Cx43 channels and signaling via IP3/Ca2+, ATP, and ROS/NO propagate radiation-induced DNA damage to non-irradiated brain microvascular endothelial cells

Radiotherapeutic treatment consists of targeted application of radiation beams to a tumor but exposure of surrounding healthy tissue is inevitable. In the brain, ionizing radiation induces breakdown of the blood-brain barrier by effects on brain microvascular endothelial cells. Damage from directly irradiated cells can be transferred to surrounding non-exposed bystander cells, known as the radiation-induced bystander effect. We investigated involvement of connexin channels and paracrine signaling in radiation-induced bystander DNA damage in brain microvascular endothelial cells exposed to focused X-rays. Irradiation caused DNA damage in the directly exposed area, which propagated over several millimeters in the bystander area. DNA damage was significantly reduced by the connexin channel-targeting peptide Gap26 and the Cx43 hemichannel blocker TAT-Gap19. ATP release, dye uptake, and patch clamp experiments showed that hemichannels opened within 5 min post irradiation in both irradiated and bystander areas. Bystander signaling involved cellular Ca2+ dynamics and IP3, ATP, ROS, and NO signaling, with Ca2+, IP3, and ROS as crucial propagators of DNA damage. We conclude that bystander effects are communicated by a concerted cascade involving connexin channels, and IP3/Ca2+, ATP, ROS, and NO as major contributors of regenerative signal expansion

Méthodes alternatives in vitro pour l’étude des interactions hôte-pathogène du poumon

Les maladies respiratoires, qu’elles touchent les animaux et/ou les hommes, ont un impact sanitaire et économique considérable sur notre société. Pouvoir mieux les contrôler, les traiter et les prédire, nécessite de pouvoir les étudier. Pour cela des modèles d’études pertinents, reproductibles, efficaces aisés d’utilisation, et alternatifs à l’expérimentation animale doivent être proposés. D’énormes progrès méthodologiques ont été réalisés ces dernières années avec l’émergence de modèles in vitro qui miment le poumon en reproduisant la diversité des types cellulaires, l’architecture du tissu et certaines de ses fonctionnalités (activité ciliaire, sécrétion). Cette revue présente les avancées dans la génération de ces modèles chez le bovin : les organoïdes, les cultures Air-liquide-interface (ALI) et les coupes fines de poumon (PCLS). Ils sont utilisés pour mieux décrire et comprendre les processus physiopathologiques induits par des infections (virus, bactérie, parasite) respiratoires et permettent de tester des approches prophylactiques ou curatives

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

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/)

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 &lt; 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

Troubles digestifs chez la femme enceinte (traitements allopathique, homéopathique et conseils)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Evaluation in vitro de la sensibilité du VIH-2 aux inhibiteurs de protéase

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

La douleur des prélèvements veineux chez l'enfant est-elle prise en compte en secteur libéral extra-hospitalier ? (état des lieux sur le secteur Marne-la-Vallée)

Objectif : évaluer la prise en charge de la douleur provoquée lors des prélèvements veineux chez l enfant lors des prescriptions et des réalisations en milieu libéral extrahospitalier. Favoriser les changements de pratique par l enquête elle-même. Matériel et méthodes : Une enquête déclarative de type qualitative a été réalisée auprès de 21 médecins généralistes, de 11 pédiatres et de 5 biologistes du secteur de marne la vallée (77). Les questions portaient sur les connaissances des moyens antalgiques dans ce type de geste, les connaissances des recommandations dans ce domaine, et sur les opinions des médecins et biologistes sur l utilisation des moyens antalgiques dans ce geste. Résultats : une disparité de pratique existe entre pédiatres et généralistes. On note une amélioration globale des pratiques et une sensibilité plus grande vis-à-vis de la douleur de l enfant, puisque la majorité des médecins déclare utiliser des moyens antalgiques (avec les limites liées au caractère déclaratif de l enquête). Cependant, le geste est encore trop souvent considéré comme anxiogène plus que comme douloureux notamment chez les généralistes. Les recommandations restent peu connues et mal suivies. Les moyens non médicamenteux de prévention de cet acte douloureux sont mieux connus mais probablement sous-utilisés. Cette enquête semble avoir sensibilisé certains interviewés à l intérêt d une bonne prise en charge de la douleur provoquée. Conclusion : La bonne diffusion des recommandations et des nouvelles informations dans le domaine de la prise en charge de la douleur de l enfant est essentielle auprès des professionnels extrahospitaliers pour favoriser les changements de pratiques. Nous proposons l approche directe lors d enquêtes et audits pour améliorer cette diffusion.PARIS6-Bibl. St Antoine CHU (751122104) / SudocSudocFranceF

Release of short chain fatty acids from cream lipids by commercial lipases and esterases

Lipases and esterases are frequently used in dairy production processes to enhance the buttery flavour of the end product. Short chain fatty acids, and especially butanoic acid, play a key role in this and different enzymes with specificity towards short chain fatty acids are commercially available as potent flavouring tools. We have compared six lipases/esterases associated with buttery flavour production. Although specificity to short chain fatty acids was ascribed to each enzyme, clear differences in free fatty acid profiles were found when these enzymes were applied on cream. Candida cylindraceae lipase was the most useful enzyme for buttery flavour production in cream with the highest yield of free fatty acids (57 g oleic acid 100 g-1 fat), no release of long chain fatty acids and specificity towards butanoic acid

Intra-articular electrotransfer of mouse soluble tumour necrosis factor receptor in a murine model of rheumatoid arthritis

Background Rheumatoid arthritis (RA) is a chronic autoimmune diseasethat causes inflammation and destruction of the joints. In the collagen-induced arthritis mouse model of RA, we developed a nonviral gene therapymethod designed to block in situ the main cytokine tumour necrosis factor(TNF)-αMethods Electrotransfer was used to deliver a plasmid encoding extracellu-lar domain of mouse soluble TNF-α receptor type I fused to the Fc fragment ofmouse immunoglobulin (Ig)G1 (pTNFR-Is) corresponding to a dimeric TNF-αsoluble receptor fusion protein (mTNFR-Is/Ig).Results Delivery of the plasmid into the knees at symptom onset improvedthe histological inflammation and destruction not only at the knees, but alsoat the ankles, indicating a local and a regional therapeutic effect. The p lasmidwas detected in synovial membrane and meniscus specimens from the injectedjoints. In the synovial membrane, 15 days post-injection, interleukin (IL)-17and TNF-α mRNAs expression were increased, whereas IL-10 mRNA wasunchanged. However, the empty plasmid exerted a pro-inflammatory effect30 days post-injection.Conclusions These data indicate that local nonviral gene therapy againstTNF-α is effective, although further work is needed to decrease plasmidinduced inflammation