Les temporalités des médicaments : trajectoires en soins palliatifs à l'hôpital

A partir d'un terrain ethnographique réalisé au sein d'une équipe mobile de soins palliatifs d'un hôpital universitaire, cette thèse de doctorat porte sur les médicaments dans le contexte de la fin de vie. Au carrefour d'une socio-anthropologie de la maladie grave, du mourir et des médicaments, elle interroge les rapports à la morphine, ainsi qu'à certains psychotropes et sédatifs utilisés en soins palliatifs. Entre temporalité vécue et temporalité institutionnelle, les manières d'investir le temps lorsqu'il est compté, y sont centrales. Dans une dimension microsociale, les résultats montrent que l'introduction de certains médicaments comme la morphine et l'entrée en scène d'une équipe mobile de soins palliatifs sont des points de repère et peuvent sonner comme une annonce, sorte de sanction, dans la trajectoire incertaine de la personne malade. En outre, les médicaments permettent d'agir sur « le temps qui reste » en plus de soulager les symptômes lorsque la maladie grave bascule en maladie incurable. Ils font l'objet d'usages détournés du but initial de soulagement des symptômes pour repousser, altérer ou accélérer la mort dans une perspective de maîtrise de sa fin de vie. Dans une dimension mésosociale, ce travail considère les médicaments à la base d'échanges entre groupements professionnels sur fond d'institutionnalisation des soins palliatifs par rapport à d'autres segments de la médecine actifs dans la gestion de la fin de vie. Dans une médecine caractérisée par l'incertitude et les décisions -avec une teinte toute particulière en Suisse où le suicide assisté est toléré - les médicaments en soins palliatifs peuvent être considérés comme des instruments de mort, qu'ils soient redoutés ou recherchés. Interrogeant les risques de reproduire un certain nombre d'inégalités de traitements à l'approche de la mort, qui s'accentuent dans un contexte de plus en plus favorable aux pratiques euthanasiques, ce travail se propose, en définitive, de discuter le temps contraint de la mort dans les institutions hospitalo-universitaires, entre acharnement et abstention thérapeutique.¦-¦Based on ethnographie fieldwork conducted within a palliative care mobile team in an academic hospital, this doctoral thesis focuses on medicines used in end of life contexts. At the intersection of a socio-anthropology of illness, dying and pharmaceuticals, the relations to morphine, as well as to some psychotropic and sedative drugs used in palliative care are questioned. Between "lived" experiences of temporality and institutional temporality, the ways by which actors invest time when it is counted, appeared to be central. In a microsocial dimension, the results showed that introducing drugs such as morphine, as well as the arrival of a palliative care mobile team, are landmarks and sound like an announcement, a sort of sanction, during the uncertain trajectory of the ill person. In addition, medicines can act on "the remaining time" when severe illness shifts into incurable illness. Indeed, medicines are being diverted from the initial aim of symptom relief in order to defer, alter or hasten death in a perspective of control over one's death. In a mesosocial dimension, pharmaceuticals are seen as core to professional exchanges and to palliative care institutionalisation compared to other active medical segments in end of life care. In a medical context characterised by uncertainty and decision-taking-with a special shade in Switzerland where assisted suicide is tolerated - palliative medicines can be seen as instruments of death, whether sought or feared. Questioning the risks of reproducing treatment inequalities at the approach of death, which are accentuated in a context increasingly favorable to euthanasia practices, this study aims, ultimately, at discussing death's constrained time in academic hospitals, between therapeutic intervention and abstention.

NEUROPATHOPHYSIOLOGICAL MECHANISMS IN GLUTARIC ACIDURIA TYPE I: 3-HYDROXYGLUTARIC ACID LEADS TO AMMONIA INCREASE AND NON-APOPTOTIC CELL DEATH

A 3D in vitro model of rat organotypic brain cell cultures in aggregates was used to investigate neurotoxicity mechanisms in glutaric aciduria type I (GA-I). 1 mM glutarate (GA) or 3-hydroxyglutarate (3OHGA) were repeatedly added to the culture media at two different time points. In cultures treated with 3OHGA, we observed an increase in lactate in the medium, pointing to a possible inhibition of Krebs cycle and respiratory chain. We further observed that 3OHGA and to a lesser extend GA induced an increase in ammonia production with concomitant decrease of glutamine concentrations, which may suggest an inhibition of the astrocytic enzyme glutamine synthetase. These previously unreported findings may uncover a pathogenic mechanism in this disease which has deleterious effects on early stages of brain development. By immunohistochemistry we showed that 3OHGA increased non-apoptotic cell death. On the cellular level, 3OHGA and to a lesser extend GA led to cell swelling and loss of astrocytic fibers whereas a loss of oligodendrocytes was only observed for 3OHGA. We conclude that 3OHGAwas the most toxic metabolite in our model for GA-I. 3OHGA induced deleterious effects on glial cells, an increase of ammonia production, and resulted in accentuated cell death of non-apoptotic origin.

TAT-RasGAP317-326-mediated tumor cell death sensitization can occur independently of Bax and Bak.

The increase of cancer specificity and efficacy of anti-tumoral agents are prime strategies to overcome the deleterious side effects associated with anti-cancer treatments. We described earlier a cell-permeable protease-resistant peptide derived from the p120 RasGAP protein, called TAT-RasGAP317-326, as being an efficient tumor-specific sensitizer to apoptosis induced by genotoxins in vitro and in vivo. Bcl-2 family members regulate the intrinsic apoptotic response and as such could be targeted by TAT-RasGAP317-326. Our results indicate that the RasGAP-derived peptide increases cisplatin-induced Bax activation. We found no evidence, using in particular knock-out cells, of an involvement of other Bcl-2 family proteins in the tumor-specific sensitization activity of TAT-RasGAP317-326. The absence of Bax and Bak in mouse embryonic fibroblasts rendered them resistant to cisplatin-induced apoptosis and consequently to the sensitizing action of the RasGAP-derived peptide. Surprisingly, in the HCT116 colon carcinoma cell line, the absence of Bax and Bak did not prevent cisplatin-induced apoptosis and the ability of TAT-RasGAP317-326 to augment this response. Our study also revealed that p53, while required for an efficient genotoxin-induced apoptotic response, is dispensable for the ability of the RasGAP-derived peptide to improve the capacity of genotoxins to decrease long-term survival of cancer cells. Hence, even though genotoxin-induced Bax activity can be increased by TAT-RasGAP317-326, the sensitizing activity of the RasGAP-derived peptide can operate in the absence of a functional mitochondrial intrinsic death pathway.

Alcohol-attributable mortality in Switzerland in 2011--age-specific causes of death and impact of heavy versus non-heavy drinking.

BACKGROUND: Alcohol use causes high burden of disease and injury globally. Switzerland has a high consumption of alcohol, almost twice the global average. Alcohol-attributable deaths and years of life lost in Switzerland were estimated by age and sex for the year 2011. Additionally, the impact of heavy drinking (40+grams/day for women and 60+g/day for men) was estimated. METHODS: Alcohol consumption estimates were based on the Addiction Monitoring in Switzerland study and were adjusted to per capita consumption based on sales data. Mortality data were taken from the Swiss mortality register. Methodology of the Comparative Risk Assessment for alcohol was used to estimate alcohol-attributable fractions. RESULTS: Alcohol use caused 1,600 (95% CI: 1,472 - 1,728) net deaths (1,768 deaths caused, 168 deaths prevented) among 15 to 74 year olds, corresponding to 8.7% of all deaths (men: 1,181 deaths; women: 419 deaths). Overall, 42,627 years of life (9.7%, 95% CI: 40,245 - 45,008) were lost due to alcohol. Main causes of alcohol-attributable mortality were injuries at younger ages (15-34 years), with increasing age digestive diseases (mainly liver cirrhosis) and cancers (particularly breast cancers among women). The majority (62%) of all alcohol-attributable deaths was caused by chronic heavy drinking (men: 67%; women: 48 %). CONCLUSION: Alcohol is a major cause of premature mortality in Switzerland. Its impact, among young people mainly via injuries, among men mainly through heavy drinking, calls for a mix of preventive actions targeting chronic heavy drinking, binge drinking and mean consumption.

Molecular autopsy in sudden cardiac death and its implication for families: discussion of the practical, legal and ethical aspects of the multidisciplinary collaboration.

Sudden cardiac death (SCD) is a major cause of premature death in young adults and children in developed countries. Standard forensic autopsy procedures are often unsuccessful in determining the cause of SCD. Post-mortem genetic testing, also called molecular autopsy, has revealed that a non-negligible number of these deaths are a result of inherited cardiac diseases, including arrhythmic disorders such as congenital long QT syndrome and Brugada syndrome. Due to the heritability of these diseases, the potential implications for living relatives must be taken into consideration. Advanced diagnostic analyses, genetic counselling, and interdisciplinary collaboration should be integral parts of clinical and forensic practice. In this article we present a multidisciplinary collaboration established in Lausanne, with the goal of properly informing families of these pathologies and their implications for surviving family members. In Switzerland, as in many other countries, legal guidelines for genetic testing do not address the use of molecular tools for post-mortem genetic analyses in forensic practice. In this article we present the standard practice guidelines established by our multidisciplinary team.