Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The underlying cause of morbidity in cystic fibrosis (CF) is the decline in lung function, which results in part from chronic inflammation. Inflammation and infection occur early in infancy in CF and the role of innate immune defense in CF has been highlighted in the last years. Once thought simply to be consumers of bacteria, macrophages have emerged as highly sensitive immune cells that are located at the balance point between inflammation and resolution of this inflammation in CF pathophysiology. In order to assess the potential role of macrophage in CF, we review the evidence that: (1) CF macrophage has a dysregulated inflammatory phenotype; (2) CF macrophage presents altered phagocytosis capacity and bacterial killing; and (3) lipid disorders in CF macrophage affect its function. These alterations of macrophage weaken innate defense of CF patients and may be involved in CF disease progression and lung damage.
ISSN: 1569-1993

hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/file/Chouly-The%20impact%20of%20impaired%20macrophage%20functions.pdf
DOI : 10.1016/j.jcf.2016.10.011

Éditeur(s) : HAL CCSD Wiley-VCH Verlag
Résumé : International audience
Deciphering the assembly history of the Milky Way is a formidable task, which becomes possible only if one can produce high-resolution chrono-chemo-kinematical maps of the Galaxy. Data from large-scale astrometric and spectroscopic surveys will soon provide us with a well-defined view of the current chemo-kinematical structure of the Milky Way, but will only enable a blurred view on the temporal sequence that led to the present-day Galaxy. As demonstrated by the (ongoing) exploitation of data from the pioneering photometric missions CoRoT, Kepler, and K2, asteroseismology provides the way forward: solar-like oscillating giants are excellent evolutionary clocks thanks to the availability of seismic constraints on their mass and to the tight age-initial-mass relation they adhere to. In this paper we identify five key outstanding questions relating to the formation and evolution of the Milky Way that will need precise and accurate ages for large samples of stars to be addressed, and we identify the requirements in terms of number of targets and the precision on the stellar properties that are needed to tackle such questions. By quantifying the asteroseismic yields expected from PLATO for red-giant stars, we demonstrate that these requirements are within the capabilities of the current instrument design, provided that observations are sufficiently long to identify the evolutionary state and allow robust and precise determination of acoustic-mode frequencies. This will allow us to harvest data of sufficient quality to reach a 10% precision in age. This is a fundamental pre-requisite to then reach the more ambitious goal of a similar level of accuracy, which will only be possible if we have to hand a careful appraisal of systematic uncertainties on age deriving from our limited understanding of stellar physics, a goal which conveniently falls within the main aims of PLATO's core science.
ISSN: 0004-6337

hal-01541393
https://hal.archives-ouvertes.fr/hal-01541393
ARXIV : 1706.3778
BIBCODE : 2017AN....338..644M
DOI : 10.1002/asna.201713385

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 Public Library of Science
Résumé : International audience
BACKGROUND: While a great number of papers have been published on the short-term effects of air pollution on mortality, few have tried to assess whether this association varies according to the neighbourhood socioeconomic level and long-term ambient air concentrations measured at the place of residence. We explored the effect modification of 1) socioeconomic status, 2) long-term NO2 ambient air concentrations, and 3) both combined, on the association between short-term exposure to NO2 and all-cause mortality in Paris (France).METHODS: A time-stratified case-crossover analysis was performed to evaluate the effect of short-term NO2 variations on mortality, based on 79,107 deaths having occurred among subjects aged over 35 years, from 2004 to 2009, in the city of Paris. Simple and double interactions were statistically tested in order to analyse effect modification by neighbourhood characteristics on the association between mortality and short-term NO2 exposure. The data was estimated at the census block scale (n=866).RESULTS: The mean of the NO2 concentrations during the five days prior to deaths were associated with an increased risk of all-cause mortality: overall Excess Risk (ER) was 0.94% (95%CI=[0.08;1.80]. A higher risk was revealed for subjects living in the most deprived census blocks in comparison with higher socioeconomic level areas (ER=3.14% (95%CI=[1.41-4.90], p extless0.001). Among these deprived census blocks, excess risk was even higher where long-term average NO2 concentrations were above 55.8 μg/m3 (the top tercile of distribution): ER=4.84% (95%CI=[1.56;8.24], p for interaction=0.02).CONCLUSION: Our results show that people living in census blocks characterized by low socioeconomic status are more vulnerable to air pollution episodes. There is also an indication that people living in these disadvantaged census blocks might experience even higher risk following short-term air pollution episodes, when they are also chronically exposed to higher NO2 levels
ISSN: 1932-6203

hal-01187406
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187406
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187406/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187406/file/journal.pone.0131463.PDF
DOI : 10.1371/journal.pone.0131463

