Éditeur(s) : HAL CCSD European Respiratory Society
Résumé : International audience
ISSN: 0903-1936

hal-01117958
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117958
DOI : 10.1183/09031936.00111113
PUBMED : 24687678

Éditeur(s) : HAL CCSD Elsevier - Oxford University Press
Résumé : International audience
Meeting Abstract: P171
ISSN: 1873-9946

hal-01359565
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359565
DOI : 10.1093/ecco-jcc/jjw019.290

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans.
ISSN: 0041-008X

inserm-00872871
http://www.hal.inserm.fr/inserm-00872871
DOI : 10.1016/j.taap.2012.05.004
PUBMED : 22617429

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Objectives To investigate the association between priapism in men with sickle cell anemia (SCA) and hemorheological and hemolytical parameters. Materials and Methods Fifty-eight men with SCA (median age: 38 years) were included; 28 who had experienced priapism at least once during their life (priapism group) and 30 who never experienced this complication (control group). Twenty-two patients were treated with hydroxycarbamide, 11 in each group. All patients were at steady state at the time of inclusion. Hematological and biochemical parameters were obtained through routine procedures. The Laser-assisted Optical Rotational Cell Analyzer was used to measure red blood cell (RBC) deformability at 30 Pa (ektacytometry) and RBC aggregation properties (laser backscatter versus time). Blood viscosity was measured at a shear rate of 225 s(-1) using a cone/plate viscometer. A principal component analysis was performed on 4 hemolytic markers (i.e., lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT), total bilirubin (BIL) levels and reticulocyte (RET) percentage) to calculate a hemolytic index. Results Compared to the control group, patients with priapism exhibited higher ASAT (p = 0.01), LDH (p = 0.03), RET (p = 0.03) levels and hemolytic indices (p = 0.02). Higher RBC aggregates strength (p = 0.01) and lower RBC deformability (p = 0.005) were observed in patients with priapism compared to controls. After removing the hydroxycarbamide-treated patients, RBC deformability (p = 0.01) and RBC aggregate strength (p = 0.03) were still different between the two groups, and patients with priapism exhibited significantly higher hemolytic indices (p = 0.01) than controls. Conclusion Our results confirm that priapism in SCA is associated with higher hemolytic rates and show for the first time that this complication is also associated with higher RBC aggregate strength and lower RBC deformability.
ISSN: 1932-6203

hal-01390971
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390971
DOI : 10.1371/journal.pone.0154866
PUBMED : 27145183

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The use of recombinant antigens has been shown to improve both the sensitivity and the standardization of the serological diagnosis of Farmer's lung disease (FLD). The aim of this study was to complete the panel of recombinant antigens available for FLD serodiagnosis with antigens of Lichtheimia corymbifera, known to be involved in FLD. L. corymbifera proteins were thus separated by 2D electrophoresis and subjected to western blotting with sera from 7 patients with FLD and 9 healthy exposed controls (HEC). FLD-associated immunoreactive proteins were identified by mass spectrometry based on a protein database specifically created for this study and subsequently produced as recombinant antigens. The ability of recombinant antigens to discriminate patients with FLD from controls was assessed by ELISA performed with sera from FLD patients (n = 41) and controls (n = 43) recruited from five university hospital pneumology departments of France and Switzerland. Forty-one FLD-associated immunoreactive proteins from L. corymbifera were identified. Six of them were produced as recombinant antigens. With a sensitivity and specificity of 81.4 and 77.3% respectively, dihydrolipoyl dehydrogenase was the most effective antigen for discriminating FLD patients from HEC. ELISA performed with the putative proteasome subunit alpha type as an antigen was especially specific (88.6%) and could thus be used for FLD confirmation. The production of recombinant antigens from L. corymbifera represents an additional step towards the development of a standardized ELISA kit for FLD diagnosis.
ISSN: 1932-6203

hal-01368315
https://hal.archives-ouvertes.fr/hal-01368315
DOI : 10.1371/journal.pone.0160888
PUBMED : 27490813
PUBMEDCENTRAL : PMC4973876

Éditeur(s) : HAL CCSD
Résumé : National audience
Objectives To define the different stages of spontaneous labour. To determine the indications, modalities of use and the effects of administering synthetic oxytocin. And to describe undesirable maternal and perinatal outcomes associated with the use of synthetic oxytocin. Method A systematic review was carried out by searching Medline database and websites of obstetrics learned societies until March 2016. Results The 1st stage of labor is divided in a latence phase and an active phase, which switch at 5 cm of cervical dilatation. Rate of cervical dilatation is considered as abnormal below 1 cm per 4 hour during the first part of the active phase, and blow 1 cm per 2 hours above 7 cm of dilatation. During the latent phase of the first stage of labor, i.e. before 5 cm of cervical dilatation, it is recommended that an amniotomy not be performed routinely and not to use oxytocin systematically. It is not recommended to expect the active phase of labor to start the epidural analgesia if patient requires it. If early epidural analgesia was performed, the administration of oxytocin must not be systematic. If dystocia during the active phase, an amniotomy is recommended in first-line treatment. In the absence of an improvement within an hour, oxytocin should be administrating. However, in the case of an extension of the second stage beyond 2 hours, it is recommended to administer oxytocin to correct a lack of progress of the presentation. If dynamic dystocia, it is recommended to start initial doses of oxytocin at 2 mUI/min, to respect at least 30 min intervals between increases in oxytocin doses delivered, and to increase oxytocin doses by 2 mUI/min intervals without surpassing a maximum IV flow rate of 20 mUI/min. The reported maternal adverse effects concern uterine hyper-stimulation, uterine rupture and postpartum haemorrhage, and those of neonatal adverse effects concern foetal heart rate anomalies associated with uterine hyper-stimulation, neonatal morbidity and mortality, neonatal jaundice, weak suck/poor breastfeeding latch and autism. Conclusion The widespread use of oxytocin during spontaneous labour must not be considered as simply another inoffensive prescription without any possible deleterious consequences for mother or foetus. Conditions for administering the oxytocin must therefore respect medical protocols. Indications and patient consent have to be report in the medical file. © 2016 Elsevier Masson SAS
Revue Sage - Femme

hal-01467543
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467543
DOI : 10.1016/j.sagf.2016.11.006

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : National audience
o abstract
ISSN: 1166-7087

hal-01477211
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01477211
DOI : 10.1016/j.purol.2016.07.209
PUBMED : 27969303

Éditeur(s) : HAL CCSD Wiley-VCH Verlag
Résumé : International audience
Saccharopolyspora rectivirgula is the principal cause of farmer's lung disease (FLD). Serodiagnosis is based on immunoprecipitation techniques or enzyme immunoassays with homemade crude antigens and is not standardized. We aimed to produce specific recombinant antigens for the development of a standardized ELISA. We recruited 41 patients and 43 healthy exposed controls from five university hospital pneumology departments in France and Switzerland. S. rectivirgula proteins were extracted, separated by 2D electrophoresis, and subjected to Western blotting, with sera from FLD patients or controls. FLD-specific proteins were identified by MS and were produced as recombinant antigens. The diagnostic performance of ELISA tests using the recombinant antigens was assessed with all the sera from FLD patients and controls. We identified 25 FLD-specific proteins, some of which play important roles in transport, nutrition, or virulence. We produced 17 of these proteins as recombinant antigens and assessed their suitability for inclusion in the ELISA test. A combination of three of these proteins (SR1FA, SR17, and SR22) proved remarkably effective at discriminating between patients and controls, with a sensitivity of 83% and a specificity of 77%. The recombinant antigens produced in this study constitute a major step toward the improvement of diagnostic performance and the standardization of FLD serodiagnosis.
ISSN: 1862-8346

hal-01115880
https://hal.archives-ouvertes.fr/hal-01115880
DOI : 10.1002/prca.201400024
PUBMED : 25264606

Éditeur(s) : HAL CCSD
Résumé : National audience
Aspirin (acetylsalicylic acid) has been used ever since the Antiquity for its painkilling and anti-inflammatory effects. Its antiplatelet properties have then extended its indications to the field of coronaropathy and vascular cerebral disease, and finally to vascular placental disease. Aspirin has been widely prescribed since the 1980's to prevent pre-eclampsia, intra-uterine growth retardation and fetal death of vascular origin. It has also been proposed to prevent unexplained recurrent miscarriages. Its use during pregnancy is considered as safe, provided the daily doses do not exceed 100mg. Aspirin has been proven efficient to prevent pre-eclampsia and fetal growth restriction in high-risk patients. The benefits of prescribing aspirin have been demonstrated neither for vascular placental disease prevention in low risk patients, nor in cases of unexplained recurrent miscarriages.
La Revue De Medecine Interne

hal-01659441
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01659441
DOI : 10.1016/j.revmed.2017.10.419
PUBMED : 29129461

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 muM (OCT1 inhibition by allethrin) to 77.6 muM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 muM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.
ISSN: 1932-6203

hal-01477206
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01477206
DOI : 10.1371/journal.pone.0169480
PUBMED : 28099443

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
OBJECTIVES: The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). DESIGN AND METHODS: Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. RESULTS: Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4 T-cell counts and CD4 T/CD8 T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4 T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. CONCLUSION: When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation.
ISSN: 0269-9370

hal-00875175
https://hal.archives-ouvertes.fr/hal-00875175
DOI : 10.1097/QAD.0b013e32835844d9
PUBMED : 22842994

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Chlordecone is a persistent organochlorine pesticide that was used in the French West Indies until the early 1990s for banana weevil borer control. Human exposure to this chemical in this area still occurs nowadays due to consumption of contaminated food. Although adverse effects on neurodevelopment, including tremors and memory deficits, have been documented in experimental studies conducted with rodents exposed during the gestational and neonatal periods, no study has been conducted yet to determine if chlordecone alters child development. This study examines the relation of gestational and postnatal exposure to chlordecone to infant development at 18 months of age in a birth-cohort of Guadeloupean children. In a prospective longitudinal study conducted in Guadeloupe (Timoun mother-child cohort study), exposure to chlordecone was measured at birth from an umbilical cord blood sample (n=141) and from a breast milk sample collected at 3 months postpartum (n=75). Toddlers were assessed using an adapted version of the Ages and Stages Questionnaire. Higher chlordecone concentrations in cord blood were associated with poorer fine motor scores. When analyses were conducted separately for boys and girls, this effect was only observed among boys. These results suggest that prenatal exposure to chlordecone is associated with specific impairments in fine motor function in boys, and add to the growing evidence that exposure to organochlorine pesticides early in life impairs child development.
ISSN: 0161-813X

hal-00875907
https://hal.archives-ouvertes.fr/hal-00875907
PUBMED : 23376090
DOI : 10.1016/j.neuro.2013.01.007

