Le partage du savoir dans les arts du soin : mélanges en l'honneur de Marco Vannotti

La circularité relationnelle du savoir-être : l'enseignement post-grade selon une perspective systémique / Marco Vannotti - La passion de transmettre : une lecture platonicienne en hommage à M. Vannotti / Michèle Gennart - «Apprendre à coopérer pour apprendre» : la construction des échanges coopératifs / Olivier Real del Sarte - Apprendre à traiter les enfants battus : la transformation de l'intervenant / Stefano Cirillo - Fin de thérapie / Ferenc Rakoczy - La transmission du savoir psychiatrique à la Policlinique Médicale Universitaire : les liaisons dangereuses / Christian Marin - Entre transmission et acquisition des savoirs : le poids de la parole / Brikela Sulstarova - La volonté de faire sens en médecine : clinique, intersubjectivité, et reconnaissance / Francesco Panese - Médecine et rationalité / Jean Starobinski

A fatal overdose of cocaine associated with coingestion of marijuana, buprenorphine, and fluoxetine. Body fluid and tissue distribution of cocaine and its metabolites determined by hydrophilic interaction chromatography-mass spectrometry(HILIC-MS).

Chromatographic separation of highly polar basic drugs with ideal ionspray mass spectrometry volatile mobile phases is a difficult challenge. A new quantification procedure was developed using hydrophilic interaction chromatography-mass spectrometry with turbo-ionspray ionization in the positive mode. After addition of deuterated internal standards and simple clean-up liquid extraction, the dried extracts were reconstituted in 500 microL pure acetonitrile and 5 microL was directly injected onto a Waters Atlantis HILIC 150- x 2.1-mm, 3-microm column. Chromatographic separations of cocaine, seven metabolites, and anhydroecgonine were obtained by linear gradient-elution with decreasing high concentrations of acetonitrile (80-56% in 18 min). This high proportion of organic solvent makes it easier to be coupled with MS. The eluent was buffered with 2 mM ammonium acetate at pH 4.5. Except for m-hydroxy-benzoylecgonine, the within-day and between-day precisions at 20, 100, and 500 ng/mL were below 7 and 19.1%, respectively. Accuracy was also below +/- 13.5% at all tested concentrations. The limit of quantification was 5 ng/mL (%Diff < 16.1, %RSD < 4.3) and the limit of detection below 0.5 ng/mL. This method was successfully applied to a fatal overdose. In Switzerland, cocaine abuse has dramatically increased in the last few years. A 45-year-old man, a known HIV-positive drug user, was found dead at home. According to relatives, cocaine was self-injected about 10 times during the evening before death. A low amount of cocaine (0.45 mg) was detected in the bloody fluid taken from a syringe discovered near the corpse. Besides injection marks, no significant lesions were detected during the forensic autopsy. Toxicological investigations showed high cocaine concentrations in all body fluids and tissues. The peripheral blood concentrations of cocaine, benzoylecgonine, and methylecgonine were 5.0, 10.4, and 4.1 mg/L, respectively. The brain concentrations of cocaine, benzoylecgonine, and methylecgonine were 21.2, 3.8, and 3.3 mg/kg, respectively. The highest concentrations of norcocaine (about 1 mg/L) were measured in bile and urine. Very high levels of cocaine were determined in hair (160 ng/mg), indicating chronic cocaine use. A low concentration of anhydroecgonine methylester was also found in urine (0.65 mg/L) suggesting recent cocaine inhalation. Therapeutic blood concentrations of fluoxetine (0.15 mg/L) and buprenorphine (0.1 microg/L) were also discovered. A relatively high concentration of Delta(9)-THC was measured both in peripheral blood (8.2 microg/L) and brain cortex (13.5 microg/kg), suggesting that the victim was under the influence of cannabis at the time of death. In addition, fluoxetine might have enhanced the toxic effects of cocaine because of its weak pro-arrhythmogenic properties. Likewise, combination of cannabinoids and cocaine might have increase detrimental cardiovascular effects. Altogether, these results indicate a lethal cocaine overdose with a minor contribution of fluoxetine and cannabinoids.

