Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Diagnosis of toxoplasmic encephalitis (TE) in patients with AIDS is not straightforward because clinicians rely initially on an empiric diagnosis based on clinical and radiographic improvement to specific anti-Toxoplasma gondii therapy. There is therefore a need for biological tools to improve the diagnosis of TE, especially in tropical areas where this diagnosis is likely to be underestimated. The use of PCR testing in blood samples for the diagnosis of TE has been limited by its poor sensitivity in the studies conducted in Europe. In tropical South America, the results of PCR sensitivity in blood samples were controversial. Considering that T. gondii strains from tropical South America have substantial genetic and pathogenic differences with those from USA and Europe, it is therefore important to re-evaluate the performance of the PCR assay in blood samples for the diagnosis of TE in AIDS patients from this region. Our results showed that the only interest of PCR would be in the most severe forms of TE with altered consciousness because PCR is more likely to be positive. We also provided important genotyping data on T. gondii strains isolated in human cases of toxoplasmosis in the Caribbean and in South America.
ISSN: 1935-2727

hal-01503761
https://hal-unilim.archives-ouvertes.fr/hal-01503761
https://hal-unilim.archives-ouvertes.fr/hal-01503761/document
https://hal-unilim.archives-ouvertes.fr/hal-01503761/file/journal.pntd.0004790.pdf
DOI : 10.1371/journal.pntd.0004790

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: HCV treatment uptake has drastically increased in HIV-HCV coinfected patients in France since direct-acting antiviral (DAA) treatment approval, resulting in HCV cure in 63% of all HIV-HCV patients by the end of 2015. We investigated the impact of scaling-up DAA on HCV prevalence in the whole HIV population and in various risk groups over the next 10 years in France using a transmission dynamic compartmental model.Methods: The model was based on epidemiological data from the French Dat’AIDS cohort. Eight risk groups wereconsidered, including high-risk (HR) and low-risk (LR) men who have sex with men (MSM) and male/female heterosexuals,intra-venous drug users, or patients from other risk groups. The model was calibrated on prevalence and incidence dataobserved in the cohort between 2012 and 2015.Results: On January 1, 2016, 156,811 patients were registered as infected with HIV in France (24,900 undiagnosedpatients) of whom 7938 (5.1%) had detectable HCV-RNA (722 undiagnosed patients). Assuming a treatmentcoverage (TC) rate of 30%/year (i.e., the observed rate in 2015), model projections showed that HCV prevalenceamong HIV patients is expected to drop to 0.81% in 2026. Sub-analyses showed a similar decrease of HIV-HCVprevalence in most risk groups, including LR MSM. Due to higher infection and reinfection rates, predicted prevalencein HR MSM remained stable from 6.96% in 2016 to 6.34% in 2026. Increasing annual TC rate in HR MSM to 50/70%would decrease HCV prevalence in this group to 2.35/1.25% in 2026. With a 30% TC rate, undiagnosed patients wouldaccount for 34% of HCV infections in 2026.Conclusions: Our model suggests that DAA could nearly eliminate coinfection in France within 10 years for most riskgroups, including LR MSM. Elimination in HR MSM will require increased TC.
ISSN: 1741-7015

Droits : info:eu-repo/semantics/OpenAccess
inserm-01685739
http://www.hal.inserm.fr/inserm-01685739
http://www.hal.inserm.fr/inserm-01685739/document
http://www.hal.inserm.fr/inserm-01685739/file/2017%2C%20Virlogeux%20-%20Modeling%20HIV-HCV%20coinfection.pdf
DOI : 10.1186/s12916-017-0979-1

Éditeur(s) : HAL CCSD
Résumé : International audience
OBJECTIVES: Semen composition is influenced by HIV-1 infection, yet the impact of semen components on HIV infection of primary target cells has only been studied in samples from HIV-uninfected donors. DESIGN: We compared the effect of seminal plasma from chronically HIV-infected (SP+) versus uninfected donors (SP-) on HIV-1 infection of PBMCs and CD4+T cells. METHODS: Primary cells were infected with HIV-1 in the presence of SP+ or SP- and analyzed for infection level, metabolic activity, HIV receptor expression, proliferation and activation. SP+ and SP- were compared for infection-enhancing peptides, cytokines and prostaglandin E2 levels. RESULTS: SP- efficiently enhanced HIV-1 R5 infection of CD4+ T cells, whereas SP+ enhancing activity was significantly reduced. RANTES concentrations were elevated in SP+ relative to SP-, while the concentrations of infectivity-enhancing peptides (SEVI, SEM1, SEM2) were similar. CCR5 membrane expression levels were reduced on CD4+T cells shortly post-exposure to SP+ compared with SP- and correlated to R5-tropic HIV-1 infection levels, and CCR5 ligands' concentrations in semen. SP+ and SP- displayed similar enhancing activity on PBMC infection by X4-tropic HIV-1. Addition/depletion of RANTES from seminal plasmas modulated their effect on PBMC infection by R5-tropic HIV-1. CONCLUSIONS: Semen from HIV-infected donors exhibit a significantly reduced enhancing potential on CD4+ T cell infection by R5-tropic HIV-1 when compared with semen from uninfected donors. Our data indicate that elevated seminal concentrations of RANTES in HIV+ men can influence the ability of semen to enhance infection.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0
AIDS