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : National audience
Objectif Analyser les caractéristiques virologiques et les complications des syndromes grippaux chez les diabétiques en période hivernale. Patients et Méthodes Étude conduite dans 6 hôpitaux (Montpellier, Lyon, Cochin, Bichat, Limoges, Rennes) au cours de 3 saisons grippales (2012-2013, 2013-2014 et 2014-2015), sur 1 451 adultes hospitalisés avec syndrome grippal récent (début ≤ 7 jours), associant un signe respiratoire (toux, dys-pnée) et un signe systémique (fièvre, céphalées, malaise, myalgies). Les virus respiratoires étaient recherchés par RT-PCR sur prélèvement naso-pharyngé ou LBA (Centre National de Référence, Lyon). La vaccination anti-grippale, la présence d'un diabète, les comorbidités, les complications en cours d'hospitalisation (insuffisance rénale, cardiaque, respiratoire, pneumonie, décès) et la durée moyenne de séjour (DMS) étaient enregistrées. Les facteurs de risque de complications ont été étudiés par régression logistique multivariée ajustée sur âge, sexe, infection grippale, vaccination, diabète et antécédents de pathologies rénale, cardiaque ou respiratoire. Résultats Les hospitalisations ont eu lieu dans des services de maladies respiratoires, médecine interne, MIT et réanimation. Un diabète était présent chez 368 sujets (non traités : 15 %, ADO : 41 %, insuline : 27 %, mixte : 17 %). Les diabétiques étaient plus âgés (71 ± 15 vs 65 ± 20 ans, P < 0,001) et présentaient plus souvent un antécédent de pathologie rénale (18 % vs 8 %, P < 0,00001) ou cardiaque (19 % vs 11 %, P < 0,001). Leur couverture vaccinale était meilleure (60 % vs 46 %). Les données virologiques étaient comparables : grippe 38,9 % (76,1 % type A) vs 39,2 % ; (74,1 % type A) ; autres virus respiratoires : 17,0 % vs 19,9 %. La DMS était un peu plus élevée chez les diabétiques (9,1 ± 9 vs 8,9 ± 11, P = 0,015), avec une tendance à un risque de décès plus élevé (6,25 % vs 3,97 %, P 0,07). En analyse multivariée, le diabète était un facteur de risque de complications à type d'insuffisance rénale (OR : 1,66, IC 95 % : 1,10-2,52) mais pas d'insuffisance cardiaque, respiratoire ou de décès. Les complications n'étaient pas modi-fiées par les résultats virologiques. Conclusions Le diabète est un facteur de risque de complications rénales chez les patients hospitalisés avec syndrome grippal
ISSN: 1262-3636

hal-01300779
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01300779
DOI : 10.1016/S1262-3636(16)30020-9

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay. The compound 6E11, a natural product derivative, was characterized as a positive hit. Interestingly, this flavanone compound: inhibits necroptosis induced by death receptors ligands TNF-α (Tumor Necrosis Factor) or TRAIL (TNF-Related Apoptosis-Inducing Ligand); is an extremely selective inhibitor, among kinases, of human RIPK1 enzymatic activity with a nM Kd; has a non-ATP competitive mode of action and a novel putative binding site; is weakly cytotoxic towards human primary blood leukocytes or retinal pigment epithelial cells at effective concentrations; protects human aortic endothelial cells (HAEC) from cold hypoxia/reoxygenation injury more effectively than necrostatin-1 (Nec-1) and Nec-1s. Altogether, these data demonstrate that 6E11 is a novel potent small molecular inhibitor of RIPK1-driven necroptosis.
ISSN: 2045-2322

hal-01616456
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456/file/s41598-017-12788-4.pdf
DOI : 10.1038/s41598-017-12788-4

Éditeur(s) : HAL CCSD European Respiratory Society
Résumé : International audience
Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis. We retrospectively analysed all the genetic diagnoses made between 2007-2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-Associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival. 237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40-60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046). TERT/TERC DAV were associated with specific clinical and biological features and reduced transplantfree survival. ©ERS 2016.
ISSN: 0903-1936

hal-01467555
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467555
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467555/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467555/file/Prevalence%20and%20characteristics%20of%20TERT.pdf
DOI : 10.1183/13993003.02115-2015

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC.
ISSN: 0300-483X

hal-00682486
https://hal.archives-ouvertes.fr/hal-00682486
DOI : 10.1016/j.tox.2011.11.011
PUBMED : 22138297

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
The premature loss of ovarian function may have physical and psychological consequences. A better understanding of its mechanism is therefore needed. Because they are affecting the oocyte quality, the decline of the ovarian reserve and high maternal age are implicated in many defects leading to chromosomal defects, modifications of gene expression or alterations of the mitochondrial pattern of the oocyte. However, cellular therapies such as ovarian follicle activation or isolation of ovarian stem cells are promising treatments of ovarian failure
Le diagnostic d’insuffisance ovarienne chez une femme ayant un projet d’enfanter aura des conséquences non seulement physiques mais également psychologiques. L’optimisation des stratégies de prise en charge thérapeutique nécessite une meilleure compréhension des mécanismes de survenue de cette défaillance. Les mécanismes responsables de la constitution et du maintien de la réserve ovarienne commencent à être élucidés. Avec le déclin de la réserve ovarienne, la qualité ovocytaire diminue, accentuant la baisse de la fertilité associée à l’âge maternel. Les ovocytes et les embryons résultant de patientes âgées présentent des taux d’aneuploïdies élevés, liés à des défauts de cohésion chromosomique et d’instabilité du fuseau méiotique, diminution de la capacité de réparation de l’ADN, altération de l’expression des gènes ou à une altération du fonctionnement mitochondrial. Avec la possibilité d’activer in vitro la folliculogenèse et l’isolement de cellules souches ovariennes, plusieurs pistes de thérapie cellulaire commencent à se développer et semblent très prometteuses.
ISSN: 1297-9589

