La décroissance comme fait spirituel: :du numineux à la question du mal

National audienceLa décroissance apparait souvent dans le discours critique sur l'environnement et le progrès comme un simple changement sur le plan économique et politique, or cette orientation implique un changement profond dans notre rapport à la nature. Si le sujet contemporain ne modifie pas sa relation spirituelle avec une nature enfin considérée comme son équivalent en essence, l'échec est certain. La techno-science ne peut donc continuer à prendre, selon les mots de Martin Heidegger, le réel comme fonds et pas plus comme objet inerte

Archéologie de l’imaginaire du feu, le principe de précaution des origines ou de la machine de Marly à la centrale nucléaire

Evoquer l’image du feu c’est dès l’abord constater l’ambiguïté profonde avec laquelle nous appréhendons cet élément. Il est célébré comme une innovation décisive dans l’histoire de l’humanité et sa chaleur ne laisse pas d’être équivoque si l’on évoque sa flamme. Moyen de cuire les aliments, il représente une étape importante dans l’hominisation, mais son pouvoir est destructeur et réduit aussi la vie à néant. Instrument de purification rituelle dans la plupart des religions, il est aussi le g..

La consumació de la potència: l’apocalipsi, una exigència antropològica de tots els temps

En el número 48 de la revista L'Espill trobaràs un dossier monogràfic sobre "Cap a un col·lapse de la civilització industrial?", amb contribucions d'Antonio Turiel, Luc Semal, Ernest Garcia, Paul R. Ehrlich, Anne H. Ehrlich i Alain Gras. A més, articles d'Antoni Mora, François Rastier, Simona Škrabec, Joan Ramon Resina, Jacobo Muñoz Veiga, Faust Ripoll Domènech, Tobies Grimaltos Mascarós i Narcís Selles Rigat, així com documents del Manifest «Darrera crida», un full de dietari de Vicent Alonso i una conversa amb Tomàs Llorens

Impact of the cytochrome P450 2B6 genetic polymorphisms on EFV and NVP plasma concentrations of HIV-1 infected patients from Rwanda

