A Leithead, Bridget K Gunson, Sophie Lord, James W Ferguson, Gideon M Hirschfield
AIM: To establish the impact of portal hypertension (PH) on wait-list/post-transplant outcomes in patients with polycystic liver disease (PCLD) listed for liver transplantation. METHODS: A retrospective single-centre case controlled study of consecutive patients listed for liver transplantation over 12 years was performed from our centre. PH in the PCLD cohort was defined by the one or more of following parameters: (1) presence of radiological or endoscopic documented varices from our own centre or the referral centre; (2) splenomegaly (> 11 cm) on radiology in absence of splenic cysts accounting for increased imaging size; (3) thrombocytopenia (platelets < 150 × 10(9)/L); or (4) ascites without radiological evidence of hepatic venous outflow obstruction from a single cyst...
December 7, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27992413/genome-wide-association-study-of-primary-sclerosing-cholangitis-identifies-new-risk-loci-and-quantifies-the-genetic-relationship-with-inflammatory-bowel-disease
#14
Sun-Gou Ji, Brian D Juran, Sören Mucha, Trine Folseraas, Luke Jostins, Espen Melum, Natsuhiko Kumasaka, Elizabeth J Atkinson, Erik M Schlicht, Jimmy Z Liu, Tejas Shah, Javier Gutierrez-Achury, Kirsten M Boberg, Annika Bergquist, Severine Vermeire, Bertus Eksteen, Peter R Durie, Martti Farkkila, Tobias Müller, Christoph Schramm, Martina Sterneck, Tobias J Weismüller, Daniel N Gotthardt, David Ellinghaus, Felix Braun, Andreas Teufel, Mattias Laudes, Wolfgang Lieb, Gunnar Jacobs, Ulrich Beuers, Rinse K Weersma, Cisca Wijmenga, Hanns-Ulrich Marschall, Piotr Milkiewicz, Albert Pares, Kimmo Kontula, Olivier Chazouillères, Pietro Invernizzi, Elizabeth Goode, Kelly Spiess, Carmel Moore, Jennifer Sambrook, Willem H Ouwehand, David J Roberts, John Danesh, Annarosa Floreani, Aliya F Gulamhusein, John E Eaton, Stefan Schreiber, Catalina Coltescu, Christopher L Bowlus, Velimir A Luketic, Joseph A Odin, Kapil B Chopra, Kris V Kowdley, Naga Chalasani, Michael P Manns, Brijesh Srivastava, George Mells, Richard N Sandford, Graeme Alexander, Daniel J Gaffney, Roger W Chapman, Gideon M Hirschfield, Mariza de Andrade, Simon M Rushbrook, Andre Franke, Tom H Karlsen, Konstantinos N Lazaridis, Carl A Anderson
Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A...
February 2017: Nature Genetics
https://www.readbyqxmd.com/read/27880989/validation-of-the-prognostic-value-of-histologic-scoring-systems-in-primary-sclerosing-cholangitis-an-international-cohort-study
#15
Elisabeth M G de Vries, Manon de Krijger, Martti Färkkilä, Johanna Arola, Peter Schirmacher, Daniel Gotthardt, Benjamin Goeppert, Palak J Trivedi, Gideon M Hirschfield, Henriette Ytting, Ben Vainer, Henk R van Buuren, Katharina Biermann, Maren H Harms, Olivier Chazouilleres, Dominique Wendum, Astrid D Kemgang, Roger W Chapman, Lai Mun Wang, Kate D Williamson, Annette S H Gouw, Valerie Paradis, Christine Sempoux, Ulrich Beuers, Stefan G Hübscher, Joanne Verheij, Cyriel Y Ponsioen
Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement...
March 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27806199/new-approaches-to-investigate-drug-induced-hypersensitivity
#16
REVIEW
Monday O Ogese, Shaheda Ahmed, Ana Alferivic, Catherine J Betts, Anne Dickinson, Lee Faulkner, Neil French, Andrew Gibson, Gideon M Hirschfield, Michael Kammüller, Xiaoli Meng, Stefan F Martin, Philippe Musette, Alan Norris, Munir Pirmohamed, B Kevin Park, Anthony W Purcell, Colin F Spraggs, Jessica Whritenour, Dean J Naisbitt
The workshop on "New Approaches to Investigate Drug-Induced Hypersensitivity" was held on June 5, 2014 at the Foresight Center, University of Liverpool. The aims of the workshop were to (1) discuss our current understanding of the genetic, clinical, and chemical basis of small molecule drug hypersensitivity, (2) highlight the current status of assays that might be developed to predict potential drug immunogenicity, and (3) identify the limitations, knowledge gaps, and challenges that limit the use of these assays and utilize the knowledge gained from the workshop to develop a pathway to establish new and improved assays that better predict drug-induced hypersensitivity reactions during the early stages of drug development...