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
BACKGROUND:Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While βS -haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA.PROCEDURE:Steady-state haemorheological profile, biological parameters, βS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA.RESULTS:Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the βS -haplotypes in our study.CONCLUSION:Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.
ISSN: 1545-5009

hal-01668317
https://hal.univ-antilles.fr/hal-01668317
DOI : 10.1002/pbc.26455
PUBMED : 28097791

Éditeur(s) : HAL CCSD Elsevier Science
Résumé : International audience
Some anthropogenic noise is now considered pollution, with evidence building that noise from human activities such as transportation, construction and exploration can impact behaviour and physiology in a broad range of taxa. However, relatively little research has considered the effects of repeated or chronic noise; extended exposures may result in habituation or sensitisation, and thus changes in response. We conducted a field-based experiment at Moorea Island to investigate how repeated exposure to playback of motorboat noise affected a coral reef fish (Dascyllus trimaculatus). We found that juvenile D. trimaculatus increased hiding behaviour during motorboat noise after two days of repeated exposure, but no longer did so after one and two weeks of exposure. We also found that naïve individuals responded to playback of motorboat noise with elevated ventilation rates, but that this response was diminished after one and two weeks of repeated exposure. We found no strong evidence that baseline blood cortisol levels, growth or body condition were affected by three weeks of repeated motorboat-noise playback. Our study reveals the importance of considering how tolerance levels may change over time, rather than simply extrapolating from results of short-term studies, if we are to make decisions about regulation and mitigation.
ISSN: 0013-9327

Droits : http://creativecommons.org/licenses/by/
hal-01357915
https://hal-univ-perp.archives-ouvertes.fr/hal-01357915
https://hal-univ-perp.archives-ouvertes.fr/hal-01357915/document
https://hal-univ-perp.archives-ouvertes.fr/hal-01357915/file/1-s2.0-S0269749116304468-main.pdf
DOI : 10.1016/j.envpol.2016.05.058

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: Dairy working increases the prevalence of lower airway respiratory diseases, especially COPD and asthma. Epidemiological studies have reported that chronic inhalation of organic dusts released during specific daily tasks could represent a major risk factor for development of these pathologies in dairy workers. Knowledge on size, nature and biological activity of such organic dusts remain however limited. OBJECTIVE: To compare size distribution, microbial composition and cellular effects of dusts liberated by the spreading of straw bedding in five French dairy farms located in Brittany. RESULTS: Mechanized distribution of straw bedding generated a cloud of inhalable dusts in the five dairy farms' barns. Thoracic particles having a 3-7.5µm size constituted 58.9-68.3% of these dusts. Analyses of thoracic dusts by next generation sequencing showed that the microbial dust composition differed between the five French farms, although Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria represent more than 97.5% of the bacterial phyla detected in each sample. Several bacteria genera comprising of human pathogenic species, such as Pseudomonas, Staphylococcus, Thermoactinomyces or Saccharopolyspora were identified. Cladosporium and Alternaria fungal genera, which are potent environmental determinants of respiratory symptoms, were detected in dusts collected in the five farms and their levels reached 15.5-51.1% and 9-24.7% of assignable fungal sequences in each sample, respectively. Finally, all dust samples significantly and strongly increased the expression of the pro-inflammatory TNF-α, IL-1β, IL-6 and IL-8 cytokines at both mRNA and protein levels in human monocyte-derived macrophages. Their effects were dose-dependent and detectable from 1µg/ml. The intensity of the macrophage responses however differed according to the samples. CONCLUSIONS: Our results strengthen the hypothesis that organic dusts released during the distribution of straw bedding are mainly constituted of thoracic particles which are small enough to deposit on lower bronchial epithelium of dairy farmers and induce inflammation.
Environmental Research

hal-01579610
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579610
DOI : 10.1016/j.envres.2017.07.025
PUBMED : 28735230

