Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD

Pain Reactivity and Plasma β-Endorphin in Children and Adolescents with Autistic Disorder

International audienceBackground: Reports of reduced pain sensitivity in autism have prompted opioid theories of autism and have practical care ramifications. Our objective was to examine behavioral and physiological pain responses, plasma β-endorphin levels and their relationship in a large group of individuals with autism.Methodology/Principal Findings: The study was conducted on 73 children and adolescents with autism and 115 normal individuals matched for age, sex and pubertal stage. Behavioral pain reactivity of individuals with autism was assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and child psychiatrist during blood drawing), and compared to controls during venepuncture. Plasma β-endorphin concentrations were measured by radioimmunoassay. A high proportion of individuals with autism displayed absent or reduced behavioral pain reactivity at home (68.6%), at day-care (34.2%) and during venepuncture (55.6%). Despite their high rate of absent behavioral pain reactivity during venepuncture (41.3 vs. 8.7% of controls, P<0.0001), individuals with autism displayed a significantly increased heart rate in response to venepuncture (P<0.05). Moreover, this response (Δ heart rate) was significantly greater than for controls (mean±SEM; 6.4±2.5 vs. 1.3±0.8 beats/min, P<0.05). Plasma β-endorphin levels were higher in the autistic group (P<0.001) and were positively associated with autism severity (P<0.001) and heart rate before or after venepuncture (P<0.05), but not with behavioral pain reactivity.Conclusions/Significance: The greater heart rate response to venepuncture and the elevated plasma β-endorphin found in individuals with autism reflect enhanced physiological and biological stress responses that are dissociated from observable emotional and behavioral reactions. The results suggest strongly that prior reports of reduced pain sensitivity in autism are related to a different mode of pain expression rather than to an insensitivity or endogenous analgesia, and do not support opioid theories of autism. Clinical care practice and hypotheses regarding underlying mechanisms need to assume that children with autism are sensitive to pain

Modulation of Brain β-Endorphin Concentration by the Specific Part of the Y Chromosome in Mice

International audienceBackground: Several studies in animal models suggest a possible effect of the specific part of the Y-chromosome (Y NPAR) on brain opioid, and more specifically on brain b-endorphin (BE). In humans, male prevalence is found in autistic disorder in which observation of abnormal peripheral or central BE levels are also reported. This suggests gender differences in BE associated with genetic factors and more precisely with Y NPAR. Methodology/Principal Findings: Brain BE levels and plasma testosterone concentrations were measured in two highly inbred strains of mice, NZB/BlNJ (N) and CBA/HGnc (H), and their consomic strains for the Y NPAR. An indirect effect of the Y NPAR on brain BE level via plasma testosterone was also tested by studying the correlation between brain BE concentration and plasma testosterone concentration in eleven highly inbred strains. There was a significant and major effect (P,0.0001) of the Y NPAR in interaction with the genetic background on brain BE levels. Effect size calculated using Cohen's procedure was large (56% of the total variance). The variations of BE levels were not correlated with plasma testosterone which was also dependent of the Y NPAR. Conclusions/Significance: The contribution of Y NPAR on brain BE concentration in interaction with the genetic background is the first demonstration of Y-chromosome mediated control of brain opioid. Given that none of the genes encompassed by the Y NPAR encodes for BE or its precursor, our results suggest a contribution of the sex-determining region (Sry, carried by Y NPAR) to brain BE concentration. Indeed, the transcription of the Melanocortin 2 receptor gene (Mc2R gene, identified as the proopiomelanocortin receptor gene) depends on the presence of Sry and BE is derived directly from proopiomelanocortin. The results shed light on the sex dependent differences in brain functioning and the role of Sry in the BE system might be related to the higher frequency of autistic disorder in males

SPECTRES D'EXCITATION DE LA LUMINESCENCE EXCITONIQUE DU CdS

Nous avons étudié comparativement, sur la base de travaux antérieurs de Gross et al. [5], les spectres d'excitation de trois types principaux d'échantillons : «purs», «impurs» et «pollués en surface». Cela nous a permis de distinguer deux canaux principaux de transfert de l'excitation dans le crystal, lorsque l'énergie d'excitation est supérieure au «gap». Le canal principal est la création de paires électron-trou libres qui peuvent, à des degrés divers selon les échantillons, se lier pour former des excitons. Mais la création immédiate d'excitons dans leur bande est également possible, avec participation de phonons optiques longitudinaux (LO). Cette contribution à la luminescence excitonique devient prépondérante lorsque les paires électron-trou ne forment que très peu d'excitons, ce qui est le cas dans les cristaux impurs. Les échantillons pollués en surface forment à cet égard un surprenant cas intermédiaire entre échantillons «purs» et «impurs». Il apparaît alors que les excitons créés avec une énergie cinétique assez grande, en perdent rapidement une quantité égale à un nombre entier de fois celle d'un phonon LO, et que la thermalisation finale ne peut être réalisée, la durée d'interaction avec les phonons acoustiques étant en moyenne plus longue que la durée de vie totale des excitons. Cela donne naissance à des pics très marqués dans les spectres, séparés de l'énergie d'un phonon LO. Un calcul théorique assez simple permet de corroborer ce point de vue en précisant l'intensité relative des pics. On en tire des renseignements sur la nature des mécanismes de perte d'énergie des excitons, leur recombinaison radiative directe ou indirecte et leurs mécanismes de piégeage sur des impuretés. De manière plus globale, cette étude met en relief deux points essentiels : d'une part la validité de la notion de bande d'exciton, même à des énergies cinétiques bien supérieures à l'énergie de liaison ; d'autre part l'opposition fondamentale entre les paires électron-trou où les deux particules gardent un comportement incohérent et les excitons caractérisés par la notion de " souvenir des conditions d'excitation ". Cette notion prend toute son importance dans les expériences d'orientation de spin par pompage optique.On the basis of earlier works by Gross et al., we have studied and compared the excitation spectra of three main types of samples : " pur " " impur " and surface-polluted. This lead us to distinguish two main channels for the transfer of excitation in the crystal, when exciting energy is greater than the gap. The main channel is creation of free electron-hole pairs which may be bound to form excitons. But the straight forward creation of excitons in their band is possible, with longitudinal optical phonon participation. This contribution to the excitonic luminescence becomes the most important when only a few free pairs are bound into excitons, a situation which happens in doped material. From this point of view, the surface-polluted samples form a surprizing intermediate case between pur and doped samples. Then, it comes out that the created excitons lose very quickly a kinetic energy NℏΩ, where ℏΩ is the energy of one LO phonon ; and that the thermalization does not occur, because the total lifetime of excitons is shorter than the interactions time with acoustical phonons. This gives rise to peaks in the spectra, separated by ℏΩ. A rather simple calculation corroborates this point of view and reproduces the correct ratio of the intensities of the peaks. One deduces informations about the mechanisms of energy relaxation, binding on impurities, and radiative recombination of excitons. From a more general point of view, this study points out first the validity of the notion of exciton band, even at kinetic energies much greater than the binding energy ; second, the opposition between electron-hole pairs (where the two particles behave without any coherence) and the excitons, characterized by a " memory of their excitation conditions ". This notion happens to be of most importance in the experiments of spin orientation by optical pumping

Trace metals dynamics under contrasted land uses: contribution of statistical, isotopic, and EXAFS approaches

International audienceThree sub-basins of the Seine River (France) under contrasted land uses (i.e., forested, agricultural, and urban) have been investigated in order to assess the origin and seasonal variation of trace metals, and evaluate their geochemical background and dynamics. Our results highlight a high anthropogenic impact on all elements for both the dissolved and particulate fractions. The main source for each element in the dissolved phase was determined and shows that transition and post-transition metals mainly originate from forested areas, while alkali and alkaline earth elements, metalloids, and halogens rather originate from agricultural land use. Conversely, for the particulate phase, most of the elements cannot be associated with a specific land use. Seasonal variation of elements was assessed according to the forested and agricultural land uses, and geochemical backgrounds were determined using average export rates, highlighting that the geochemical background for the forested land use is higher than the agricultural one for most of the elements. Finally, to confirm those results, Zn dynamics in the three characteristic sub-basins and between the different land uses was investigated using a combination of Zn speciation, Zn isotopic ratio, and Zn export rates

Cours d'étude pour l'instruction du Prince de Parme... / par M. l'Abbé de Condillac... ; tome premier, Grammaire

Antep.Entre p. 2 y 3 grab. calc. ret. del autor: "F.G Lardy fc., 1789"Error de pag., p. 443 repetidaEnc. PastaSign.: A-S12, T

Assessment of quantitative and semi-quantitative biological test methods of artesunate in vitro

International audienceArtesunate is the current most potent antimalarial drug widely used for the treatment of malaria. Considering the emergence of artemisinin resistance, several situations may require a simple method for artesunate quantification. We thus developed a quantitative and a semi-quantitative biological method for the determination of artesunate in liquid samples. The tests are based on the measurement of samples’ antimalarial activity on Plasmodium falciparum 3D7 using a modified SYBR Green I drug susceptibility test. For the quantitative test, we established a standard curve that resulted from a dose–response curve and evaluated its performances using controls samples. Whereas the linear regression analysis between artesunate concentration and antimalarial activity showed promising results (linearity range 1.5–24.6 ng/mL, r2 = 0.9373), we found that artesunate content of the controls was significantly overestimated (p = 0.0313). For the semi-quantitative test, we compared the antimalarial activities of samples collected during permeation studies of artesunate to that of a reference (artesunate IC50) by statistical analysis. We demonstrated that antimalarial activities of samples from permeation tests using a powder formulation of artesunate were greater than those of samples from tests using a solution formulation. Bioassays can be simple techniques to assess artesunate in liquid samples, particularly in resource-limited settings. Comparison with reference methods is still recommended when accurate drug quantification is required