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Comprend des références bibliographiques

Human leukocytes differentially express endocannabinoid-glycerol lipases and hydrolyze 2-arachidonoyl-glycerol and its metabolites from the 15-lipoxygenase and cyclooxygenase pathways

2-Arachidonoyl-glycerol (2-AG) is an endocannabinoid with anti-inflammatory properties. Blocking 2-AG hydrolysis to enhance CB2 signaling has proven effective in mouse models of inflammation. However, the expression of 2-AG lipases has never been thoroughly investigated in human leukocytes. Herein, we investigated the expression of seven 2-AG hydrolases by human blood leukocytes and alveolar macrophages (AMs) and found the following protein expression pattern: monoacylglycerol (MAG lipase; eosinophils, AMs, monocytes), carboxylesterase (CES1; monocytes, AMs), palmitoyl-protein thioesterase (PPT1; AMs), α/β-hydrolase domain (ABHD6; mainly AMs), ABHD12 (all), ABHD16A (all), and LYPLA2 (lysophospholipase 2; monocytes, lymphocytes, AMs).We next found that all leukocytes could hydrolyze 2-AG and its metabolites derived from cyclooxygenase-2 (prostaglandin E2-glycerol [PGE2-G]) and the 15-lipoxygenase (15-hydroxy-eicosatetraenoyl-glycerol [15-HETE-G]). Neutrophils and eosinophils were consistently better at hydrolyzing 2-AG and its metabolites than monocytes and lymphocytes. Moreover, the efficacy of leukocytes to hydrolyze 2-AG and its metabolites was 2-AG ≥ 15-HETE-G >> PGE2-G for each leukocyte. Using the inhibitors methylarachidonoyl-fluorophosphonate (MAFP), 4-nitrophenyl-4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184), Palmostatin B, 4′-carbamoylbiphenyl-4-yl methyl(3-(pyridin-4-yl)benzyl)carbamate, Nmethyl-N-[[3-(4-pyridinyl)phenyl]methyl]-4′-(aminocarbonyl) [1,1′-biphenyl]-4-yl ester carbamic acid (WWL70), 4′-[[[methyl[[3-(4-pyridinyl)phenyl]methyl]amino]carbonyl]oxy]-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (WWL113), tetrahydrolipstatin, and ML349, we could not pinpoint a specific hydrolase responsible for the hydrolysis of 2-AG, PGE2-G, and 15-HETE-G by these leukocytes. Furthermore, JZL184, a selective MAG lipase inhibitor, blocked the hydrolysis of 2-AG, PGE2-G, and 15-HETE-G by neutrophils and the hydrolysis of PGE2-G and 15-HETE-G by lymphocytes, two cell types with limited/no MAG lipase. Using an activity-based protein profiling (ABPP) probe to label hydrolases in leukocytes, we found that they expressmanyMAFP-sensitive hydrolases and an unknown JZL184-sensitive hydrolase of ~52 kDa. Altogether, our results indicate that human leukocytes are experts at hydrolyzing 2-AG and its metabolites via multiple lipases and probably via a yet-to-be characterized 52 kDa hydrolase. Blocking 2-AG hydrolysis in humans will likely abrogate the ability of human leukocytes to degrade 2-AG and its metabolites and increase their anti-inflammatory effects in vivo

The Current States, Challenges, Ongoing Efforts, and Future Perspectives of Pharmaceutical Excipients in Pediatric Patients in Each Country and Region

A major hurdle in pediatric formulation development is the lack of safety and toxicity data on some of the commonly used excipients. While the maximum oral safe dose for several kinds of excipients is known in the adult population, the doses in pediatric patients, including preterm neonates, are not established yet due to the lack of evidence-based data. This paper consists of four parts: (1) country-specific perspectives in different parts of the world (current state, challenges in excipients, and ongoing efforts) for ensuring the use of safe excipients, (2) comparing and contrasting the country-specific perspectives, (3) past and ongoing collaborative efforts, and (4) future perspectives on excipients for pediatric formulation. The regulatory process for pharmaceutical excipients has been developed. However, there are gaps between each region where a lack of information and an insufficient regulation process was found. Ongoing efforts include raising issues on excipient exposure, building a region-specific database, and improving excipient regulation; however, there is a lack of evidence-based information on safety for the pediatric population. More progress on clear safety limits, quantitative information on excipients of concern in the pediatric population, and international harmonization of excipients’ regulatory processes for the pediatric population are required

L’Échelle du climat de prévention de la violence : traduction, adaptation et évaluation psychométrique de la version canadienne-française

Introduction: Violence in psychiatric settings has negative consequences on patients, staff, and the institution alike. Efforts to prevent violence cannot currently be assessed due to a lack of suitable indicators. The Violence Prevention Climate Scale (VPC-14) is a validated tool that can be filled out by both staff and patients to assess the violence prevention climate in mental health care units. Objective: This study aimed to conduct the translation and adaptation of the VPC-14 to a French Canadian context, and to assess its psychometric properties in general and forensic psychiatric settings. Methods: This study followed a transcultural approach for validating measuring instruments. Psychometric properties were assessed in 308 patients and staff from 4 mental health and forensic hospitals in Quebec (Canada). Content validity was assessed using a bilingual participant approach. Internal validity was examined through exploratory factor analysis and internal consistency for each care setting using Cronbach’s alpha coefficient analysis. Results: The Échelle modifiée du climat de prévention de la violence [Modified Violence Prevention Climate Scale] (VPC-M-FR) consists of 23 items with a 3-factor structure: 1) staff action, 2) patient action, and 3) the therapeutic environment. Cronbach’s alphas ranging from 0.69 to 0.89 were obtained for the internal consistency of the scale. Discussion and conclusion: The VPC-M-FR has satisfactory psychometric properties for measuring the violence prevention climate in mental health and forensic settings. By measuring the violence prevention climate from the standpoint of patients and staff, targeted preventive measures can be implemented to improve safety for all.Introduction : La violence en milieu psychiatrique entraîne des conséquences néfastes pour les patients, les intervenants et les organisations. Pourtant, les efforts pour la prévenir ne peuvent être évalués faute d’indicateurs adéquats. Le Violence Prevention Climate Scale (VPC-14), complété par les intervenants et les patients, est un outil validé qui évalue le climat de prévention de violence. Objectif : Cette étude vise à traduire et adapter le VPC-14 au contexte québécois et à en vérifier la fiabilité et la validité en psychiatrie générale et légale. Méthodes : En se basant sur la méthode de validation transculturelle d’instruments de mesure, les propriétés psychométriques ont été évaluées auprès de 308 patients et intervenants de 4 hôpitaux et instituts de santé mentale et médico-légale québécois. La validité de construit a été examinée par une analyse factorielle exploratoire et la cohérence interne par l’analyse du coefficient alpha de Cronbach. Résultats : L’Échelle modifiée du climat de prévention de la violence (VPC-M-FR) comprend 23 énoncés avec une structure à 3 facteurs : 1) les actions des intervenants, 2) les actions des patients et 3) l’environnement thérapeutique. Des coefficients alpha de Cronbach variant de 0,69 à 0,89 ont été obtenus pour la consistance interne de l’échelle. Discussion et conclusion : Le VPC-M-FR possède des propriétés psychométriques satisfaisantes pour mesurer le climat de prévention de la violence en milieu de santé mentale et médico-légal. En tenant compte de la perspective des intervenants et des patients, des interventions ciblées de prévention pourront être mises en œuvre afin d’améliorer la sécurité de tous