Résumé : La drépanocytose est une hémoglobinopathie aux formes et aux sévérités cliniques très hétérogènes qui affectent de nombreux organes chez les patients touchés. Pour cette raison le terme de syndrome drépanocytaire majeur est généralement employé. Tous les syndromes drépanocytaires majeurs ont en commun une mutation ponctuelle du gène β-globine appelée mutation βs . Cette mutation βs conduit à la synthèse de la protéine d'hémoglobine S (HbS) caractérisée par sa capacité à polymériser dans sa forme désoxygénée. La polymérisation de l'HbS est l'élément déclencheur de la falciformation du globule rouge et conduit à de nombreuses altérations hématologiques et hémorhéologiques. Ces dernières sont à l'origine de troubles de l'hémodynamique, de l'oxygénation sanguine et de la perfusion tissulaire en oxygène. Il en résulte de nombreuses complications aigues (crise vaso-occlusive, accident vasculaire cérébral, syndrome thoracique aigu etc.) et/ou chroniques (glomérulopathie, ostéonécrose de la tête fémorale etc.) causés par un défaut d'oxygénation des tissus.
Sickle cell anemia is a hemoglobinopathy forms and severities very heterogeneous clinical affecting many organs in affected patients. For this reason the term major sickle cell syndrome is generally used. All major sickle cell syndromes have a common point mutation in the gene called β-globin mutation βs. This βs mutation leads to the synthesis of the protein hemoglobin S (HbS) is characterized by its ability to polymerize in its deoxygenated form. The polymerization of HbS is the trigger for the sickling of red blood cells and leads to many Hematological and hemorheological. These are at the origin of disorders hemodynamics, blood oxygenation and tissue perfusion with oxygen. This results in many acute complications (vaso-occlusive crisis, stroke, acute chest syndrome, etc..) And / or chronic (glomerulopathy, osteonecrosis of the femoral head etc.). Caused by a defect of tissue oxygenation.

http://www.theses.fr/2012AGUY0563/document

Éditeur(s) : HAL CCSD European Respiratory Society
Résumé : International audience
There are conflicting data regarding the magnitude and determinants of chronic obstructive pulmonary disease (COPD) risk in farmers.In a cross-sectional study of 917 nonfarming working controls and 3787 farmers aged 40-75 years, we assessed respiratory symptoms, tobacco exposure, job history (without direct exposure measurement) and lung function. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) extless0.70) and by the Quanjer reference equation (post-bronchodilator FEV1/FVC extlesslower limit of normal (LLN)).The prevalence (95% CI) of COPD according to the GOLD criterion was 5.1% (4.4-5.8%) and 2.9% (1.8-4.0%) in farmers and controls, respectively (p=0.005), and 3.1% (2.5-3.6%) and 1.5% (0.7-2.3%), respectively, for the LLN criterion (p extless0.01). For both COPD criteria after adjustment for age, sex and smoking status, COPD prevalence was similar in controls and crop farmers. Compared to controls, four job categories had a higher prevalence of COPD according to the GOLD criterion, namely, cattle breeders, swine breeders, poultry breeders and breeders of two or more livestock types. Among cattle breeders, only those from Franche-Comté had higher prevalence of COPD according to both GOLD and LLN criteria.The prevalence of COPD in farmers is higher than in nonfarming working controls, and depends on the farming activity, the region and the criterion used to define COPD
ISSN: 0903-1936

hal-01216204
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01216204
DOI : 10.1183/13993003.00153-2015
PUBMED : 26453630

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The present study investigated cerebral and muscle hemoglobin oxygen saturation (tissue oxygen index, TOI) in children with sickle cell anemia (SS), sickle cell hemoglobin C disease (SC) and healthy children (AA). TOI was measured by near-infrared spectroscopy (NIRS) and spectral analysis of the TOI variability was used to assess flowmotion and vasomotion. Arterial oxyhemoglobin saturation (SpO2), hemorheological and hematological parameters were also measured in SS and SC children. Both TOI were lower in SS compared to both AA and SC children, with SC exhibiting lower values than AA children. Cerebral vasomotion expressed in absolute values was enhanced in SS compared to AA and SC children. Muscle vasomotion did not differ between the three groups. Hematocrit, SpO2 and red blood cell deformability were positively associated with cerebral TOI in SS children. We demonstrated that 1) cerebral and muscle TOI were markedly decreased in SS children while the decrease of TOI was milder in SC children, 2) cerebral TOI level was associated with several biological markers in SS children only and 3) cerebral vasomotion was enhanced in SS, possibly to counterbalance the effects of chronic cerebral hypoxia.
ISSN: 1079-9796

inserm-01519106
http://www.hal.inserm.fr/inserm-01519106
http://www.hal.inserm.fr/inserm-01519106/document
http://www.hal.inserm.fr/inserm-01519106/file/2017%2C%20Charlot%20-%20Cerebral%20and%20muscle%20microvascular%20oxygenation%20in%20children%20with%20sickle%20celle%20disease.pdf
DOI : 10.1016/j.bcmd.2017.03.015

