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

Fatty acid amide hydrolase: from characterization to therapeutics.

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family that terminates the action of several endogenous lipid messengers, including oleamide and the endocannabinoid anandamide. The hydrolysis of such messengers leads to molecules devoid of biological activity, and, therefore, modulates a number of neurobehavioral processes in mammals, including pain, sleep, feeding, and locomotor activity. Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAH inhibitors are the topic of this review

Beta-lactams derived from a carbapenem chiron are selective inhibitors of human fatty acid amide hydrolase versus human monoacylglycerol lipase

A library of 30 beta-lactams has been prepared from (3R,4R)-3-[(R)-1'-(tbutyldimethylsilyloxy)-ethyl]-4-acetoxy-2-azetidinone, and the corresponding deacetoxy derivative, by sequential N- and O-functionalizations with various omega-alkenoyl and omega-arylalkanoyl chains. All compounds were selective inhibitors of hFAAH versus hMGL, and IC(50) values in the nanomolar range (5-14 nM) were recorded for the best representatives. From time-dependent preincubation and rapid dilution studies, and from docking analyses in a homology model of the target enzyme, a reversible mechanism of inhibition of hFAAH is proposed

(S)-1-(Pent-4’-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): synthesis, biological evaluation and molecular modelling

A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4’-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesized in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, ?-lactamic inhibitors of endocannabinoid-degrading enzymes (hFAAH and hMAGL). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected thousandfold decrease of activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the ?-lactam core) could be explained on the basis of docking studies into a revisited model of hFAAH active site, considering one or two water molecules in interaction with the catalytic triad

Ability of the third-generation FloTrac/Vigileo software to track changes in cardiac output in cardiac surgery patients: a polar plot approach.

International audienceOBJECTIVE: To evaluate the ability of the third-generation (3.01) of FloTrac/Vigileo monitor (Edwards Lifesciences, Irvine, CA) to follow variations in cardiac output (∆CO) using the new polar plot approach. DESIGN: Prospective interventional study. SETTING: Single hospital university study. PARTICIPANTS: Twenty-five patients referred for cardiac surgery. INTERVENTIONS: CO was measured simultaneously by 3 to 5 bolus thermodilution (COtd measurements), using a pulmonary artery catheter and by arterial pulse contour analysis, using the FloTrac/Vigileo (COvi). Data were collected at eight time points: before incision, after sternotomy, before and after protamine sulfate infusion, at the start of sternal closure, at the end of surgery, on arrival to intensive care unit, and after a standardized volume expansion with 500 mL of hetastarch 6%. MEASUREMENTS AND MAIN RESULTS: One-hundred thirty-five pairs of CO data were collected; the mean bias of all CO measurements corrected for repeated measures was 0.2 L/min with limits of agreements of -3.3 L/min and +2.9 L/min. The percentage error was 66.5%. The polar plot analysis included 71 significant ∆CO and showed a mean polar angle of -3.4 degrees with 95% polar percentage error equivalent limits of -61 to 55; 69% of analysed data points fell within the 30-degree limits and provided a correct polar concordance rate. CONCLUSIONS: Third-generation FloTrac/Vigileo software still lacks the accuracy to reliably detect changes in cardiac output (∆CO) in cardiac surgery. Improvements to FloTrac/Vigileo CO algorithm and software still are needed in this particular setting

Gene x environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms

International audienceSeveral 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

Efficacy of parent-mediated communication-focused treatment in toddlers with autism (PACT) delivered via videoconferencing: A randomised controlled trial study protocol

International audienceIntroduction Intervention in the preschool period is currently recommended for autism spectrum disorder. Therapies delivered by parents are particularly suitable for young children. Preschool Autism Communication Trial (PACT) is a parent-mediated therapy that has shown a significant and sustained impact on autism symptom reduction. However, access to such evidence-based therapies for families is limited due to autism centres located in large urban areas. Using videoconferencing to deliver PACT training to parents may improve accessibility for families living in underserved areas. Methods and analysis This single-blind randomised controlled trial, involving six sites in France, will investigate the efficacy of a telehealth, videoconferencing-based, parent-mediated PACT therapy on autism symptoms, over a 12-month period. It will compare PACT plus treatment as usual (TAU) against TAU only in a cohort of 238 toddlers (119 per group) aged 18-36 months at inclusion and living with their families more than 40 min away from the specialist centres for autism. Primary outcome will include change of overall autism score on the Autism Diagnostic Observation Scale (ADOS) at 12 months. Secondary outcomes will measure change in child skills, child functioning, impact on parents (stress, health, priorities) and implementation characteristics. Repeated measures analyses will be used to test the effect of PACT intervention on the overall ADOS module 1 score over the 12-month study period. Linear mixed models will be used with time, treatment allocation and the interaction between treatment and time as fixed effects and individual variation as random effect. Ethics and dissemination This protocol (V.5, date: 25 October 2019) is approved by the French National Review Board (reference no 2018-A02516-49). The results will be disseminated via peer-reviewed journals Trial registration number NCT04244721