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International audience; In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden.

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation. This work was supported by grants from: L.M.S.: Instituto de Salud Carlos III and co-funded by FEDER (PI18/00998), FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (C.D.: BFU2017-87721; M.L.: RTI2018–101840-B-I00; R.N.: RTI2018-099413-B-I00 and RED2018-102379-T), Xunta de Galicia (M.L.: 2016-PG068; R.N.: 2016-PG057 and 2020-PG015), Fundación BBVA (R.N.: Fundación Atresmedia (to M.L. and R.N.), Fundación La Caixa (to M.L. and R.N.), Fundación Jesus Serra and European Foundation for the Study of Diabetes (to R.N.). The research leading to these results also received funding from the European Community’s H2020 Framework Programme under the following grant: ERC Synergy Grant-2019-WATCH- 810331 to M.S., V.P. and R.N. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. This work was supported by Inserm, Fondation pour la Recherche Médicale, ANR-EPITRACES (to E.V.). Research from the M.F. laboratory was supported by the Spanish Agencia Estatal de Investigación, co-funded by the FEDER Programme of the EU (BFU2016-80899-P and PID2019-105739GB-I00 grants; AEI/FEDER, UE). M.F. is recipient of a Ramón y Cajal award (RYC-2014-16779). C.F. is a recipient of a Sara Borrel award (ISCIII CD19/0078). O.A. is a recipient of the Miguel Servet grant (ISCIIII). Sí

Background Students are a vulnerable group for the indirect impact of the COVID-19 pandemic, particularly their mental health. This paper examined the cross-national variation in students’ depressive symptoms and whether this can be related to the various protective measures implemented in response to the initial stage of the COVID-19 outbreak. Methods Student data stem from the COVID-19 International Student Well-being Study, covering 26 countries during the first wave of the COVID-19 pandemic. Country-level data on government responses to the COVID-19 pandemic were retrieved from the Oxford COVID-19 Tracker. Multilevel analyses were performed to estimate the impact of the containment and economic support measures on students’ depressive symptoms (n = 78 312). Results School and workplace closures, and stay-at-home restrictions were positively related to students’ depressive symptoms during the COVID-19 pandemic, while none of the economic support measures significantly related to depressive symptoms. Countries’ scores on the index of these containment measures explained 1.5% of the cross-national variation in students’ depressive symptoms (5.3%). This containment index’s effect was stable, even when controlling for the economic support index, students’ characteristics, and countries’ epidemiological context and economic conditions. Conclusions Our findings raise concerns about the potential adverse effects of existing containment measures (especially the closure of schools and workplaces and stay-at-home restrictions) on students’ mental health.

This update describes the different strategies that can be implemented to secure intubation procedure in the ICU through optimisation of preoxygenation, airway management and endotracheal intubation in critically ill patients. These proposals are based on the latest French and international guidelines, as well as on the most recent literature on the subject. They emphasise the need for optimal anticipation and preparation for this period of high risk of complications. They also emphasise the need to take human factors into account, rather than simply introducing new devices or improving technical skills. They emphasise the role of the airway management team and of their communication, and the use of validated protocols and readily available cognitive aids. Proposed optimal management is presented in an algorithm. The importance of limiting attempts, recognising failure early, and moving to the next step in the algorithm are emphasised. They recommend the early use of a videolaryngoscope (if possible, with a remote screen visible to all), and supraglottic devices to oxygenate the patient in case of failure. In case of “can’t intubate-can’t oxygenate situation”, cricothyroidotomy using the scalpel, finger, and bougie procedure is suggested. Additional suggestions are made regarding the management of haemodynamics and peri-intubation mechanical ventilation., Cette mise au point décrit les différentes stratégies qui peuvent être mises en place pour sécuriser l’intubation en réanimation : optimisation de la préoxygénation, de la gestion des voies aériennes et de l’intubation endotrachéale chez des patients en état critique. Ces propositions se basent aussi bien sur les dernières recommandations françaises et internationales, mais également sur la littérature la plus récente sur le sujet. Elles mettent l’accent sur la nécessité d’une anticipation et d’une préparation optimales de cette période à risque important de complications. Elles soulignent également la prise en compte des facteurs humains, plutôt que la simple introduction de nouveaux dispositifs ou l’amélioration des compétences techniques. Elles soulignent le rôle de l’équipe chargée de la gestion des voies aériennes et de la communication, tout en s’appuyant sur des protocoles validés et des aides cognitives immédiatement disponibles. La gestion optimale est présentée dans un algorithme. L’importance de limiter les tentatives, de reconnaître rapidement l’échec et de passer à l’étape suivante de l’algorithme sont mises en avant. Elles recommandent l’utilisation précoce d’un vidéolaryngoscope (si possible avec un écran déporté visible par tous), et des dispositifs supraglottiques pour oxygéner le patient en cas d’échec. En cas de sauvetage, la procédure de cricothyroïdotomie au scalpel, au doigt et au mandrin est suggérée. Des propositions supplémentaires sont faites concernant la gestion de l’hémodynamique et de la ventilation mécanique péri-intubation.

Gastroparesis is the most common gastric motility disorder. The cardinal symptoms are nausea, vomiting, gastric fullness, early satiety, or bloating, associated with slow gastric emptying in the absence of mechanical obstruction. Delayed gastric emptying is demonstrated by a gastric emptying scintigraphy or by a breath test. Gastroparesis can be idiopathic, post-operative, secondary to diabetes, iatrogenic, or post-infectious. Therapeutic care must be multidisciplinary including nutritional, medical, endoscopic and surgical modes. The complications of delayed gastric emptying must be sought and addressed, particularly malnutrition, in order to identify and correct vitamin deficiencies and fluid and electrolyte disturbances. An etiology should be identified and treated whenever possible. Improvement in symptoms can be treated by dietary regimes and pharmaceutical treatments, including prokinetics. If these are not effective, specialized endoscopic approaches such as endoscopic or surgical pyloromyotomy aim at relaxing the pyloric sphincter, while the implantation of an electrical stimulator of gastric muscle should be discussed in specialized centers.

La mention ' Activité Physique Adaptée et Santé ' (APA) permet aux étudiants de travailler auprès d'un public atteint de pathologies ou nécessitant une réadaptation à l'activité physique. Cette formation englobe le développement des connaissances sur les pathologies, la conception de projet ou encore, la conduite et l'évaluation de programmes spécifiques de réadaptation afin de devenir EAPA (enseignants en activité physique adaptée).A travers 4 grandes parties, cet ouvrage permet aux candidats à l'entrée dans le cursus et aux étudiants en cours de formation, de :1. de visualiser l'ensemble des métiers liés à l'APA et d'en connaître les différentes spécificités ;2. connaître les compétences transversales aux métiers associés à la mention : développement des qualités physiques et prophylaxie, les publics, leurs besoins et les modalités d'intervention, la ou les prévention(s) par l'exercice physique, la Loi Santé et ses champs d'application¿;3. développer des connaissances professionnelles nécessaires au futur parcours professionnel (douleur, lombalgie, bases de la préparation physique...) ;4. développer des compétences disciplinaires¿: nutrition, micronutrition, interventions non-médicamenteuses etc.Chaque chapitre est traversé de témoignages (étudiants, enseignants, formateurs universitaires), autant de regards croisés sur le parcours universitaire et les contenus de la formation, et se conclut par des quiz et des questions, qui permettent de tester ses connaissances. Grâce aux nombreux encarts ' Le saviez-vous ', ' Astuce pratique ' et ' Focus ', cet ouvrage offre toutes les clés pour réussir en STAPS.