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

Résumé : Cette étude a pour missions essentielles de comprendre et d’expliquer comment le passage d’une langue à une autre voire le mélange des deux codes langagiers qui se côtoient au sein de la population de la Guadeloupe, département français d’outre-mer, le français et le créole, peuvent, dans le cadre des échanges médicaux éducatifs, influencer la compréhension des mécanismes de la maladie par le patient, son acceptation et sa gestion.La justification de cette étude tient du constat que la prévalence de cette maladie chronique en Guadeloupe, l’asthme bronchique, est relativement importante, que la prise en charge reste perfectible malgré les recommandations de bonnes pratiques édictées par les sociétés savantes, et que certains patients ont du mal à comprendre les termes utilisés en français par leur médecin lors de l’annonce du diagnostic, ainsi que par les éducateurs chargés de leur apporter les outils de bonne gestion de cette maladie, ce qui n’est pas sans incidents en termes de morbidité et de mortalité.L’auteur décompose sa recherche autour de cinq grands thèmes :- La description du territoire d’étude, sur le plan géographico-climatique, historico-économique, sanitaire et social, la naissance d’une ère culturelle nouvelle générant une langue partagée par plus de 95% de la population et transmise au sein des familles et dans la communauté.- La présentation de l’éducation thérapeutique, démarche considérée par la communauté scientifique comme essentielle pour améliorer la prise en charge du patient et l’autogestion de la maladie, les plans gouvernementaux successifs traitant de cette matière.- L’état des connaissances sur l’asthme bronchique en France, dans le monde et en Guadeloupe plus particulièrement.- L’impact de la langue créole dans le processus de compréhension de la maladie à travers la relation soignant-soigné, et ses conséquences chez les natifs bilingues en termes d’acquisitions des outils d’autogestion en comparaison à l’utilisation du français.- La formulation de propositions de contextualisation didactique, tant en termes de formation des professionnels de santé par la préconisation de l’utilisation de la langue créole, par l’adaptation des outils psychopédagogiques au contexte local, que d’encouragement du patient à utiliser sa langue maternelle dans l’expression de ses ressentis.La recherche montre que la langue créole, utilisée autant au cours de la consultation par le médecin traitant et par le malade que pendant les séances d’éducation thérapeutique par les éducateurs et le public, influence les indicateurs de gestion de cette maladie.En conclusion, l’auteur défend l’hypothèse selon laquelle l’utilisation de la langue créole dans les échanges médicaux éducatifs chez les adolescents asthmatiques bilingues français-créole favoriserait la compréhension des mécanismes de la maladie asthmatique, la prise de conscience de sa gravité et la nécessité de se soigner pour éviter les complications, corollaire d’une bonne qualité de vie.
In Guadeloupe, a French Overseas Territory, the population uses French and Creole linguistic codes. The main goals of this thesis are to understand and to explain how a better use of French and Creole, within the framework of educational medical exchanges, can improve the understanding of the mechanisms of the disease by the patient, its acceptance and its management.The bronchial asthma is a chronic disease, which affects an important part of the Guadeloupian population. In spite of the recommendations promulgated by the medical scholars, the care of the patients can be improved in Guadeloupe. Certain patients have difficulty understanding the terms used in French by their doctor during the announcement of the diagnosis, as well as by the educators in charge of bringing them the tools of good management of this disease what is not without incidents in terms of morbidity and mortality.The author elaborates his research around five main themes:- The thorough description of the space studied in this thesis; the geography of the land, the history of the population, the impact of the economic; the presentation of the social and health care infrastructures; and furthermore the birth of a new cultural era generating a language shared by more than 95 % of the population and passed on within families and communities.- The presentation of the therapeutic education, the approach considered by the scientific community as essential to improve the management of the patient and the self-management of the disease, the successive governmental plans dealing with this subject.- The state of the knowledge on the bronchial asthma in France, in the world and in Guadeloupe more particularly.- The impact of the Creole language in the process of understanding of the disease within the healthcare relationships and its consequences at the bilingual natives in terms of acquisitions of the tools of self-management in comparison to the use of French.- The formulation of proposals of didactic contextualization regarding the training of the healthcare professionals; the recommendation to the healthcare workers to use the Creole language; the adaptation of the psycho-pedagogical tools to the local context; the encouragement to the patients to use their native language in the expression of their feelings.- Researches show that the Creole language used during the consultation by the regular doctor, but also during the educational sessions therapeutics by the educators influence the indicators of management of this disease. In conclusion, the author defends the hypothesis according to which, the use of the Creole language in the educational medical exchanges at the bilingual asthmatic teenagers French-Creole would favor the understanding of the mechanisms of the asthmatic disease, the awareness of its gravity and the necessity of looking after oneself to avoid the complications, corollary of a good quality of life.