Epidemiologie der Osteoporose. [The epidemiology of osteoporosis].

Osteoporosis is characterized by low bone mass, micro architectural impairment of bone tissue, and a subsequent in crease in fracture risk. Fractures or the vertebrae and distal forearm, as well as the proximal femur, or hip fracture, are included. Hip fracture is associated with high mortality, morbidity and medical expenses. There is a dramatic increase in the incidence of hip fracture with age. Hip fracture incidence is 350 times higher in women aged 85 years and over comparatively to women between 35 and 44 years of age. In recent studies in Switzerland, it was observed that the annual age adjusted incidence rate of hip fracture was comparable with similar rates for white population in industrialized countries, although in men the rates were relatively high. Among the major risk factors for osteoporosis are age, female gender, white and Asian race, and menopause. Postmenopausal estrogen replacement therapy reduces bone resorption. Family history of osteoporosis, frail constitution, as well as excessive alcohol intake, cigarette smoking, chronic insufficient nutritional calcium intake and physical inactivity are other risk factors. A cardinal element is the peak bone mass reached in the third or fourth decade of life. Independently of osteoporosis, falls are a key agent in fractures; several medical conditions and drugs increase the risk of falling. There is an enormous social and financial cost of osteoporosis; the annual cost of medical treatment only for hip fracture is close to Fr. 200 million in Switzerland. The burden of osteoporosis is likely to increase in the future because of the demographic aging of the population unless large scale preventive interventions are undertaken.

13q deletion syndrome and retinoblastoma in identical dichorionic diamniotic monozygotic twins.

PURPOSE: To report the case of identical dichorionic diamniotic female twins with unilateral retinoblastoma in 13q deletion syndrome. METHODS: Clinical and ophthalmoscopic evaluation, combination of multiple ligation-dependent probe amplification, array-comparative genomic hybridization analyses, and magnetic resonance imaging were performed. RESULTS: Peculiar facial features, marked hypotonia, gastroesophageal reflux, interatrial septal defect with left to right shunt and light dilatation of right chambers, 5th finger hypoplasia, 3rd-5th toes clinodactyly, 2nd toe overlapped to 3rd toe, and cutis marmorata were found. Ophthalmoscopic evaluation revealed unilateral retinoblastoma in both girls. Magnetic resonance imaging detected corpus callosum hypoplasia in both twins. A 34.4-Mb deletion involving bands 13q13.2-q21.33 and including the RB1 gene was identified in both twins. The deletion was not present in the DNA of their parents and older brother. CONCLUSIONS: Dysmorphic features in children must be always suspicious of 13q deletion syndrome and a short ophthalmoscopic follow-up is necessary to detect the presence of a retinoblastoma.

CD36 deficiency leads to choroidal involution via COX2 down-regulation in rodents.

BACKGROUND: In the Western world, a major cause of blindness is age-related macular degeneration (AMD). Recent research in angiogenesis has furthered the understanding of choroidal neovascularization, which occurs in the "wet" form of AMD. In contrast, very little is known about the mechanisms of the predominant, "dry" form of AMD, which is characterized by retinal atrophy and choroidal involution. The aim of this study is to elucidate the possible implication of the scavenger receptor CD36 in retinal degeneration and choroidal involution, the cardinal features of the dry form of AMD. METHODS AND FINDINGS: We here show that deficiency of CD36, which participates in outer segment (OS) phagocytosis by the retinal pigment epithelium (RPE) in vitro, leads to significant progressive age-related photoreceptor degeneration evaluated histologically at different ages in two rodent models of CD36 invalidation in vivo (Spontaneous hypertensive rats (SHR) and CD36-/- mice). Furthermore, these animals developed significant age related choroidal involution reflected in a 100%-300% increase in the avascular area of the choriocapillaries measured on vascular corrosion casts of aged animals. We also show that proangiogenic COX2 expression in RPE is stimulated by CD36 activating antibody and that CD36-deficient RPE cells from SHR rats fail to induce COX2 and subsequent vascular endothelial growth factor (VEGF) expression upon OS or antibody stimulation in vitro. CD36-/- mice express reduced levels of COX2 and VEGF in vivo, and COX2-/- mice develop progressive choroidal degeneration similar to what is seen in CD36 deficiency. CONCLUSIONS: CD36 deficiency leads to choroidal involution via COX2 down-regulation in the RPE. These results show a novel molecular mechanism of choroidal degeneration, a key feature of dry AMD. These findings unveil a pathogenic process, to our knowledge previously undescribed, with important implications for the development of new therapies.

