Der göttliche Sieburg? Die Rezeption von „Gott in Frankreich?“ in Deutschland und Frankreich

Friedrich Sieburg, correspondent allemand du journal " Frankfurter Zeitung " à Paris pendant les années 1920, s’impose définitivement dans la conscience des deux pays comme "connaisseur " avec son livre « Gott in Frankreich ? Ein Versuch » paru pour la première fois en 1929. Peu d’intellectuels polarisent tant leurs contemporains que Sieburg. C’est exactement ici que l’article trouve sa place : une image différenciée de l’accueil général dans l’entre-deux-guerres, de la réception du public dans les deux pays (l’œuvre parait pour la première fois en France en 1930 avec l’intitulé « Dieu est-il français ?) sera dressée pour plus comprendre le phénomène Sieburg et la fascination exercée par lui. Cette question est particulièrement intéressante parce qu’il y a des éditions différentes du livre pour le public français et le public allemand car l’éditeur Bernard Grasset édulcore et modifie la version originale en allemand pour le public français

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR (RT-qPCR). Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC

Affrontement comme vecteur de réconciliation : Gilbert Badia et ses réseaux dans les transferts entre France, RDA et RFA

Ce travail examine le médiateur franco-allemand Gilbert Badia (1916-2004) et ses réseaux culturels dans les relations conflictuelles entre France-RDA-RFA dans l’après-guerre. L’analyse se penche sur son milieu personnel ainsi que sa sphère littéraire et culturelle. De plus, l’influence de ses implications économiques, politiques et sociales sont à explorer. En tant que traducteur, professeur d'Université, germaniste et historien, un réseau diachronique de personnes et de textes s'établit autour de lui depuis les années 1940, dans lequel circulent des discours et des images spécifiques. Une analyse de l'engagement de Badia en dehors des catégories normatives montre que, dans un contexte historiquement très complexe, les prédispositions individuelles conduisent à un engagement et à un intérêt pour « l'autre » – avec des effets assez fructueux. Outre la construction d'un univers textuel, des échanges intellectuels et parfois amicaux ont lieu malgré – ou précisément à cause – du contexte historique conflictuel. L'exemple de l'acteur Badia met en évidence la problématique à laquelle de nombreux médiateur.e.s (intellectuels) ont été confrontés au XXe siècle : l'effort de concilier esprit critique et fidélité à un idéal (politique). L'engagement de Badia illustre que des aspects tels que le conflit, l’hybridité, l'ambivalence et l'influence politique ne doivent pas être rejetés en bloc, mais plutôt être compris comme des composantes nécessaires de tout transfert culturel. Les résultats sont transmissibles aux médiateur.e.s contemporain.e.s et leurs situations ainsi qu’à d’autres champs socio-politiques et socio-culturels.This dissertation deals with the figure of the german-french mediator Gilbert Badia (1916-2004) and his cultural networks within the conflict-ridden German-German-French relations after 1945. To this end, in addition to the literary-cultural field around Badia, his personal environment is also examined as well as which economic, political, and social entanglements influenced him. As a translator, University professor, Germanist and historian, a diachronic network of people and texts has been established around him since the 1940s, in which specific discourses and images circulate. The example of Badia highlights the problematic that numerous (intellectual) mediators faced in the 20th century: the effort to reconcile critical reflection and fidelity to a (political) ideal. An analysis of Badia's engagement beyond normative categories shows, that within the historically conflictual complex context, individual predispositions lead to engagement and interest in the "other" – with quite fruitful effects. In addition to the construction of a textual universe, intellectual and sometimes friendly exchange takes place despite – or precisely because of – the difficult foreign policy context. The example of Badia illustrates that aspects such as conflicts, ambivalences and political influence should not be rejected, but rather understood as necessary and important components of any cultural transfer. The results can be applied to contemporary mediators and their situation, as well as to other conflictual socio-political and socio-cultural settings beyond the german-french context

Variability in the ratio of mutant to wildtype myosin heavy chain present in the soleus muscle of patients with familial hypertrophic cardiomyopathy. A new approach for the quantification of mutant to wildtype protein

AbstractThe ratio of mutant to wildtype myosin heavy chain (β-isoform, β-MHC) in the soleus muscle of patients with familial hypertrophic cardiomyopathy was determined by a combination of HPLC, mass spectrometry and capillary zone electrophoresis. In two patients, one with a Val 606 Met mutation and another with a Gly 584 Arg mutation, the fraction of mutant β-MHC was only 12±6% and 23±0.7% of total β-MHC, respectively. These results demonstrate the necessity to determine the ratio of mutant to wildtype protein for the interpretation of functional studies on biopsy material from heterozygous patients with an inherited disease

The INVENT COVID trial: a structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri®) in subjects with acute respiratory distress syndrome induced by COVID-19

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact. METHODS: This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics. DISCUSSION: The current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay. TRIAL STATUS: Protocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT04794088 . Registered on 11 March 2021

The INVENT COVID trial: a structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri®) in subjects with acute respiratory distress syndrome induced by COVID-19

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact. METHODS: This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics. DISCUSSION: The current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay. TRIAL STATUS: Protocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT04794088 . Registered on 11 March 2021

Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial

Abstract Purpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI − 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (− 1.17 ml/kg, 95% CI − 1.87 to − 0.44). Conclusions IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23)

Evolution of micromorphological and chemical characters in the lichen-forming fungal family Pertusariaceae

Micromorphological characters of the fruiting bodies, such as ascus-type and hymenial amyloidity, and secondary chemistry have been widely employed as key characters in Ascomycota classification. However, the evolution of these characters has yet not been studied using molecular phylogenies. We have used a combined Bayesian and maximum likelihood based approach to trace character evolution on a tree inferred from a combined analysis of nuclear and mitochondrial ribosomal DNA sequences. The maximum likelihood aspect overcomes simplifications inherent in maximum parsimony methods, whereas the Markov chain Monte Carlo aspect renders results independent of any particular phylogenetic tree. The results indicate that the evolution of the two chemical characters is quite different, being stable once developed for the medullary lecanoric acid, whereas the cortical chlorinated xanthones appear to have been lost several times. The current ascus-types and the amyloidity of the hymenial gel in Pertusariaceae appear to have been developed within the family. The basal ascus-type of pertusarialean fungi remains unknown. (c) 2006 The Linnean Society of London, Biological Journal of the Linnean Society, 2006, 89, 615-626