Demonstration of a Hybrid Space Architecture During RIMPAC 2020

The Micro-Satellite Military Utility (MSMU) Project Arrangement (PA) is an agreement under the Responsive Space Capabilities (RSC) Memorandum of Understanding (MOU) that involves the Departments and Ministries of Defence of Australia, Canada, Germany, Italy, the Netherlands, New Zealand, Norway, United Kingdom and United States. MSMU’s charter is to inform a space enterprise that provides military users with reliable access to a broad spectrum of information in an opportunistic environment. Research and Development teams from MSMU partner nations supported Exercise Rim of the Pacific (RIMPAC) 2020 which took place 17 to 31 August 2020 in the Hawaiian region. RIMPAC 2020 provided an opportunity to explore the military utility of a Hybrid Space Architecture (HSA) of satellites including traditional government and commercial satellites, as well as micro-satellites and nanosatellites, by leveraging contributions across the MSMU partner nations. The objective was to continue testing the hypothesis that an HSA, mostly composed of small satellites, can bring significant value to the operational theatre. The MSMU PA partner nations have leveraged several multi-national exercises, with the first being the Exercise RIMPAC 2018. Previous exercises enabled multinational technology advancements, interoperability testing, process refinement, and capability developments to make advancements towards MSMU’s goal to address the warfighter’s need for diverse ISR capabilities. The most recent accomplishment was a major integration effort across mission planning tools, space-based Intelligence, Surveillance and Reconnaissance (ISR) data providers, and exploitation tools. The MSMU team accessed ~256 space-based sensors (EO – Electro Optical, SAR – Synthetic Aperture Radar, AIS – Automatic Identification System) to collect maritime domain and ISR data over a harbor, airfields and open sea. Data was exploited via international channels in order to determine the success rate of capturing pertinent data to be later exploited and disseminated. This paper describes results from the experiment and offers insights into the HSA military utility

Internal deformation of the subducted Nazca slab inferred from seismic anisotropy

Within oceanic lithosphere a fossilized fabric is often preserved originating from the time of plate formation. Such fabric is thought to form at the mid-ocean ridge when olivine crystals align with the direction of plate spreading1, 2. It is unclear, however, whether this fossil fabric is preserved within slabs during subduction or overprinted by subduction-induced deformation. The alignment of olivine crystals, such as within fossil fabrics, can generate anisotropy that is sensed by passing seismic waves. Seismic anisotropy is therefore a useful tool for investigating the dynamics of subduction zones, but it has so far proved difficult to observe the anisotropic properties of the subducted slab itself. Here we analyse seismic anisotropy in the subducted Nazca slab beneath Peru and find that the fast direction of seismic wave propagation aligns with the contours of the slab. We use numerical modelling to simulate the olivine fabric created at the mid-ocean ridge, but find it is inconsistent with our observations of seismic anisotropy in the subducted Nazca slab. Instead we find that an orientation of the olivine crystal fast axes aligned parallel to the strike of the slab provides the best fit, consistent with along-strike extension induced by flattening of the slab during subduction (A. Kumar et al., manuscript in preparation). We conclude that the fossil fabric has been overprinted during subduction and that the Nazca slab must therefore be sufficiently weak to undergo internal deformation

Régulation de l'inflammation par les lipides bioactifs : interactions biosynthétiques et fonctionnelles entre les endocannabinoïdes et les éicosanoïdes

