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Khoo E.Y.H.,National University of Singapore | Stevenson M.C.,University of Nottingham | Leverton E.,University of Nottingham | Cross R.,IQur Ltd. | And 8 more authors.
Digestive Diseases and Sciences | Year: 2012

Background: Hyperalimentation for 4 weeks is associated with raised liver enzymes and liver fat content (LFC), which are two common features found in individuals with diabetes. Aim: We evaluated the effect of two mixed meal challenges on LFC, liver enzymes and serum bio-markers of liver injury and fibrosis in 16 healthy volunteers (HV) and subjects with type 2 diabetes (T2DM). Methods: Subjects (HV: 9 male, 7 female, aged 57.9 ± 1.7 years, body mass index (BMI) 27.1 kg/m2; and T2DM: 11 male, 5 female, aged 62.1 ± 1.3 years, BMI 28.0 ± 0.4 kg/m2) consumed two meals at 1 h (884 kcal) and at 6 h (1,096 kcal). LFC determined by 1H magnetic resonance spectroscopy, serum levels of liver enzymes, hyaluronic acid (HA), procollagen III N-terminal peptide (P3NP) and tissue inhibitor metalloproteinase-1 (TIMP-1) were estimated at time 0 (fasting) and 9 h (postprandial). Results: Fasting LFC was higher in the T2DM group 7.6 % (4.9, 15.4) [median (inter-quartile range)] than in the HV group 2.3 % (0.8, 5.1) (p<0.05) while levels of HA, P3NP and TIMP-1 were similar. Following the meal challenge there was no significant change in LFC. Subjects with T2DM had higher post-prandial rise in alanine transaminase (ALT) (p = 0.014), serum HA (p = 0.007) and P3NP (p = 0.015) compared with HV. Fasting LFC correlated with a greater post-prandial increase in P3NP levels in all subjects (Pearson correlation r = 0.53, p = 0.001). Conclusions: In subjects with T2DM, a mixed meal challenge is associated with a significant elevation in the serum levels of ALT, HA and P3NP without significant changes in LFC. These markers should be performed in the fasted state. © Springer Science+Business Media, LLC 2012.

Holmes K.,University of Leeds | Shepherd D.A.,University of Leeds | Ashcroft A.E.,University of Leeds | Whelan M.,IQur Ltd. | And 2 more authors.
Journal of Biological Chemistry | Year: 2015

Macromolecular complexes are responsible for many key biological processes. However, in most cases details of the assembly/disassembly of such complexes are unknown at the molecular level, as the low abundance and transient nature of assembly intermediates make analysis challenging. The assembly of virus capsids is an example of such a process. The hepatitis B virus capsid (core) can be composed of either 90 or 120 dimers of coat protein. Previous studies have proposed a trimer of dimers as an important intermediate species in assembly, acting to nucleate further assembly by dimer addition. Using novel geneticallyfused coat protein dimers, we have been able to trap higherorder assembly intermediates and to demonstrate for the first time that both dimeric and trimeric complexes are on pathway to virus-like particle (capsid) formation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

iQUR Ltd | Date: 2010-10-22

The invention provides a protein comprising a first and a second copy of hepatitis B core antigen (HBcAg) in tandem, in which one or both of the copies of HBcAg comprises influenza virus A surface polypeptide M2 or a fragment thereof in the e

Trepo E.,Free University of Colombia | Potthoff A.,Medizinische Hochschule | Pradat P.,Hospices Civils de Lyon | Pradat P.,French Institute of Health and Medical Research | And 19 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: Fibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients with mild liver fibrosis. In addition, we evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test. Methods: Two separate cohorts of HCV patients (Brussels, Belgium/Hannover, Germany) were retrospectively analyzed. Only patients with a fibrosis Ishak or METAVIR score of F0-F1 at baseline were included. Patients were classified as progressors if they showed an increase ≥2 fibrosis stages at the second histological evaluation after a follow-up ≥5 years. The CRS was calculated locally. Genotyping was performed by PCR and oligonucleotide ligation with the resulting signal detected with a Luminex® 200TM and computer analysis. Results: In Brussels, 12/25 patients progressed (48%); similarly in Hannover, 16/31 (52%) patients progressed. In both sample sets, the CRS was significantly associated with fibrosis progression (p = 0.050 in Brussels; p = 0.018 in Hannover). The ELF test was only a significant predictor in Hannover (p = 0.015). In multivariate analysis the CRS remained the only variable associated with fibrosis progression (odds-ratio = 2.23, 95%CI 1.21-4.11 p = 0.01). Conclusions: Although conducted on a limited number of patients, this study in two independent centres confirms that the CRS predicts fibrosis progression in initially mild CHC. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Parkes J.,University of Southampton | Guha I.N.,University of Nottingham | Roderick P.,University of Southampton | Harris S.,University of Southampton | And 7 more authors.
Journal of Viral Hepatitis | Year: 2011

Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy. © 2010 Blackwell Publishing Ltd.

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