Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1.

The recent identification of two new thrombin receptors, PAR3 and PAR4, led us to re-examine the basis for endothelial cell responses to thrombin. Human umbilical vein endothelial cells (HUVEC) are known to express PAR1 and the trypsin/tryptase receptor, PAR2. Northern blots detected both of those receptors and, to a lesser extent, PAR3, but PAR4 message was undetectable and there was no response to PAR4 agonist peptides. To determine whether PAR3 or any other receptor contributes to thrombin signaling in HUVEC, PAR1 cleavage was blocked with two selective antibodies and PAR1 activation was inhibited with the antagonist, BMS200261. The antibodies completely inhibited HUVEC responses to thrombin, but BMS200261 was only partly effective, even though separate studies established that the antagonist completely inhibits PAR1 signaling at the concentrations used. Since peptides mimicking the PAR1 tethered ligand domain can also activate PAR2, we asked whether the remaining thrombin response in the presence of the antagonist could be due in part to the intermolecular transactivation of PAR2 by cleaved PAR1. Evidence that transactivation can occur was obtained in COS-7 cells co-expressing PAR2 and a variant of PAR1 that can be cleaved, but not signal. There was a substantial response to thrombin only in cells expressing both receptors. Conversely, in HUVEC, complete blockade of the thrombin response by the PAR1 antagonist occurred only when signaling through PAR2 was also blocked. From these observations we conclude that 1) PAR1 is the predominant thrombin receptor expressed in HUVEC and cleavage of PAR1 is required for endothelial cell responses to thrombin; 2) although PAR3 may be expressed, there is still no evidence that it mediates thrombin responses; 3) PAR4 is not expressed on HUVEC; and 4) transactivation of PAR2 by cleaved PAR1 can contribute to endothelial cell responses to thrombin, particularly when signaling through PAR1 is blocked. Such transactivation may limit the effectiveness of PAR1 antagonists, which compete with the tethered ligand domain rather than preventing PAR1 cleavage

Panton-Valentine Leukocidin and Staphyloccoccal Skin Infections in Schoolchildren1

The Panton-Valentine leukocidin is associated with staphylococcal skin and pulmonary infections. We describe a school outbreak of skin infections and the public health response to it. Nasal carriage of a Panton-Valentine leukocidin–positive Staphylococcus aureus clone was detected only in previously ill classmates and their family members

Quantitative super-resolution imaging reveals protein stoichiometry and nanoscale morphology of assembling HIV-Gag virions

The HIV structural protein Gag assembles to form spherical particles of radius ∼70 nm. During the assembly process, the number of Gag proteins increases over several orders of magnitude from a few at nucleation to thousands at completion. The challenge in studying protein assembly lies in the fact that current methods such as standard fluorescence or electron microscopy techniques cannot access all stages of the assembly process in a cellular context. Here, we demonstrate an approach using super-resolution fluorescence imaging that permits quantitative morphological and molecular counting analysis over a wide range of protein cluster sizes. We applied this technique to the analysis of hundreds of HIV-Gag clusters at the cellular plasma membrane, thus elucidating how different fluorescent labels can change the assembly of virions

Trade-Off between Toxicity and Signal Detection Orchestrated by Frequency- and Density-Dependent Genes

Behaviors in insects are partly highly efficient Bayesian processes that fulfill exploratory tasks ending with the colonization of new ecological niches. The foraging (for) gene in Drosophila encodes a cGMP-dependent protein kinase (PKG). It has been extensively described as a frequency-dependent gene and its transcripts are differentially expressed between individuals, reflecting the population density context. Some for transcripts, when expressed in a population at high density for many generations, concomitantly trigger strong dispersive behavior associated with foraging activity. Moreover, genotype-by-environment interaction (GEI) analysis has highlighted a dormant role of for in energetic metabolism in a food deprivation context. In our current report, we show that alleles of for encoding different cGMP-dependent kinase isoforms influence the oxidation of aldehyde groups of aromatic molecules emitted by plants via Aldh-III and a phosphorylatable adaptor. The enhanced efficiency of oxidation of aldehyde odorants into carboxyl groups by the action of for lessens their action and toxicity, which should facilitate exploration and guidance in a complex odor environment. Our present data provide evidence that optimal foraging performance requires the fast metabolism of volatile compounds emitted by plants to avoid neurosensory saturation and that the frequency-dependent genes that trigger dispersion influence these processes

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Epidémiologie et dépistage du cancer de la prostate par le dosage du PSA chez les hommes de plus de 50 ans

Le cancer de la prostate est en passe de devenir le cancer le plus fréquemment diagnostiqué chez l'homme. Ce cancer est la deuxième cause de mortalité après le cancer du poumon. Si son incidence a désormais tendance à se stabiliser, elle a fortement augmenté ces dernières années. Ce phénomène est lié d'une part à l'allongement de la durée de vie, et d'autre part aux examens para-cliniques comme le dosage de l'Antigène Prostatique Spécifique (PSA), et les biopsies de la prostate écho-guidées qui permettent de déceler à un stade précoce des cancers qui il y a quelques années passaient inaperçus ou auraient été décelés à un stade plus avancé. Le dépistage du cancer de la prostate par le dosage du PSA est à l'origine d'une polémique opposant d'un côté des sociétés savantes, comme l'Association Française d'Urologie ou l'American Cancer Society, et l'Agence Nationale d'Accréditation et d'Evaluation en Santé (ANAES). En 1999, elles ont édité des recommandations contraires avant de tomber d'accord fin 2003, pour autoriser un dépistage individuel chez les hommes âgés de 50 à 75 ans. L'ANAES a toutefois émis des réserves sur l'intérêt en terme de mortalité et de morbidité de cette prévention. Dans ce contexte, le but de notre étude a été d'évaluer pour 2003, la prescription du dosage de PSA chez les hommes de plus de cinquante ans, ressortissants de régime agricole et du régime des travailleurs indépendants en Aquitaine. Le codage des actes de biologie médicale a permis de recueillir les données et d'apprécier la position des médecins sur la prescription de ce dosage. En 2003, la population d'étude est composée de 114 691 hommes de plus de 50 ans et un homme sur trois a eu dans l'année au moins un dosage de PSA. 1 % de ces dosages ont permis de faire le diagnostic de cancer. L'incidence du cancer de la prostate en 2003, est de 337 nouveaux cas pour 100 000 hommes et la prévalence de 3 %. Ces chiffres sont comparables à la population générale en France et dans les autres pays occidentaux. Un grand nombre de dosages ont été réalisés chez des hommes de plus de 80 ans. Si l'intérêt d'un traitement radical agressif du cancer de la prostate chez un homme de plus de 75 ans est nul, le dépistage peut néanmoins garder un intérêt. Dépister une maladie n'implique pas forcément de la traiter de façon agressive. Des traitements palliatifs n'ayant pas d'incidence délétère sur la qualité de vie du patient peuvent avoir un impact positif. Les réserves de l'ANAES ne sont pas partagées par un grand nombre de médecins.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Efetividade das técnicas expiratórias passivas não convencionais na bronquiolite viral aguda: uma revisão da literatura

Projeto de Graduação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Licenciado em FisioterapiaObjetivo: Determinar a efetividade das técnicas expiratórias passivas não convencionais em recém-nascidos com bronquiolite viral aguda (BVA). Metodologia: Pesquisa computadorizada nas bases de dados PubMed/PEDro/Lilacs/Cochrane/Rcaap e Scielo para identificar estudos que avaliam a efetividade das técnicas expiratórias passivas não convencionais em recém-nascidos com BVA. Resultados: Nesta revisão foram incluídos 5 estudos envolvendo 881 pacientes. Dos estudos incluídos nesta revisão verificou-se que somente 2 demonstraram efetividade em utentes com BVA. Conclusão: As técnicas expiratórias passivas não convencionais não demonstraram melhoria na gravidade da bronquiolite ao nível da pontuação clínica, nem na redução do tempo de recuperação ou do tempo de permanência hospitalar.Objective: To determine the effectiveness of non-conventional passive expiratory techniques in newborns with acute viral bronchiolitis (AVB). Methodology: Computerized research in the PubMed/PEDro/Lilacs/Cochrane/Rcaap and Scielo databases to identify studies evaluating the effectiveness of non-conventional passive expiratory techniques in newborns with AVB. Results: Five studies involving 881 patients were included in this review. Of the studies included in this review, it was verified that only 2 demonstrated effectiveness in patients with BVA. Conclusion: Non-conventional passive expiratory techniques have not demonstrated improvement in bronchiolitis severity by means of clinical scores, nor in the reduction of recovery or hospital stay time.N/

Penser l’ancien droit public. Regards croisés sur les méthodes des juristes (III)

L’ouvrage s’inscrit dans le sillage de deux précédents volumes, intitulés Penser l’ordre juridique médiéval et moderne et Penser l’ancien droit privé, qui tentaient d’évaluer la tendance des historiens des facultés de droit à jeter un voile dogmatique, sinon trompeur, sur les réalités normatives du passé. Consacré à l’écriture de l’histoire du droit public, ce troisième et dernier volume a pour ambition de livrer une réflexion épistémologique sur l’un des enjeux de l’historiographie juridique : peut-on penser l’ancien droit public à partir des catégories juridiques contemporaines ? Il semble en effet que le droit public – au moins en France – ait largement échappé à de tels questionnements, qui ont pourtant fait l’objet de débats nourris dans la plupart des autres champs de la connaissance historique. Afin de combler ce manque en revenant sur le dilemme bien connu du rapport de la recherche historique au présent, l’ouvrage interroge des concepts souvent considérés comme quasiment atemporels ; que l’on pense à la liberté, la justice, l’État ou l’impôt. Plus largement, les trois volumes des Regards croisés sur les méthodes des juristes souhaitent contribuer aux débats sur la place de l’analyse historique du droit