hal-01274885
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274885
DOI : 10.1097/QAD.0000000000001048
PUBMED : 26854806

Éditeur(s) : HAL CCSD
Résumé : International audience
o abstract
Revue Des Maladies Respiratoires

hal-01647782
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01647782
DOI : 10.1016/j.rmr.2017.07.017
PUBMED : 28939155

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
ObjectivesTo compare the efficacy, in current clinical practice, of ă first regimens containing abacavir with lamivudine (ABC/3TC) or ă tenofovir with emtricitabine (TDF/FTC) in patients with baseline viral ă load 100000 HIV-1 RNA copies/mL. ă MethodsUsing a prospective cohort, we selected all patients starting a ă first HIV regimen based either on ABC/3TC or on TDF/FTC. The propensity ă score (PS) method was used to limit the indication bias due to the ă observational nature of the data. Adjusting and weighting methods via PS ă were used to compare the effectiveness of a first regimen containing ă ABC/3TC or TDF/FTC. The primary outcome was treatment failure by month ă 12 (M12). ă ResultsOverall, 2781 patients started an antiretroviral (ARV) regimen ă with ABC/3TC or TDF/FTC each in combination with efavirenz, boosted ă atazanavir or boosted darunavir. Among the 2472 uncensored patients ă before M12, 962 (39%) had a baseline viral load 100000 copies/mL of ă whom 294 were in treatment failure at or before M12. Our analyses showed ă no difference between ABC/3TC and TDF/FTC in the risk of treatment ă failure at M12 in patients starting an ARV regimen with a high viral ă load (100000 copies/mL). ă ConclusionsUsing a large prospectively collected cohort of patients ă seeking care in France, we found no evidence that ABC/3TC based regimens ă led to more failures than TDF/FTC based ones in patients with high ă baseline viral loads.
ISSN: 1464-2662

hal-01482656
https://hal.archives-ouvertes.fr/hal-01482656
DOI : 10.1111/hiv.12306

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
The aim of the study was to investigate the impact of first-line combined antiretroviral therapy (cART) regimen on the course of CD8 + T-cell counts in human immunodeficiency virus (HIV)-infected patients. A retrospective observational study conducted on the French DAT'AIDS Cohort of HIV-infected patients. We selected 605 patients initiating a first-line cART between 2002 and 2009, and which achieved a sustained undetectable HIV plasma viral load (pVL) for at least 12 months without cART modification. The evolution of CD8 + T-cell counts according to cART regimen was assessed. CD8 + T-cell counts were assessed in 572 patients treated with 2NRTIs+1PI/r (n= 297), 2NRTIs+1NNRTI (n= 207) and 3NRTIs (n= 68). In multivariate analysis, after 12 months of follow-up, the 3NRTIs regimen was associated with a significantly smaller decrease of CD8 + T-cell count compared with NNRTI-containing regimens (–10.2 cells/mL in 3NRTIs vs –105.1 cells/mL; P=0.02) but not compared with PI-containing regimens (10.2 vs –60.9 cells/mL; P=0.21). After 24 months, the 3NRTIs regimen was associated with a smaller decrease of CD8 + T-cell count and % compared with PI/r-and NNRTI-containing regimens (0.2 in 3NRTIs vs –9.9 with PI/r-regimens, P=0.001, and vs –11.1 with NNRTI-regimens, p < 0.0001). A focus analysis on 11 patients treated with an INSTI-containing cART regimen during the study period showed after 12 months of follow-up, a median decrease of CD8 + T-cell count of –155 [inter quartile range: –302; –22] cells/mL. Our data highlight the fact that cART regimens have differential effects on CD8 pool down regulation. Abbreviations: cART = combined antiretroviral therapy, HIV = human immunodeficiency virus, INSTI = integrase strand transfer inhibitor, NNRTI = non-nucleotide reverse transcriptase inhibitor, NRTI = nucleotide reverse transcriptase inhibitor, PI/r = Ritonavir-boosted protease inhibitor, pVL = plasma viral load.
ISSN: 0025-7974

inserm-01408002
http://www.hal.inserm.fr/inserm-01408002
http://www.hal.inserm.fr/inserm-01408002/document
http://www.hal.inserm.fr/inserm-01408002/file/2016%2C%20Poizot-Martin%20-%20First-line%20cART%20regimen%20impacts%20the%20course%20of%20CD8%2B%20T-cell%20counts%20in%20HIV-infected%20patients.pdf
DOI : 10.1097/MD.0000000000005087

Éditeur(s) : HAL CCSD
Résumé : International audience
o abstract
Revue Des Maladies Respiratoires

hal-01647076
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01647076
DOI : 10.1016/j.rmr.2017.07.022
PUBMED : 28935495

Éditeur(s) : HAL CCSD BMJ Publishing Group
Résumé : International audience
BACKGROUND: Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (ADPD), the most common of which is the p.G2019S substitution that has been found at varying frequencies worldwide. Because of the size of the LRRK2 gene, few studies have analysed the entire gene in large series of ADPD families. METHODS: We performed extensive mutation analyses of all 51 coding exons of the LRRK2 gene in index cases from 226 Parkinson's disease families compatible with autosomal dominant inheritance, mostly from France (n = 182) and North Africa (n = 14). RESULTS: We found 79 sequence variants, 29 of which were novel. Eight potentially or proven pathogenic mutations were found in 22 probands (9.7%). There were four novel amino acid substitutions that are potentially pathogenic (p.S52F, p.N363S, p.I810V, p.R1325Q) and two novel variants, p.H1216R and p.T1410M, that are probably not causative. The common p.G2019S mutation was identified in 13 probands (5.8%) including six from North Africa (43%). The known heterozygous p.R1441H and p.I1371V mutations were found in two probands each, and the p.E334K variant was identified in one single patient. Most potentially or proven pathogenic mutations were located in the functional domains of the Lrrk2 protein. CONCLUSION: This study leads us to conclude that LRRK2 mutations are a common cause of autosomal dominant Parkinson's disease in Europe and North Africa.
ISSN: 0022-2593

inserm-00529272
http://www.hal.inserm.fr/inserm-00529272
DOI : 10.1136/jmg.2008.062612
PUBMED : 19357115

Éditeur(s) : HAL CCSD
Résumé : International audience
Up-to-date estimates of the health outcomes of preterm children are needed for assessing perinatal care, informing parents, making decisions about care, and providing evidence for clinical guidelines. To determine survival and neonatal morbidity of infants born from 22 through 34 completed weeks' gestation in France in 2011 and compare these outcomes with a comparable cohort in 1997. The EPIPAGE-2 study is a national, prospective, population-based cohort study conducted in all maternity and neonatal units in France in 2011. A total of 2205 births (stillbirths and live births) and terminations of pregnancy at 22 through 26 weeks' gestation, 3257 at 27 through 31 weeks, and 1234 at 32 through 34 weeks were studied. Cohort data were collected from January 1 through December 31, 1997, and from March 28 through December 31, 2011. Analyses for 1997 were run for the entire year and then separately for April to December; the rates for survival and morbidities did not differ. Data are therefore presented for the whole year in 1997 and the 8-month and 6-month periods in 2011. Survival to discharge and survival without any of the following adverse outcomes: grade III or IV intraventricular hemorrhage, cystic periventricular leukomalacia, severe bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher), or necrotizing enterocolitis (stages 2-3). A total of 0.7% of infants born before 24 weeks' gestation survived to discharge: 31.2% of those born at 24 weeks, 59.1% at 25 weeks, and 75.3% at 26 weeks. Survival rates were 93.6% at 27 through 31 weeks and 98.9% at 32 through 34 weeks. Infants discharged home without severe neonatal morbidity represented 0% at 23 weeks, 11.6% at 24 weeks, 30.0% at 25 weeks, 47.5% at 26 weeks, 81.3% at 27 through 31 weeks, and 96.8% at 32 through 34 weeks. Compared with 1997, the proportion of infants surviving without severe morbidity in 2011 increased by 14.4% (P < .001) at 25 through 29 weeks and 6% (P < .001) at 30 through 31 weeks but did not change appreciably for those born at less than 25 weeks. The rates of antenatal corticosteroid use, induced preterm deliveries, cesarean deliveries, and surfactant use increased significantly in all gestational-age groups, except at 22 through 23 weeks. The substantial improvement in survival in France for newborns born at 25 through 31 weeks' gestation was accompanied by an important reduction in severe morbidity, but survival remained rare before 25 weeks. Although improvement in survival at extremely low gestational age may be possible, its effect on long-term outcomes requires further studies. The long-term results of the EPIPAGE-2 study will be informative in this regard.
ISSN: 2168-6211

hal-01258705
http://hal.univ-brest.fr/hal-01258705
PUBMED : 25621457
DOI : 10.1001/jamapediatrics.2014.3351

Éditeur(s) : HAL CCSD
Résumé : International audience
OBJECTIVES: We investigated the relationship between lung cancer and occupational exposure to welding activity in ICARE, a population-based case-control study. METHODS: Analyses were restricted to men (2276 cases, 2780 controls). Welding exposure was assessed through detailed questionnaires, including lifelong occupational history. ORs were computed using unconditional logistic regression, adjusted for lifelong cigarette smoking and occupational exposure to asbestos. RESULTS: Among the regular welders, welding was associated with a risk of lung cancer (OR=1.7, 95% CI 1.1 to 2.5), which increased with the duration (OR=2.0, 95% CI 1.0 to 3.9 when duration extgreater10 years), and was maximum 10-20 years since last welding. The risk was more pronounced in case of gas welding (OR=2.0, 95% CI 1.2 to 3.3), when the workpiece was covered by paint, grease, or other substances (OR=2.0, 95% CI 1.2 to 3.4) and when it was cleaned with chemical substances before welding. No statistically significant increase in lung cancer risk was observed among occasional welders. CONCLUSIONS: Although these results should be confirmed, we showed that type of welding and mode of workpiece preparation are important determinants of the lung cancer risk in regular welders
Occupational and Environmental Medicine

hal-01274887
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274887
DOI : 10.1136/oemed-2015-102964
PUBMED : 26865654

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Few studies have been undertaken to assess the possible effects of bisphenol A (BPA) on the reproductive hormone balance in animals or humans with often contradictory results. We investigated possible direct endocrine disruption by BPA of the fetal testes of 2 rat strains (14.5-17.5 days post-coitum) and humans (8-12 gestational weeks) and under different culture conditions. BPA concentrations of 10-8M and 10-5M for 72h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain. The suppressive effects at 10-5M were seen as early as 24h and 48h in both strains. BPA at 10-7-10-5M for 72h suppressed the levels of fetal rat Leydig cell insulin-like factor 3 (INSL3). BPA exposure at 10-8M, 10-7M, and 10-5M for 72h inhibited testosterone production in fetal human testes. For the lowest doses, the effects observed occurred only when no gonadotrophin was added to the culture media and were associated with a poorly preserved testicular morphology. We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.
ISSN: 1932-6203

hal-01121759
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01121759
PUBMED : 25706302
DOI : 10.1371/journal.pone.0117226

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.
ISSN: 1098-3600

hal-01134364
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134364
DOI : 10.1038/gim.2015.29
PUBMED : 25790162

Éditeur(s) : HAL CCSD
Résumé : International audience
Febrile illness is a common cause of attendance at emergency departments. The purpose of this study was to describe infectious aetiologies of fever in a tropical setting. We prospectively included 1443 febrile patients, all French Guiana residents, who presented at Cayenne Hospital emergency department. This report will propose an overview of aetiologies of febrile illness in French Guiana, and tropical diseases such as malaria and arbovirus infections are discussed. Almost 30% of fevers remained unexplained. Further prospective multicentre studies are warranted to improve the diagnosis of overlooked pathogens in French Guiana. Such studies would lead to conclusions of specific interest in the travel medicine field.
Transactions of the Royal Society of Tropical Medicine and Hygiene / Transactions of the Royal Society for Tropical Medicine and Hygiene

pasteur-00584097
https://hal-riip.archives-ouvertes.fr/pasteur-00584097
DOI : 10.1016/j.trstmh.2008.06.011
PUBMED : 18640694

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
ISSN: 2045-2322

Droits : http://creativecommons.org/licenses/by/
hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/file/The%20environmental%20carcinogen-CCBY%20%281%29.pdf
DOI : 10.1038/srep30776