January 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27784538/phenotyping-and-auto-antibody-production-by-liver-infiltrating-b-cells-in-primary-sclerosing-cholangitis-and-primary-biliary-cholangitis
#17
Brian K Chung, Bardia T Guevel, Gary M Reynolds, D B R K Gupta Udatha, Eva Kristine Klemsdal Henriksen, Zania Stamataki, Gideon M Hirschfield, Tom Hemming Karlsen, Evaggelia Liaskou
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are immune-mediated biliary diseases that demonstrate prominent and restricted genetic association with human leukocyte antigen (HLA) alleles. In PBC, anti-mitochondrial antibodies (AMA) are specific and used as diagnostic biomarkers. PSC-relevant auto-antibodies remain controversial despite a distinct HLA association that mirrors archetypical auto-antigen driven disorders. Herein, we compared antibody-secreting B cells (ASCs) in PSC and PBC liver explants to determine if liver-infiltrating ASCs represent an opportune and novel source of disease-relevant auto-antibodies...
February 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/27647428/gut-and-liver-t-cells-of-common-clonal-origin-in-primary-sclerosing-cholangitis-inflammatory-bowel-disease
#18
Eva Kristine Klemsdal Henriksen, Kristin Kaasen Jørgensen, Fatemeh Kaveh, Kristian Holm, David Hamm, Johanna Olweus, Espen Melum, Brian K Chung, Tor J Eide, Knut E A Lundin, Kirsten Muri Boberg, Tom H Karlsen, Gideon M Hirschfield, Evaggelia Liaskou
BACKGROUND & AIMS: Recruitment of gut-derived memory T-cells to the liver is believed to drive hepatic inflammation in primary sclerosing cholangitis (PSC). However, whether gut-infiltrating and liver-infiltrating T-cells share T cell receptors (TCRs) and antigenic specificities is unknown. We used paired gut and liver samples from PSC patients with concurrent inflammatory bowel disease (PSC-IBD), and normal tissue samples from colon cancer controls, to assess potential T cell clonotype overlap between the two compartments...
January 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/27601441/mesenchymal-stromal-cells-and-liver-fibrosis-a-complicated-relationship
#19
REVIEW
Debashis Haldar, Neil C Henderson, Gideon Hirschfield, Philip N Newsome
Mesenchymal stromal cell (MSC) therapy demands the attention of clinicians and scientists because of its potential in clinical fields that are bereft of medical options, but also because of the controversies that underlie its mode of action. MSCs are potent immune modulators, yet their biologic activity may not be innate, requiring licensing by their microenvironment. This property has prompted researchers to explore unique ways in which MSCs may be able to exert distinct biologic effects in different pathologic settings...
December 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27532829/a-placebo-controlled-trial-of-obeticholic-acid-in-primary-biliary-cholangitis
#20
RANDOMIZED CONTROLLED TRIAL
Frederik Nevens, Pietro Andreone, Giuseppe Mazzella, Simone I Strasser, Christopher Bowlus, Pietro Invernizzi, Joost P H Drenth, Paul J Pockros, Jaroslaw Regula, Ulrich Beuers, Michael Trauner, David E Jones, Annarosa Floreani, Simon Hohenester, Velimir Luketic, Mitchell Shiffman, Karel J van Erpecum, Victor Vargas, Catherine Vincent, Gideon M Hirschfield, Hemant Shah, Bettina Hansen, Keith D Lindor, Hanns-Ulrich Marschall, Kris V Kowdley, Roya Hooshmand-Rad, Tonya Marmon, Shawn Sheeron, Richard Pencek, Leigh MacConell, Mark Pruzanski, David Shapiro
BACKGROUND: Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS: In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo...
August 18, 2016: New England Journal of Medicine
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