Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders

Changes in genetic and/or environmental factors to developing neural circuits and subsequent synaptic functions are known to be a causative underlying the varied socio-emotional behavioural patterns associated with autism spectrum disorders (ASD). Seven transmembrane G protein-coupled receptors (GPCRs) comprising the largest family of cell-surface receptors, mediate the transfer of extracellular signals to downstream cellular responses. Disruption of GPCR and their signalling have been implicated as a convergent pathologic mechanism of ASD. Here, we aim to review the literature about the 23 GPCRs that are genetically associated to ASD pathology according to Simons Foundation Autism Research Initiative (SFARI) database such as oxytocin (OXTR) and vasopressin (V1A, V1B) receptors, metabotropic glutamate (mGlu5, mGlu7) and gamma-aminobutyric acid (GABAB) receptors, dopamine (D1, D2), serotoninergic (5-HT1B and additionally included the 5-HT2A, 5-HT7 receptors for their strong relevance to ASD), adrenergic ($\beta$2) and cholinergic (M3) receptors, adenosine (A2A, A3) receptors, angiotensin (AT2) receptors, cannabinoid (CB1) receptors, chemokine (CX3CR1) receptors, orphan (GPR37, GPR85) and olfactory (OR1C1, OR2M4, OR2T10, OR52M1) receptors. We discussed the genetic variants, relation to core ASD behavioural deficits and update on pharmacological compounds targeting these 23 GPCRs. Of these OTR, V1A, mGlu5, D2, 5-HT2A, CB1, and GPR37 serve as the best therapeutic targets and have potential towards core domains of ASD pathology. With a functional crosstalk between different GPCRs and converging pharmacological responses, there is an urge to develop novel therapeutic strategies based on multiple GPCRs to reduce the socioeconomic burden associated with ASD and we strongly emphasize the need to prioritize the increased clinical trials targeting the multiple GPCRs

Dogs used as a large animal model of obesity-related insulin resistance

As for ethical and other reasons, studies of the pathophysiological mechanisms of obesity and its association with insulin resistance (IR) cannot be performed in man, researchers have to use appropriate animal models. Although dogs fed on a high-fat diet seem to meet the requirements to study this human syndrome, the canine model has hardly been used. Our objective was to study the lipoprotein metabolism and reverse cholesterol transport in healthy dogs, then in dogs with insulin resistance. We also aimed to describe the plasmatic changes associated with insulin resistance, and quantify the expression of genes involved in this disorder, in insulin target tissues (visceral adipose tissue and skeletal muscle). In healthy dogs, apoB100 exclusively appears in VLDL, whose high production is associated with a high fractional catabolism (5-fold greater than that of human). LDL-apoB100 metabolism is similar in dogs and humans. Our results showed that the healthy dog does not exhibit any CETP activity in vivo, and that reverse cholesterol transport is very active, with substantial selective uptake of HDL esterified cholesterol. Consequently, among species with no CETP activity, dogs provide an adequate model to study changes in this selective cholesterol uptake. The anomalies observed in lipoprotein profiles produced by FPLC in IR obese dogs were identical to those seen in IR man. Insulin resistance is associated with a decreased production of LDL apo B100, due to a reduced production, despite the increased catabolism. Both transcription and plasmatic results confirmed those found in man (overexpression of leptin mRNA, underexpression of adiponectin, GLUT4, LPL, PPAR and UCP mRNAs). Therefore, dogs could provide a useful research model, particularly to elucidate the molecular mechanisms involved in the development of insulin resistance and dyslipidemia.Pour des raisons notamment éthiques, il n'est pas possible d'étudier chez l'homme les phénomènes physiopathologiques associés à l'évolution conjointe de l'obésité et de la baisse de sensibilité à l'insuline. L'établissement de modèles animaux reflétant la pathologie humaine paraît donc indispensable. Le chien soumis à un régime hyperlipidique semblait répondre aux critères de sélection d'un modèle adapté à l'étude de ce syndrome. Il n'avait cependant été que peu exploré. Le but de notre travail a été d'une part, d'étudier le métabolisme des lipoprotéines et le transport inverse du cholestérol chez le chien sain, puis chez le chien insulinorésistant (IR) et d'autre part, de caractériser l'évolution des modifications plasmatiques associées à l'insulinorésistance, puis de quantifier, au sein de certains tissus cibles de l'insuline (tissus adipeux viscéral et musculaire), l'expression de gènes impliqués dans ce désordre métabolique. Chez le chien sain, l'apo B100 (apolipoprotéine B100) apparaît exclusivement dans les VLDL dont la production élevée est associée à un catabolisme important, égal à 5 fois celui de l'homme. Ces lipoprotéines subissent une lipolyse partielle, formant les LDL qui contiennent donc aussi de l'apoB100. L'apoB100 des LDL a un métabolisme similaire à celui de l'homme. Le chien sain ne manifeste pas d'activité CETP (cholesterol ester tranfer protein) in vivo, mais présente un transport inverse du cholestérol très actif, notamment associé à une importante capture sélective du cholestérol estérifié des HDL. Le chien pourrait donc s'avérer le meilleur modèle pour l'étude de la modulation de cette voie de retour du cholestérol. Les profils lipidiques des lipoprotéines, obtenus par chromatographie FPLC chez le chien obèse IR, ont montré les mêmes perturbations que chez l'homme IR. La production d'apo B100 dans les VLDL est augmentée et la lipolyse diminuée. La concentration en apo B100 des LDL est diminuée, conséquence d'une production réduite et d'un catabolisme augmenté. Les résultats obtenus aux niveaux transcriptionnel et plasmatique sont également conformes aux observations effectuées chez l'homme (surexpression du gène de la leptine, sous-expression de celui de l'adiponectine, du GLUT4, de la lipoprotéine lipase, des PPAR et des UCP notamment). Sur les deux plans de l'étude, nos résultats confirment que le chien pourrait constituer un bon modèle d'étude, notamment pour l'élucidation des mécanismes moléculaires impliqués dans le développement de l'insulinorésistance et des dyslipidémies

