Blocking the receptor EP3 to PGE2 as a way to safely prevent atherothrombosis

Aspirin inhibits the platelet production of thromboxane A2 and its beneficial effect on myocardial infarction was demonstrated more than two decades ago. This result validated the strategy aimed at targeting platelet function to prevent myocardial infarction. Since then, numerous drugs targeting various activators of platelets have been developed to further improve prevention. However, the beneficial effect of all these drugs on atherothrombosis is limited by an increased risk of bleeding, because they target thrombosis effectors which are also key players in hemostasis. Since aspirin blocks the generation of numerous prostanoids, including inhibitors of platelet activation, targeting one of them might allow the antithrombotic activity to be maintained without promoting bleeding. In examining the roles of various arachidonic acid metabolites on atherothrombosis, we studied the prostaglandin E2 (PGE2). In vivo, PGE2 facilitates the responses of platelets to all their various activators through its receptor EP3. PGE2 is produced in relatively high amounts in the context of chronic inflammation such as atherosclerosis, and aggravates murine atherothrombosis. Conversely, PGE2 is not involved in hemostasis. As expected, blocking EP3 strikingly reduced atherothrombosis in mice without impacting bleeding tests. In a recent paper published in Prostaglandins & Other Lipid Mediators, we reviewed literature data about the effect of PGE2 and its receptor EP3 on platelet thrombosis and hemostasis in mice and humans. We concluded that cumulated data now justifies validating the role of EP3 blockers with phase III trials to safely improve the prevention of myocardial infarction

Microstructure and electrical properties of (Ba0.6Sr0.4)0.85Bi0.1TiO3 ceramics prepared by single-step, liquid-phase, solid-state reactive sintering

(Ba0.6Sr0.4)0.85Bi0.1TiO3 ceramics have been obtained by single-step, liquid-phase, solid-state reactive sintering in the temperature range 1250–1350 °C using stoichiometric amounts of BaTiO3, SrTiO3 and Bi4Ti3O12. Their microstructure and electrical properties have been studied by X-Ray diffraction and fluorescence, scanning and transmission electron microscopy and impedance spectroscopy. The relative density, Dr, relative permittivity, ε′r, and dissipation factor, tan δ, at room temperature and the bulk and grain boundary resistivity, Rb and Rgb, and activation energies, Eba and Egba, are approximately independent of the sintering temperature with values around e.g. Dr ~97.5 %, ε′r ~1790, tan δ ~0.06 %, R500oCb ~26 kΩ cm, Egba ~1.03 eV, R500oCgb ~217 kΩ cm and Egba ~1.41 eV. By contrast, the temperature coefficient of capacitance, TCC, increases linearly from ~10 ppm oC−1 to ~21 ppm oC−1 on increasing sintering temperature. Comments on the influence of the sintering temperature on the chemical composition of the ceramics are made

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Blocking the receptor EP3 to PGE2 as a way to safely prevent atherothrombosis

Aspirin inhibits the platelet production of thromboxane A2 and its beneficial effect on myocardial infarction was demonstrated more than two decades ago. This result validated the strategy aimed at targeting platelet function to prevent myocardial infarction. Since then, numerous drugs targeting various activators of platelets have been developed to further improve prevention. However, the beneficial effect of all these drugs on atherothrombosis is limited by an increased risk of bleeding, because they target thrombosis effectors which are also key players in hemostasis. Since aspirin blocks the generation of numerous prostanoids, including inhibitors of platelet activation, targeting one of them might allow the antithrombotic activity to be maintained without promoting bleeding. In examining the roles of various arachidonic acid metabolites on atherothrombosis, we studied the prostaglandin E2 (PGE2). In vivo, PGE2 facilitates the responses of platelets to all their various activators through its receptor EP3. PGE2 is produced in relatively high amounts in the context of chronic inflammation such as atherosclerosis, and aggravates murine atherothrombosis. Conversely, PGE2 is not involved in hemostasis. As expected, blocking EP3 strikingly reduced atherothrombosis in mice without impacting bleeding tests. In a recent paper published in Prostaglandins & Other Lipid Mediators, we reviewed literature data about the effect of PGE2 and its receptor EP3 on platelet thrombosis and hemostasis in mice and humans. We concluded that cumulated data now justifies validating the role of EP3 blockers with phase III trials to safely improve the prevention of myocardial infarction

Exploration de la rupture des plaques d'athérosclérose et du devenir des plaquettes agrégées in vivo par mircroscopie électronique à balayage

La thrombose est souvent liée à la survenue d une rupture de la plaque d athérosclérose qui expose le tissu sous endothélial thrombogène aux plaquettes sanguines circulantes. L un des problèmes actuels est l identification des mécanismes qui sont à l origine de la fracture. Nous avons testé l hypothèse que la vasoconstriction, induite par le LTC4 ou le thromboxane A2 (TXA2), joue un rôle dans la rupture de plaques d athérosclérose et dans la formation de l athérothrombose. Dans ce travail nous avons adapté la technique classique de la microscopie électronique pour observer les ruptures survenues sur une plaque d athérosclérose. Avec cette méthode, nous avons montré qu une vasoconstriction peut engendrer des ruptures de plaques, mais seulement lorsque ces plaques sont fragilisées (dites vulnérables ) soit par un régime riche en graisse ou après exposition de la souris à un lipopolysaccharide extrait de membranes bactériennes. Nous avons montré aussi que la plaque produit du TXA2, et que l absence de son récepteur chez les souris apoE-/- déficientes en TP prévient la rupture des plaques vulnérabilisées. La vasoconstriction constitue donc un élément déterminant dans la rupture des plaques vulnérables. Les résultats de ce travail identifient le TXA2 comme étant une éventuelle cible thérapeutique pour prévenir les ruptures des plaques. D autre part, les analyses par microscopie électronique à balayage de la thrombose in vivo, et les analyses en microscopie électronique en transmission (MET) de l ultrastructure des plaquettes agrégées in vitro, ont montré que les plaquettes activées fusionnent entre elle permettant ainsi la cicatrisation de l endothélium lésé.Rupture of atherosclerotic plaques exposes sub-endothelial thrombogenic material to circulating platelets, frequently leads to thrombus formation. At present, the mechanisms behind plaque ruptures are not well understood. We studied the hypothesis that vasoconstriction induced by LTC4 or thromboxane A2 (TXA2) plays an important role in plaque rupture and formation of atherothombosis. We used scanning electron microscopy to study rupture of the plaque in detail. We were able to show that vasoconstriction leads to plaque rupture, but only after plaques have been vulnerabilized by high fat diet, or by exposure of mice to lipopolysaccharide extracted from bacterial membranes. We could also show that plaques produce TXA2. As consequence the absence of TP, a receptor for TXA2 in apoE-/- mice prevented rupture of vulnerable plaques. Vasoconstriction is hence a determining factor in the rupture of vulnerable plaques. Our work has identified TXA2 as a potential therapeutic target in preventing plaque rupture. Moreover, analysis of the thrombosis in vivo by scanning electron microscopy, and the in vitro study of the ultra structure of aggregated platelets by transmission electron microscopy, showed that activated platelets fuse together to heal the injured endothelium.STRASBOURG-Bib.electronique 063 (674829902) / SudocSudocFranceF

Rôle de la prostaglandine E2 dans l'hémostase artérielle et l'athérothrombose

Les prostanoïdes sont des lipides dérivés de l acide arachidonique (AA) jouant un rôle important dans le contrôle de l homéostasie vasculaire. La prostaglandine E2 (PGE2), l un d eux facilite l agrégation de plaquettes faiblement stimulées in vitro, en diminuant leur seuil d activation. Ce mécanisme est dépendant de l activation du récepteur EP3, un des quatre récepteurs de la PGE2. La PGE2 facilite la thrombose veineuse due à l administration d AA mais son rôle en physiopathologie doit être défini. Ce travail montre que la paroi artérielle soumise à des stress inflammatoires produit de la PGE2. Dans plusieurs modèles, nous avons montré que cette PGE2 produite par la paroi facilite la thrombose artérielle. Puis, nous avons montré que les plaques d athérosclérose murines contiennent de grandes quantités de PGE2 et que cette PGE2 intra-plaque est fonctionnelle et capable d activer son récepteur EP3. Nous avons aussi indirectement prouvé que la PGE2 peut franchir la plaque pour activer son récepteur EP3 présent sur les plaquettes sanguines. Finalement, l athérothrombose provoquée in vivo par la rupture mécanique d une plaque est significativement diminuée quand les plaquettes sont dépourvues de EP3. En conclusion, la PGE2 facilite l initiation de la thrombose artérielle et aggrave l athérothrombose. L inhibition du récepteur EP3 plaquettaire devrait être utile dans le traitement de l athérothrombose.Prostanoids, bioactive lipids derived from arachidonic acid (AA) are important for vascular homeostasis. Among them, prostaglandin E2 (PGE2) enhances aggregation of platelets sub-maximally stimulated in vitro. This results from activation of EP3, one of the four PGE2 receptors, which decreases the threshold at which agonists activate platelets to aggregate. Although PGE2 altered venous thrombosis induced by administration of AA, its role in physiopathological conditions has remained speculative. We report here that arterial wall subjected to inflammatory stimuli produces PGE2. In several models, we show that PGE2 by arterial wall facilitates arterial thrombosis. Next, we detected PGE2 in murine atherosclerotic plaques. We demonstrate that this plaque-produced PGE2 is not altered and is still able to activate EP3. In addition, we present evidences that PGE2 can leave the plaque and activate EP3 on blood platelets. Consistent with these findings, we observed that atherothrombosis induced in vivo by mechanical rupture of the plaque was drastically decreased when platelets lacked EP3. In conclusion, PGE2 facilitates the initiation of arterial thrombosis and hence contributes to atherothrombosis. Inhibition of its platelets EP3 receptor should improve prevention of atherothrombosis.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Exploration du rôle de deux eicosanoïdes dans la rupture de plaque d'athérosclérose

Les facteurs et mécanismes conduisant aux complications de l athérosclérose, telles que l infarctus du myocarde et l accident vasculaire cérébral, ne sont pas bien compris. Il est établi que c est la survenue d une thrombose qui engendre ces complications. Cette thrombose est souvent liée à la survenue d une fracture sur la plaque qui expose le tissu sous-endothélial thrombogène aux plaquettes sanguines circulantes. L un des problèmes actuels est l identification des mécanismes qui sont à l origine de cette fracture. J ai testé l hypothèse qu un vasospasme engendre une rupture, en raison de tension mécanique induite par ce vasospasme entre la zone athéroscléreuse rigide, et la zone saine plus souple. Mon travail fait clairement apparaître qu une vasoconstriction peut engendrer des ruptures de plaques, mais seulement lorsque ces plaques sont fragilisées (dites vulnérables). De plus, j ai montré qu un candidat possible pouvant déclencher ce vasospasme est le thromboxane A2, qui est une molécule produite par la plaque. L ensemble de ces résultats devrait permettre d ajuster le traitement de l angor, et particulièrement celui de l angor instable.The mechanisms leading to the Atherosclerosis complications, for example myocardial infarction or stroke, are not fully understood. The occurence of thrombosis results from plaque rupture, which exposes the subendothelial tissue to circulating platelets. The main current question is to identify which mechanisms are directly responsible for the rupture. Therefore I hypothesized that vasoconstriction is a direct player in rupture; mechanical tension induced by the vasoconstriction between atherosclerotic area and healthy vascular wall could be sufficient for breaking the plaque. My work demonstrates that vasoconstriction can induce plaque ruptures, but only when these plaques are fragilized (vulnerable). Moreover, I suggest that TXA2 could be the molecule triggering vasoconstriction and I show that TXA2 is produced by the plaque. These data could held to improve the treatment of angina, and particularly the unstable angina.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Dynamics of plant use of a pest insect in an agricultural landscape studied using isotopic and molecular analyses

Dynamics of plant use of a pest insect in an agricultural landscape studied using isotopic and molecular analyses. ESA-INTECOL 2005 JOINT MEETING :Ecology at multiple scales/Ecologie : une question d'échelle