Rôle de la P-glycoprotéine, un transporteur ABC, sur la distribution cardiaque et tissulaire de la dompéridone et répercussions possibles sur l'intervalle QT

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Quand la Gymnastique Holistique Ehrenfried et l’art-thérapie s’allient pour élargir la conscience de soi : étude exploratoire

Cette recherche dont l’expérience et ses conclusions sont relatées dans le présent rapport est née au carrefour de deux pratiques qui peuvent sembler, en apparence, appartenir à des univers théoriques et pratiques éloignés : l’éducation somatique et l’art-thérapie. En effet, l’éducation somatique, et plus spécifiquement la Gymnastique Holistique Ehrenfried, est une pratique orientée vers le corps et le développement de la conscience corporelle, dans une perspective de mieux-être, d’abord physique. Quant à l’art-thérapie, il s’agit d’une approche utilisée dans le cadre de démarches de développement personnel, d’interventions psychosociales ou de psychothérapie et qui fait appel à des médiums artistiques. Ce désir de se faire rencontrer ces deux univers a pris naissance dans une intuition que le corps, l’esprit et le monde émotionnel sont étroitement interreliés. Malgré le fait que la science ait confirmé cette hypothèse (Levine, 2019; van der Kolk, 1996; Scaer, 2001), force est d’admettre que l’intervention psychosociale, et en particulier les approches psychothérapeutiques, intègrent peu la perspective du corps dans les modalités d’intervention. De plus, les neurosciences nous apprennent que le cerveau enregistre des mémoires implicites auxquelles le corps donne directement accès (Cozolino, 2016; LeDoux, 2015). C’est ce que l’on constate notamment chez les victimes souffrant d’un trouble de stress post-traumatique. L’art-thérapie d'inspiration gestaltiste adhère à ces idées et se déploie dans cette perspective où le travail thérapeutique fait appel au corps (Hamel, 2014). La Gymnastique Holistique Ehrenfried (GHE) est une approche en éducation somatique dans laquelle l’éducateur somatique propose des expérimentations favorisant la détente, la mobilité, la souplesse, la tonicité, tout en étant attentif aux comportements individuels qui permettent à chacun de devenir ce qu’il est. Sans en être un objectif explicite, il a toutefois été observé que cette approche sur la prise de conscience corporelle peut provoquer des émotions qui surviennent durant ou après la séance. nous semble donc intéressant et pertinent d’étudier si et comment la GHE favorise la conscience de soi globale. Plus concrètement cette présente recherche souhaite répondre à ces questions : La GHE, cette méthode d’éducation somatique, favorise-t-elle une conscience de soi, qui va au-delà des sensations strictement physiques? Une séance d’art-thérapie en groupe, suivant la GHE, permettrait-elle d’intégrer une plus grande conscience de soi? Et cette conscience de soi peut-elle se dévoiler dans une création artistique en argile? Les liens entre la Gestalt-thérapie et la GHE ont déjà été étudiés mais leur articulation à la pratique de l’art-thérapie est à parfaire et sera développée dans cette recherche. Cette étude exploratoire permettra de mieux comprendre aux plans théoriques et cliniques comment fonctionne l’art-thérapie lorsqu’elle est soutenue par une approche en éducation somatique. De plus, s’il s’avère effectivement que la GHE favorise un ressenti qui dépasse la conscience corporelle, elle devient alors une approche intéressante à intégrer à l'art-thérapie. En somme, la recherche pourrait ainsi encourager la collaboration entre les approches psychologiques et les approches somatiques. Ce rapport se décline en six chapitres. Dans un premier temps, une brève présentation de la problématique sera faite, suivie d’une recension des écrits présentant l’état actuel des connaissances sur les effets de l’art-thérapie, de l’éducation somatique et de la GHE. Par la suite, le cadre théorique présentera l’éducation somatique, la GHE, la Gestalt-thérapie et l’art-thérapie gestaltiste. Puis, la méthodologie de la recherche qui a été mise en oeuvre sera décrite. Les résultats seront ensuite présentés et feront l’objet d’une discussion dans un dernier chapitre. Puis suivra la conclusion

Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination

<p>Abstract</p> <p>Background</p> <p>The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate.</p> <p>Methods</p> <p>A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS) model and then refined by a mechanistic transport-based (MTB) model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of <it>in vitro </it>measurements of drug permeability to the <it>in vivo </it>situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues.</p> <p>Results</p> <p>This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model.</p> <p>Conclusion</p> <p>Being built prior to <it>in vivo </it>data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters.</p> <p>The physiological based model is novel and unique and brought effective information on drug transporters.</p

Normal Human Merkel Cells are Present in Epidermal Cell Populations Isolated and Cultured from Glabrous and Hairy Skin Sites

The Merkel cell is a highly specialized cell that primarily acts as a slowly adapting mechanoreceptor. Merkel cells are scarce in normal skin but can be identified by the expression of distinct keratin filaments. Merkel cells constitute a very unique population and many questions still remain as to their origin, number, proliferative capacity, and functions in cutaneous biology. The dissociation of epidermal cells from skin is a widely used technique to extract and culture keratinocytes. We took advantage of a two-step extraction method to quantify keratin-20-expressing Merkel cells among total cutaneous cells obtained from either hairy or glabrous skin biopsies. Flow cytometry analysis revealed that keratin-20-labeled Merkel cells represent between 3.6% and 5.7% of freshly dissociated basal epidermal cells. No significant differences were seen between samples derived from glabrous palmar and hairy anatomic sites, from children and adult, respectively. We also report on the presence of Merkel cells in primary and first subcultures of epidermal cells indicating their capacity to remain viable after extraction from skin of various anatomic sites. To our knowledge, this is the first demonstration of nontumorigenic human Merkel cells in culture in vitro. The persistence of a small number of Merkel cells in culture suggests that, with the development of appropriate culture conditions, these cells could be amplified and further studied to unravel long-standing questions relative to their paracrine function or epithelial origin

Floating solar panels on reservoirs impact phytoplankton populations:A modelling experiment

Floating solar photovoltaic (FPV) deployments are increasing globally as the switch to renewable energy intensifies, representing a considerable water surface transformation. FPV installations can potentially impact aquatic ecosystem function, either positively or negatively. However, these impacts are poorly resolved given the challenges of collecting empirical data for field or modelling experiments. In particular, there is limited evidence on the response of phytoplankton to changes in water body thermal dynamics and light climate with FPV. Given the importance of understanding phytoplankton biomass and species composition for managing ecosystem services, we use an uncertainty estimation approach to simulate the effect of FPV coverage and array siting location on a UK reservoir. FPV coverage was modified in 10 % increments from a baseline with 0 % coverage to 100 % coverage for three different FPV array siting locations based on reservoir circulation patterns. Results showed that FPV coverage significantly impacted thermal properties, resulting in highly variable impacts on phytoplankton biomass and species composition. The impacts on phytoplankton were often dependent on array siting location as well as surface coverage. Changes to phytoplankton species composition were offset by the decrease in phytoplankton biomass associated with increasing FPV coverage. We identified that similar phytoplankton biomass reductions could be achieved with less FPV coverage by deploying the FPV array on the water body's faster-flowing area than the central or slower flowing areas. The difference in response dependent on siting location could be used to tailor phytoplankton management in water bodies. Simulation of water body-FPV interactions efficiently using an uncertainty approach is an essential tool to rapidly develop understanding and ultimately inform FPV developers and water body managers looking to minimise negative impacts and maximise co-benefits

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20 : G protein- coupled receptors

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.Peer reviewe

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570