International audience; Multiple transitions between gravity levels will occur during planetary exploration missions. In reaction to these gravitational transitions, physiological adaptation will be initiated. However, the physiological effects of longduration exposures to hypogravity and hypergravity are poorly understood. In this review we present an overview of how humans perceive gravity, review sex-based differences in adaptation to changes in gravity, and introduces rather limited evidence currently available related to the effects of partial gravity. The paper then argues that there is a need for more research to better understand the extent and dynamics of physiological adaptation mechanisms during gravity level transitions in spaceflight and proposes a need for artificial gravity (AG) as a multi-system countermeasure and explore the efficacy of AG as countermeasure between short and very long-arm centrifuges. Discussed here are the effects of acute short-arm AG application. The topical review also discusses the usage of chronic AG application via the innovative large-radius Hypergravity Human Habitat, H 3 , concept.

RationaleCongenital Central Hypoventilation Syndrome (CCHS) is characterized by life-threatening sleep hypoventilation, and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome.ObjectivesTo determine whether Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms.MethodsApneas were classified as central, obstructive or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparation.Measurements and Main ResultsThe median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b27Ala/+ pups versus 0.6/min (0.4-1.0) in wildtypes (P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7s (1.1-1.9) in wildtypes (P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared to wildtypes. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal with respect to phrenic activity onset (P < 0.001).ConclusionsThe Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely due to hypoglossal dysgenesis. These results thus demand attention towards obstructive events in infants with CCHS.

International audience; Introduction: This study aimed to assess if an interference effect could blunt the neuromuscular gains induced by a same-session combined rehabilitation in hemodialysis (HD) patients. Methods: Patients exercised twice a week, for 16 weeks, over their HD sessions. They were either always trained with resistance and endurance exercises (continuous training, “CONT”) or alternatively with 1 week of resistance alternated with 1 week of endurance (discontinuous training, “DISC”). Adherence and workload were continuously recorded. Short Physical Performance Battery (SPPB) score, one-leg balance test, and handgrip and quadriceps strength were evaluated before and after training intervention. Results: Adherence to both programs was high (>90%). SPPB score had significantly improved (CONT: +1.5 point, DISC: +1.2 pt, p < 0.001), like one-leg balance test (CONT: +3.7 s, DISC: +5.5 s, p < 0.05), handgrip strength of exercised (CONT: +5.5 kg, DISC: +5.6 kg, p < 0.001) and of nonexercised arm (CONT: +4.4 kg, DISC: +2.8 kg, p < 0.01) as well as maximal quadriceps strength (+22 N·m for dominant and +29 N·m for nondominant leg in both groups, p < 0.001) bearing no difference between the trainings. Conclusion: Same-session combined training does not induce an interference effect in HD patients and temporal separation of exercises does not optimize strength gains. These practical data may be relevant for clinicians and practitioners to alternate endurance and resistance exercises.

Oxidative/carbonyl stress is elevated in lower-limb muscles of patients with chronic obstructive pulmonary disease (COPD). Carnosine is a skeletal muscle antioxidant particularly present in fast-twitch fibers. The aims of the present study were to compare muscle carnosine, oxidative/carbonyl stress, antioxidants, and fiber characteristics between patients with COPD and healthy controls (HCs) and between patients after stratification for airflow limitation (mild/moderate vs. severe/very severe), as well as to investigate correlates of carnosine in patients with COPD. A vastus lateralis muscle biopsy was obtained from 40 patients with stable COPD and 20 age- and sex-matched HCs. Carnosine, oxidative/carbonyl stress, antioxidants, fiber characteristics, quadriceps strength and endurance (QE), V(O2)peak (incremental cycle test), and physical activity (PA) were determined. Patients with COPD had a similar carnosine concentration [4.16mmol/kg wet weight (WW; SD = 1.93)] to HCs [4.64mmol/kg WW (SD = 1.71)] and significantly higher percentage of fast-twitch fibers and lower QE, V(O2)peak, and PA versus HCs. Patients with severe/very severe COPD had a 31% lower carnosine concentration [3.24mmol/kg WW (SD = 1.79); n = 15] versus patients with mild/moderate COPD [4.71mmol/kg WW (SD = 1.83); n = 25; P = 0.02] and significantly lower V(O2)peak and PA versus patients with mild/moderate COPD. Carnosine correlated significantly with QE (r(s) = 0.427), V(O2)peak (r(s) = 0.334), PA (r(s) = 0.379), and lung function parameters in patients with COPD. In conclusion, despite having the highest proportion of fast-twitch fibers, patients with severe/very severe COPD displayed a 31% lower muscle carnosine concentration compared with patients with mild/moderate COPD. As no other markers of oxidative/carbonyl stress or antioxidants were affected, the observed carnosine deficiency is thought to be a possible first sign of muscle redox balance abnormalities.NEW & NOTEWORTHY Carnosine, particularly present in fast-twitch fibers, was investigated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD). Carnosine concentration was similar between patients with COPD and healthy controls but was 31% lower in patients with severe/very severe COPD, despite their high proportion of fast-twitch fibers, versus patients with mild/moderate COPD. As no other markers of oxidative/carbonyl stress or antioxidants were affected, the observed carnosine deficiency is thought to be a possible first sign of muscle redox balance abnormalities.

Noninvasive ventilation (NIV) is the gold standard treatment for chronic alveolar hyopoventilation in patients with neuromuscular diseases. During the past decades, alongside the advances in ventilators, the development of telemedicine and ambulatory management, focus has shifted from the effectiveness of NIV as a single modality to that of the currently available multiple NIV techniques. The aim of this thesis is to describe the different techniques and to identify targets for NIV optimization in this population. The patient-machine interface and ventilation parameters are key targets and are assessed in detail.Identifying the superiority of a specific interface was not possible, but our results underline the importance of rigorous monitoring when masks are changed. Although our results also show that a significant proportion of patients are not optimally ventilated, we could not identify a template for ventilator settings in this population.Managing ventilation thus remains for the moment an activity requiring specialist input and individual adjustment. Improving patients' phénotype is necessary to develop recommendations. In the short term, the development and implementation of telemedicine is likely to play a major role in improving access to specialist input and NIV follow-up, allowing early individualized management in the ambulatory setting., La ventilation non invasive (VNI) nocturne représente le traitement de référence de l'hypoventilation alvéolaire chronique des patients neuromusculaires. Au cours des dernières décennies en parallèle des progrès des dispositifs et du développement de la télémédecine et de l'ambulatoire, on ne s'intéresse plus à l'efficacité de la VNI en tant que « technique » mais aux « techniques de VNI » dans cette population. L'objectif de cette thèse est d'établir un état des lieux de ces techniques et d'identifier les cibles d'optimisation de la VNI chez ces patients. Le prisme de l'interface et des paramètres de ventilation représentent des cibles de choix et ont été évaluées plus spécifiquement dans le cadre de cette thèse.Nous n'avons pas été en mesure d'établir la supériorité d'un type d'interface dans cette indication mais nos résultats soulignent la nécessité d'une surveillance rigoureuse en cas de changement de masque. D'autre part, bien que nos résultats suggèrent une proportion significative de patients insuffisamment ventilés, nous n'avons pas pu identifier de “paradigme” pour les réglages de la VNI dans cette population.La prise en charge ventilatoire reste donc, à ce stade, affaire de spécialistes nécessitant un haut niveau d'expertise et des ajustements personnalisés. Un meilleur phénotypage des patients est nécessaire afin de développer des recommandations. Dans un futur proche, le développement et l'implémentation de la télémédecine devront jouer un rôle majeur dans l'accessibilité aux équipes spécialisées et au suivi de la VNI pour une prise en charge précoce et personnalisée des patients tout en favorisant l'ambulatoire.

International audience; The TREK-1 channel belongs to the TREK subfamily of two-pore domains channels that are activated by stretch and polyunsaturated fatty acids and inactivated by Protein Kinase A phosphorylation. The activation of this potassium channel must induce a hyperpolarization of the resting membrane potential and a shortening of the action potential duration in neurons and cardiac cells, two phenomena being beneficial for these tissues in pathological situations like ischemia-reperfusion. Surprisingly, the physiological role of TREK-1 in cardiac function has never been thoroughly investigated, very likely because of the lack of a specific inhibitor. However, possible roles have been unraveled in pathological situations such as atrial fibrillation worsened by heart failure, right ventricular outflow tract tachycardia or pulmonary arterial hypertension. The inhomogeneous distribution of TREK-1 channel within the heart reinforces the idea that this stretch-activated potassium channel might play a role in cardiac areas where the mechanical constraints are important and need a particular protection afforded by TREK-1. Consequently, the main purpose of this mini review is to discuss the possible role played by TREK -1 in physiological and pathophysiological conditions and its potential role in mechano-electrical feedback. Improved understanding of the role of TREK-1 in the heart may help the development of promising treatments for challenging cardiac diseases.

International audience

The heterotrimeric Sec61 protein complex forms the functional core of the so-called translocon that forms an aqueous channel in the endoplasmic reticulum (ER). The primary role of the Sec61 complex is to allow protein import in the ER during translation. Surprisingly, a completely different function in intracellular Ca2+ homeostasis has emerged for the Sec61 complex, and the latter is now accepted as one of the major Ca2+-leak pathways of the ER. In this review, we first discuss the structure of the Sec61 complex and focus on the pharmacology and regulation of the Sec61 complex as a Ca2+-leak channel. Subsequently, we will pay particular attention to pathologies that are linked to Sec61 mutations, such as plasma cell deficiency and congenital neutropenia. Finally, we will explore the relevance of the Sec61 complex as a Ca2+-leak channel in various pathophysiological (ER stress, apoptosis, ischemia-reperfusion) and pathological (type 2 diabetes, cancer) settings.

International audience

Background: There is an alarming and constant worldwide progression of physical inactivity and sedentary behaviors in children and adolescents. The present paper summarizes findings from France’s 2020 Report Card on physical activity for children and youth, comparing its results to its 2 previous editions (2016 and 2018). Methods: France’s 2020 Report Card follows the standardized methodology established by the Active Healthy Kids Global Matrix, grading 10 common physical activity indicators using the best available evidence. The grades were informed by national surveys, peer-reviewed literature, government and nongovernment reports, and online information. Results: The expert panel awarded the following grades: Overall Physical Activity: D; Organized Sport Participation and Physical Activity: C−; Active Play: INC; Active Transportation: C−; Sedentary Behaviors: D−; Family and Peers: D−; Physical Fitness: D; School: B−; Community and the Built Environment: F; Government: C. Conclusions: This 2020 edition of France’s Report Card again highlights the alarming levels of physical activity and sedentary behaviors among French children and adolescents, calling for the development of effective national action. It also draws attention to the particular deleterious effects of the COVID-19 confinement on youth’s movement behaviors, which significantly worsened the situation.

International audience; Objective: To investigate the efficacy of the Diabeloop Generation-1 (DBLG1) closed-loop system to control the hypoglycaemia induced by physical activity (PA) in real-life conditions.Methods: This was a post-hoc analysis of the Diabeloop WP7 multicentre randomized controlled trial. Glycaemic outcomes were compared between days with and without PA in 56 patients with type 1 diabetes (T1D) using DBLG1 for 12 weeks. After the patient announces a PA, DBLG1 reduces insulin delivery and, if necessary, calculates the amount of preventive carbohydrates (CHO).Results: Daily time spent in the interstitial glucose range

International audience; Purpose: This quality improvement project evaluated interventions implemented to enhance individual adherence to a lung-protective ventilation strategy and its triad: low tidal volume, PEEP ≥ 5, recruitment manoeuvres.Methods For two years, nine anaesthesia workstations were connected to an automated cloud-based analytics software tool, which automatically recorded ventilation parameters as soon as a new patient case was opened. Four quality improvement periods were determined over the first year: baseline, intervention, no intervention, intervention + digital. In the second year, the digital strategy was continued for nine months, followed by a final “overtime” period. Baseline and no intervention periods included no training. The intervention period included both conventional and educational programs. The digital period included pop-up messages, which automatically appeared on the screen of the anaesthesia data management system when patients were intubated. The primary endpoint was provider adherence to the recommended triad.Results: From October 2018 to December 2020, 12,883 procedures were performed. Data were available for 8968 procedures: baseline (n = 2361), intervention (n = 2423), no intervention (n = 1064), intervention + digital (n = 1862), overtime (n = 1258). Age, Predicted Body Weight, ASA score, type of surgery and airway management were similar between periods. At baseline, 75.2% of procedures reported low tidal volume but only 6.9% involved the complete triad. At over time, Triad was 22% (p

(1) Background: Insomnia is the most prevalent sleep disorder worldwide and cognitive behavioral therapy is the front-line treatment. Digital health technologies have a role to play in screening and delivering interventions remotely and without the need for human intervention. The KANOPEE app, which provides a screening and behavioral intervention for insomnia symptoms through an interaction with a virtual agent, showed encouraging results in previous studies during and after the COVID-19 lockdown, but has not yet been evaluated in a controlled study. This study aims at comparing the benefits of KANOPEE, a smartphone application dealing with insomnia complaints, with another application proposing an electronic sleep diary named “My Sleep Diary”. The acceptance and potential benefits of these digital solutions are tested in real-life settings (i.e., without soliciting human medical resources) and in the general population. (2) Methods: Subjects were included if they downloaded one of the apps between December 2020 and October 2021, and were of legal age. Both apps were available on downloading platforms in France. Primary outcome was Insomnia Severity Index (ISI), and secondary outcomes were total sleep time (TST), sleep efficiency (SE) and wake time after sleep onset (WASO). (3) Results: A total of 535 users completed the intervention with KANOPEE and 489 users completed My Sleep Diary, both for 17 days. KANOPEE users improved their ISI score significantly more than sleep diary users (interaction Time*Group: F(2,2002) = 17.3, p < 0.001). Similar results were found for nocturnal sleep parameters (TST) (KANOPEE users gained 48 min of sleep after intervention, while My Sleep Diary users gained only 16 min of sleep), and particularly in the population with moderate to severe initial sleep complaints (F(4,1980) = 8.9, p < 0.001). Other sleep markers (SE and WASO) were significantly improved in the KANOPEE users compared to the sleep diary ones (p < 0.001). (4) Conclusions: KANOPEE provides significantly greater benefits than an electronic sleep diary regarding reduction of insomnia complaints and estimated nocturnal sleep characteristics in a self-selected sample of the general population. Population with the most severe initial ISI score (≥15) benefited the most from the KANOPEE App compared to filling up a simple sleep diary.

