ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Caractérisation de nouveaux acteurs de la mort des neurones granulaires de cervelet

Les acteurs moléculaires des modes de mort cellulaire alternatives à l'apoptose sont très mal connus en particulier pour les neurones. La mort des neurones granulaires de cervelet (NGC) induite par déplétion potassique présente toutes les caractéristiques de l'apoptose. L'induction de la voie de signalisation JNK constitue une étape primordiale dans l'activation des caspases. Cependant, la cascade de mort des NGC ne se limite pas à cette voie mais nécessite également une voie indépendante des caspases. Contrairement à d'autres modèles neuronaux, l'autophagie ne participe pas au déroulement de la mort des NGC. Nous avons également identifié la protéine Alix, qui joue un rôle crucial dans la formation des corps multivésiculaires, comme un acteur essentiel de la mort des NGC. Pour assurer sa fonction pro-apoptotique, Alix recrute les protéines Alg-2 et CIN85 suggérant qu'Alix pourrait connecter le trafic vésiculaire à la mort neuronale.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Mécanismes d'action d'Alix et de ses partenaires ALG-2 et PYK2 dans la survie et la mort neuronale

'Les neurones granulaires de cervelet (NGC) survivrent en présence de forte concentration de potassium (K+ 25mM) mais meurent lorsque ils sont placés en milieu appauvri en potassium (5mM). Alix et Alg-2 contrôlent la mort in vitro de ces neurones induite par retrait de potassium. Les recherches que j'ai conduites au cours de ma thèse se sont attachées à définir les mécanismes moléculaires sous-tendant la fonction pro-apoptotique du couple Alix/ Alg-2. J'ai montré qu'Alix et Alg-2 s'associent à la pro-caspase-8, et vérifié la pertinence fonctionnelle de ces interactions dans le modèle de mort des NGC. Outre une implication d'Alix et d'Alg-2 dans la mort cellulaire induite par retrait de support trophique, j'ai mis en évidence la participation d'Alix à la cascade apoptotique déclenchée à la suite d'un stress au réticulum endoplasmique induit par une perturbation d'homéostasie calcique, ainsi qu'une association calcium dépendante du couple Alix/Alg-2 et la caspase-9. L'ensemble de nos résultats suggère que l'association calcium dépendante d'Alix avec Alg-2 pourrait favoriser le recrutement des caspase-8 et-9 au sein de plates formes macromoléculaires, ce qui mènerait à leur activation. En outre je me suis également intéressée à Pyk2, un potentiel régulateur négatif du coulpe Alix/Alg-2. Nous avons montré que Pyk2 est impliqué dans la voie de survie des NGC en conditions dépolarisantes et que cette kinase s'active en milieu appauvri en K+ afin d'assurer une réponse de protection contre le stress.ln an effort to uncover the molecular mechanisms underlying the function of Alix and AIg-2 in cell death, we have found that Alix and AIg-2 can Ca2+-dependently associate with caspase-8 in BHK-21 cells. We investigated the possible existence of an Alix! AIg-2-caspase-8 relationship during cerebellar granule neuron death induced in vitro byeither potassium depletion or Alix overexpression. We showed that Alix is found in a caspase-8-containing complex following K+ depletion-induced CGN apoptosis. Moreover, we demonstrated that caspase-8 functions as initiator caspase in the apoptotic pathway induced by Alix overexpression. ln a recent work, we gained evidence that the dosure of these Ca2+ channels, which follows the shift to K5 medium,could trigger compensatory Ca2+ mobilization from intracellular stores (Strappazzon, 2007). This prompted us to tum our attention to the putative functional relevance of Alix!Alg-2-caspase-8 interaction to ER stress-induced death.Using both dividing BHK-21 cells and post-mitotic CGN exposed to the ER stressor thapsigargin, we gathered several evidence supporting the idea that Alix, like its binding partner AIg-2, is involved in ER stress-induced death, linking specifficaly two initiator caspases: caspase-8 and -9. Overall our findings suggest that Alix, through its association with AIg-2, is a key mediator of the apoptotic Ca2+ signaling machinery. We also demonstrates the role of Pyk2 in mediating the trophic effect of membrane depolarization in CGN and its possible involvement in survival via the regulation of the binding between Alix and AIg-2 through phosphorylation of Alix.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

