Ontological exercises to overcome mismatch diseases’ obstacles to holistic health

The current urban environment inhabited by humans in North America reflects profound changes in its physical and social architecture that occurred more rapidly than the human biological capacity to adapt. This mismatch between self and environment can result in ailments and diseases that are physical (e.g. metabolic syndrome) and psychological (e.g. anxiety, depression). These mismatch ailments act insidiously, as their chronic/diffuse nature makes them go generally unnoticed. However, their effects are no less important on overall wellbeing and deserve attention from health professionals. The overarching hypothesis is that ontological exercises, i.e. practices that are aimed to foster a deeper understanding of the nature of being, promote holistic health to counterbalance the feeling of threat arising from the disconnect between post-modern society and the ancestral makeup of human beings. Numerous cultural practices have emphasized exercises aimed at operating transformative changes to increase wellbeing, empathy, compassion and pro-social behaviors. Ontological exercises from ancient Greeks, Buddhists and Native Americans will be explored in this context

The TAK1→IKKβ→TPL2→MKK1/MKK2 Signaling Cascade Regulates IL-33 Expression in Cystic Fibrosis Airway Epithelial Cells Following Infection by Pseudomonas aeruginosa

In cystic fibrosis (CF), chronic respiratory infections result in an exaggerated and uncontrolled inflammatory response that ultimately lead to a decrease in pulmonary function. We have previously described the presence of the alarmin IL-33 in lung explants from CF patients. The signals regulating IL-33 expression in the airway epithelium following a gram-negative bacterial infection are currently unknown. Our objective was to characterize the pathways in CF airway epithelial cells (AECs) leading to an increase in IL-33 expression. We found that, in CF AECs expressing a deletion of a phenylalanine at position 508 of the gene coding for Cystic Fibrosis Transmembrane Conductance Regulator (CFTRdelF508), exposure to live Pseudomonas aeruginosa upregulates IL-33 via the TLR2 and TLR5 signalling pathways. This up-regulation can be partially or fully reverted by pre-incubating CFTRdelF508 AECs with a CFTR corrector (VX-809) and/or a CFTR potentiator (VX-770). Similarly, incubation with the CFTR corrector and/or the CFTR potentiator also decreased IL-8 expression in response to infection. Moreover, using different protein kinase inhibitors that target elements downstream of TLR signalling, we show that the TAK1→IKKβ→TPL2→MKK1/MKK2 pathway regulates IL-33 expression following an infection with P. aeruginosa. Our findings represent the first characterization of the signals regulating IL-33 expression in CF airway epithelial cells in response to a bacterial infection

Le mouvement énactif et le problème difficile de la conscience

La phénoménalité de l’expérience, soit le fait que les choses nous apparaissent avec un effet subjectif, demeure l’une des questions les plus importantes pour la philosophie de l’esprit contemporaine. La difficulté de fournir quelque analyse fonctionnelle ou d’identifier quelque mécanisme physique qui nous permette d’expliquer adéquatement ce qui constitue la phénoménalité est ce qui donne toujours lieu au « problème difficile de la conscience ». Ce travail examine les contributions d’un ensemble de perspectives relativement récentes – les approches énactives de la cognition – en lien avec ce problème philosophique. Les positions énactives considèrent la cognition comme un faire et comme une activité que déploie un sujet incarné, plutôt qu’une réception et un traitement passif de l’information. Ce changement de perspective nous incite du même coup à reconcevoir la phénoménalité sur la base de l’ensemble des interactions entre l’organisme et son environnement et nous offre des pistes de réflexion nouvelles pour résoudre le saut explicatif entre les données phénoménales et les données empiriques. En explorant les trois principales représentantes de ce courant de recherche – l’énactivisme autopoïétique, l’énactivisme sensorimoteur et l’énactivisme radical – ce mémoire fournit une synthèse compréhensible des principales ressources dont dispose le mouvement énactif en lien avec le problème difficile de la conscience. En outre, la comparaison de ces trois points de vue met en lumière une différence fondamentale entre deux conceptions opposées du naturalisme philosophique à l’œuvre dans le mouvement énactif. La perspective transcendantale d’héritage husserlien que souhaite préserver le camp autopoïétique est présentée comme une impasse qui devrait être délaissée au profit d’une intégration plus poussée des théories sensorimotrice et radicale avec les neurosciences.The phenomenality of experience—the fact that things appear for us with a subjective character—is still one of the most important questions for contemporary philosophy of mind. The difficulty to provide any functional analysis or to identify any physical mechanism which would allow us to explain adequately what phenomenality consists in, is what gives rise to the ongoing “hard problem of consciousness”. This work explores the contributions of a relatively new set of perspectives on cognition—the enactive approaches—in light of the hard problem. The enactive positions consider cognition as a doing or an activity deployed by an embodied subject, rather that a passive reception and processing of information. This change of perspective invites us at the same time to reconceive phenomenality on the basis of the whole set of interactions between the organism and its environment and provides us with new ways to reflect on how to possibly resolve the “explanatory gap” between phenomenal and empirical data. By elaborating on the three main figures of this orientation of research—autopoïetic enactivism, sensorimotor enactivism and radical enactivism—this thesis provides an intelligible synthesis of the main ressources in the hands of the enactive movement to progress on the hard problem of consciousness. Additionally, the comparison of these three points of view brings forth a fundamental difference between two opposite conceptions of philosophical naturalism whithin the enactive movement. The transcendantal perspective of husserlian background which the autopoïetic movement seeks to preserve is shown to lead to a dead-end, which should be abandonned for the sake of a deeper integration of sensorimotor and radical positions with the neurosciences

Étude du rôle préactivateur de la protéine S100A9 sur les neutrophiles dans la goutte

La goutte est une arthrite particulièrement douloureuse due à une réponse immunitaire contre des cristaux d’urate monosodique (MSU). Le neutrophile est un leucocyte qui contribue grandement à la perpétuation de l’inflammation lors d’une crise de goutte. Avant d’être recrutés au site d’inflammation, les neutrophiles rencontrent plusieurs médiateurs pro-inflammatoires, dont la protéine S100A9. Nous montrons ici que S100A9 accentue plusieurs réponses effectrices des neutrophiles humains aux MSU, notamment la production de dérivés réactifs de l’oxygène (ROS), la sécrétion de CXCL8/IL-8 et d’IL-1β et la glycolyse. S100A9 augmente également la mobilisation intracellulaire de calcium du neutrophile en plus d’augmenter la phosphorylation des tyrosines, la phosphorylation des sérines des substrats de la PKC, d’AKT et de la p38. Nous avons identifié un des mécanismes par lesquels S100A9 contribue à la pathogenèse de la goutte ainsi que les voies de signalisation impliquées dans ce phénomène qui sont des cibles thérapeutiques potentielles pour cette maladie.Gout is the common and painful type of inflammatory arthritis. It is caused by an immune response against monosodium urate crystals (MSU) that form in the affected joint. Neutrophils are the most abundant leukocytes in the gout joint and play a key role in perpetuating inflammation during a gout flare. During their recruitment to the site of inflammation, neutrophils are exposed to several pro-inflammatory mediators such as S100A9. Although blocking S100A9 dampens MSU-induced inflammation, the role of this protein in the pathogenesis of gout remains incompletely characterized. We identified a novel role for S100A9 in MSU-induced inflammation, the priming of neutrophils towards MSU activation. We provide evidence for the ability of S100A9 to enhance several effector functions of human neutrophils triggered by MSU including the production of reactive oxygen species (ROS), the secretion of CXCL8/IL-8 and IL-1β as well as glycolysis. As for intracellular signaling, S100A9 increases the mobilisation of calcium, induces tyrosine phosphorylation of intracellular proteins as well as serine phosphorylation of PKC, AKT and p38 kinase. In summary, we report for the first time that S100A9 acts as a priming agent during MSU-induced inflammation and identify the underlying signaling pathways that could be targeted to treat gout

Les métamorphoses de la sirène au cinéma

La sirène, créature née à l’Antiquité, par sa double nature, paraît toujours en devenir, en transition. Ni tout à fait oiseau ou poisson, ni tout à fait femme, elle est coincée entre deux mondes : entre la terre et la mer, entre la fille et la femme. Elle est, à la limite, inadaptée au monde terrestre à cause de sa nature animale et/ou divine, et pourtant irrésistiblement attirée par lui et attirante pour lui. Complexe, elle est le fantasme même, le besoin de croire « qu’il y a des rêves meilleurs » (H.G. Wells, Miss Waters, Éditions Mercure de France, Collection Folio, Saint-Amand, 1984, page 101). Elle n’a cessé d’être réadaptée et déclinée, dès les origines du cinéma et du cinéma d’animation. Ce mémoire se consacre aux métamorphoses aussi bien physiques, psychiques que symboliques de la sirène, dans le champ du cinéma. Elles seront étudiées, en premier lieu, au cours de l’Histoire du cinéma, et feront l’objet d’une définition de ce que l’on pourrait qualifier de « film de sirène », ses codes et ses figures récurrentes, soulevant les problématiques de la mise en scène subaquatique. Et en second lieu, au sein des films même, de leur narration. Nous verrons ainsi que ces transformations peuvent être la métaphore des mutations pubertaires comme celle d’un passage d’une société à une autre

PERC rule to exclude the diagnosis of pulmonary embolism in emergency low-risk patients: study protocol for the PROPER randomized controlled study.