State-of-the-Art review.; International audience; Maintaining energy balance is essential for survival and health. This physiological function is controlled by the brain, which adapts food intake to energy needs. Indeed, the brain constantly receives a multitude of biological signals that are derived from digested foods, or that originate from the gastrointestinal tract, energy stores (liver and adipose tissues), and from other metabolically active organs (muscles). These signals, which include circulating nutrients, hormones, and neuronal inputs from the periphery, collectively provide information on the overall energy status of the body. In the brain, several neuronal populations can specifically detect these signals. Nutrient-sensing neurons are found in discrete brain areas and are highly enriched in the hypothalamus. In turn, specialized brain circuits coordinate homeostatic responses acting mainly on appetite, peripheral metabolism, activity and arousal. Accumulating evidence shows that hypothalamic microglial cells located at the vicinity of these circuits can influence the brain control of energy balance. However, microglial cells could have opposite effects on energy balance, i.e., homeostatic or detrimental, and the conditions for this shift are not totally understood yet. One hypothesis relies on the extent of microglial activation, and nutritional lipids can considerably change it.

International audience

AimTo investigate if the artificial delivery of microRNAs naturally present in the breastmilk can impact the gut and brain of young rats according to weaning.MethodsAnimals from a new transgenic rat line expressing green-fluorescent protein in the endocrine lineage (cholecystokinin expressing cells) received at Day-12, near neural diversification, a single oral bolus of mir-320-3p or miR-375-3p, embedded in DiOleyl-Succinyl-Paromomycin (DOSP), and were further early (Day-15) or regularly (Day-30) weaned. Relevant miRNA (miR-320-3p, miR-375-3p, miR-375-5p, miR-16-5p, miR-132-3p, miR-504), polr3d, hspb6, inflammation, enteroendocrine, and circadian clock-related mRNAs, chromatin complexes, and duodenal cell density were assayed at 8h post-inoculation and at Day-45.ResultsThe miR-320-3p/DOSP induced immediate effects on H3K4me3 chromatin complexes with polr3d promoter (pConclusionAddressing oral miRNA-320-3p loads to duodenal cell lineage is paving the way for the design of new therapeutics, manipulating long term consequences of early life stress.

International audience

International audience; Aneurysm is the second-most common disease affecting the aorta worldwide after atherosclerosis. While several clinical metabolomic studies have been reported, no study has reported deep metabolomic phenotyping in experimental animal models of aortic aneurysm. We performed a targeted metabolomics study on the blood and aortas of an experimental mice model of aortic aneurysm generated by high-cholesterol diet and angiotensin II in Ldlr−/− mice. The mice model showed a significant increase in media/lumen ratio and wall area, which is associated with lipid deposition within the adventitia, describing a hypertrophic remodeling with an aneurysm profile of the abdominal aorta. Altered aortas showed increased collagen remodeling, disruption of lipid metabolism, decreased glucose, nitric oxide and lysine metabolisms, and increased polyamines and asymmetric dimethylarginine (ADMA) production. In blood, a major hyperlipidemia was observed with decreased concentrations of glutamine, glycine, taurine, and carnitine, and increased concentrations of the branched amino acids (BCAA). The BCAA/glycine and BCAA/glutamine ratios discriminated with very good sensitivity and specificity between aneurysmatic and non-aneurysmatic mice. To conclude, our results reveal that experimental induction of aortic aneurysms causes a profound alteration in the metabolic profile in aortas and blood, mainly centered on an alteration of NO, lipid, and energetic metabolisms.

International audience; Objective: Waiting time for a consultation for chronic pain is a widespread health problem. This paper present the design of an ontology use to assess patients referred to a consultation for chronic pain. Methods: We designed OntoDol, an ontology of pain domain for patient triage based on priority degrees. Terms were extracted from clinical practice guidelines and mapped to SNOMED-CT concepts through the Python module Owlready2. Selected SNOMED-CT concepts, relationships, and the TIME ontology, were implemented in the ontology using Protégé. Decision rules were implemented with SWRL. We evaluated OntoDol on 5 virtual cases. Results: OntoDol contains 762 classes, 92 object properties and 18 SWRL rules to assign patients to 4 categories of priority. OntoDol was able to assert every case and classify them in the right category of priority. Conclusion: Further works will extend OntoDol to other diseases and assess OntoDol with real world data from the hospital.

Specialized pro-resolving lipid mediators (SPMs) as lipoxins (LX), resolvins (Rv), protectins (PD) and maresins (MaR) promote the resolution of inflammation. We and others previously reported reduced levels of LXA4 in bronchoalveolar lavages from cystic fibrosis (CF) patients. Here, we investigated the role of CF airway epithelium in SPMs biosynthesis, and we evaluated its sex specificity. Human nasal epithelial cells (hNEC) were obtained from women and men with or without CF. Lipids were quantified by mass spectrometry in the culture medium of hNEC grown at air-liquid interface and the expression level and localization of the main enzymes of SPMs biosynthesis were assessed. The 5-HETE, LXA4, LXB4, RvD2, RvD5, PD1 and RvE3 levels were significantly lower in samples derived from CF patients compared with non-CF subjects. Within CF samples, the 12-HETE, 15-HETE, RvD3, RvD4, 17-HODHE and PD1 were significantly lower in samples derived from females. While the mean expression levels of 15-LO, 5-LO and 12-LO do not significantly differ either between CF and non-CF or between female and male samples, the SPMs content correlates with the level of expression of several enzymes involved in SPMs metabolism. In addition, the 5-LO localization significantly differed from cytoplasmic in non-CF to nucleic (or nuclear envelope) in CF hNEC. Our studies provided evidence for lower abilities of airway epithelial cells derived from CF patients and more markedly, females to produce SPMs. These data are consistent with a contribution of CF airway epithelium in the abnormal resolution of inflammation and with worse pulmonary outcomes in women.

