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Rossi-Tamisier M.,Center Hospitalo University Timone | Gerolami R.,Center Hospitalo University Conception | Colson P.,Center Hospitalo University Timone | Colson P.,Aix - Marseille University
Journal of Clinical Virology | Year: 2013

Background: Hepatitis E virus (HEV) is an emerging clinical threat in Europe among kidney and liver-transplant recipients. The incidence and prevalence of HEV infection in this special population are poorly known. False-negative results have been observed for anti-HEV IgG detection in severely immunocompromized persons. Moreover, large discrepancies have been reported between rates of anti-HEV IgG detection in blood donors and hepatitis E cases. Objectives: To compare anti-HEV IgG and IgM prevalence using two different commercial microplate enzyme-immuno assays (MEIAs) (Adaltis and Wantai) in 64 kidney-/liver-transplant recipients. Study design: Serum samples tested in our routine clinical practice over the 12/2009-12/2011 period with Adaltis MEIAs were retrospectively tested using Wantai MEIAs. IgG-positive sera were further tested by an immunoblot while those found IgM-positive were further tested with an immunochromatography rapid test and for the presence of HEV RNA. Results: Positive results on anti-HEV IgG testing were obtained for seven (10.9%) compared to 20 (31.3%) serum samples with Adaltis and Wantai assays, respectively (p= 0.005). Then, 6/7 (86%) of the serum samples positive with Adaltis and 16/20 (80%) of those positive with Wantai were positive with the immunoblot. One patient with chronic HEV infection was IgG-negative with both MEIAs. Regarding anti-HEV IgM, Adaltis and Wantai assays were concordant for 97% of the serum samples, prevalence being 8% with both MEIAs. Conclusions: The accuracy of currently available commercial or in-house anti-HEV IgG MEIAs should be tested comparatively on a panel of serum samples collected from solid organ-transplant recipients, including some who experienced PCR-documented HEV infection. © 2012 Elsevier B.V.


Gerolami R.,Center Hospitalo University Conception | Gerolami R.,Jean Moulin University Lyon 3 | Borentain P.,Center Hospitalo University Conception | Borentain P.,Jean Moulin University Lyon 3 | And 5 more authors.
Journal of Clinical Virology | Year: 2011

Background: Acute hepatitis E is associated with a higher rate of mortality as compared to hepatitis A or B infections in some series. To date no treatment has been recommended for acute hepatitis E. However, ribavirin has been recently reported to be highly effective to treat solid-organ-transplant recipients chronically infected with hepatitis E virus (HEV). Objective and study design: We report here on the use of ribavirin to treat severe acute HEV infection in a non-immunocompromized patient. This 61-year-old-man presented with acute hepatitis with HEV genotype 3. Seven days after admission, prothrombin index was 38%, bilirubinaemia was 550 μmol/L and alanine aminotransferases level was still increasing, reaching 4565. IU/L. No hepatic encephalopathy was noted. Ribavirin (1200. mg/day) was introduced. Results: Liver biological tests showed rapid improvement concurrently with a decrease in HEV RNA levels in serum samples. Therapy was interrupted after 21 days. At that time, ALT had normalized, bilirubinemia was 138 μmol/L, and HEV RNA was almost undetectable in the serum. Conclusion: Ribavirin therapy could be an effective treatment of severe acute hepatitis E. © 2011 Elsevier B.V.


Colson P.,Center Hospitalo University Timone | Colson P.,Aix - Marseille University | Borentain P.,Center Hospitalo University Conception | Queyriaux B.,Institute of Veille Sanitaire | And 9 more authors.
Journal of Infectious Diseases | Year: 2010

Background: The source and route of autochthonous hepatitis E virus (HEV) infections are not clearly established in industrialized countries despite evidence that it is a zoonosis in pigs. We investigated the role of figatellu, a traditional pig liver sausage widely eaten in France and commonly consumed raw, as a source of HEV infection. Methods: A case-control study was conducted of 3 patients who presented autochthonous hepatitis E and 15 members of their 3 different families. Anti-HEV immunoglobulin G and immunoglobulin M antibody testing was performed with commercial assays. HEV RNA was detected in serum samples of patients and in pig liver sausages by means of real-time polymerase chain reaction and sequenced by means of in-house sequencing assays. Genetic links between HEV sequences were analyzed. Results: Acute or recent HEV infection, defined by detection of anti-HEV immunoglobulin M antibodies and/ or HEV RNA, was observed in 7 of 13 individuals who ate raw figatellu and 0 of 5 individuals who did not eat raw figatellu ( ). Moreover, HEV RNA of genotype Pp.041 3 was recovered from 7 of 12 figatelli purchased in supermarkets, and statistically significant genetic links were found between these sequences and those recovered from patients who ate raw figatellu. Conclusion: Our findings strongly support the hypothesis of HEV infection through ingestion of raw figatellu. © 2010 by the Infectious Diseases Society of America. All rights reserved.