Transitions familiales et brouilles conjugales : cumulation ou compensation des problèmes d'intimité à travers les phases du parcours de vie familial ?

Cette étude esquisse, sur la base d'un grand échantillon représentatif et longitudinal de couples vivant en Suisse et du point de vue des femmes ayant répondu à l'enquête, un tableau de l'évolution des problèmes conjugaux rencontrés au cours des différentes phases de la vie familiale. Le processus de dégradation de la relation est reconstitué à partir de 2 mesures faites dans un intervalle de 5 ans. La genèse des difficultés conjugales est considérée à travers le prisme des transitions familiales, en particulier la naissance des enfants, leur entrée à l'école et leur départ du domicile parental. L'analyse révèle le potentiel déstabilisateur de ces transitions pour le couple. Les bouleversements de l'équilibre relationnel évoluent, dans certains cas, vers un cumul de difficultés qui envahissent l'espace conjugal pour déboucher sur une situation rapidement inextricable.

Embryonic vascular endothelial cells are malleable to reprogramming via Prox1 to a lymphatic gene signature.

BACKGROUND: In vivo studies demonstrate that the Prox1 transcription factor plays a critical role in the development of the early lymphatic system. Upon Prox1 expression, early lymphatic endothelial cells differentiate from the cardinal vein and begin to express lymphatic markers such as VEGFR-3, LYVE-1 and Podoplanin. Subsequent in vitro studies have found that differentiated vascular endothelial cells can be reprogrammed by Prox1 to express a lymphatic gene profile, suggesting that Prox1 can initiate the expression of a unique gene signature during lymphangiogenesis. While the in vitro data suggest that gene reprogramming occurs upon Prox1 expression, it is not clear if this is a direct result of Prox1 in vascular endothelial cells in vivo. RESULTS: Overexpression of Prox1 in vascular endothelial cells during embryonic development results in the reprogramming of genes to that of a more lymphatic signature. Consequent to this overexpression, embryos suffer from gross edema that results in embryonic lethality at E13.5. Furthermore, hemorrhaging and anemia is apparent along with clear defects in lymph sac development. Alterations in junctional proteins resulting in an increase in vascular permeability upon Prox1 overexpression may contribute to the complications found during embryonic development. CONCLUSION: We present a novel mouse model that addresses the importance of Prox1 in early embryonic lymphangiogenesis. It is clear that there needs to be a measured pattern of expression of Prox1 during embryonic development. Furthermore, Prox1 reprograms vascular endothelial cells in vivo by creating a molecular signature to that of a lymphatic endothelial cell.

From Support to Control : A Configurational Perspective on Conjugal Quality

The topic of conjugal quality provides an empirical illustration of the relevance of the configurational perspective on families. Based on a longitudinal sample of 1,534 couples living in Switzerland drawn from the study "Social Stratification, Cohesion and Conflict in Contemporary Families", we show that various types of interdependencies with relatives and friends promote distinct conflict management strategies for couples as well as unequal levels of conjugal quality. We find that configurations characterized by supportive and non-interfering relationships with relatives and friends for both partners are associated with higher conjugal quality, while configurations characterized by interference are associated with lower conjugal quality.

La traduzione poetica del Cinquecento e le "Metamorfosi d'Ovidio" dell'Anguillara

La thèse est articulée en trois grandes sections, consacrées respectivement: (I) à la traduction poétique en Italie à partir des années 1540 jusqu'à la fin du XVIème siècle (II), à la réception des Métamorphoses d'Ovide à travers la réflexion théorique et les réécritures en italien (III), à la plus célèbre des versions italiennes du poème latin, celle de Giovanni Andrea dell'Anguillara (1507-1570 env.), parue à Venise en 1561. Le premier chapitre (La traduzione poetica nel Cinquecento) prend en considération plus d'une trentaine de traductions d'auteurs classiques parues en Italie entre 1540 et 1580. L'examen détaillé du péritexte qui accompagne les éditions (préfaces, commentaires, dédicaces) montre l'existence d'un riche débat autour de la traduction littéraire ainsi que la présence d'un public vaste et diversifié comme destinataire de ces oeuvres. Dans ce contexte, la traduction en langue vulgaire de l'oeuvre d'Ovide, et particulièrement des Métamorphoses, constitue un cas fort intéressant. Le deuxième chapitre (Aspetti della ricezione delle Metamorfosi nel Cinquecento) offre un ample aperçu sur la réception du poème latin à travers ses principales éditions, commentaires et interprétations. En s'appuyant sur les travaux de A. Moss et D. Javitch, ce chapitre (II. 2 Usi e funzioni delle Metamorfosi in ambito teorico e poetico) montre les contradictions existant dans les jugements sur les Métamorphoses au XVIème siècle, partagés entre l'admiration pour la virtuosité du poète latin et l'écho des préjugés moraux et stylistiques hérités de la critique ancienne. La poétique du Cinquecento en effet devait faire face à deux problèmes majeurs posés par le texte d'Ovide: au niveau structurel son caractère polycentrique et digressif, inconciliable avec le modèle épique virgilien chéri par le siècle; au niveau thématique la présence de récits de phénomènes jugés invraisemblables, comme notamment celui de la métamorphose. L'analyse des traductions des Métamorphoses en italien entre 1530 et 1570 prend en considération autant les réécritures partielles (dues aux poètes Luigi Alamanni, Bernardo Tasso, Girolamo Parabosco) que les versions intégrales du poème. Parmi ces dernières, une attention particulière a été réservée à l'adaptation du vénitien Ludovico Dolce, Le Trasformationi (1553), libre réécriture sur le modèle du Roland Furieux. La dernière partie du travail est entièrement consacrée à la célèbre version de Giovanni Andrea dell'Anguillara, poète et traducteur dans le cercle du cardinal Alessandro Farnese. Comme le démontre l'analyse comparée du texte italien et de l'original latin, cette «belle infidèle» (qui supplanta la version de Dolce et fut réimprimée maintes fois jusqu'au XIX siècle) doit son succès à son parfait équilibre entre fidélité à la structure du poème et une attitude très libre dans la narration, qui n'hésite pas à actualiser et «contaminer» le texte ovidien avec des auteurs modernes tels que l'Arioste ou Bandello. L'appendice comprend une bibliographie exhaustive des éditions de la traduction d'Anguillara parues au XVIème siècle.