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2019-2020Les maladies inflammatoires chroniques sont un fardeau de santé important à travers le monde. Les traitements actuellement disponibles soulagent la douleur et l’inflammation, mais leurs effets secondaires rendent leur utilisation à long terme risquée. À la lumière de cette problématique, la communauté scientifique s’intéresse au potentiel d’anti-inflammatoires naturels comme les endocannabinoïdes. Les endocannabinoïdes sont des lipides endogènes qui activent les récepteurs cannabinoïdes (CB1 et CB2). Ils régulent ainsi divers processus physiologiques tels l’appétit, l’adipogénèse et la nociception. Les deux endocannabinoïdes les mieux caractérisés, le 2-AG et l’AEA, peuvent également moduler l’inflammation en activant le récepteur CB2 à la surface des cellules immunitaires. Les souris déficientes pour le récepteur CB2 présentent un phénotype inflammatoire exacerbé, suggérant que ce récepteur est anti-inflammatoire. Cependant, le rôle des endocannabinoïdes dans l’inflammation est beaucoup plus complexe puisqu’ils peuvent être métabolisés en une grande variété de médiateurs lipidiques de l’inflammation. Leur voie de dégradation principale est leur hydrolyse en acide arachidonique (AA), qui sert de précurseur à la biosynthèse d’éicosanoïdes pro-inflammatoires comme le leucotriène B4 et la prostaglandine E2. Ils peuvent également être métabolisés directement par certaines enzymes impliquées dans la synthèse d’éicosanoïdes, pour générer des médiateurs comme les prostaglandines-glycérol (PG-G). Par conséquent, les endocannabinoïdes peuvent générer un profil unique d’effets pro- et anti-inflammatoires. Des stratégies thérapeutiques visant à bloquer l’hydrolyse des endocannabinoïdes pour amplifier leurs effets anti-inflammatoires ont été étudiées, mais une très grande proportion de cette recherche a été effectuée sur des animaux. Les façons dont les endocannabinoïdes sont synthétisés et dégradés par les leucocytes humains, ainsi les effets de leurs métabolites sur les fonctions de ces cellules, sont mal définis. Bien que les résultats obtenus dans des modèles animaux soient prometteurs, ces mécanismes doivent être mieux caractérisés chez l’humain avant qu’il ne soit envisageable de les manipuler afin de traiter les maladies inflammatoires. Le premier objectif de mon doctorat était de caractériser les voies de dégradation et de biosynthèse des endocannabinoïdes chez les leucocytes humains. Nous avons documenté l’expression de toutes les lipases hydrolysant le 2-AG, chez plusieurs types leucocytaires. Ces résultats ont souligné que chaque leucocyte exprime plusieurs 2-AG hydrolases et que les inhibiteurs sélectifs actuellement disponibles n’inhibent que partiellement l’hydrolyse du 2-AG chez ces cellules. Ces données ont également démontré que les leucocytes humains hydrolysent très efficacement le 2-AG, une découverte qui nous a permis de mettre en évidence une nouvelle voie de biosynthèse du 2-AG par les leucocytes. En présence d’inhibiteurs d’hydrolyse, les neutrophiles, éosinophiles et monocytes stimulés avec de l’AA ont produit des quantités de 2-AG environ 1000 fois supérieures aux niveaux rapportés dans la littérature. Ils ont également transformé d’autres acides gras polyinsaturés en leurs endocannabinoïdes-glycérol respectifs. Nous avons démontré que cette voie de biosynthèse est dépendante de la réacylation des acides gras dans les phospholipides membranaires, et que leur métabolisme subséquent en endocannabinoïdes implique possiblement l’acide lysophosphatidique comme intermédiaire. Cette étude est la première à rapporter une biosynthèse significative d’endocannabinoïdes par les leucocytes humains, et à démontrer que cette biosynthèse est indépendante de la voie classique de biosynthèse du 2-AG. Nous avions également pour objectif de caractériser l’impact du 2-AG et des PG-G sur les fonctions des leucocytes humains. Nous avons démontré qu’en présence d’IL-5, une cytokine impliquée dans l’inflammation éosinophilique présente dans l’asthme, le 2-AG induit une migration importante des éosinophiles. Cet effet du 2-AG requiert à la fois l’activation du récepteur CB2 et l’hydrolyse du 2-AG en AA pour produire des métabolites de la 15-lipoxygénase. Ceci souligne que l’hydrolyse du 2-AG permet la production de médiateurs causant des effets pro-inflammatoires et qu’il serait souhaitable de bloquer cette hydrolyse in vivo. Finalement, nous avons étudié l’effet de la PGE2-G sur les fonctions des neutrophiles et démontré qu’elle inhibe plusieurs fonctions effectrices de ces cellules. Cet effet inhibiteur nécessite l’hydrolyse de la PGE2-G en PGE2 par les neutrophiles, et l’activation du récepteur EP2 à leur surface. Nos travaux permettront de mieux comprendre la façon dont l’hydrolyse des endocannabinoïdes devrait être bloquée chez les humains, ainsi que tous les effets biologiques qui en découleront. Le but ultime est de développer de nouveaux traitements contre les maladies