Darbousset R.,French Institute of Health and Medical Research | Delierneux C.,University of Liège | Mezouar S.,French Institute of Health and Medical Research | Hego A.,University of Liège | And 9 more authors.
Blood | Year: 2014

Adenosine triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophil (PMN) functions. PMNs have recently been implicated in the initiation of thrombosis. We investigated the role of ATP and adenosine in PMN activation and recruitment at the site of endothelial injury. Following binding to the injured vessel wall, PMNs are activated and release elastase. The recruitment of PMNs and the subsequent fibrin generation and thrombus formation are strongly affected in mice deficient in the P2X1-ATP receptor and in wild-type (WT) mice treated with CGS 21680, an agonist of the A2A adenosine receptor or NF449, a P2X1 antagonist. Infusion of WT PMNs into P2X1-deficient mice increases fibrin generation but not thrombus formation. Restoration of thrombosis requires infusion of both platelets and PMNs from WT mice. In vitro, ATP activates PMNs, whereas CGS 21680 prevents their binding to activated endothelial cells. These data indicate that adenosine triphosphate (ATP) contributes to polymorphonuclear neutrophil (PMN) activation leading to their adhesion at the site of laser-induced endothelial injury, a necessary step leading to the generation of fibrin, and subsequent platelet-dependent thrombus formation. Altogether, our study identifies previously unknown mechanismsby which ATP and adenosine are key molecules involved in thrombosis by regulating the activation state of PMNs. © 2014 by The American Society of Hematology.


Kaba M.,Aix - Marseille University | Kaba M.,Center Hospitalo University Timone | Moal V.,Aix - Marseille University | Gerolami R.,Center Hospitalo University Conception | And 2 more authors.
Intervirology | Year: 2013

Mammalian hepatitis E virus (HEV), the etiological agent of hepatitis E in humans, is a recently discovered infectious agent. It was identified for the first time in 1983 using electron microscopy on a faecal specimen of a person infected with non-A, non-B enterically-transmitted hepatitis. Based on retrospective and prospective studies, HEV was long described as one of the leading causes of acute viral hepatitis in tropical and subtropical countries, whereas in developed countries hepatitis E was considered an imported disease from HEV hyperendemic countries. Data from studies conducted during the past decade have greatly shifted our knowledge on the epidemiology and clinical spectrum of HEV. Recently, it has been shown that contrary to previous beliefs, hepatitis E is also an endemic disease in several developed countries, particularly in Japan and in Europe, as evidenced by reports of high anti-HEV immunoglobulin G prevalence in healthy individuals and an increasing number of non-travel-related acute hepatitis E cases. Moreover, a porcine reservoir and growing evidence of zoonotic transmission have been reported in these countries. This review summarizes the current knowledge on the epidemiology and prevention of transmission of mammalian HEV. Copyright © 2013 S. Karger AG, Basel.


Colson P.,Institut Universitaire de France | Colson P.,Aix - Marseille University | Romanet P.,Institut Universitaire de France | Moal V.,Hopital Conception | And 5 more authors.
Emerging Infectious Diseases | Year: 2012

During January-March 2011, diagnoses of hepatitis E virus (HEV) infection increased in Marseille University hospitals in southeastern France. HEV genotype 4, which is described almost exclusively in Asia, was recovered from 2 persons who ate uncooked pork liver sausage. Genetic sequences were 96.7% identical to those recently described in swine in Europe.


Bouamra Y.,Center Hospitalo University Timone | Benali S.,Center Hospitalo University Conception | Tissot-Dupont H.,Center Hospitalo University Conception | Tamalet C.,Center Hospitalo University Timone | And 3 more authors.
Journal of Clinical Microbiology | Year: 2013

We report an autochthonous hepatitis E virus (HEV)-hepatitis B virus co-primary infection in a 41-year-old man having sex with men and infected with human immunodeficiency virus (HIV). This case prompts testing for HEV in HIV-infected patients with acute hepatitis even if primary infection with another hepatitis virus is diagnosed. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Colson P.,Center Hospitalo University Timone | Colson P.,Aix - Marseille University | Gayet S.,Center Hospitalo University Sainte Marguerite | Gerolami R.,Center Hospitalo University Conception
Antiviral Therapy | Year: 2011

HCV displays considerable levels of nucleotide and amino acid diversity. Recently, the relevance of natural polymorphisms in worldwide isolates has been addressed in view of future protease inhibitor (PI)-based treatments; geno-type-and subtype-specific natural polymorphisms within HCV NS3 protease were identified at amino acid sites associated either with resistance to PIs or with compensatory mutations. Here, we describe a case of chronic infection with HCV of genotype 3 subtype h (HCV-3h), formerly only described from three patients originating from Somalia, and we provide the first NS3 protease sequence for such strains. NS3 protease sequences of HCV-3h recovered in the present study harbour specific amino acid residues not encountered in other reference HCV genotypes and sub-types at nine of the 181 NS3 protease positions; none of these amino acids are known to confer resistance to PIs. Of note, 5′ untranslated region sequence-based genotyping classifies them into genotype 1. ©2011 International Medical Press.


Mezouar S.,Aix - Marseille University | Mege D.,Aix - Marseille University | Darbousset R.,Aix - Marseille University | Farge D.,Service de Medecine Interne et Pathologie Vasculaire | And 5 more authors.
Seminars in Oncology | Year: 2014

Platelet-derived microparticles (PMPs) represent the most abundant microparticle (MP) subtype. Their presence reflects platelet activity, physiopathology, and the thrombotic state of cancer patients. The quantity and composition of PMPs strictly depends on the way MPs were generated. Because platelets play a key role in cancer progression, as well as formation of metastasis, PMPs also may be important in the proliferation of cancer cells, cancer cell interactions, metastatic progression, angiogenesis, and inflammation. Alternatively, the concentration of circulating PMPs may differ according to the stage of a cancer and thus potentially could be used as a biomarker. Here we review the mechanisms underlying the generation and composition of PMPs and the clinical and experimental studies describing the involvement of PMPs in cancer and the Trousseau syndrome. Lastly, we focus on their clinical relevance, as well as their potential application as biomarkers in cancer. © 2014 Elsevier Inc.


Mezouar S.,Aix - Marseille University | Darbousset R.,Aix - Marseille University | Dignat-George F.,Aix - Marseille University | Dignat-George F.,Center Hospitalo University Conception | And 2 more authors.
International Journal of Cancer | Year: 2015

Venous thromboembolism constitutes one of the main causes of death during the progression of a cancer. We previously demonstrated that tissue factor (TF)-bearing cancer cell-derived microparticles accumulate at the site of injury in mice developing a pancreatic cancer. The presence of these microparticles at the site of thrombosis correlates with the size of the platelet-rich thrombus. The objective of this study was to determine the involvement of TF expressed by cancer cell-derived microparticles on thrombosis associated with cancer. We observed that pancreatic cancer cell derived microparticles expressed TF, its inhibitor tissue factor pathway inhibitor (TFPI) as well as the integrins αvβ1 and αvβ3. In mice bearing a tumor under-expressing TF, a significant decrease in circulating TF activity associated with an increase bleeding time and a 100-fold diminished fibrin generation and platelet accumulation at the site of injury were observed. This was mainly due to the interaction of circulating cancer cell-derived microparticles expressing TFPI with activated platelets and fibrinogen. In an ectopic model of cancer, treatment of mice with Clopidogrel, an anti-platelet drug, decreased the size of the tumors and restored hemostasis by preventing the accumulation of cancer cell-derived microparticles at the site of thrombosis. In a syngeneic orthotopic model of pancreatic cancer Clopidogrel also significantly inhibited the development of metastases. Together, these results indicate that an anti-platelet strategy may efficiently treat thrombosis associated with cancer and reduce the progression of pancreatic cancer in mice. What's new? Tissue factor (TF) plays a key role in coagulation and is capable of activating inflammatory and angiogenic responses, potentially facilitating the progression of cancer. As a result, anticoagulant or antiplatelet drugs could be effective means of prevention for tumor progression and metastasis. Here, pancreatic cancer cell-derived microparticles were found to express TF and its inhibitor TFPI. The microparticles interacted with platelets, with effects on bleeding and platelet accumulation, in mice. In cancer mouse models, treatment with the antiplatelet drug clopidogrel restored hemostasis, resulted in decreased tumor size, and prevented the development of metastases. © 2014 UICC.

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