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BackgroundTo date, all studies conducted on breast cancer diagnosis have focused on the expression of the full-length 66-kDa estrogen receptor alpha (ERα66). However, much less attention has been paid to a shorter 46-kDa isoform (ERα46), devoid of the N-terminal region containing the transactivation function AF-1. Here, we investigated the expression levels of ERα46 in breast tumors in relation to tumor grade and size, and examined the mechanism of its generation and its specificities of coregulatory binding and its functional activities.MethodsUsing approaches combining immunohistochemistry, Western blotting, and proteomics, antibodies allowing ERα46 detection were identified and the expression levels of ERα46 were quantified in 116 ERα-positive human breast tumors. ERα46 expression upon cellular stress was studied, and coregulator bindings, transcriptional, and proliferative response were determined to both ERα isoforms.ResultsERα46 was expressed in over 70% of breast tumors at variable levels which sometimes were more abundant than ERα66, especially in differentiated, lower-grade, and smaller-sized tumors. We also found that ERα46 can be generated via internal ribosome entry site-mediated translation in the context of endoplasmic reticulum stress. The binding affinities of both unliganded and fully-activated receptors towards co-regulator peptides revealed that the respective potencies of ERα46 and ERα66 differ significantly, contributing to the differential transcriptional activity of target genes to 17β estradiol (E2). Finally, increasing amounts of ERα46 decrease the proliferation rate of MCF7 tumor cells in response to E2.ConclusionsWe found that, besides the full-length ERα66, the overlooked ERα46 isoform is also expressed in a majority of breast tumors. This finding highlights the importance of the choice of antibodies used for the diagnosis of breast cancer, which are able or not to detect the ERα46 isoform. In addition, since the function of both ERα isoforms differs, this work underlines the need to develop new technologies in order to discriminate ERα66 and ERα46 expression in breast cancer diagnosis which could have potential clinical relevance.
ISSN: 1465-5411

inserm-01412032
http://www.hal.inserm.fr/inserm-01412032
http://www.hal.inserm.fr/inserm-01412032/document
http://www.hal.inserm.fr/inserm-01412032/file/13058_2016_Article_780.pdf
DOI : 10.1186/s13058-016-0780-7

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
OBJECTIVES: Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. METHODS: We conducted a French nationwide retrospective study that included 47 patients with GPA-related TBS. RESULTS: Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P = 0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose ≥30 mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. CONCLUSION: TBS represents severe and refractory manifestations with a high rate of restenosis. High-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis.
ISSN: 1462-0324

hal-01155105
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01155105
DOI : 10.1093/rheumatology/kev129
PUBMED : 26001634

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
OBJECTIVES:Blood rheology plays a key role in the pathophysiology of sickle cell anaemia (SS) and sickle cell haemoglobin C disease (SC), but its evolution over the lifespan is unknown.MATERIALS AND METHODS:Blood viscosity, red blood cell (RBC) deformability and aggregation, foetal haemoglobin (HbF) and haematocrit were measured in 114 healthy individuals (AA), 267 SS (161 children + 106 adults) and 138 SC (74 children + 64 adults) patients.RESULTS:Our results showed that 1) RBC deformability is at its maximal value during the early years of life in SS and SC populations, mainly because HbF level is also at its peak, 2) during childhood and adulthood, hydroxycarbamide treatment, HbF level and gender modulated RBC deformability in SS patients, independently of age, 3) blood viscosity is higher in older SS and SC patients compared to younger ones and 4) haematocrit decreases as SS patients age.CONCLUSION:The hemorheological changes detected in older patients could play a role in the progressive development of several chronic disorders in sickle cell disease, whose prevalence increases with age. Retarding these age-related haemorheological impairments, by using suitable drugs, may minimize the risks of vaso-occlusive events and chronic disorders.
ISSN: 1932-6203

Droits : http://creativecommons.org/licenses/by/
hal-01669747
https://hal.univ-antilles.fr/hal-01669747
DOI : 10.1371/journal.pone.0158182
PUBMED : 27355589
PUBMEDCENTRAL : PMC4927160

Éditeur(s) : HAL CCSD Impact journals
Résumé : International audience
Interleukin (IL)-33 has been recently reported to be strongly pro-fibrogenic in various models of liver disease. Our aim was to study the role of endogenous IL-33 in a diet-induced model of steatohepatitis. IL-33 deficient mice and wild type (WT) littermates received a high-fat diet (HFD), or a standard diet for 12 weeks. The HFD-induced steatohepatitis was associated with an upregulation of IL-33 transcripts and protein. An insulin tolerance test revealed lower systemic insulin sensitivity in IL33-/-HFD mice than in WT-HFD mice. Nevertheless, IL-33 deficiency did not affect the severity of liver inflammation by histological and transcriptomic analyses, nor the quantity of liver fibrosis. Livers from HFD mice had more myeloid populations, markedly fewer NKT cells and higher proportion of ST2+ Treg cells and ST2+ type 2 innate lymphoid cells (ILC2), all unaffected by IL-33 deficiency. In conclusion, deficiency of endogenous IL-33 does not affect the evolution of experimental diet-induced steatohepatitis towards liver fibrosis.
ISSN: 1949-2553

hal-01578584
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578584
DOI : 10.18632/oncotarget.18335
PUBMED : 28611297

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Cytomegalovirus (CMV) infection is common among HIV-infected patients but its repercussion on the course of CD4+ and CD8+ T cells after cART initiation remains elusive. The French Dat'AIDS cohort enrolled 5,688 patients on first-line cART, from which we selected patients who achieved HIV suppression for at least 12 months without modification of cART, and for whom CMV serostatus was available. Five hundred and three patients fulfilled the selection criteria (74% male, median age 43 yrs, 15.5% CDC stage C), of whom 444 (88.3%) were seropositive for CMV (CMV+). Multivariate analyses using mixed-linear models adjusted for the time from HIV suppression, sex, age, transmission risk group, duration of HIV follow-up, the interaction between time from HIV suppression and CMV+ serol-ogy, and the nadir CD4 count revealed a negative correlation between CMV+ and CD4: CD8 ratio (coeff. =-0.16; p = 0.001). This correlation was also observed among patients displaying optimal CD4 recovery (!500 cells/mm3 at M12; coeff. =-0.24; p = 0.002). Hence, CMV+ serostatus antagonizes normalization of the CD4:CD8 ratio, although further analyses of the impact of co-morbidities that associate with CMV serostatus, like HCV infection, are needed to elucidate this antagonism formally. However, this might reflect a premature T cell senescence, thus advocating for a close monitoring of T cells in CMV co-infected patients. In addition, our results raise the question of the benefit of treatment for asymptomatic CMV co-infection in HIV-infected patients.
ISSN: 1932-6203

inserm-01418700
http://www.hal.inserm.fr/inserm-01418700
http://www.hal.inserm.fr/inserm-01418700/document
http://www.hal.inserm.fr/inserm-01418700/file/journal.pone.0165774.PDF
DOI : 10.1371/journal.pone.0165774

Éditeur(s) : HAL CCSD
Résumé : International audience
Early antifungal therapeutic strategies are proposed during invasive fungal infection (IFI), but antifungal stewardship programs should institute a systematic reevaluation of prescriptions, particularly in the context of empirical treatment. Here, we aimed to evaluate the performances and particularly the negative predictive value (NPV) of diagnostic strategies, including a whole blood panfungal quantitative PCR assay (PF-qPCR) in a high risk population for IFI. The first step was to standardize and optimize a new PF- rtPCR targeting ITS2 region. Then, this method was evaluated in a multicenter prospective study including 313 patients with suspected IFI for whom an early antifungal treatment was prescribed. All patients enrolled at day 0 of their treatment benefited from serum Aspergillus galactomannan (GM) antigen detection twice a week, weekly PF-qPCR assay, and when indicated and feasible, CT-scan and mycological sampling. In total, 125 of 313 patients were diagnosed with IFI: 68 invasive aspergillosis (eight proven, 48 probable and 12 possible), one fusariosis, 47 candidemia, three disseminated candidiasis and six cryptococcosis. Globally, the sensitivity of the PF-qPCR assay was only 40%, but the specificity, PPV and NPV were 96%, 88% and 69%, respectively. In the population of patients at high risk for invasive aspergillosis who also benefited from Aspergillus GM detection, the sensitivity and the NPV of the combined detection reached to 78% and 84%, respectively. Even higher NPV were obtained when combining negative PF-qPCR and CT scan (95%) as well as negative GM and CT scan (93%), thus allowing to rationalize and re-evaluate the prescription of empirical treatment in such highly selected population.
The Journal of Infection

hal-01146845
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146845
DOI : 10.1016/j.jinf.2015.04.005
PUBMED : 25896093