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.</p

Effets de la protéine C activée sur la redistribution du débit sanguin pulmonaire régional dans un modèle porcin d'agression pulmonaire aigüe (étude en tomographie par émission de positons)

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Corpus et mémoires de traduction : deux approches du lexique et de la phraséologie en traduction spécialisée

International audienc

Obésité et insulinorésistance chez des rats consommant des régimes enrichis en matières grasses ou en fructose (intervention nutritionnelle avec de l'EPA ou des flavanones)

NANTES-BU Sciences (441092104) / SudocSudocFranceF

Découverte fortuite d’une intoxication aiguë par vérapamil forme à libération prolongée : intérêt du criblage toxicologique

Objectifs : Un patient de 29 ans a été admis en soins intensifs pour hypotension résistante et anomalies du rythme cardiaque. Le service clinique suspectant une intoxication par bisoprolol, un criblage toxicologique par chromatographie liquide couplée à la spectrométrie de masse en tandem (LC-MS/MS) a été réalisé. Ce criblage n’a pas retrouvé de bisoprolol mais a mis en évidence une intoxication par vérapamil. Afin de confirmer l’intoxication, des dosages sanguins du vérapamil et de ses principaux métabolites ont été effectués quotidiennement. Méthodes : La recherche et les dosages ont été réalisés par LC-MS/MS. Les métabolites ont été préalablement identifiés après incubation du vérapamil avec des microsomes hépatiques de souris. Résultats : Sept métabolites ont été identifiés après incubation avec les microsomes hépatiques de souris. Cinq d’entre eux ont été retrouvés dans le sérum du patient. L’évolution des taux sanguins en vérapamil a montré une croissance le 1er jour (1,0 mg/L à J1, 1,7 mg/L à J2 ; valeurs thérapeutiques : 0,02 à 0,25 mg/L), un plateau pendant 3 jours puis une décroissance. Les cinétiques des principaux métabolites du vérapamil (norvérapamil et N-desalkylvérapamil) étaient comparables à celle de la molécule mère. Conclusion : Le criblage toxicologique a permis de diagnostiquer l’intoxication par vérapamil dans un contexte clinique complexe. La stagnation des taux sanguins pendant 3 jours était vraisemblablement due à une intoxication avec une forme à libération prolongée du vérapamil

Alemtuzumab as rescue therapy in a cohort of 16 aggressive multiple sclerosis patients previously treated by Mitoxantrone: an observational study.

International audienceOur study aimed to describe safety and neurological impact of alemtuzumab as last-line rescue therapy in aggressive multiple sclerosis (MS) patients, previously treated by Mitoxantrone (MITOX). Between June 2004 and October 2013, 13 patients received alemtuzumab at 20 mg/day and 3 at 12 mg/day for 5 days. EDSS, relapses, secondary progression were prospectively assessed 12 and 6 months before treatment, at baseline and every 3 months. Mean follow-up was 6.2 years [1–10]. Mean age at alemtuzumab start was 40 years [26–49] for 8 Secondary Progressive (SP) and 30 years [26–35] for 8 Relapsing-Remitting (RR) patients. MS duration was 13.7 (±3) and 8.3 (±4) years, respectively. During the 12 months before alemtuzumab, annual relapse rate was 0.75 and 3.14, respectively and the 16 patients accumulated 2–30 new gadolinium enhancing lesions. 4 patients (suboptimal responders) received alemtuzumab during MITOX and 12 patients 1–7.8 years after MITOX. Out of 8 SPMS, 2 were disease free up to last visit (4.7 and 8 years), 5 improved or stabilized but only transiently and 1 worsened. Out of 8 RRMS, 1 remained stable up to last visit (8.7 years) despite 1 relapse and active MRI at 18 months and 7 improved (1–4 point EDSS): 4 remained disease free up to last visit (12, 24, 38 months and 7 years), 2 were successfully retreated at 25 and 33 months and 1 worsened progressively 24 months after alemtuzumab. 2 patients developed Grave’s disease and 1 hypothyroidism. Alemtuzumab controls aggressive RRMS despite previous use of MITOX