Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population. HIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24). Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed. Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955.
ISSN: 1058-4838

hal-01118447
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118447
PUBMED : 25139963
DOI : 10.1093/cid/ciu659

Éditeur(s) : HAL CCSD Paris, Masson et Cie
Résumé : National audience
Decreased frequency of pulmonary exacerbations, mainly related to immunomodulatory effects of macrolide antibiotics, has been demonstrated in bronchiectasis and chronic obstructive pulmonary diseases (COPD). Due to its tolerance, azithromycin is the antibiotic of choice for maintenance therapy at the dose of 250 mg per day or 500 mg × 3 per week (for body weight >55 kg). Maintenance therapy with macrolide could be proposed in selected patients with bronchiectasis or COPD with more than 3 acute exacerbations in the previous year or decreased lung function despite compliance with optimum treatment. The risk of sudden cardiac death with azithromycin is rare and controversial. It should be avoided in patients with a high baseline risk of cardiovascular disease, QT>450 msec, pulse rate>100 bpm and potential drug interactions, particularly those known to cause QT prolongation. It is recommended to search for hearing deficit (audiometry) and sputum culture positive for mycobacteria. Patients must also be aware that it can rapidly lead to macrolide resistance in commensal or pathogenic flora. Follow-up evaluation every 3 month can be proposed with medical history (hearing deficit) and electrocardiography. After one year, the treatment should be stopped in the absence of reduction in the frequency of exacerbations.
Points essentielsLes macrolides administrés au long cours permettent, grâce en partie à leurs propriétés anti-inflammatoires, de diminuer la fréquence des exacerbations dans la DDB et la BPCO.Du fait de sa tolérance, l’azithromycine est le macrolide de choix, pouvant être utilisé à la dose de 250 mg/j ou 500 mg 3 fois par semaine chez les patients de plus de 55 kg.Un traitement par macrolides au long cours pourrait être proposé à des patients atteints de DDB ou de BPCO ayant eu plus de 3 exacerbations l’année précédente ou ayant une dégradation de leur fonction respiratoire malgré un traitement de fond bien conduit.Du fait d’un risque rare et controversé de mort subite d’origine cardiaque, il ne doit pas être proposé en cas de pathologie cardiovasculaire évoluée, d’intervalle QT > 450 ms, de traitement pouvant allonger l’intervalle QT, de tachycardie > 100/min.Il est recommandé de s’assurer de l’absence de troubles auditifs (audiogramme) et de mycobactérie atypique dans les cultures des expectorations. Les patients doivent aussi être informés du risque d’apparition de résistance aux macrolides de la flore commensale et pathogène.Une surveillance clinique, avec en particulier la recherche de troubles auditifs et électrocardiographique, peut être proposée tous les 3 mois. L’absence de diminution de la fréquence des exacerbations, lors du bilan annuel, justifie l’arrêt du traitement.
ISSN: 0032-7867

hal-01073027
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01073027
DOI : 10.1016/j.lpm.2013.08.006
PUBMED : 24631048

Éditeur(s) : HAL CCSD
Résumé : National audience
Il virus dell’epatite C (HCV), a trasmissione parenterale, è stato identificato nel 1989 come il virus responsabile delle epatiti «non A non B». L’infezione colpisce circa 170 milioni di persone nel mondo e 200 000 persone in Francia hanno una replicazione virale attiva. Nei paesi industrializzati, l’epidemia ha accompagnato lo sviluppo della trasfusione sanguigna e della tossicomania endovenosa. I test enzyme-linked immunosorbent assay che individuano gli anticorpi anti-HCV hanno permesso uno screening attendibile dell’infezione a partire dal 1992. La rilevazione dell’acido ribonucleico virale C permette la diagnosi dell’infezione cronica che fa seguito all’epatite acuta in circa l’80% dei casi. La gravità dell’infezione è legata allo sviluppo progressivo di una fibrosi epatica che conduce alla cirrosi dopo una mediana di evoluzione di 30-40 anni. La malattia è, così, responsabile di circa 350 000 decessi per anno nel mondo, legati, in parti uguali, all’insufficienza epatica e al carcinoma epatocellulare. Il trattamento ha compiuto enormi progressi in 20 anni e nuove molecole antivirali sono in corso di sviluppo clinico.
EMC - AKOS - Trattato di Medicina

hal-01154232
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01154232
DOI : 10.1016/S1634-7358(15)70635-2