Objectifs: Plus de 34 millions de personnes sont infectées par le virus de l’immunodéficience humaine (VIH) etla majorité d’entre eux (22.5 millions) vit en Afrique Sub-Saharienne. Au Rwanda, où plus de 96000 individus ont eu accès aux antirétroviraux en 2013, la thérapie antirétrovirale de première ligne contient entre autres lesinhibiteurs non nucléosidiques de la transcriptase inverse, éfavirenz (EFV) ou névirapine (NVP). Une grandevariabilité interindividuelle des concentrations plasmatiques en EFV et en NVP a cependant été observée qui estpartiellement due à la forte variabilité génétique du cytochrome P450 2B6 (CYP2B6). Les objectifs de ce travailde thèse ont consisté (i) à identifier de nouveaux polymorphismes ponctuels (SNP) au niveau du gène CYP2B6,dans la population rwandaise (ii) de caractériser leurs effets sur l’activité enzymatique in vitro et in silico, (iii) à déterminer la fréquence des nouveaux SNP et de SNP connus dans une population rwandaise de patients infectés au VIH et (iv) à associer les polymorphismes et les haplotypes qui en étaient déduits aux concentrationsplasmatiques d’EFV, de NVP et de leurs principaux métabolites hydroxylés.Méthodes: Les neufs exons de CYP2B6 de 39 individus rwandais ont été séquencés. Huit nouveaux SNP ont étéexprimés dans des cellules COS-1 et la fonction enzymatique des nouvelles variantes CYP2B6 a été déterminéein vitro par l’intermédiaire des substrats bupropione et EFV. Ces résultats ont été comparés au potentiel prédictif de huit algorithmes. Des analyses de docking et des simulations de dynamique moléculaire à long terme ont décrit des changements de la structure tertiaire du CYP2B6 et du mode de liaison entre le site actif et les substrats de l’enzyme. 19 SNP ont été par la suite génotypés par une méthode de MALDI-TOF et 11 SNP ont étédiscriminés par PCR en temps réel chez 806 individus rwandais. Les concentrations plasmatiques à l’équilibre d’EFV, de NVP et des métabolites 7-OH-, 8-OH-, 8,14-OH EFV et 2-OH, 3-OH NVP ont été quantifiées par LC/MS-MS chez 431 patients rwandais traités par EFV ou NVP. L’effet du génotype sur la distribution desinhibiteurs non nucléosidiques EFV et NVP a été étudié par des tests statistiques univariés et multivariésRésultats: Trois nouveaux SNP [c.548T>G (p.V183G), c.637T>C (p.F213L), c.758G>A (p.R253H)] et cinq SNP dont la fonction n’était pas connue [c.329G>T (p.G110V), c.341T>C (p.I114T), c.444G>T (p.E148D),c.835G>C (p.A279P), c.1459C>A (p.R487S)] ont été identifiés et assignés aux cinq nouveaux allèlesCYP2B6*33 – CYP2B6*37. Les analyses in vitro ont montré que les variantes 148D, 253H, 279P et 487S sontfonctionnelles tandis que la variante 213L a une activité enzymatique réduite et les variantes 110V, 114T et183G sont non-fonctionnelles. 60% à 80% des prédictions de la fonction de chaque variante faites in silicoétaient correctes. Les simulations de dynamique moléculaire à long terme ont montré que les variantes 110V, 114T, 183G et 213L entraînent des modifications structurales au niveau d’hélices alpha et de feuillets beta qui entourent le site catalytique de l’enzyme CYP2B6. La fréquence des huit polymorphismes dans la population rwandaise était C, c.444G>T et c.835G>C) a été significativement associé à de faibles concentrations en EFV et NVP. L’haplotype TGT (c.516G>T, c.785A>G et g.21563C>T) a été fortementassocié à des concentrations plasmatiques élevées d’EFV et de NVP et à de faibles taux plasmatiques en 8-OHEFV et 3-OH NVP. Le génotype *6/*18, le polymorphisme homozygote g.21563TT ainsi que l’haplotype TGT sous sa forme homozygote ont été identifiés comme les principaux facteurs indépendants responsables des concentrations plasmatiques élevées en EFV.Conclusions: Nous avons décrit trois nouveaux SNP dont deux ont un impact sur la fonction enzymatique du CYP2B6 in vitro et assigné cinq nouveaux allèles CYP2B6 dans la population rwandaise. Nos travaux ont identifié un nouvel allèle CYP2B6 qui a été associé à des concentrations faibles d’EFV et de NVP et confirmé l’existence de marqueurs génétiques permettant de prédire des concentrations supra-thérapeutiques en EFV. Ces résultats suggèrent une stratégie individualisée de génotypage afin de soutenir l’efficacité et la persistance de lathérapie antirétrovirale en Afrique Sub-Saharienne./Objectives: Over 34 million individuals are living worldwide with the human immunodeficiency virus (HIV) and the majority living in Sub-Saharan Africa (22.5 million). In Rwanda, more than 96000 patients were receiving antiretroviral drugs by 2013. The Rwandese first-line treatment is a non-nucleoside reverse transcriptase inhibitor based regimen containing either efavirenz (EFV) or nevirapine (NVP). High interindividual variations in EFV and NVP plasma concentrations have been reported which are partiallycaused by the high genetic variability of the cytochrome P450 2B6 (CYP2B6). The aims of this thesis project were (i) to identify new single nucleotide polymorphisms (SNP) within the CYP2B6 gene, (ii) to characterize in vitro and in silico their effects on the enzyme activity,(iii) to determine the frequency of new and known SNP in HIV-infected patients from Rwanda and (iv) to correlate the SNP/haplotypes with plasma concentrations of EFV, NVP and their main hydroxy metabolites.Methods: The nine CYP2B6 exons of 39 individuals from Rwanda were sequenced. Eight new nonsynonymous SNP were recombinantly expressed in COS-1 cells and the new CYP2B6 variants werefunctionally characterized in vitro using the substrates bupropion and EFV. The results were compared with the functional prediction potency of eight algorithms. Docking and long-term molecular dynamic (MD) simulations were performed to describe structural changes and interaction modifications between the substrates and the CYP2B6 binding pocket. 19 SNP were genotyped with a MALDI-TOF genotyping method and 11 SNP were discriminated with real time PCR in 806 individuals from Rwanda. Steady-state EFV, NVP and their main hydroxy metabolites 7-OH-, 8-OH-, 8,14-OH EFV and 2-OH, 3-OH NVP werequantified using LC/MS-MS in 431 Rwandese patients under EFV or NVP therapy. Uni- and multivariatestatistical analyses were performed to assess the genotype significance in EFV and NVP drug distribution.Results: Three new [c.548T>G (p.V183G), c.637T>C (p.F213L), c.758G>A (p.R253H)] and five uncharacterized non-synonymous SNP [c.329G>T (p.G110V), c.341T>C (p.I114T), c.444G>T (p.E148D), c.835G>C (p.A279P), c.1459C>A (p.R487S)] were identified and five novel alleles termed CYP2B6*33 – CYP2B6*37 were assigned. In vitro analysis revealed that the variants 148D, 253H, 279P and 487S were functional whereas the variant 213L showed a reduced enzyme activity and the variants 110V, 114T and183G were complete loss-of-function variants. 60% to 80% of the in silico functional predictions of each variant were correct. The MD simulations showed that only the variants 110V, 114T, 183G and 213L had structural modifications in alpha-helices and beta-strands surrounding the catalytic site of the CYP2B6 enzyme. The frequency of the eight polymorphisms in the Rwandese population was C, c.444G>T, c.835G>C) was significantly associated to low EFV and NVP concentrations. The “CYP2B6-TGT” haplotype (c.516T, c.785G, g.21563T) was strongly related to high EFV and NVP and low 8-OH EFV and 3-OH NVP plasma concentrations. The *6/*18 genotype, the homozygous g.21563TT SNP and the homozygous TGT haplotype were found as the most relevant independent factors to account for high EFV concentrations.Conclusions: We have described three novel SNP with two altering the CYP2B6 enzyme function in vitro and assigned five new CYP2B6 alleles in a Rwandese population. Our research work allowed us to identify a new CYP2B6 allele which was correlated to low EFV and NVP concentrations and to confirm the existence of genetic markers predicting supra-therapeutic EFV plasma concentrations. Our results suggest an individualized genotyping strategy to sustain the efficiency and the durability of the antiretroviral therapy in Sub-Saharan Africa

Compliance with the current recommendations for prescribing antibiotics for paediatric community-acquired pneumonia is improving: data from a prospective study in a French network

International audienceBACKGROUND: Lower respiratory tract infection is a common cause of consultation and antibiotic prescription in paediatric practice. The misuse of antibiotics is a major cause of the emergence of multidrug-resistant bacteria. The aim of this study was to evaluate the frequency, changes over time, and determinants of non-compliance with antibiotic prescription recommendations for children admitted in paediatric emergency department (PED) with community-acquired pneumonia (CAP).METHODS: We conducted a prospective two-period study using data from the French pneumonia network that included all children with CAP, aged one month to 15 years old, admitted to one of the ten participating paediatric emergency departments. In the first period, data from children included in all ten centres were analysed. In the second period, we analysed children in three centers for which we collected additional data. Two experts assessed compliance with the current French recommendations. Independent determinants of non-compliance were evaluated using a logistic regression model. The frequency of non-compliance was compared between the two periods for the same centres in univariate analysis, after adjustment for confounding factors.RESULTS: A total of 3034 children were included during the first period (from May 2009 to May 2011) and 293 in the second period (from January to July 2012). Median ages were 3.0 years [1.4-5] in the first period and 3.6 years in the second period. The main reasons for non-compliance were the improper use of broad-spectrum antibiotics or combinations of antibiotics. Factors that were independently associated with non-compliance with recommendations were younger age, presence of risk factors for pneumococcal infection, and hospitalization. We also observed significant differences in compliance between the treatment centres during the first period. The frequency of non-compliance significantly decreased from 48 to 18.8 % between 2009 and 2012. The association between period and non-compliance remained statistically significant after adjustment for confounding factors. Amoxicillin was prescribed as the sole therapy significantly more frequently in the second period (71 % vs. 54.2 %, p < 0.001).CONCLUSIONS: We observed a significant increase in the compliance with recommendations, with a reduction in the prescription of broad-spectrum antibiotics, efforts to improve antibiotic prescriptions must continue

High Burden of Non-Influenza Viruses in Influenza-Like Illness in the Early Weeks of H1N1v Epidemic in France

BACKGROUND: Influenza-like illness (ILI) may be caused by a variety of pathogens. Clinical observations are of little help to recognise myxovirus infection and implement appropriate prevention measures. The limited use of molecular tools underestimates the role of other common pathogens. OBJECTIVES: During the early weeks of the 2009-2010 flu pandemic, a clinical and virological survey was conducted in adult and paediatric patients with ILI referred to two French University hospitals in Paris and Tours. Aims were to investigate the different pathogens involved in ILI and describe the associated symptoms. METHODS: H1N1v pandemic influenza diagnosis was performed with real time RT-PCR assay. Other viral aetiologies were investigated by the molecular multiplex assay RespiFinder19®. Clinical data were collected prospectively by physicians using a standard questionnaire. RESULTS: From week 35 to 44, endonasal swabs were collected in 413 patients. Overall, 68 samples (16.5%) were positive for H1N1v. In 13 of them, other respiratory pathogens were also detected. Among H1N1v negative samples, 213 (61.9%) were positive for various respiratory agents, 190 in single infections and 23 in mixed infections. The most prevalent viruses in H1N1v negative single infections were rhinovirus (62.6%), followed by parainfluenza viruses (24.2%) and adenovirus (5.3%). 70.6% of H1N1v cases were identified in patients under 40 years and none after 65 years. There was no difference between clinical symptoms observed in patients infected with H1N1v or with other pathogens. CONCLUSION: Our results highlight the high frequency of non-influenza viruses involved in ILI during the pre-epidemic period of a flu alert and the lack of specific clinical signs associated with influenza infections. Rapid diagnostic screening of a large panel of respiratory pathogens may be critical to define and survey the epidemic situation and to provide critical information for patient management

EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation