“¡Qué enfermedad tan sublime!”: ‘Une visite inopportune’ [1988] de Copi o la “comedia de la muerte”

Le 11 décembre 1987, Copi, mourant de la nouvelle maladie qui terrorise le monde, et ayant gagné l’estime de plus d’un intellectuel, reçoit le Grand Prix de Littérature Dramatique décerné par la Ville de Paris. Malheureusement, trois jours plus tard, le 14 décembre, il décède à l’hôpital Claude-Bernard à Paris. Copi était conscient de l’arrivée d’une « visite » qui l’amènera à créer l’une de ses meilleures pièces : Une visite inopportune [1988]. Dans cette étude, nous voulons commémorer, d’une certaine manière, l’ingéniosité créative avec laquelle Copi a affronté son agonie due au sida et mettre en évidence la validité d’une pièce autobiographique créée au milieu d’une maladie qui condamne les homosexuels dans les années 1980, en France (et dans le monde entier). D’abord, nous tenterons de contextualiser brièvement les premières années de la pandémie en France afin de mettre en relation cette pièce avec l’écriture du sida. Ensuite, nous analyserons les ressources dramaturgiques que Copi a utilisées avec humour pour mettre en scène « l’anniversaire de mon sida » et nous mettrons en évidence l’importance de cette subversive « comédie de la mort ».

Um diálogo inaudito entre Canguilhem e Foucault

O artigo aborda algumas das diferenças entre a “história epistemológica” de Georges Canguilhem e a “história arqueológica”, tal como praticada por Michel Foucault. Prioriza-se o estudo do conceito de a priori biológico (ou fisiológico), cuja criação Canguilhem atribui a dois autores da tradição filosófica e fisiológica francesa: Auguste Comte e Claude Bernard. Em textos não muito frequentados, Canguilhem recorre a essa tradição para elaborar uma outra interpretação do empreendimento crítico kantiano, que compreende as condições de possibilidade do conhecimento (a priori) num sentido diverso daquele proposto por Foucault.

La Critique et le dépassement de la « méthode expérimentale » dans Thérèse Raquin

This article makes the case for reading Zola’s protagonists Laurent and Thérèse as literary foils for one of the founding fathers of the experimental method, namely the physiologist Claude Bernard, and his wife, Fanny Martin. Drawing more particularly on elements from Bernard’s and Martin’s lives, as well as Bernard’s scientific writings, the article shows that Zola ‘performs’ two grueling experiments in the aforementioned novel: the first one, initiated by the author himself, results in the death of three protagonists and the paralysis of the fourth one; the second experiment, initiated by Laurent, reveals that the latter’s evaluation of Thérèse and his ensuing hypothesis are seriously flawed. In fact, Laurent’s gaze is marred by his tendency to ‘dirty’ nature (‘salir la nature,’ to borrow Zola’s expression), and his experiment doesn’t turn out the way he had originally planned, as both lovers turned murderers end up committing suicide together. This article thus argues that, in Thérèse Raquin, Zola resorts to critical posturing as a vivisector in a text that can be read as a revenge narrative which gestures towards the possibility for vivisectors to be ‘redeemed’ as individuals made fully capable of feeling compassion for their objects through angelic intervention.

Autonomic Regulation of Kidney Function

A potential role for the renal innervation was first described in 1859 by Claude Bernard, who observed an increase in urine flow following section of the greater splanchnic nerve, which included the renal nerves. Subsequent studies provided little further clarity, leading Homer Smith in 1951 to declare that the renal innervation had little or no significance in controlling kidney hemodynamic or excretory function. However, since the 1960s, there has been increased attention to how the renal nerves may contribute to the deranged control of blood pressure and heart function cardiovascular diseases. The efferent (sympathetic) nerves have neuroeffector junctions which provide close contact with all vascular and tubular elements of the kidney. Activation of the sympathetic nerves at the resistance vessels, that is, the interlobular arteries afferent and even arterioles, modulates both renal blood flow and glomerular filtration rate; at the juxtaglomerular granular cells, they cause renin release and subsequent angiotensin II generation, and at the tubules there is a neurally stimulated increase in epithelial cell sodium transport. Less is known of the role of the afferent nerves, which primarily innervate the renal pelvis, and to a lesser degree the cortex and medulla. Their role is uncertain but sensory information passing to the brain can influence renal efferent nerve activity, forming the basis of both inhibitory and excitatory reno-renal reflexes. Increasingly, it is perceived that in a range of cardiovascular diseases such as cardiac failure, chronic renal disease, and hypertension, there is an inappropriate sympatho-excitation related to alterations in afferent renal nerve activity, which exacerbates the disease progression. The importance of the renal innervation in these disease processes has been emphasized in clinical studies where renal denervation in humans has been found to reduce blood pressure in resistant hypertensive patients and to ameliorate the progression of cardiac and kidney diseases, diabetes, and obesity and hypertension. The importance of both systemic and renal inflammatory responses in activating the neurohumoral control of the kidney is a continuing source of investigation.

922 A novel autotaxin inhibitor, IOA-289, modulates tumor, immune and stromal cell function and has monotherapy activity in fibrotic cancer models

BackgroundAutotaxin (ATX) is a secreted glycoprotein that hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). The expression of both ATX and LPA is elevated in most solid tumors and plasma. LPA signaling directly modulates tumor cell function and contributes to the development of the fibrotic tumor microenvironment, a mechanism by which tumors evade host immunity and impairs response to therapy. IOA-289 is a potent, orally available autotaxin inhibitor which is being developed as a novel treatment of solid tumours burdened with a high degree of fibrosis.MethodsInhibition of ATX activity in human plasma was determined by measuring reduction in LPA species as quantified by LC-MS/MS. In vitro activity on biomarkers of fibrosis was assessed using the BioMAP screen and fibroblast cell cultures. T cell migration was measured using 48-well chemotaxis chambers. PK/PD studies were performed following a single oral dose of IOA-289 in mice, and plasma LPA was used as a PD biomarker. In vivo efficacy was studied in two models of breast cancer, 4T1 and E0771. Bioinformatics used TCGA and GTEX publicly available datasets.ResultsIOA-289 inhibits plasma LPA18:2 with an IC50 of 36nM, with similar results for other LPA species. IOA-289 inhibited fibrosis relevant factors in the BioMAP phenotypic screen, including sIL-6, MCP-1, αSMA, collagen-III, and sVEGF. In further studies, IOA-289 inhibited the secretion of PAI-1 and IL-6 by stimulated fibroblasts. LPA and cancer cell conditioned media inhibited T cell chemotaxis in vitro and the effect was overcome in the presence of IOA-289. The efficacious human dose of IOA-289 was determined following PK/PD studies using plasma LPA as a biomarker of response to ATX inhibition. In vivo studies showed that IOA-289 inhibited metastasis of 4T1 cells, enhanced the infiltration of T cells into 4T1 s.c. implanted tumors and prevented the growth of primary, orthotopically implanted E0771 tumors. Bioinformatics analysis demonstrated elevated ATX expression in pancreatic cancer (PDAC), and PDAC patient plasma showed a correlation of ATX levels with CA-19-9.ConclusionsThe ATX/LPA pathway represents a novel target for anti-cancer therapy with actions on the tumor, immune cell and stromal environment. IOA-289 is a highly potent and selective inhibitor of ATX with demonstrated monotherapy activity in cancer models. Based on the mechanism of action we are investigating combinations of IOA-289 with chemotherapy, immunotherapy and novel agents in ongoing preclinical studies. An acceptable safety and PK profile support the clinical development of IOA-289 which is currently in a phase I clinical trial.Ethics ApprovalThe 4T1 study was approved by The University Claude Bernard Lyon 1 Ethics Board; approval number DR2014-38 (vM). The E0771 study was reviewed and approved by the Institutional Animal Care and Use Committee of the contract research organization (Covance, Ann Arbor, MI, USA), an AAALAC International accredited program.

Upper Gastrointestinal Bleeding in Adults Under Veno-Arterial Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Study

Objective. Upper gastrointestinal bleeding is a common complication in adults treated with veno-arterial Extracorporeal Membrane Oxygenation (VA-ECMO) for refractory cardiogenic shock or cardiac arrest. We aimed to determine risk factors, prevalence and outcomes associated with upper gastrointestinal bleeding (UGIB) in adult patients under VA-ECMO.Design. We conducted a retrospective cohort study (2014-2017) on consecutive VA-ECMO patients.Setting. Medical and Infectious Disease intensive care unit of university hospital Bichat-Claude Bernard in Paris, France.Patients. UGIB was defined as 1) an overt bleeding (hematemesis, melena, hematochezia), or 2) acute anemia associated with a lesion diagnosed on upper gastrointestinal endoscopy. Cause-specific models were used to identify factors associated with UGIB and death, respectively.Measurements and Main Results. 257 patients were included, of whom 48 (19%) were diagnosed with UGIB after a median of 18 [7; 43] days following cannulation; median SAPS II was 59 [43; 76]. 100 (39%) patients were implanted after cardiac surgery. Mortality occurred in 31 (65%) patients with UGIB and 121 (58%) patients without. UGIB patients had longer ICU stays (41 [19; 82] vs. 15 [6; 26]; p<.01), longer ECMO (10.5 [7; 15] vs 6 [3; 10]; p <.01) and mechanical ventilation durations (31 [18; 45] vs. 9 [5; 18]; p <.01) in days, as compared to non-UGIB patients. Ninety-nine upper gastrointestinal endoscopies (UGE) were performed and the most frequent lesions detected were gastro-duodenal ulcers (n=28, 28%), leading to 12/99 therapeutic procedures. Neither antiplatelet therapy prior to ICU admission nor a history of peptic ulcer were associated with UGIB in univariate analysis. By multivariate analysis (table), a BMI (body mass index) > 30 kg/m2 (Cause-specific hazard ratio (CSHR) [95% CI]): 3.06 [1.56; 5.98]), and extracorporeal cardiopulmonary resuscitation (ECPR) (CSHR 2.34 [1.03; 5.35]) were independently associated with an increased risk of UGIB. Conclusions. In adult patients under VA-ECMO, obesity and ECPR were independently associated with UGIB. This study highlights the potential role of obesity and acute ischemia reperfusion injury in the pathophysiology of VA-ECMO-associated UGIB.

Claude Bernard (1813-1878) e a Medicina Experimental

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escrito clave de Claude Bernard: “Sobre el progreso en las ciencias fisiológicas”

Publicado en 1865, el mismo año de la publicación de la Introduction a L’Étude de la Médecine Expérimentale, el artículo “Du progrès dans les sciences physiologiques” discute aquellos presupuestos del de la Fisiología Experimental que más reticencias suscitaban en la comunidad de médicos y fisiólogos a los que Claude Bernard quería persuadir sobre la viabilidad y fertilidad de su programa de investigación. Claude Bernard pone en evidencia la raigambre vitalista de muchos de las suspicacias suscitadas por la experimentación con seres vivos; y también muestra que la organización funcional no es un obstáculo para el desarrollo de esa estrategia de investigación que él patrocinaba. Por el contrario, esa organización es un presupuesto indiscutible, aunque también inexplicable, de todo abordaje experimental de los seres vivos.