hal-01231432
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01231432
DOI : 10.1016/j.gyobfe.2015.10.008
PUBMED : 26597936

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
STUDY QUESTION: Do mild analgesics affect the endocrine system of the human adult testis? SUMMARY ANSWER: Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro. WHAT IS KNOWN ALREADY: Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line. STUDY DESIGN, SIZE, DURATION: Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods. MAIN RESULTS AND THE ROLE OF CHANCE: The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play. LIMITATIONS, REASONS FOR CAUTION: Our studies were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.
ISSN: 0268-1161

inserm-00866016
http://www.hal.inserm.fr/inserm-00866016
PUBMED : 23670170
DOI : 10.1093/humrep/det112

Éditeur(s) : HAL CCSD Publisher : Paris : Baillière [1980-. Latest Publisher : Paris : Elsevier
Résumé : National audience
Pneumocystis jiroveci (anciennement P. carinii) est un champignon opportuniste responsable de pneumopathies chez les patients immunodéprimés. Les pneumocystoses des patients non infectés par le VIH se distinguent des pneumocystoses du sida par des difficultés diagnostiques accrues, et un pronostic plus sombre. Il est donc indispensable de cibler les immunodépressions les plus à risque, qui bénéficieront d’un traitement par triméthoprime-sulfaméthoxazole à faible dose au long cours, très efficace en prophylaxie des pneumocystoses : ainsi, les vascularites des moyens et petits vaisseaux, les hémopathies lymphoïdes B (leucémie lymphoïde chronique ou aiguë, lymphome malin non hodgkinien) et les cancers solides sous corticothérapie prolongée doivent faire envisager cette prophylaxie. À l’inverse, la généralisation de la prophylaxie à l’ensemble des patients porteurs de pathologies inflammatoires sous corticothérapie n’est pas justifiée. La prise en charge des pneumocystoses des patients non infectés par le VIH suit les principes établis pour les pneumocystoses du sida. Le diagnostic de certitude repose sur la mise en évidence de kystes de P. jiroveci sur des prélèvements respiratoires, tandis que la PCR ne permet pas formellement, en 2015, de différencier colonisation et infection. Le traitement repose sur le triméthoprime-sulfaméthoxazole à fortes doses. Par contre, l’intérêt de la corticothérapie adjuvante pour les patients hypoxémiques, parfaitement documenté au cours du sida, est discuté pour les autres immunodépressions, d’autant que les patients sont en général déjà sous corticoïdes au moment du diagnostic de pneumocystose. Celle-ci est cependant préconisée par plusieurs experts et sociétés savantes, compte tenu du bénéfice démontré sur la morbi-mortalité au cours du sida. Abstract Pneumocystis jiroveci (formerly P. carinii) is an opportunistic fungus responsible for pneumonia in immunocompromised patients. Pneumocystosis in non-HIV-infected patients differs from AIDS-associated pneumocystosis in mostly two aspects: diagnosis is more difficult, and prognosis is worse. Hence, efforts should be made to target immunocompromised patients at higher risk of pneumocystosis, so that they are prescribed long-term, low-dose, trimethoprime-sulfamethoxazole, highly effective for pneumocystosis prophylaxis. Patients at highest risk include those with medium and small vessels vasculitis, lymphoproliferative B disorders (chronic or acute lymphocytic leukaemia, non-Hodgkin lymphoma), and solid cancer on long-term corticosteroids. Conversely, widespread use of prophylaxis in all patients carrier of inflammatory diseases on long-term corticosteroids is not warranted. The management of pneumocystosis in non-AIDS immunocompromised patients follows the rules established for AIDS patients. The diagnosis relies on the detection of P. jiroveci cyst on respiratory samples, while PCR does not reliably discriminate infection from colonization, in 2015. High-doses trimethoprim-sulfamethoxazole is, by far, the treatment of choice. The benefit of adjuvant corticosteroid therapy for hypoxic patients, well documented in AIDS patients, has a much lower level of evidence in non-HIV-infected patients, most of them being already on corticosteroid by the time of pneumocystosis diagnosis anyway. However, based on its striking impact on morbi-mortality in AIDS patients, adjuvant corticosteroid is recommended in hypoxic, non-HIV-infected patients with pneumocystosis by many experts and scientific societies
ISSN: 0248-8663