http://www.theses.fr/2015AGUY0827/document

Éditeur(s) : HAL CCSD Springer/Terra Scientific Publishing Company
Résumé : International audience
We carried out a detailed paleomagnetic, rock-magnetic, and Thellier paleointensity study of all similar to 3.6 My Pliocene lava flow succession in southern Georgia. An earlier study (Camps et al., 1996) revealed that several consecutive lava flows record an intermediate polarity direction at the base of the section followed by a thick reverse polarity zone. The transitional field was interpreted as an excursion within chron 2Ar or all upper Cochiti-Gilbert reversal. New paleomagnetic data reported here have been obtained from nearby lava successions. In total, about 170 standard paleomagnetic cores belonging to 22 lava flows were collected during the 2005 sample collection campaign. Rock-magnetic experiments showed that the remanence is carried by Ti-poor titanomagnetite in most of the samples. The fraction of grains with multidomain magnetic structure does not seem to be important. Characteristic remanent magnetization was successfully determined oil all samples. The direct correlation with the original (Thoki) sequence, previous preliminary measurements of natural remanent magnetization (Sologashvili, 1986), and field observations allowed us to establish a new magnetic stratigraphy. The lower part of section is characterized by intermediate magnetic polarity followed by thick reversely magnetized lavas. The upper sequence, represented by 18 consecutive flows yielded normal magnetic polarity. The mean paleointensity of the intermediate field is drastically reduced with respect to the post-transitional field strength. Based on all available radiometric ages and new paleomagnetic data, it may be speculated that Gilbert-Gauss (R-N) reversal was recorded at the upper part of sequence. Lower intermediate polarity flows possibly represent a form of precursor of this reversal that is similar to the Matuyama-Brunhes geomagnetic transition.
ISSN: 1343-8832

hal-00413099
https://hal.archives-ouvertes.fr/hal-00413099

Éditeur(s) : HAL CCSD
Résumé : Visceral leishmaniasis is a life-threatening systemic disease caused by Leishmania protozoans, L. donovani and L. infantum, which invade mononuclear phagocytes in the lymphoid organs and the liver. The control of the hepatic parasite burden depends on the granuloma formation, which is favored by a Th1 immune response in a Th2 tissue microenvironment. The aim of this work was to study the role of the recently described Th2 cytokine IL-33 in this complex immune response, which remains partially misunderstood. IL-33 dosages in different patient sera and IL-33+ cells detected in the liver of a patient from Rennes suggested that IL-33 could be a biomarker for active visceral leishmaniasis. As IL-33 was described in hepatic stellate cells during chronic hepatitis, these cells were exposed to L. donovani in primary culture. The cell permissivity to L. donovani and the parasite persistence during a long term culture led us to propose hepatic stellate cells as a new type of sanctuary cells, which could partially explain asymptomatic carriage. However, these cells were apparently not the main source of IL-33 during visceral leishmaniasis. In infected BALB/c and C57BL/6 mice, IL-33 was detected in the liver in non stellate cells preferentially localized in granulomas. The presence of cells expressing its specific receptor ST2 in the liver led us to explore the role of the IL-33/ST2 axis. BALB/c mice deficient in ST2 or treated with recombinant IL-33 and infected with L. donovani revealed that IL-33 downregulates the expression of Th1 key cytokines (IL-12, IFN-γ) and the recruitment of neutrophils and monocytes. Finally, IL-33 acts as a susceptibility factor during visceral leishmaniasis. Besides, the model of L. donovani infected C57BL/6 mice deficient in IL-33 or treated with recombinant IL-33 suggests possible differential roles of IL-33 depending on the immune environment related to the host genetic background.
La leishmaniose viscérale est une maladie systémique mortelle en l’absence de traitement. Elle est due aux protozoaires Leishmania donovani et L. infantum, parasites des phagocytes mononucléés, capables d’envahir les organes lymphoïdes et le foie. Le contrôle de l’infection hépatique repose sur la mise en place d’une réponse granulomateuse efficace, promue par une réponse immunitaire Th1, dans un environnement tissulaire Th2. L’objectif de ce travail était l'étude du rôle d’une cytokine Th2 récemment décrite, l’IL-33, dans cette réponse hépatique complexe encore partiellement incomprise. Des dosages d’IL-33 sur des sérums de patients et la détection de cellules IL-33+ dans le foie d’un patient rennais ont placé l’IL-33 comme un biomarqueur possible de la maladie active. L’IL-33 étant exprimée dans les cellules étoilées du foie au cours d’hépatites chroniques, ces cellules ont été exposées à L. donovani. Leur permissivité aux leishmanies sans toxicité apparente ni perturbation de leurs propriétés fonctionnelles, ainsi que la persistance des leishmanies sur une culture de plusieurs semaines, nous ont conduit à proposer les cellules étoilées comme cellules sanctuaires possibles pour les leishmanies viscérotropes, contribuant donc potentiellement au portage asymptomatique. En revanche, elles ne sont pas apparues comme une source majeure d'IL-33 au cours de la leishmaniose viscérale. Chez des souris C57BL/6 et BALB/c infectées par L. donovani, l'IL-33 a été observée dans des cellules ne s'apparentant pas à des cellules étoilées, et principalement localisées dans les granulomes. Des cellules exprimant son récepteur ST2 ayant été également observées dans le foie, un rôle de l’axe IL-33/ST2 a été recherché. Les résultats obtenus chez des souris BALB/c déficientes en ST2 ou traitées par de l'IL-33 recombinante suggèrent que l'IL-33 régule négativement l'expression de cytokines Th1 (IL-12, IFN-γ) et l'infiltrat de neutrophiles et monocytes dans le foie, limitant ainsi le contrôle de la charge parasitaire. Ainsi, l'IL-33 semble être un facteur de susceptibilité pour la leishmaniose viscérale. En parallèle, des travaux entrepris sur des souris C57BL/6 infectées par L. donovani suggèrent de possibles rôles différentiels de l'IL-33 en fonction de l'environnement immunitaire inhérent au fond génétique de l'hôte.
https://tel.archives-ouvertes.fr/tel-01126847

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2013REN1B002
tel-01126847
https://tel.archives-ouvertes.fr/tel-01126847
https://tel.archives-ouvertes.fr/tel-01126847/document
https://tel.archives-ouvertes.fr/tel-01126847/file/2013REN1B002.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
We report paleomagnetic results from four overlapping stratigraphic sections (55 flows) through the lava pile in Tjörnes peninsula (North Iceland). The initial aim of our study was to check the existence of intermediate directions previously interpreted as belonging to the Matuyama-Brunhes geomagnetic reversal (MBR), and complete this record with Thellier-Thellier paleointensity determinations and 40Ar/39Ar radioisotopic dating. The directional results corroborate the findings by Kristjánsson et al. (1988): a sequence of reversed, transitional, normal, and transitional polarity (R-T-N-T) is found in each section. The polarity change is characterized by a jump from reversed virtual geomagnetic poles (VGPs) to a quasi-cluster of transitional VGPs located over China, followed by a second jump to a cluster of normal polarity before moving again towards intermediate polarities. Reversely magnetized flows exhibit a magnetic mineralogy well suited for paleointensity determination. Of these 25 flows, 20 yielded paleointensity estimates of good quality. Unfortunately, the systematic presence of coarse multidomain (MD) titanomagnetite in the transitional and normal polarity flows hampered paleointensity estimates for these flows. The Virtual Dipole Moments (VDM) calculated for the reversed polarity flows vary from 4.9 to 7.0 × 1022 Am2 with an arithmetic mean value of 5.5 ± 0.8 × 1022 Am2. This value is identical to the mean VDM obtained for the 0.3-5 Ma time window and thus strengthens the conclusion that the recent geomagnetic field strength is anomalously high compared to that older than 0.3 Ma. 40Ar/39Ar isochron ages were obtained with the incremental heating technique on groundmass separates or phenocryst-poor whole rock samples. Six of the transitionally magnetized lavas yielded isochron ages that are indistinguishable from one another at the 95% confidence level. The weighted average age is 862 ± 51 ka. In the upper part of this volcanic sequence, the normally magnetized flows yielded a weighted average age of 787 ± 40 ka. This finding supports the conclusion that a geomagnetic excursion within the Matuyama chron is recorded in the lower part of the Tjörnes volcanic sequence, whereas only the latest portion of the MBR is recorded by flows in the upper part of the lava pile. This conclusion is supported via comparison of the VGPs obtained from the lavas with those predicted by a geomagnetic field model.
ISSN: 0012-821X

hal-00618515
https://hal.archives-ouvertes.fr/hal-00618515
https://hal.archives-ouvertes.fr/hal-00618515/document
https://hal.archives-ouvertes.fr/hal-00618515/file/Camps-epsl2011.pdf
DOI : 10.1016/j.epsl.2011.07.026