Background Sudden cardiac deaths are twice more frequent in diabetic patients with cardiac autonomic neuropathy. Sudden cardiac death etiologies remain unclear and no recommendations are made to identify factors associated with cardiorespiratory arrest in diabetic patients. We hypothesized, from two clinical cases, that impaired hypoxic ventilatory drive, induced by diabetic autonomic neuropathy, is a cause of misdiagnosed severe cardiac events. Case presentation We describe the cases of two patients with isolated low blood saturation on pulse oximeter during the systematic nurse check-up (77% and 85% respectively) contrasting with the absence of any complaint such as dyspnea, polypnea or other respiratory insufficiency signs observed during the clinical examination. Arterial blood gas measurements subsequently confirmed that blood oxygen saturation was low and both patients were indeed hypoxemic. Patient 1 suffered from vascular overload complicated by cardiac arrest caused by hypoxemia in light of the quick recovery observed after ventilation. Pulmonary edema was diagnosed in patient 2. The common denominator of these 2 cases described in this brief report is the absence of respiratory failure clinical signs contrasting with the presence of confirmed hypoxemia. Also, in both cases, such absence of precursory signs seems to be induced by an impaired ventilatory drive to hypoxemia. This appears to be related to the autonomic diabetic neuropathy encountered in those 2 patients. Conclusions Therefore, we describe, in this brief report, cardiac autonomic neuropathy as a cause of impaired hypoxic ventilatory drive involved in severe acute cardiorespiratory events in two type 1 diabetic patients. We assume that altered response to hypoxemia due to cardiac autonomic neuropathy and non-functional central neurological breathing command could play a key role in sudden deaths among diabetic patients. An important point is that hypoxemia can be easily missed since no clinical signs of respiratory failure are reported in these two clinical cases. Systematic screening of cardiac autonomic neuropathy in diabetic patients and proactive detection of impaired hypoxic ventilatory drive for early management (e.g. treatment of hypoxemia) should be systematically undertaken in diabetic patients to prevent its dramatic consequences such as cardiorespiratory arrest and death.

International audience; Le lactate a pendant de trop nombreuses années été considéré comme un simple déchet du métabolisme glycolytique, potentiellement délétère pour les organes étant donné le lien entre sa production et l’acidification du microenvironnement. Cette vision a été remise en cause par des études récentes qui placent le métabolisme du lactate au centre de l'homéostasie énergétique de l’organisme, et qui participent à sa réhabilitation en tant que métabolite majeur situé au carrefour du métabolisme glycolytique et oxydatif. De plus, cette littérature très dynamique ne cesse de mettre en lumière de nouveaux mécanismes par lesquels le lactate régule la physiologie cellulaire et notamment les processus de plasticité , en réponse aux modifications environnementales et métaboliques. Ainsi, il apparait que le lactate assure une communication métabolique inter-cellulaire et inter-tissulaire, non seulement par le transport de carbones et d’électrons entre différents compartiments, mais aussi grâce à son rôle de molécule de signalisation.

Pulmonary arterial hypertension (PAH) is a devastating cause of PH due to a progressive narrowing of the distal pulmonary arteries (, L'hypertension artérielle pulmonaire (HTAP) est une maladie cardio-pulmonaire dévastatrice due à une obstruction progressive des artères pulmonaires distales (

International audience; On one side, decompression sickness (DCS) with neurological disorders lead to a reshuffle of the cecal metabolome of rats. On the other side, there is also a specific and different metabolomic signature in the cecum of a strain of DCS-resistant rats, that are not exposed to hyperbaric protocol. We decide to study a conventional strain of rats that resist to an accident-provoking hyperbaric exposure, and we hypothesize that the metabolomic signature put forward may correspond to a physiological response adapted to the stress induced by diving. The aim is to verify and characterize whether the cecal compounds of rats resistant to the provocative dive have a cecal metabolomic signature different from those who do not dive. 35 asymptomatic diver rats are selected to be compared to 21 rats non-exposed to the hyperbaric protocol. Because our aim is essentially to study the differences in the cecal metabolome associated with the hyperbaric exposure, about half of the rats are fed soy and the other half of maize in order to better rule out the effect of the diet itself. Lower levels of IL-1β and glutathione peroxidase (GPX) activity are registered in blood of diving rats. No blood cell mobilization is noted. Conventional and ChemRICH approaches help the metabolomic interpretation of the 185 chemical compounds analyzed in the cecal content. Statistical analysis show a panel of 102 compounds diet related. 19 are in common with the hyperbaric protocol effect. Expression of 25 compounds has changed in the cecal metabolome of rats resistant to the provocative dive suggesting an alteration of biliary acids metabolism, most likely through actions on gut microbiota. There seem to be also weak changes in allocations dedicated to various energy pathways, including hormonal reshuffle. Some of the metabolites may also have a role in regulating inflammation, while some may be consumed for the benefit of oxidative stress management.

International audience; Feed efficiency is a complex trait of interest in animal breeding to reduce environmental impact of livestock herding and the cost of animal feed. A divergent selection on feed efficiency was carried out in pigs for more than 10 generations at an INRAE experimental unit, establishing lines of relative high- and low-feed efficiency in large white pigs. The objective of this study was to identify the molecular mechanisms underlying the divergence in feed efficiency between the two pig lines in the duodenum. We focused on the duodenum because of its sensory role in the hunger satiety pathways.Duodenum mucosal samples were collected in post-weaning pigs from the two divergent lines either after a 12 h period of feed restriction, or with a 10 h period of feed restriction followed by a 2 h period of ad libitum feed access (n = 6 per group and per line). Transcritomes and methylomes were analysed by poly-A RNA sequencing (RNA-seq) and by methylated DNA precipitation followed by sequencing (MeDP-seq), respectively. Transcriptomic reads were analysed with nf-core/rnaseq and limma-voom. MeDP-seq reads were analysed with nf-core/chipseq and the BayMeth method.A total of 962 genes were differentially expressed in the duodenum mucosa between the conditions (fasted vs fed), in contrast with 318 differentially expressed genes when comparing the divergent lines. The DNA methylome of the duodenum mucosa was unaffected by short term feed intake, but was distinct between the lines. More transcripts were affected by short term feed intake in the feed-efficient line than in the other line, including genes of the incretine secretion pathways involved in the production of GIP and GLP-1.Thus the duodenum transcriptomic response to short term feed intake was distinct in feed efficient and less efficient pig lines. These differences might in part be due to differences in DNA methylation profiles.

International audience; Gastric electrical stimulation (GES) is currently used as an alternative treatment for medically refractory gastroparesis. GES has been initially developed to accelerate gastric motility, in order to relieve the symptoms of the patients. Subsequent studies, unfortunately, failed to demonstrate the acceleration of gastric emptying using high-frequency stimulation – low energy stimulation although the technique has shown a clinical impact with a reduction of nausea and vomiting for patients with gastroparesis. The present review details the clinical efficacy of GES in gastroparesis as well as its putative mechanisms of action.