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Metalloproteases involved in extracellular matrix remodeling play a pivotal role in cell response by regulating the bioavailability of cytokines and growth factors. Recently, the disintegrin and metalloprotease, ADAMTS1 has been demonstrated to be able to activate the transforming growth factor TGF-β, a major factor in fibrosis and cancer. The KTFR sequence from ADAMTS1 is responsible for the interaction with the LSKL peptide from the latent form of TGF-β, leading to its activation. While the atomic details of the interaction site can be the basis of the rational design of efficient inhibitory molecules, the binding mode of interaction is totally unknown. In this study, we show that recombinant fragments of human ADAMTS1 containing KTFR sequence keep the ability to bind the latent form of TGF-β. The recombinant fragment with the best affinity is modeled to investigate the binding mode of LSKL peptide with ADAMTS1 at the atomic level. Using a combined approach with molecular docking and multiple independent molecular dynamics (MD) simulations, we provide the binding mode of LSKL peptide with ADAMTS1. The MD simulations starting with the two lowest energy model predicted by molecular docking shows stable interactions characterized by 3 salt bridges (K3-NH3+ with E626-COO−; L4-COO− with K619-NH3+; L1-NH3+ with E624-COO−) and 2 hydrogen bonds (S2-OH with E623-COO−; L4-NH with E623-COO−). The knowledge of this interaction mechanism paves the way to the design of more potent and more specific inhibitors against the inappropriate activation of TGF-β by ADAMTS1 in liver diseases
ISSN: 1476-9271

hal-01269916
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01269916
DOI : 10.1016/j.compbiolchem.2016.01.012
PUBMED : 26878129

Éditeur(s) : HAL CCSD
Résumé : National audience
El virus de la hepatitis C (VHC), que se transmite por vía parenteral, fue identificado en 1989 como el virus responsable de las hepatitis «no A no B». La infección afecta a alrededor de 170 millones de personas en el mundo. En Francia, por ejemplo, 200.000 personas tienen una replicación viral activa. En los países industrializados, la epidemia ha sido la consecuencia de la práctica de la transfusión sanguínea y de la toxicomanía intravenosa. El método ELISA (ensayo por inmunoabsorción ligado a enzimas), que identifica los anticuerpos anti-VHC, posibilita la detección fiable de la infección desde 1992. La detección del ácido ribonucleico viral C permite el diagnóstico de la infección crónica, consecutiva a la hepatitis aguda, en alrededor del 80% de los casos. La gravedad de la infección se debe al desarrollo progresivo de una fibrosis hepática que, tras una mediana de evolución de 30-40 años, conduce a la cirrosis. Así, la enfermedad es responsable de unos 350.000 fallecimientos por año a escala mundial, relacionados a partes iguales con la insuficiencia hepática y el carcinoma hepatocelular. El tratamiento ha progresado de forma considerable en 20 años y hay nuevas moléculas antivirales en fase de desarrollo clínico.
EMC - Tratado de Medicina

hal-01154228
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01154228
DOI : 10.1016/S1636-5410(15)70945-1

Éditeur(s) : HAL CCSD Massachusetts Medical Society
Résumé : International audience
o abstract
ISSN: 0028-4793

hal-01390975
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390975
DOI : 10.1056/NEJMoa1515319
PUBMED : 27626530

Éditeur(s) : HAL CCSD Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists
Résumé : International audience
Schistosome infection is a major public health concern affecting millions of people living in tropical regions of Africa, Asia, and South America. Schistosomes cause mild clinical symptoms in most subjects, whereas a small proportion of individuals presents severe clinical disease (as periportal fibrosis (PPF)) that may lead to death. Severe PPF results from an abnormal deposition of extracellular matrix proteins in the periportal spaces due to a chronic inflammation triggered by eggs and schistosome Ags. Extracellular matrix protein production is regulated by a number of cytokines, including IFN-gamma. We have now screened putative polymorphic sites within this gene in a population living in an endemic area for Schistosoma mansoni. Two polymorphisms located in the third intron of the IFN-gamma gene are associated with PPF. The IFN-gamma +2109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-gamma +3810 G/A polymorphism is associated with less PPF. The polymorphisms result in changes in nuclear protein interactions with the intronic regions of the gene, suggesting that they may modify IFN-gamma mRNA expression. These results are consistent with the results of previous studies. Indeed, PPF is controlled by a major locus located on chromosome 6q22-q23, closely linked to the gene encoding the alpha-chain of the IFN-gamma receptor, and low IFN-gamma producers have been shown to have an increased risk of severe PPF. Together, these observations support the view that IFN-gamma expression and subsequent signal transduction play a critical role in the control of PPF in human hepatic schistosome infection (S. mansoni).
ISSN: 0022-1767

Droits : http://creativecommons.org/licenses/by-nc-nd/
hal-01211760
https://hal.archives-ouvertes.fr/hal-01211760
https://hal.archives-ouvertes.fr/hal-01211760/document
https://hal.archives-ouvertes.fr/hal-01211760/file/J%20Immunol-2003-Chevillard-5596-601.pdf
DOI : 10.4049/jimmunol.171.10.5596

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
BACKGROUND: Early in life, cystic fibrosis (CF) patients are infected with microorganisms. The role of macrophages has largely been underestimated in literature, whereas the focus being mostly on neutrophils and epithelial cells. Macrophages may however play a significant role in the initiating stages of this disease, via an inability to act as a suppressor cell. Yet macrophage dysfunction may be the first step in cascade of events leading to chronic inflammation/infection in CF. Moreover, reports have suggested that CFTR contribute to altered inflammatory response in CF by modification of normal macrophage functions. OBJECTIVES: In order to highlight possible intrinsic macrophage defects due to impaired CFTR, we have studied inflammatory cytokines secretions, recognition of pathogens and phagocytosis in peripheral blood monocyte-derived macrophages from stable adult CF patients and healthy subjects (non-CF). RESULTS: In CF macrophage supernatants, concentrations of sCD14, IL-1β, IL-6, TNF-α and IL-10 were strongly raised. Furthermore expression of CD11b and TLR-5 were sorely decreased on CF macrophages. Beside, no difference was observed for mCD14, CD16, CD64, TLR-4 and TLR1/TLR-2 expressions. Moreover, a strong inhibition of phagocytosis was observed for CF macrophages. Elsewhere CFTR inhibition in non-CF macrophages also led to alterations of phagocytosis function as well as CD11b expression. CONCLUSIONS: Altogether, these findings demonstrate excessive inflammation in CF macrophages, characterized by overproduction of sCD14 and inflammatory cytokines, with decreased expression of CD11b and TLR-5, and impaired phagocytosis. This leads to altered clearance of pathogens and non-resolution of infection by CF macrophages, thereby inducing an exaggerated pro-inflammatory response.
ISSN: 1932-6203

inserm-00872278
http://www.hal.inserm.fr/inserm-00872278
http://www.hal.inserm.fr/inserm-00872278/document
http://www.hal.inserm.fr/inserm-00872278/file/Impaired_Functions.accepted.pdf
DOI : 10.1371/journal.pone.0075667

Éditeur(s) : HAL CCSD Institute of Electrical and Electronics Engineers (IEEE)
Résumé : International audience
Non-alcoholic fatty liver disease (NAFLD) is defined as an excessive accumulation of fat in the liver in the absence of excessive drinking of alcohol. Initially considered as benign and self-limited, NAFLD may progress to the malignant stage of non-alcoholic steatohepatitis (NASH) characterized by degenerate hepatocellular ballooning and lobular inflammation. NASH can lead to hepatic fibrosis and ultimately to cirrhosis and hepatocellular carcinoma. Unfortunately, the transition from NAFLD to NASH is difficult to detect so far. In this paper, we propose to evaluate the characterization of NASH using mid infrared fiber evanescent wave spectroscopy on blood serum. We used an heuristic variable selection method and a generalized linear model to classify NAFLD and NASH spectra. The obtained results proved that this technique is a promising non-invasive and simple diagnosis tool for NASH.
ISSN: 1557-170X

inserm-01476033
http://www.hal.inserm.fr/inserm-01476033
http://www.hal.inserm.fr/inserm-01476033/document
http://www.hal.inserm.fr/inserm-01476033/file/EMBC_2016_CameraReady.pdf
DOI : 10.1109/EMBC.2016.7591507

Éditeur(s) : HAL CCSD American Society for Investigative Pathology
Résumé : International audience
Recent studies suggest that psoriasis may be more severe in patients with nonalcoholic fatty liver disease, particularly in those with the inflammatory stage of steatohepatitis [nonalcoholic steatohepatitis (NASH)]. Herein, we investigated the impact of diet-induced steatohepatitis on the severity of imiquimod-induced psoriasiform dermatitis. Mice fed with a high-fat diet developed steatohepatitis reminiscent of human NASH with ballooning hepatocytes and significant liver fibrosis. Mice with steatohepatitis also displayed moderate cutaneous inflammation characterized by erythema, dermalinfiltrates of CD45(+) leukocytes, and a local production of IL-17A. Moreover, steatohepatitis was associated with an epidermal activation of caspase-1 and cutaneous overexpression of IL-1 beta. Imiquimod-induced psoriasiform dermatitis was exacerbated in mice with steatohepatitis as compared to animals fed with a standard diet. Scale formation and acanthosis were aggravated, in correlation with increased IL-17A and IL-22 expression in inflamed skins. Finally, intradermal injection of IL-17A in standard diet-fed mice recapitulated the cutaneous pathology of mice with steatohepatitis. The results show that high-fat diet induced steatohepatitis aggravates the inflammation in psoriasiform dermatitis, via the cutaneous production of IL-17A. In agreement with clinical data, this description of a novel extrahepatic manifestation of NASH should sensitize dermatologists to the screening and the management of fatty liver in psoriatic patients.
ISSN: 0002-9440

hal-01390977
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390977
DOI : 10.1016/j.ajpath.2016.05.012
PUBMED : 27423696

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Mechanical forces influence the growth and shape of virtually all tissues and organs. Recent studies show that increased cell contractibility, growth and differentiation might be normalized by modulating cell tensions. Particularly, the role of these tensions applied by the extracellular matrix during liver fibrosis could influence the hepatocarcinogenesis process. The objective of this study is to determine if 3D stiffness could influence growth and phenotype of normal and transformed hepatocytes and to integrate extracellular matrix (ECM) stiffness to tensional homeostasis. We have developed an appropriate 3D culture model: hepatic cells within three-dimensional collagen matrices with varying rigidity. Our results demonstrate that the rigidity influenced the cell phenotype and induced spheroid clusters development whereas in soft matrices, Huh7 transformed cells were less proliferative, well-spread and flattened. We confirmed that ERK1 played a predominant role over ERK2 in cisplatin-induced death, whereas ERK2 mainly controlled proliferation. As compared to 2D culture, 3D cultures are associated with epithelial markers expression. Interestingly, proliferation of normal hepatocytes was also induced in rigid gels. Furthermore, biotransformation activities are increased in 3D gels, where CYP1A2 enzyme can be highly induced/activated in primary culture of human hepatocytes embedded in the matrix. In conclusion, we demonstrated that increasing 3D rigidity could promote proliferation and spheroid developments of liver cells demonstrating that 3D collagen gels are an attractive tool for studying rigidity-dependent homeostasis of the liver cells embedded in the matrix and should be privileged for both chronic toxicological and pharmacological drug screening.
ISSN: 0730-2312

hal-01196600
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01196600
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01196600/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01196600/file/Increasing%203D%20Matrix%20Rigidity_accepted.pdf
DOI : 10.1002/jcb.25356

Éditeur(s) : HAL CCSD
Résumé : International audience
Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.
Eur Respir Rev

hal-01063982
https://hal.archives-ouvertes.fr/hal-01063982
DOI : 10.1183/09059180.00001814
PUBMED : 24881074