hal-01237080
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237080
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237080/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237080/file/Pneumocystose%20chez%20les%20patients%20immunod%C3%A9prim%C3%A9s%20non%20infect%C3%A9s%20par%20le%20VIH.pdf
DOI : 10.1016/j.revmed.2015.10.002

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
STUDY QUESTION: Is prenatal exposure to persistent organic pollutants (POPs) associated with variations of sex hormone levels in cord blood? SUMMARY ANSWER: Prenatal exposure to a number of POPs is associated with a disruption of hormone levels in cord blood, with sex specificities. WHAT IS KNOWN ALREADY: Epidemiological studies have reported disorders of reproductive health, in relation with POPs exposure during early life and the endocrine disruption properties of these chemicals have been suggested as possible mechanisms. STUDY DESIGN, SIZE, DURATION: A subset of 282 mother-child pairs was selected from the prospective population-based PELAGIE birth cohort (n = 3421, 2002-2006, Brittany, France). Pregnant women were recruited before 19 weeks of gestation and followed until delivery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sex hormone levels including sex hormone-binding globulin (SHBG), estradiol (E2), total testosterone (T), free testosterone (fT = T/SHBG) and the aromatase index (AI = T/E2) were measured in 282 cord blood samples. Anti-Müllerian hormone (AMH) was measured in male newborns only. Pesticide concentrations of α-endosulfan, β-hexachlorocyclohexane (β-HCH), γ-HCH, dieldrin, pp'-dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), heptachlor epoxide (HCE), as well as PCBs (congeners 153, 187 and the sum of anti-estrogenic PCBs 118, 138, and 170) and decabrominated diphenyl ether (BDE209) were also measured in cord blood. Associations between sex hormones and POPs exposure were explored using multiple linear regressions adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: High PCB levels were associated with an increase of SHBG (P-trend extless 0.01) and AMH (P-trend extless 0.05) and a decrease of fT (P-trend extless 0.05) and AI (P-trend extless 0.01). High pesticide levels, particularly α-endosulfan and HCE, were associated with an increase of SHBG (P extless 0.05) and E2 (P extless 0.01) and a decrease of fT (P extless 0.05) and AI (P extless 0.01). Several of these associations were stronger, or specific, among male or female newborns. The associations were not altered in the sensitivity analyses. LIMITATIONS, REASONS FOR CAUTION: The study population was of relatively small sample size, and some compounds rarely detected in cord blood. The high level of correlation between POPs makes it difficult to identify the most contributing POPs. Hormone measurements were performed at birth (in cord blood) and may not adequately represent the infant endocrine system. Multiple statistical testing may have led to false-positive associations. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in discordance with those reported in the only published study of the kind but in accordance with studies about prenatal exposure to other endocrine disruptors such as phthalates. These findings may help understanding the pathways involved in adverse reproductive outcomes associated with POPs exposure. STUDY FUNDING/COMPETING INTERESTS: The PELAGIE cohort is funded by Inserm, French Ministry of Health, French Ministry of Labor, InVS, ANR, ANSES, and French Ministry of Ecology. None of the authors has any competing interest to declare
ISSN: 0268-1161

hal-01220641
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01220641
DOI : 10.1093/humrep/dev260
PUBMED : 26493407