International audience; Aims: Virtual reality hypnosis (VRH) has been used successfully in various clinical settings to decrease anxiety and the sensation of pain. We aimed to investigate the feasibility and safety of VRH in patients undergoing electrophysiology and pacing procedures under conscious sedation. Methods: During a two-month period, VRH support was proposed and accepted by 25 patients undergoing electrophysiological procedures. Data were compared with a control group (n = 61) enrolled during the following three-month period. Both groups underwent the measurement of the duration of intervention, the consumption of analgesics and hypnotics, and their pain and comfort using a validated visual analogue scale (VAS 0−10). Results: The baseline characteristics were comparable in both groups, including age. There were no differences in procedure duration (46 (±29) vs. 56 (±32) min, p = 0.18) or in hypnotic/antalgic consumption (midazolam 1.95 (±1.44) vs. 2.00 (±1.22) mg, p = 0.83; sufentanyl 3.78 (±2.87) vs. 3.58 (±2.48) μg, p = 0.9) between the control and VRH groups. In a multivariate analysis, the use of VRH was independently associated with lower comfort during the procedure assessed by postoperative visual analogue scale (OR 15.00 [95% CI 4.77−47.16], p < 0.01). There was no influence of VRH use on pain or drug consumption. Conclusions: In our experience, compared with VRH, human care is preferable during procedures in electrophysiology lab to improve the comfort of the patient. VRH has no influence on pain or drug consumption.

Background Whether sepsis-associated diaphragm dysfunction may improve despite the exposure of mechanical ventilation in critically ill patients is unclear. This study aims at describing the diaphragm function time course of septic and non-septic mechanically ventilated patients. Methods Secondary analysis of two prospective observational studies of mechanically ventilated patients in whom diaphragm function was assessed twice: within the 24 h after intubation and when patients were switched to pressure support mode, by measuring the endotracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (Ptr,stim). Change in diaphragm function was expressed as the difference between Ptr,stim measured under pressure support mode and Ptr,stim measured within the 24 h after intubation. Sepsis was defined according to the Sepsis-3 international guidelines upon inclusion. In a sub-group of patients, the right hemidiaphragm thickness was measured by ultrasound. Results Ninety-two patients were enrolled in the study. Sepsis upon intubation was present in 51 (55%) patients. In septic patients, primary reason for ventilation was acute respiratory failure related to pneumonia (37/51; 73%). In non-septic patients, main reasons for ventilation were acute respiratory failure not related to pneumonia (16/41; 39%), coma (13/41; 32%) and cardiac arrest (6/41; 15%). Ptr,stim within 24 h after intubation was lower in septic patients as compared to non-septic patients: 6.3 (4.9–8.7) cmH2O vs. 9.8 (7.0–14.2) cmH2O (p = 0.004), respectively. The median (interquartile) duration of mechanical ventilation between first and second diaphragm evaluation was 4 (2–6) days in septic patients and 3 (2–4) days in non-septic patients (p = 0.073). Between first and second measurements, the change in Ptr,stim was + 19% (− 13–61) in septic patients and − 7% (− 40–12) in non-septic patients (p = 0.005). In the sub-group of patients with ultrasound measurements, end-expiratory diaphragm thickness decreased in both, septic and non-septic patients. The 28-day mortality was higher in patients with decrease or no change in diaphragm function. Conclusion Septic patients were associated with a more severe but reversible impaired diaphragm function as compared to non-septic patients. Increase in diaphragm function was associated with a better survival.

In acute malaria, the bulk of erythrocyte loss occurs after therapy, with a nadir of hemoglobin generally observed 3–7 days after treatment. The fine mechanisms leading to this early post-treatment anemia are still elusive. We explored pathological changes in RBC subpopulations by quantifying biochemical and mechanical alterations during severe malaria treated with artemisinin derivatives, a drug family that induce “pitting” in the spleen. In this study, the hemoglobin concentration dropped by 1.93 G/dl during therapy. During the same period, iRBC accounting for 6.12% of all RBC before therapy (BT) were replaced by pitted-RBC, accounting for 5.33% of RBC after therapy (AT). RBC loss was thus of 15.9%, of which only a minor part was due to the loss of iRBC or pitted-RBC. When comparing RBC BT and AT to normal controls, lipidomics revealed an increase in the cholesterol/phosphatidylethanolamine ratio (0.17 versus 0.24, p < 0.001) and cholesterol/phosphatidylinositol ratio (0.36 versus 0.67, p = 0.001). Using ektacytometry, we observed a reduced deformability of circulating RBC, similar BT and AT, compared to health control donors. The mean Elongation Index at 1.69Pa was 0.24 BT and 0.23 AT vs. 0.28 in controls (p < 0.0001). At 30Pa EI was 0.56 BT and 0.56 AT vs. 0.60 in controls (p < 0.001). The retention rate (rr) of RBC subpopulations in spleen-mimetic microsphere layers was higher for iRBC (rr = 20% p = 0.0033) and pitted-RBC (rr = 19%, p = 0.0031) than for healthy RBC (0.12%). Somewhat surprisingly, the post-treatment anemia in malaria results from the elimination of RBC that were never infected.

International audience; Dyslipidemia is a key modifiable causal risk factor involved in the development of atherosclerotic cardiovascular disease. Recently, the G protein-coupled receptor 146 (GPR146), a member of the G-coupled protein receptors' family, has been shown to be a regulator of plasma cholesterol. Inhibition of hepatic GPR146 in mice displays protective effect against both hypercholesterolemia and atherosclerosis. Here, we characterize a genetically engineered human induced pluripotent stem cell (hiPSC) model invalidated for GPR146 (ITXi001-A-1) using CRISPR-Cas9 editing technology. Differentiation of ITXi001-A-1 towards hepatic fate will provide a suitable model for deciphering the molecular mechanisms sustaining the beneficial metabolic effects of GPR146 inhibition.

Background Trials comparing early and delayed strategies of renal replacement therapy in patients with severe acute kidney injury may have missed differences in survival as a result of mixing together patients at heterogeneous levels of risks. Our aim was to evaluate the heterogeneity of treatment effect on 60-day mortality from an early vs a delayed strategy across levels of risk for renal replacement therapy initiation under a delayed strategy. Methods We used data from the AKIKI, and IDEAL-ICU randomized controlled trials to develop a multivariable logistic regression model for renal replacement therapy initiation within 48 h after allocation to a delayed strategy. We then used an interaction with spline terms in a Cox model to estimate treatment effects across the predicted risks of RRT initiation. Results We analyzed data from 1107 patients (619 and 488 in the AKIKI and IDEAL-ICU trial respectively). In the pooled sample, we found evidence for heterogeneous treatment effects (P = 0.023). Patients at an intermediate-high risk of renal replacement therapy initiation within 48 h may have benefited from an early strategy (absolute risk difference, − 14%; 95% confidence interval, − 27% to − 1%). For other patients, we found no evidence of benefit from an early strategy of renal replacement therapy initiation but a trend for harm (absolute risk difference, 8%; 95% confidence interval, − 5% to 21% in patients at intermediate-low risk). Conclusions We have identified a clinically sound heterogeneity of treatment effect of an early vs a delayed strategy of renal replacement therapy initiation that may reflect varying degrees of kidney demand-capacity mismatch.