Éditeur(s) : HAL CCSD American Society for Biochemistry and Molecular Biology
Résumé : International audience
Chronic low grade inflammation is closely linked to obesity-associated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (±INDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6 β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HS+INDO-fed mice remained insulin-sensitive. However, mice fed HF/HS+INDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.
ISSN: 0021-9258

hal-01074835
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01074835
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01074835/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01074835/file/JBC-2013-525220v2-Kristiansen-POSTPRINT.pdf
DOI : 10.1074/jbc.M113.525220

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: There is no recommendation for treating pulmonary hypertension (PH) when associated with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To evaluate the effect of PH-specific therapy in patients with COPD. METHODS: All successive patients with severe PH [mean pulmonary arterial pressure (mPAP) ≥35 mm Hg] and COPD, who received specific PH medication and who underwent right heart catheterization at baseline and after 3-12 months of treatment, were analyzed from a prospective database. RESULTS: Twenty-six patients were included with a median follow-up of 14 months. Mean forced expiratory volume in 1 s was 57 ± 20% of predicted, and mean forced expiratory volume in 1 s/forced vital capacity was 47 ± 12%. Dyspnea was New York Health Association classification stage (NYHA) II in 15%, NYHA III in 81% and NYHA IV in 4%. First-line treatments were endothelin receptor antagonists in 11 patients, phosphodiesterase-5 inhibitors in 11 patients, calcium blocker in 1 patient, combination therapy in 3 patients including 2 with a prostanoid. After 6 ± 3 months, pulmonary vascular resistance decreased from 8.5 ± 3 to 6.6 ± 2 Wood units (p extless 0.001), with significant improvement of cardiac index from 2.44 ± 0.43 to 2.68 ± 0.63 liters × min × m-2 (p = 0.015) and mPAP from 48 ± 9 to 42 ± 10 mm Hg (p = 0.008). There was no significant difference in dyspnea, 6-min walking distance, echocardiographic parameters or N-terminal pro-brain natriuretic peptide levels. There was no significant difference in arterial oxygen saturation after 3-12 months of treatment. CONCLUSIONS: Specific PH medications may improve hemodynamic parameters in COPD patients with severe PH. Appropriate prospective randomized studies are needed to evaluate the potential long-term clinical benefit of treatment
Respiration; International Review of Thoracic Diseases

hal-01239807
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01239807
DOI : 10.1159/000431380
PUBMED : 26277885

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The Tarim and Junggar basins in central Asia are capped by a thick pile of conglomerates, called the Xiyu Formation, that are commonly linked to a change in climate and/or accelerated uplift near the Plio-Pleistocene boundary. In order to better understand their origin and significance, we carried out a combined structural and magnetostratigraphic study in the Quilitage syncline (southern Tianshan), where the base of the Xiyu conglomerates is observed at both sides of the syncline. A balanced cross-section shows that, even at a local-scale, the base of the Xiyu conglomerates cannot be regarded as a single continuous stratigraphic layer. On the southern flank of the Quilitage syncline, we collected 172 samples collected for magnetostratigraphic dating identify 17 polarity chrons that date the new section from 5.2 to ~ 1.7 Ma and constrain the base of the Xiyu conglomerate here at ~ 1.7 Ma. This is 4.2 Ma younger than the age of the Xiyu previously found on the northern limb of the same syncline. Together with other magnetostratigraphic studies carried out around the Tianshan, our study unambiguously demonstrates that the onset of deposition of the Xiyu conglomerates is diachronous, and that the conglomerates are systematically younger toward the basin. Consequently, the Xiyu Formation should not be considered as a chronostratigraphic marker related to any particular tectonic or climatic event, but is instead a prograding gravel wedge that has prograded over the underthrusting forelands. A synthesis of chronologic and structural results yields progradation rates over the last 10 Ma on the order of ~ 2.0 mm/yr and ~ 3.9 mm/yr south and north of the Tianshan Mountains respectively. These rates are comparable to the shortening rate across the Tianshan range, suggesting that underthrusting is the main factor governing the progradation rate of the Xiyu Formation.
ISSN: 0012-821X

insu-00414151
https://hal-insu.archives-ouvertes.fr/insu-00414151
https://hal-insu.archives-ouvertes.fr/insu-00414151/document
https://hal-insu.archives-ouvertes.fr/insu-00414151/file/Charreau-EPSL-2009.pdf
DOI : 10.1016/j.epsl.2009.07.035