inflammatoires chroniques, qui maximiseront les effets analgésiques et anti-inflammatoires des endocannabinoïdes tout en limitant leurs effets néfastes.Chronic inflammatory diseases are an important health burden worldwide. The currently available treatments alleviate pain and inflammation, but their numerous adverse effects make their long term use difficult. Therefore, the scientific community is studying the anti-inflammatory potential of mediators such as endocannabinoids. Endocannabinoids are endogenous lipids that activate the cannabinoid receptors, namely CB1 and CB2. In doing so, they regulate various physiological functions and cognitive processes functions such as appetite, adipogenesis and nociception. The two best-characterized endocannabinoids, 2-AG and AEA, also exert effects on immune cell functions, leading to the modulation of immunity and inflammation. They do so by activating the CB2 receptor, which is expressed in the periphery, notably on immune cells. Notably, it was shown that mice lacking the CB2 receptor display an exacerbated inflammatory phenotype, suggesting that CB2 activation by endocannabinoids is anti-inflammatory. However, the biological effects of endocannabinoids are far more complex, given that they can be metabolized into a wide variety of bioactive lipids. The main degradation pathway for 2-AG and AEA is their hydrolysis into arachidonic acid (AA), a fatty acid that acts a precursor for the biosynthesis of several pro-inflammatory eicosanoids such as leukotriene B4 and prostaglandin E2. They can also be directly metabolized by eicosanoid-biosynthetic enzymes, which generates mediators such as glyceryl-prostaglandins (PG-Gs). Therefore, endocannabinoids can generate an intriguing profile of pro- and anti-inflammatory effects, depending on the balance between their catabolic pathways and receptor activation. Therapeutic strategies aiming at blocking endocannabinoid hydrolysis to amplify their anti-inflammatory effects have been extensively studied. However, most of these studies were conducted in animals. Endocannabinoid metabolism by human leukocytes, as well as the effects of their metabolites on human leukocytes functions, are poorly defined. Although the data obtained from animal models is promising, these mechanisms must be characterized in humans before they can be manipulated to treat inflammatory diseases. Our first aim was to characterize endocannabinoid biosynthetic and hydrolytic pathways in human leukocytes. We documented the expression of several 2-AG hydrolases in human neutrophils, eosinophils, monocytes, lymphocytes and alveolar macrophages. The data we obtained underscored that each cell type expresses several 2-AG hydrolases, and that the selective inhibitors that are currently available only partially block 2-AG degradation by leukocytes. Our results also show that human leukocytes are experts at hydrolyzing 2-AG, a finding that allowed us to establish a novel 2-AG biosynthetic pathway in human leukocytes. In the presence of 2-AG hydrolysis inhibitors, neutrophils, eosinophils and monocytes stimulated with AA produced 2-AG in amounts ~ 1000 times greater than those previously reported. They also converted other polyunsaturated fatty acids into their glycerol-containing endocannabinoid counterparts. We showed that this endocannabinoid biosynthetic pathway depends on fatty acid reacylation into membrane phospholipids, and that their subsequent metabolism into endocannabinoid likely requires the production of a lysophosphatidic acid intermediate. This study is the first one to report a significant endocannabinoid synthesis by human leukocytes, and to show that this biosynthesis is independent from the classical 2-AG biosynthetic pathway. We also aimed to characterize the impact of 2-AG and PG-Gs on human leukocyte functions. We showed that in the presence of IL-5, a cytokine involved in the eosinophilic inflammation found in asthma, 2-AG induces eosinophil migration. This requires the activation of the CB2 receptor, as well as 2-AG hydrolysis into AA to produce 15-lipoxygenase metabolites. This underscores that 2-AG hydrolysis by eosinophils allows for the synthesis of mediators that have pro-inflammatory effects, and that blocking this hydrolysis in vivo may be beneficial. We also studied the biological effects of PGE2-G and found that it inhibits several effector functions of human neutrophils. This inhibitory effect requires PGE2-G hydrolysis into PGE2 by neutrophils, and the activation of the EP2 receptor on their surface. Our work will allow a better understanding of how endocannabinoid hydrolysis should be blocked in humans, and of the biological effects that will result from this inhibition. The goal is to develop new treatments against chronic inflammatory diseases, which will enhance the analgesic and anti-inflammatory effects of endocannabinoids while limiting their deleterious effects

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Comprend des références bibliographique