The screening of skeletal muscle diseases constitutes an unresolved challenge. Currently, exercise tests or plasmatic tests alone have shown limited performance in the screening of subjects with an increased risk of muscle oxidative metabolism impairment. Intensity-adjusted energy substrate levels of lactate (La), pyruvate (Pyr), β-hydroxybutyrate (BOH) and acetoacetate (AA) during a cardiopulmonary exercise test (CPET) could constitute alternative valid biomarkers to select “at-risk” patients, requiring the gold-standard diagnosis procedure through muscle biopsy. Thus, we aimed to test: (1) the validity of the V’O2-adjusted La, Pyr, BOH and AA during a CPET for the assessment of the muscle oxidative metabolism (exercise and mitochondrial respiration parameters); and (2) the discriminative value of the V’O2-adjusted energy and redox markers, as well as five other V’O2-adjusted TCA cycle-related metabolites, between healthy subjects, subjects with muscle complaints and muscle disease patients. Two hundred and thirty subjects with muscle complaints without diagnosis, nine patients with a diagnosed muscle disease and ten healthy subjects performed a CPET with blood assessments at rest, at the estimated 1st ventilatory threshold and at the maximal intensity. Twelve subjects with muscle complaints presenting a severe alteration of their profile underwent a muscle biopsy. The V’O2-adjusted plasma levels of La, Pyr, BOH and AA, and their respective ratios showed significant correlations with functional and muscle fiber mitochondrial respiration parameters. Differences in exercise V’O2-adjusted La/Pyr, BOH, AA and BOH/AA were observed between healthy subjects, subjects with muscle complaints without diagnosis and muscle disease patients. The energy substrate and redox blood profile of complaining subjects with severe exercise intolerance matched the blood profile of muscle disease patients. Adding five tricarboxylic acid cycle intermediates did not improve the discriminative value of the intensity-adjusted energy and redox markers. The V’O2-adjusted La, Pyr, BOH, AA and their respective ratios constitute valid muscle biomarkers that reveal similar blunted adaptations in muscle disease patients and in subjects with muscle complaints and severe exercise intolerance. A targeted metabolomic approach to improve the screening of “at-risk” patients is discussed.

International audience; Abstract The effect of pain and analgesics on stress biomarkers is not well studied. We evaluated the effect of acute pain and analgesics on serum cortisol and copeptin in an experimental pain model in healthy volunteers. Healthy volunteers presented at 8 a.m. for an experimental pain stimulation. Cortisol and copeptin levels were measured before, during and after electrophysiological stimulation, first before and then during opioid delivery. Difference in biomarker levels compared to baseline levels was calculated, and potential influencing factors were evaluated by linear regression analysis. Cortisol decreased by 13% during the 10 min of rest at baseline, but copeptin did not change significantly. Cortisol had a median decrease of −24% or −83 nmol/l (−44 to −124 nmol/l, p = 0.0002) during the electrophysiological stimulation training session, while the median difference for copeptin was −22% or −1.01 pmol/l (−2.35 to 0.08 pmol/l, p = 0.0003). After administration of opioids, cortisol did not decrease but increased by 3% (p = 0.043), indicating an increasing opioids effect on cortisol. This effect was not visible for copeptin (median change −0.003 pmol/l (−0.50 to 0.24), p = 0.45). In this experimental pain model performed in the morning, moderate pain did not have a relevant effect on cortisol or copeptin levels, whereas opioids led to a discrete peak of cortisol. Clinicaltrials.gov identifier: NCT01975753 (registered on November 5, 2013, before start of recruitment).

International audience; Chronic low back pain is the number one cause of years lived with disability. In about 40% of patients, chronic lower back pain is related to intervertebral disc (IVD) degeneration. The standard-of-care focuses on symptomatic relief, while surgery is the last resort. Emerging therapeutic strategies target the underlying cause of IVD degeneration and increasingly focus on the relatively overlooked notochordal cells (NCs). NCs are derived from the notochord and once the notochord regresses they remain in the core of the developing IVD, the nucleus pulposus. The large vacuolated NCs rapidly decline after birth and are replaced by the smaller nucleus pulposus cells with maturation, ageing, and degeneration. Here, we provide an update on the journey of NCs and discuss the cell markers and tools that can be used to study their fate and regenerative capacity. We review the therapeutic potential of NCs for the treatment of IVD-related lower back pain and outline important future directions in this area. Promising studies indicate that NCs and their secretome exerts regenerative effects, via increased proliferation, extracellular matrix production, and anti-inflammatory effects. Reports on NC-like cells derived from embryonic- or induced pluripotent-stem cells claim to have successfully generated NC-like cells but did not compare them with native NCs for phenotypic markers or in terms of their regenerative capacity. Altogether, this is an emerging and active field of research with exciting possibilities. NC-based studies demonstrate that cues from developmental biology can pave the path for future clinical therapies focused on regenerating the diseased IVD.

Naked mole-rats are extraordinarily long-lived rodents that offer unique opportunities to study the molecular origins of age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the 'membrane pacemaker' hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure.

International audience; Aging is a multifactorial process that results in progressive loss of regenerative capacity and tissue function while simultaneously favoring the development of a large array of age-related diseases. Evidence suggests that the accumulation of senescent cells in tissue promotes both normal and pathological aging. Oxic stress is a key driver of cellular senescence. Because symbiotic long-lived reef corals experience daily hyperoxic and hypoxic transitions, we hypothesized that these long-lived animals have developed specific longevity strategies in response to light. We analyzed transcriptome variation in the reef coral Stylophora pistillata during the day–night cycle and revealed a signature of the FoxO longevity pathway. We confirmed this pathway by immunofluorescence using antibodies against coral FoxO to demonstrate its nuclear translocation. Through qPCR analysis of nycthemeral variations of candidate genes under different light regimens, we found that, among genes that were specifically up- or downregulated upon exposure to light, human orthologs of two “light-up” genes (HEY1 and LONF3) exhibited anti-senescence properties in primary human fibroblasts. Therefore, these genes are interesting candidates for counteracting skin aging. We propose a large screen for other light-up genes and an investigation of the biological response of reef corals to light (e.g., metabolic switching) to elucidate these processes and identify effective interventions for promoting healthy aging in humans.

International audience; The heart automaticity is a fundamental physiological function in vertebrates. The cardiac impulse is generated in the sinus node by a specialized population of spontaneously active myocytes known as "pacemaker cells." Failure in generating or conducting spontaneous activity induces dysfunction in cardiac automaticity. Several families of ion channels are involved in the generation and regulation of the heart automaticity. Among those, voltage-gated L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels play important roles in the spontaneous activity of pacemaker cells. Ca2+ channel channelopathies specifically affecting cardiac automaticity are considered rare. Recent research on familial disease has identified mutations in the Cav1.3-encoding CACNA1D gene that underlie congenital sinus node dysfunction and deafness (OMIM # 614896). In addition, both Cav1.3 and Cav3.1 channels have been identified as pathophysiological targets of sinus node dysfunction and heart block, caused by congenital autoimmune disease of the cardiac conduction system. The discovery of channelopathies linked to Cav1.3 and Cav3.1 channels underscores the importance of Ca2+ channels in the generation and regulation of heart's automaticity.