Résumé : L’HTLV-1 est l’agent étiologique de la TSP/HAM et de l’ATL. La TSP/HAM est une méningomyélite chronique d’évolution lente et progressive. La charge provirale HTLV-1 est corrélée à l’évolutivité de la maladie. La protéine virale Tax module la synthèse et la fonction de multiples protéines de la prolifération et de la survie des lymphocytes T infectés. L’expression virale n’est pas toujours détectable in vivo. Une modulation épigénétique par inhibiteurs d’HDAC a été proposée. Des travaux dans le modèle du BLV et in vitro dans l’infection à HTLV-1 ont conforté ce concept et conduit à un essai thérapeutique évaluant le VPA dans le traitement de la TSP/HAM, qui n’a pas montré d’impact sur la charge provirale. Nous nous sommes intéressés à l’effet du VPA sur les lymphocytes T CD4+ en culture, cibles du virus HTLV-1. L’expression du génome viral, surtout la balance entre les protéines Tax et HBZ a été étudiée avec ou sans VPA. Son expression serait corrélée à la charge provirale et à l’évolution de la TSP/HAM. Nous montrons qu’un tiers des cellules CD4+ infectées expriment Tax. Cette proportion augmente sous VPA. La détection de la protéine p19 est augmentée sous VPA. La stimulation par le VPA de la transcription sens du génome viral a été confirmée par quantification des messagers Tax et Gag alors que l’expression d’HBZ se trouve réprimée sous VPA. Les données cinétiques d’expression spontanée d’HBZ montrent l’existence d’un rétrocontrôle négatif exercé par HBZ sur l’expression de Tax et des gènes structuraux. Influer sur l’expression d’HBZ ouvre une voie nouvelle pour le traitement des maladies associées à HTLV-1.
HTLV-1 is the etiological agent of HAM/TSP and ATL. TSP/HAM is a chronic meningomyelitis with a course being slow and progressive. HTLV-1 proviral load correlates with disease progression. Tax protein modulates the synthesis and function of proteins involved in the regulation of infected T-lymphocytes proliferation and survival. Viral expression is not always detectable in vivo. An epigenetic modulation by the use of HDAC inhibitors has been proposed. A study in the BLV model and an in vitro study in a HTLV-1 infection have lead to a therapeutic assay in order to assess VPA in the treatment of HAM/TSP. This assay did not show any impact on the proviral load. We evaluated the impact of VPA treatment on viral genome expression in cultured lymphocytes, especially the balance between Tax and HBZ. A third of provirus-positive CD4+ T cells spontaneously became Tax-positive. The estimation rose up to two-thirds of Tax-positive infected cells when VPA was added. VPA enhanced Gag p19 protein release. VPA treatment enhanced and prolonged Tax mRNA expression, while it blocked HBZ expression. Our data are consistent with the hypothesis of a feed-back loop coordinating Tax and HBZ expression. Modulation of HBZ expression may impact the net outcome of VPA treatment on HTLV-1-infected cell proliferation and survival.

http://www.theses.fr/2011AGUY0403

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
Introduction: Hydroxyurea is an antimetabolite widely used in the treatment of myeloproliferative diseases. Usual side effects are mainly hematological, gastrointestinal, neurological disorders and induced-fevers. More rarely, hydroxyurea-induced pneumonitis are reported. Case report: We report a case of a patient treated for polycythemia vera. She was admitted 20 days after introduction of hydroxyurea for a high fever, productive cough and clear sputum associated with nausea. Chest CT-scan found diffuse bilateral ground-glass opacities. The microbiological investigations were negative. Symptoms disappeared few days after discontinuation of treatment. Its reintroduction led to recurrence of symptoms. Conclusion: This additional case completes the 15 cases of hydroxyurea-induced pneumonitis described in the literature. Two forms of this disease seem to exist: an acute form with fever occurring in the month following introduction of hydroxyurea; and a chronic form without fever. Even if it is uncommon, pulmonologists should be aware of this complication.
ISSN: 0761-8425

hal-00916333
https://hal.archives-ouvertes.fr/hal-00916333
https://hal.archives-ouvertes.fr/hal-00916333/document
https://hal.archives-ouvertes.fr/hal-00916333/file/hydroxyurA_e_version_rA_visA_e.pdf
DOI : 10.1016/j.rmr.2013.09.001