BACKGROUND: The diagnosis of Pulmonary Embolism (PE) in the emergency department (ED) is crucial. As emergency physicians fear missing this potential life-threatening condition, PE tends to be over-investigated, exposing patients to unnecessary risks and uncertain benefit in terms of outcome. The Pulmonary Embolism Rule-out Criteria (PERC) is an eight-item block of clinical criteria that can identify patients who can safely be discharged from the ED without further investigation for PE. The endorsement of this rule could markedly reduce the number of irradiative imaging studies, ED length of stay, and rate of adverse events resulting from both diagnostic and therapeutic interventions. Several retrospective and prospective studies have shown the safety and benefits of the PERC rule for PE diagnosis in low-risk patients, but the validity of this rule is still controversial. We hypothesize that in European patients with a low gestalt clinical probability and who are PERC-negative, PE can be safely ruled out and the patient discharged without further testing. METHODS/DESIGN: This is a controlled, cluster randomized trial, in 15 centers in France. Each center will be randomized for the sequence of intervention periods: a 6-month intervention period (PERC-based strategy) followed by a 6-month control period (usual care), or in reverse order, with 2 months of "wash-out" between the 2 periods. Adult patients presenting to the ED with a suspicion of PE and a low pre test probability estimated by clinical gestalt will be eligible. The primary outcome is the percentage of failure resulting from the diagnostic strategy, defined as diagnosed venous thromboembolic events at 3-month follow-up, among patients for whom PE has been initially ruled out. DISCUSSION: The PERC rule has the potential to decrease the number of irradiative imaging studies in the ED, and is reported to be safe. However, no randomized study has ever validated the safety of PERC. Furthermore, some studies have challenged the safety of a PERC-based strategy to rule-out PE, especially in Europe where the prevalence of PE diagnosed in the ED is high. The PROPER study should provide high-quality evidence to settle this issue. If it confirms the safety of the PERC rule, physicians will be able to reduce the number of investigations, associated subsequent adverse events, costs, and ED length of stay for patients with a low clinical probability of PE. TRIAL REGISTRATION: NCT02375919

Far-and mid-infrared properties of carbon layers elaborated by plasma sputtering

International audienceThe far-and mid-infrared reflectivity spectra of two carbon layers deposited on pure (100) silicon substrates by DC magnetron sputtering were investigated at room temperature in the 10-5000 cm-1 wavenumber range. Their structural and textural features were also studied by combining Raman spectroscopy, Field Emission Scanning Electron Microscopy (FESEM), High Resolution Transmission Electron Microscopy (HRTEM), X-Ray Reflectivity (XRR) and Rutherford Backscattering Spectroscopy (RBS). The set of results was used to discuss afterwards the influence of the texture on the infrared properties at varying length scale. Thereby, the two layers were found to be heterogeneous as assessed by RBS, XRR and FESEM and their thicknesses had been measured by XRR and FESEM. The information on the structural organization and " crystallite " size was given by Raman spectroscopy. The influence of both the textural and structural parameters on the measured infrared reflectivity spectra was discussed. Finally, a methodology was proposed to recover the intrinsic index of refraction and the intrinsic index of absorption of each layer

Levothyroxine treatment generates an abnormal uterine contractility patterns in an in vitro animal model

AbstractObjectiveAbnormal uterine contraction patterns were recently demonstrated in uterine strips from pregnant women treated with Levothyroxine (T4). These abnormalities were correlated with an increased risk of C-section delivery and associated surgical complications. To date, no study has investigated whether uterine contractility is modified by hypothyroidism or T4 treatment. Herein, we analyze the physiological role of T4 on uterine contractions.Study designFemale non-pregnant Sprague–Dawley rats (N = 22) were used and divided into four groups: 1) control, 2) hypothyroidism, 3) hypothyroidism treated with low T4 doses (20 μg/kg/day) and 4) with high T4 doses (100 μg/kg/day). Hypothyroidism was induced by an iodine-deficient diet. Isometric tension measurements were performed in vitro on myometrium tissues in isolated organ baths. Contractile activity parameters were quantified (amplitude, duration, frequency and area under the curve) using pharmacological tools to assess their effect.ResultsScreening of thyroid function confirmed a hypothyroid state for all rats under iodine-free diet to which T4 was subsequently administered to counterbalance hypothyroidism. Results demonstrate that hypothyroidism significantly decreased contractile duration (−17%) and increased contractile frequency (+26%), while high doses of T4 increased duration (+200%) and decreased frequency (−51%). These results thus mimic the pattern of abnormal contractions previously observed in uterine tissue from T4-treated hypothyroid pregnant women.ConclusionOur data suggest that changes in myometrial reactivity are induced by T4 treatment. Thus, in conjunction with our previous observations on human myometrial strips, management of hypothyroidism should be improved to reduce the rate of C-sections in this group of patients