International audience; The obese patient is at risk of perioperative complications including difficult airway access (intubation, difficult or impossible ventilation), and postextubation acute respiratory failure due to the formation of atelectases or to airway obstruction. The association of obstructive sleep apnoea syndrome (OSA) with obesity is very common, and induces a high risk of per and postoperative complications. Preoperative OSA screening is crucial in the obese patient, as well as its specific management: use of continuous positive pre-, per- and postoperative pressure. For any obese patient, the implementation of difficult intubation protocols and the use of protective ventilation (low tidal volume 6–8 mL/kg of ideal body weight, moderate positive end-expiratory pressure of 10 cmH20, recruitment manoeuvres in absence of contra-indications), with morphine sparing and semi-seated positioning as much as possible are recommended, associated with a close postoperative monitoring. The dosage of anaesthetic drugs is usually based on the ideal body weight or the adjusted body weight and then titrated, except for succinylcholine that is dosed according to the total body weight. Monitoring of neuromuscular blockers should be used where appropriate, as well as monitoring of the depth of anaesthesia, especially when total intravenous anaesthesia is used in association with neuromuscular blockers. The occurrence of intraoperative awareness is indeed more frequent in the obese patient than in the non-obese patient. Appropriate prophylaxis against venous thromboembolism and early mobilisation are recommended, if possible included in an early rehabilitation protocol, to further reduce postoperative complications.

International audience; Research into voluntary apnea is becoming increasingly popular in varied laboratories and in the field around the world. In the last 10 years, as many articles have been published than between 1954 and 2011. Breath-hold diving is truly an antique practice; for example, Alexandre Legrand employed professional breath hold divers called “Urinator” in his army, and Japanese Ama and Philippine Bajau people have been known to dive for hundreds of years to gather food. More recently, apnea diving became a high-level competitive sport with impressive performances (e.g., world record for static apnea of 11 mins 35 s and for depth No-Limit diving −214 m), but although constant progress is made, human performance is still far from the prowess of marine mammals (e.g., Ziphius cavirostris, apnea duration: 137 mins and 2,992 m depths). Despite major anatomical and physiological differences between humans and marine mammals, humans present with an interesting physiological response to apnea to limit the effects of hypoxia and/or pressure increase, in which the main physiological functions such as pulmonary, cardiovascular, and nervous functions can be modulated acutely and chronically. The Research Topic focuses on these varied facets but also their trainability and their consequences on health in relation to some hypoxia-related pathologies such as sleep apnea syndrome, pulmonary edema and decompression sickness.

Objectives In children, achieving an acceptable degree of accuracy from dietary or physical activity (PA) assessments remains a challenge. Children tend to overestimate their time spent in daily PA and underestimate their dietary intake of fat and sugar. Because parents play a key role in family lifestyle decisions, including children’s food choices and PA levels, it is important to investigate the responses of parents regarding their children’s lifestyle habits. We aimed to develop a Self-Administered Parental Assessment of Children’s Lifestyle (SAPLACL) questionnaire and test its feasibility and reliability in 191 parents (29 fathers and 162 mothers). Results For each part of the questionnaire, the rate of missing or improper responses ranged from 0 to 24%. The highest proportion of problems in understanding was reported for the dietary intake dimension, especially for snacking in front of the TV. Some difficulty was also found regarding the question on leisure PA. Test–retest agreement was observed in 54.7–100% of the respondents. Overall, the kappa coefficients were favorable. Thus, the parent self-report questionnaire is a valid and accurate tool for analyzing children’s lifestyle habits in France.

CT registration-derived indices provide data on regional lung functional changes in COPD. However, because unlike spirometry which involves dynamic maximal breathing maneuvers, CT-based functional parameters are assessed between two static breath-holds, it is not clear how regional and global lung function parameters relate to each other. We assessed the relationship between CT-density change (dHU), specific volume change (dsV), and regional lung tissue deformation (J) with global spirometric and plethysmographic parameters, gas exchange, exercise capacity, dyspnoea, and disease stage in a prospective cohort study in 102 COPD patients. There were positive correlations of dHU, dsV, and J with spirometric variables, DLCO and gas exchange, 6-min walking distance, and negative correlations with plethysmographic lung volumes and indices of trapping and lung distension as well as GOLD stage. Stepwise regression identified FEV1/FVC (standardized β = 0.429, p < 0.0001), RV/TLC (β = −0.37, p < 0.0001), and BMI (β = 0.27, p=β = 0.32, p=β = −0.48, p=

“Exercise starts and ends in the brain”: this was the title of a review article authored by Dr. Bengt Kayser back in 2003. In this piece of work, the author highlights that pioneer studies have primarily focused on the cardiorespiratory-muscle axis to set the human limits to whole-body exercise tolerance. In some circumstances, however, exercise cessation may not be solely attributable to these players: the central nervous system is thought to hold a relevant role as the ultimate site of exercise termination. In fact, there has been a growing interest relative to the “brain” response to exercise in chronic cardiorespiratory diseases, and its potential implication in limiting the tolerance to physical exertion in patients. To reach these overarching goals, non-invasive techniques, such as near-infrared spectroscopy and transcranial magnetic stimulation, have been successfully applied to get insights into the underlying mechanisms of exercise limitation in clinical populations. This review provides an up-to-date outline of the rationale for the “brain” as the organ limiting the tolerance to physical exertion in patients with cardiorespiratory diseases. We first outline some key methodological aspects of neuromuscular function and cerebral hemodynamics assessment in response to different exercise paradigms. We then review the most prominent studies, which explored the influence of major cardiorespiratory diseases on these outcomes. After a balanced summary of existing evidence, we finalize by detailing the rationale for investigating the “brain” contribution to exercise limitation in hitherto unexplored cardiorespiratory diseases, an endeavor that might lead to innovative lines of applied physiological research.

https://www.encephale.com/Congres/Congres-de-l-Encephale-2022/Meilleurs-posters-2022https://www.encephale.com/Actualites/2022/Posters/Modelisation-des-mecanismes-sous-jacents-de-l-electroretinogramme-pathologique-dans-la-schizophrenie; International audience

International audience; Background: The benefits of parathyroidectomy on cardiovascular risk in primary hyperparathyroidism (PHPT) are controversial. This monocentric, observational, prospective study aimed to assess the effects of parathyroidectomy on glucose and lipid metabolism in classic or mild PHPT.Methods: Patients who underwent parathyroidectomy for classic (calcemia >2.85 mmol/L) or mild PHPT (calcemia ≤2.85 mmol/L) between 2016 and 2019 were included. A metabolic assessment was performed before and 1 year after parathyroidectomy. Patients with a history of diabetes were excluded.Results: Nineteen patients had classic and 120 had mild PHPT. Ninety-five percent were normocalcemic 6 months after surgery. Fasting plasma glucose and insulin levels decreased after parathyroidectomy in patients with mild PHPT (p < 0.001). HOMA-IR decreased after surgery in the overall population (p < 0.001), while plasma adiponectin concentrations increased in patients with both classic (p = 0.005) and mild PHPT (p < 0.001). Plasma triglyceride levels decreased significantly only in patients with classic PHPT (p = 0.021). Plasma PCSK9 levels decreased in patients with mild PHPT (p < 0.001).Conclusions: Parathyroidectomy for PHPT improves insulin resistance and decreases plasma triglyceride levels in classic PHPT and plasma PCSK9 levels in mild PHPT. Further studies are needed to better characterize the consequences of such metabolic risk factors' improvements on cardiovascular events.