Characterization of NALP2 and NALP3 IL-1β processing inflammasomes

Résumé II y a cinq ans, la découverte d'un nouveau domaine, le PYD domaine, lié aux domaines de la mort, a permis la description de la nouvelle famille des NALP protéines. L'analyse structurelle de cette famille de protéines révéla la présence de deux autres domaines, impliqués dans l'oligomerisation, NACHT, et la détection des ligands, Leucine rich repeats ou LRR. Cette architecture protéique est homologue à celle qui est décrite pour les NODs, les Tol1 récepteurs et tes protéines de résistance chez les plantes. Cette homologie suggère une possible implication des NALPs dans la régulation de l'immunité innée. Premièrement, nous avons décrit les composants minimaux qui permettent à l'inflammasomeNALP3 d'activer la caspase pro-inflammatoire, caspase-1. En comparaison à NALP1, NALP3 ne contient pas de FIIND domaine, ni de CARD domaine en C-terminus et n'interagit pas avec caspase-5. Nous avons découvert une protéine très homologue au C-terminus de NALP1, Cardinal, qui se lie au NACHT domaine de NALP2 et NALP3 par l'intermédiaire de son FIIND domaine. Cardinal possède la capacité d'interagir avec caspase-l, mais seul ASC semble être nécessaire à la maturation de la prointerleukine-1β suite à la stimulation de NALP3. Deuxièmement, notre étude s'est concentrée sur la nature du stimulus capable d'induire la formation et l'activation de l'inflammasome-NALP3. Nous avons démontré que l'ajout de muramyl dipeptide (MDP), produit à partir de la digestion enzymatique de peptidoglycaris bactériens, induit à la fois l'expression de la proIL-1β par la voie NOD2 et sa maturation en IL-1β active par la voie NALP3. Bien que le MDP active l'inflammasome-NALP3, il est incapable d'induire la sécrétion de l'IL-1β mature dans la lignée cellulaire THP1, comparé aux monocytes primaires humains. Cette différence pourrait être liée à l'absence, dans les THP1, de la protéine Filamin, qui est proposée d'interagir avec Cardinal. L'implication de NALP3 dans la maturation de l'IL-lb est confirmée suite à la découverte de mutations sur le gène CIAS1/NALP3/cryopyrin associées à trois maladies auto-inflammatoires : le syndrome de Muckle-Wells (MWS), l'urticaire familial au froid (FCU) et le syndrome CINCA/NOMID. Une élévation constitutive de la maturation et de la sécrétion de la proIL-1β en absence de stimulation MDP est détectée dans les macrophages des patients Muckle-Wells. En conclusion, nos études ont démontré que l'inflammasome-NALP3 doit être finement régulé pour éviter une activité incontrôlée qui représente la base moléculaire des symptômes associés aux syndromes auto-inflammatoires liés à NALP3. Summary Five years ago, the description of the NALP family originated from the discovery of a new death-domain fold family, the PYD domain. NALP contains aprotein-protein interaction domain (PYD), an oligomerization domain (NACHT) and a ligand-sensing domain, leucine rich repeats or LRR. This protein architecture shares similarity with receptors involved in immunity, such as NODS, Toll receptors (TLRs) and related plant resistance proteins, and points to an important role of NALPs in defense mechanisms. We first described the minimal complex involved in the pro-inflammatory Interleukin-1beta (IL-1β) cytokine maturation, called the inflammasome, which contains NALP3. In contrast to NALP1, NALP3, like other members of the NALP family, is devoid of C-terminal FIIND and CARD domains and does not interact with the pro-inflammatory caspase-5. Interestingly, a homolog of the C-terminal portion of NALP1 was found in the human genome and was named Cardinal. We found that NALP2 and NALP3 interact with the CARD-containing proteins Cardinal. Cardinal is able to bind to caspase-1 but is not required for IL-1β maturation through NALP3 activation, as demonstrated for the adaptor ASC. Secondly, our study focused on the stimuli involved in the activation of the NALP3 inflammasome. MDP was shown to induce the expression of proIL1β through NOD2 and then the maturation into active IL-1β by activation of the NALP3 inflammasome. However, in the monocytic THP1 cell line, secretion of IL-1β upon MDP stimulation seems to be independent of the inflammasome activation compared to human primary monocytes. This difference might be linked to a Cardinal-interacting protein, filamin. Until now, the role of Cardinal and filamin is still unknown and remains to be elucidated. Finally, mutations in the NALP3/cryopyrin/CIAS1 gene are associated with three autoinflammatory diseases: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. Constitutive, elevated IL-1β maturation and secretion, even in the absence of MDP stimulation, was observed in macrophages from Muckle-Wells patients and confirmed a key role for the NALP3 inflammasome in innate immunity In conclusion, our studies describes the formation of the NALP3 inflammasome and suggests that this complex has to be tightly regulated to avoid an increased deregulated inflammasome activity that is the molecular basis for the symptoms associated with NALP3-dependent autoinflammatory disorders.