6-Hydroxydopamine-induced nuclear factor-kappaB activation in PC12 cells

The involvement of nuclear Factor-kappaB (NF-κB) transcription factor in PC12 cell death triggered by the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) was investigated. Results show that oxidative stress generated by 6-OHDA activates NF-κB. When the NF-κB activation was inhibited by parthenolide, PC12 cell death induced by 6-OHDA was significantly increased, thus suggesting an involvement of this transcription factor in a protective mechanism against 6-OHDA toxicity. To further assess this hypothesis, we studied the involvement of NF-κB in the protective effect of two anti-apoptotic genes, bcl-2 and bfl-1. Although Bcl-2 and Bfl-1 expression normally protects PC12 cells from 6-OHDA, parthenolide strongly decreased the beneficial effects afforded by transgene expression. These results suggest: (1) that the transcription factor NF-κB is likely associated with the protection of catecholaminergic PC12 cells and (2) that the protective effects afforded by bcl-2 and bfl-1 expression may be dependent on NF-κ activation. © 2001 Elsevier Science Inc.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A cautionary note on the use of stable transformed cells

Gene transfection and ectopic expression is a widely used method in experimental biology. In the present report, we would like to point out that this approach may, in certain circumstances, lead to a modification of the transfected cell phenotype. Indeed, we observed that after transfection of bcl-2 gene in the neuronal PC12 cell line some of the selected clones have lost their neuronal and catecholaminergic characteristics, i.e. TH expression and ability to grow neurites in response to NGF. Thus, the resistance of some PC12-Bcl-2 clones against neurotoxic insults may not necessarily reflect the potential benefit afforded by Bcl-2 expression. We therefore encouraged authors to verify cell phenotype after stable transfection to avoid misinterpretation of their results.SCOPUS: sh.jinfo:eu-repo/semantics/publishe

Analysis of skeletal remains from the Battle of Britain: A temporary cemetery of German aviators from World War II

International audienc

La mort neuronale dans les modèles expérimentaux de la maladie de Parkinson

SCOPUS: re.jinfo:eu-repo/semantics/publishe

Mort neuronale dans les modèles expérimentaux de la maladie de Parkinson

La caractérisation des mécanismes moléculaires impliqués dans la mort neuronale survenant au cours de la maladie de Parkinson idiopa-thique est indispensable pour l’élaboration de traitements capables d’arrêter l’évolution de cette maladie. Ces mécanismes ont essentiellement été décryptés grâce à deux modèles expérimentaux utilisant des neurotoxiques capables de reproduire les caractéristiques anatomo-pathologiques (dégénérescence des neurones dopaminergiques de la substance noire) et biochimiques (stress oxydatif et inhibition mito-chondriale) de la maladie de Parkinson idiopa-thique. La mort cellulaire induite dans ces modèles est de type apoptotique. La phase finale de ce processus met en jeu l’activation de la caspase effectrice de type 3. Les phases plus précoces semblent réglées par la protéine p53 et les protéines pro- et anti-apoptotiques de la famille Bcl-2 mais également modulées par le facteur transcriptionnel NFκB et les MAP-kinases. Toutes ces étapes constituent autant de cibles thérapeutiques potentielles

Nuclear factor-kappa B activation in permanent intraluminal focal cerebral ischemia in the rat.

Nuclear factor-kappa B (NF-kappa B) is an oxidative stress responsive transcription factor known to be activated in response to transient middle cerebral artery intraluminal occlusion. Since oxidative stress activation may largely occur during reperfusion, the aim of this study was to determine if permanent middle cerebral artery intraluminal occlusion without reperfusion induces NF-kappa B activation and the relationship of NF-kappa B activation to HSP70 expression and neuronal cell death. Our results suggest that permanent intraluminal occlusion is sufficient to induce NF-kappa B activation 7 h after the onset of occlusion. Interestingly, this activation seems to occur specifically in dying neurons of the penumbra area devoid of any HSP70 neuronal immunoreactivity. These findings are consistent with the suggested protective role of HSP70 expression and suggest that NF-kappa B activation observed in the penumbra area has a role in neuronal cell death after permanent intraluminal cerebral ischemia.info:eu-repo/semantics/publishe

Nuclear factor-κB activation in permanent intraluminal focal cerebral ischemia in the rat

Nuclear factor-κB (NF-κB) is an oxidative stress responsive transcription factor known to be activated in response to transient middle cerebral artery intraluminal occlusion. Since oxidative stress activation may largely occur during reperfusion, the aim of this study was to determine if permanent middle cerebral artery intraluminal occlusion without reperfusion induces NF-κB activation and the relationship of NF-κB activation to HSP70 expression and neuronal cell death. Our results suggest that permanent intraluminal occlusion is sufficient to induce NF-κB activation 7 h after the onset of occlusion. Interestingly, this activation seems to occur specifically in dying neurons of the penumbra area devoid of any HSP70 neuronal immunoreactivity. These findings are consistent with the suggested protective role of HSP70 expression and suggest that NF-κB activation observed in the penumbra area has a role in neuronal cell death after permanent intraluminal cerebral ischemia. Copyright (C) 2000 Elsevier Science Ireland Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe