Une vue globale du secteur ambulatoire: étude structurelle et fonctionnelle dans les cantons de Vaud et Fribourg. [A general view of the ambulatory care sector: Structural and functional study in the cantons of Vaud and Fribourg].

The project "Quantification and qualification of ambulatory health care", financed by the Swiss National Science Foundation and covering the Cantons of Vaud and Fribourg, has two main goals: --a structural study of the elements of the ambulatory care sector. This is done through inventories of the professions concerned (physicians, public health nurses, physiotherapists, pharmacists, medical laboratories), allowing to better characterize the "offer". This inventory work includes the collect and analysis of existing statistical data as well as surveys, by questionnaires sent (from September 1980) to the different professions and by interviews. --a functional study, inspired from the US National Ambulatory Medical Care Survey and from similar studies elsewhere, in order to investigate the modes of practice of various providers, with particular regard to interprofessional collaboration (through studying referrals from the ones to the others). The first months of the project have been used for a methodological research in this regard, centered on the use of systems analysis, and for the elaboration of adequate instruments.

Promotion de l'activité physique au cabinet médical: où en sommes- nous en Suisse [Promotion of physical activity in the primary care setting: what is the situation in Switzerland?]

If many harmful effects of a sedentary lifestyle on health are well known, we still need to better understand how effectively promoting regular physical activity in the general population. Among the currently explored strategies, screening for sedentary lifestyle and promoting physical activity in the primary care setting seem promising. Despite recommendations from governmental agencies and professional associations in favor of physical activity counseling, this approach has not been widely adopted so far. This article summarizes the steps taken in Switzerland with an aim of developing physical activity counseling in the primary care setting. It describes how the early implication of primary care physicians influenced in a concrete way the development of a project dedicated to that task.

The effects of gamma-hydroxybutyrate, baclofen and GABAB receptors on brain activity and sleep in mice and humans

Currently, there is an increased interest in γ-hydroxybutyric acid (GHB) and its effects onsleep. This compound, sometimes referred to as 'rape drug', was recently approved as atreatment for the sleep disorder narcolepsy. Although several studies suggest that GHBinduces slow-wave sleep duration and improves sleep quality by increasing EEG slow-waveactivity, others question its ability to induce physiological sleep. GHB's mechanism of actionis still unclear, although in vivo and in vitro it seems to act at high doses as a low-affinityagonist of GABAB receptors. Furthermore, the role GABAB receptors play in sleep and theelectroencephalogram (EEG) is largely unknown.The aim of this project was therefore to investigate the effects of GHB on sleep and EEG, theinvolvement of GABAB receptors in mediating these effects, as well as the intrinsic role ofeach GABAB receptor subunit in the regulation of sleep. Thus, we administered GHB andbaclofen (BAC, a high-affinity agonist at GABAB receptor) to mice lacking the different GABABreceptor subunits and to healthy human volunteers.Our results, both in mice and humans, showed that GHB produced slow waves exclusivelythrough the stimulation of GABAB receptors, but did not induce physiological sleepnecessary to reduce sleep need and to increase cognitive performance. Unlike GHB, BACaffected the homeostatic regulation of sleep (sleep need) and induced a delayedhypersomnia. Finally, GABAB receptor and its subunits seem to play an important role insleep and in particular its circadian distribution.

Evaluating fear of falling among community-dwelling older people: A qualitative pattern model based on the experience of falls

This research was conducted in the context of the project IRIS 8A Health and Society (2002-2008) and financially supported by the University of Lausanne. It was aomed at developping a model based on the elder people's experience and allowed us to develop a "Portrait evaluation" of fear of falling using their examples and words. It is a very simple evaluation, which can be used by professionals, but by the elder people themselves. The "Portrait evaluation" and the user's guide are on free access, but we would very much approciate to know whether other people or scientists have used it and collect their comments. (contact: Chantal.Piot-Ziegler@unil.ch)The purpose of this study is to create a model grounded in the elderly people's experience allowing the development of an original instrument to evaluate FOF.In a previous study, 58 semi-structured interviews were conducted with community-dwelling elderly people. The qualitative thematic analysis showed that fear of falling was defined through the functional, social and psychological long-term consequences of falls (Piot-Ziegler et al., 2007).In order to reveal patterns in the expression of fear of falling, an original qualitative thematic pattern analysis (QUAlitative Pattern Analysis - QUAPA) is developed and applied on these interviews.The results of this analysis show an internal coherence across the three dimensions (functional, social and psychological). Four different patterns are found, corresponding to four degrees of fear of falling. They are formalized in a fear of falling intensity model.This model leads to a portrait-evaluation for fallers and non-fallers. The evaluation must be confronted to large samples of elderly people, living in different environments. It presents an original alternative to the concept of self-efficacy to evaluate fear of falling in older people.The model of FOF presented in this article is grounded on elderly people's experience. It gives an experiential description of the three dimensions constitutive of FOF and of their evolution as fear increases, and defines an evaluation tool using situations and wordings based on the elderly people's discourse.

Online teaching of inflammatory skin pathology by a French-speaking International University Network

INTRODUCTION: Developments in technology, web-based teaching and whole slide imaging have broadened the teaching horizon in anatomic pathology. Creating online learning material including many types of media such as radiologic images, whole slides, videos, clinical and macroscopic photographs, is now accessible to most universities. Unfortunately, a major limiting factor to maintain and update the learning material is the amount of resources needed. In this perspective, a French-national university network was initiated in 2011 to build joint online teaching modules consisting of clinical cases and tests. The network has since expanded internationally to Québec, Switzerland and Ivory Coast. METHOD: One of the first steps of the project was to build a learning module on inflammatory skin pathology for interns and residents in pathology and dermatology. A pathology resident from Québec spent 6 weeks in France and Switzerland to develop the contents and build the module on an e-learning Moodle platform under the supervision of two dermatopathologists. The learning module contains text, interactive clinical cases, tests with feedback, virtual slides, images and clinical photographs. For that module, the virtual slides are decentralized in 2 universities (Bordeaux and Paris 7). Each university is responsible of its own slide scanning, image storage and online display with virtual slide viewers. RESULTS: The module on inflammatory skin pathology includes more than 50 web pages with French original content, tests and clinical cases, links to over 45 virtual images and more than 50 microscopic and clinical photographs. The whole learning module is being revised by four dermatopathologists and two senior pathologists. It will be accessible to interns and residents in the spring of 2014. The experience and knowledge gained from that work will be transferred to the next international resident whose work will be aimed at creating lung and breast pathology learning modules. CONCLUSION: The challenges of sustaining a project of this scope are numerous. The technical aspect of whole-slide imaging and storage needs to be developed by each university or group. The content needs to be regularly updated and its accuracy reviewed by experts in each individual domain. The learning modules also need to be promoted within the academic community to ensure maximal benefit for trainees. A collateral benefit of the project was the establishment of international partnerships between French-speaking universities and pathologists with the common goal of promoting pathology education through the use of multi-media technology including whole slide imaging.

Integrated application of geochemical and geophysical methods for hydrogeological impact assessment for tunneling in fractured rock

The interaction of tunneling with groundwater is a problem both from an environmental and an engineering point of view. In fact, tunnel drilling may cause a drawdown of piezometric levels and water inflows into tunnels that may cause problems during excavation of the tunnel. While the influence of tunneling on the regional groundwater systems may be adequately predicted in porous media using analytical solutions, such an approach is difficult to apply in fractured rocks. Numerical solutions are preferable and various conceptual approaches have been proposed to describe and model groundwater flow through fractured rock masses, ranging from equivalent continuum models to discrete fracture network simulation models. However, their application needs many preliminary investigations on the behavior of the groundwater system based on hydrochemical and structural data. To study large scale flow systems in fractured rocks of mountainous terrains, a comprehensive study was conducted in southern Switzerland, using as case studies two infrastructures actually under construction: (i) the Monte Ceneri base railway tunnel (Ticino), and the (ii) San Fedele highway tunnel (Roveredo, Graubiinden). The chosen approach in this study combines the temporal and spatial variation of geochemical and geophysical measurements. About 60 localities from both surface and underlying tunnels were temporarily and spatially monitored during more than one year. At first, the project was focused on the collection of hydrochemical and structural data. A number of springs, selected in the area surrounding the infrastructures, were monitored for discharge, electric conductivity, pH, and temperature. Water samples (springs, tunnel inflows and rains) were taken for isotopic analysis; in particular the stable isotope composition (δ2Η, δ180 values) can reflect the origin of the water, because of spatial (recharge altitude, topography, etc.) and temporal (seasonal) effects on precipitation which in turn strongly influence the isotopic composition of groundwater. Tunnel inflows in the accessible parts of the tunnels were also sampled and, if possible, monitored with time. Noble-gas concentrations and their isotope ratios were used in selected locations to better understand the origin and the circulation of the groundwater. In addition, electrical resistivity and VLF-type electromagnetic surveys were performed to identify water bearing fractures and/or weathered areas that could be intersected at depth during tunnel construction. The main goal of this work was to demonstrate that these hydrogeological data and geophysical methods, combined with structural and hydrogeological information, can be successfully used in order to develop hydrogeological conceptual models of the groundwater flow in regions to be exploited for tunnels. The main results of the project are: (i) to have successfully tested the application of electrical resistivity and VLF-electromagnetic surveys to asses water-bearing zones during tunnel drilling; (ii) to have verified the usefulness of noble gas, major ion and stable isotope compositions as proxies for the detection of faults and to understand the origin of the groundwater and its flow regimes (direct rain water infiltration or groundwater of long residence time); and (iii) to have convincingly tested the combined application of a geochemical and geophysical approach to assess and predict the vulnerability of springs to tunnel drilling. - L'interférence entre eaux souterraines et des tunnels pose des problèmes environnementaux et de génie civile. En fait, la construction d'un tunnel peut faire abaisser le niveau des nappes piézométriques et faire infiltrer de l'eau dans le tunnel et ainsi créer des problème pendant l'excavation. Alors que l'influence de la construction d'un tunnel sur la circulation régionale de l'eau souterraine dans des milieux poreux peut être prédite relativement facilement par des solution analytiques de modèles, ceci devient difficile dans des milieux fissurés. Dans ce cas-là, des solutions numériques sont préférables et plusieurs approches conceptuelles ont été proposées pour décrire et modéliser la circulation d'eau souterraine à travers les roches fissurées, en allant de modèles d'équivalence continue à des modèles de simulation de réseaux de fissures discrètes. Par contre, leur application demande des investigations importantes concernant le comportement du système d'eau souterraine basées sur des données hydrochimiques et structurales. Dans le but d'étudier des grands systèmes de circulation d'eau souterraine dans une région de montagnes, une étude complète a été fait en Suisse italienne, basée sur deux grandes infrastructures actuellement en construction: (i) Le tunnel ferroviaire de base du Monte Ceneri (Tessin) et (ii) le tunnel routière de San Fedele (Roveredo, Grisons). L'approche choisie dans cette étude est la combinaison de variations temporelles et spatiales des mesures géochimiques et géophysiques. Environs 60 localités situées à la surface ainsi que dans les tunnels soujacents ont été suiviès du point de vue temporel et spatial pendant plus de un an. Dans un premier temps le projet se focalisait sur la collecte de données hydrochimiques et structurales. Un certain nombre de sources, sélectionnées dans les environs des infrastructures étudiées ont été suivies pour le débit, la conductivité électrique, le pH et la température. De l'eau (sources, infiltration d'eau de tunnel et pluie) a été échantillonnés pour des analyses isotopiques; ce sont surtout les isotopes stables (δ2Η, δ180) qui peuvent indiquer l'origine d'une eaux, à cause de la dépendance d'effets spatiaux (altitude de recharge, topographie etc.) ainsi que temporels (saisonaux) sur les précipitations météoriques , qui de suite influencent ainsi la composition isotopique de l'eau souterraine. Les infiltrations d'eau dans les tunnels dans les parties accessibles ont également été échantillonnées et si possible suivies au cours du temps. La concentration de gaz nobles et leurs rapports isotopiques ont également été utilisées pour quelques localités pour mieux comprendre l'origine et la circulation de l'eau souterraine. En plus, des campagnes de mesures de la résistivité électrique et électromagnétique de type VLF ont été menées afin d'identifier des zone de fractures ou d'altération qui pourraient interférer avec les tunnels en profondeur pendant la construction. Le but principal de cette étude était de démontrer que ces données hydrogéologiques et géophysiques peuvent être utilisées avec succès pour développer des modèles hydrogéologiques conceptionels de tunnels. Les résultats principaux de ce travail sont : i) d'avoir testé avec succès l'application de méthodes de la tomographie électrique et des campagnes de mesures électromagnétiques de type VLF afin de trouver des zones riches en eau pendant l'excavation d'un tunnel ; ii) d'avoir prouvé l'utilité des gaz nobles, des analyses ioniques et d'isotopes stables pour déterminer l'origine de l'eau infiltrée (de la pluie par le haut ou ascendant de l'eau remontant des profondeurs) et leur flux et pour déterminer la position de failles ; et iii) d'avoir testé d'une manière convainquant l'application combinée de méthodes géochimiques et géophysiques pour juger et prédire la vulnérabilité de sources lors de la construction de tunnels. - L'interazione dei tunnel con il circuito idrico sotterraneo costituisce un problema sia dal punto di vista ambientale che ingegneristico. Lo scavo di un tunnel puô infatti causare abbassamenti dei livelli piezometrici, inoltre le venute d'acqua in galleria sono un notevole problema sia in fase costruttiva che di esercizio. Nel caso di acquiferi in materiale sciolto, l'influenza dello scavo di un tunnel sul circuito idrico sotterraneo, in genere, puô essere adeguatamente predetta attraverso l'applicazione di soluzioni analitiche; al contrario un approccio di questo tipo appare inadeguato nel caso di scavo in roccia. Per gli ammassi rocciosi fratturati sono piuttosto preferibili soluzioni numeriche e, a tal proposito, sono stati proposti diversi approcci concettuali; nella fattispecie l'ammasso roccioso puô essere modellato come un mezzo discreto ο continuo équivalente. Tuttavia, una corretta applicazione di qualsiasi modello numerico richiede necessariamente indagini preliminari sul comportamento del sistema idrico sotterraneo basate su dati idrogeochimici e geologico strutturali. Per approfondire il tema dell'idrogeologia in ammassi rocciosi fratturati tipici di ambienti montani, è stato condotto uno studio multidisciplinare nel sud della Svizzera sfruttando come casi studio due infrastrutture attualmente in costruzione: (i) il tunnel di base del Monte Ceneri (canton Ticino) e (ii) il tunnel autostradale di San Fedele (Roveredo, canton Grigioni). L'approccio di studio scelto ha cercato di integrare misure idrogeochimiche sulla qualité e quantité delle acque e indagini geofisiche. Nella fattispecie sono state campionate le acque in circa 60 punti spazialmente distribuiti sia in superficie che in sotterraneo; laddove possibile il monitoraggio si è temporalmente prolungato per più di un anno. In una prima fase, il progetto di ricerca si è concentrato sull'acquisizione dati. Diverse sorgenti, selezionate nelle aree di possibile influenza attorno allé infrastrutture esaminate, sono state monitorate per quel che concerne i parametri fisico-chimici: portata, conduttività elettrica, pH e temperatura. Campioni d'acqua sono stati prelevati mensilmente su sorgenti, venute d'acqua e precipitazioni, per analisi isotopiche; nella fattispecie, la composizione in isotopi stabili (δ2Η, δ180) tende a riflettere l'origine delle acque, in quanto, variazioni sia spaziali (altitudine di ricarica, topografia, etc.) che temporali (variazioni stagionali) della composizione isotopica delle precipitazioni influenzano anche le acque sotterranee. Laddove possibile, sono state campionate le venute d'acqua in galleria sia puntualmente che al variare del tempo. Le concentrazioni dei gas nobili disciolti nell'acqua e i loro rapporti isotopici sono stati altresi utilizzati in alcuni casi specifici per meglio spiegare l'origine delle acque e le tipologie di circuiti idrici sotterranei. Inoltre, diverse indagini geofisiche di resistività elettrica ed elettromagnetiche a bassissima frequenza (VLF) sono state condotte al fine di individuare le acque sotterranee circolanti attraverso fratture dell'ammasso roccioso. Principale obiettivo di questo lavoro è stato dimostrare come misure idrogeochimiche ed indagini geofisiche possano essere integrate alio scopo di sviluppare opportuni modelli idrogeologici concettuali utili per lo scavo di opere sotterranee. I principali risultati ottenuti al termine di questa ricerca sono stati: (i) aver testato con successo indagini geofisiche (ERT e VLF-EM) per l'individuazione di acque sotterranee circolanti attraverso fratture dell'ammasso roccioso e che possano essere causa di venute d'acqua in galleria durante lo scavo di tunnel; (ii) aver provato l'utilità di analisi su gas nobili, ioni maggiori e isotopi stabili per l'individuazione di faglie e per comprendere l'origine delle acque sotterranee (acque di recente infiltrazione ο provenienti da circolazioni profonde); (iii) aver testato in maniera convincente l'integrazione delle indagini geofisiche e di misure geochimiche per la valutazione della vulnérabilité delle sorgenti durante lo scavo di nuovi tunnel. - "La NLFA (Nouvelle Ligne Ferroviaire à travers les Alpes) axe du Saint-Gothard est le plus important projet de construction de Suisse. En bâtissant la nouvelle ligne du Saint-Gothard, la Suisse réalise un des plus grands projets de protection de l'environnement d'Europe". Cette phrase, qu'on lit comme présentation du projet Alptransit est particulièrement éloquente pour expliquer l'utilité des nouvelles lignes ferroviaires transeuropéens pour le développement durable. Toutefois, comme toutes grandes infrastructures, la construction de nouveaux tunnels ont des impacts inévitables sur l'environnement. En particulier, le possible drainage des eaux souterraines réalisées par le tunnel peut provoquer un abaissement du niveau des nappes piézométriques. De plus, l'écoulement de l'eau à l'intérieur du tunnel, conduit souvent à des problèmes d'ingénierie. Par exemple, d'importantes infiltrations d'eau dans le tunnel peuvent compliquer les phases d'excavation, provoquant un retard dans l'avancement et dans le pire des cas, peuvent mettre en danger la sécurité des travailleurs. Enfin, l'infiltration d'eau peut être un gros problème pendant le fonctionnement du tunnel. Du point de vue de la science, avoir accès à des infrastructures souterraines représente une occasion unique d'obtenir des informations géologiques en profondeur et pour échantillonner des eaux autrement inaccessibles. Dans ce travail, nous avons utilisé une approche pluridisciplinaire qui intègre des mesures d'étude hydrogéochimiques effectués sur les eaux de surface et des investigations géophysiques indirects, tels que la tomographic de résistivité électrique (TRE) et les mesures électromagnétiques de type VLF. L'étude complète a été fait en Suisse italienne, basée sur deux grandes infrastructures actuellement en construction, qui sont le tunnel ferroviaire de base du Monte Ceneri, une partie du susmentionné projet Alptransit, situé entièrement dans le canton Tessin, et le tunnel routière de San Fedele, situé a Roveredo dans le canton des Grisons. Le principal objectif était de montrer comment il était possible d'intégrer les deux approches, géophysiques et géochimiques, afin de répondre à la question de ce que pourraient être les effets possibles dû au drainage causés par les travaux souterrains. L'accès aux galeries ci-dessus a permis une validation adéquate des enquêtes menées confirmant, dans chaque cas, les hypothèses proposées. A cette fin, nous avons fait environ 50 profils géophysiques (28 imageries électrique bidimensionnels et 23 électromagnétiques) dans les zones de possible influence par le tunnel, dans le but d'identifier les fractures et les discontinuités dans lesquelles l'eau souterraine peut circuler. De plus, des eaux ont été échantillonnés dans 60 localités situées la surface ainsi que dans les tunnels subjacents, le suivi mensuelle a duré plus d'un an. Nous avons mesurés tous les principaux paramètres physiques et chimiques: débit, conductivité électrique, pH et température. De plus, des échantillons d'eaux ont été prélevés pour l'analyse mensuelle des isotopes stables de l'hydrogène et de l'oxygène (δ2Η, δ180). Avec ces analyses, ainsi que par la mesure des concentrations des gaz rares dissous dans les eaux et de leurs rapports isotopiques que nous avons effectués dans certains cas spécifiques, il était possible d'expliquer l'origine des différents eaux souterraines, les divers modes de recharge des nappes souterraines, la présence de possible phénomènes de mélange et, en général, de mieux expliquer les circulations d'eaux dans le sous-sol. Le travail, même en constituant qu'une réponse partielle à une question très complexe, a permis d'atteindre certains importants objectifs. D'abord, nous avons testé avec succès l'applicabilité des méthodes géophysiques indirectes (TRE et électromagnétiques de type VLF) pour prédire la présence d'eaux souterraines dans le sous-sol des massifs rocheux. De plus, nous avons démontré l'utilité de l'analyse des gaz rares, des isotopes stables et de l'analyses des ions majeurs pour la détection de failles et pour comprendre l'origine des eaux souterraines (eau de pluie par le haut ou eau remontant des profondeurs). En conclusion, avec cette recherche, on a montré que l'intégration des ces informations (géophysiques et géochimiques) permet le développement de modèles conceptuels appropriés, qui permettant d'expliquer comment l'eau souterraine circule. Ces modèles permettent de prévoir les infiltrations d'eau dans les tunnels et de prédire la vulnérabilité de sources et des autres ressources en eau lors de construction de tunnels.

Using STD occurence to monitor AIDS prevention : final report of the Working Group on STD Surveillance.

The overall aim of the project has been to assess the extent to which data on the frequency of occurence of STDs [Sexually transmitted diseases] might be useful in the monitoring and evaluation of AIDS prevention programmes. The objectives have been to answer the following questions: (a) Can measures of STD occurence be used as an outcome measure of AIDS/HIV preventive efforts ? In particular: -> which diseases might be useful ? -> in what ways could they be used ? (b) If measures of STD occurence can be used in this way, is existing surveillance data in Western Europe adequate for the purpose ? If not why not ? (c) What do data from existing STD surveillance systems tell us about the success or failure of AIDS prevention to date ? (d) What needs to be done in order taht STD surveillance data in the countries of Western Europe could be used for this purpose ? [Authors, p. 4]

Typing less common ovarian tumors: A training tool based on a pattern-based algorithm applied to a set of 20 virtual slides.

Context: Ovarian tumors (OT) typing is a competency expected from pathologists, with significant clinical implications. OT however come in numerous different types, some rather rare, with the consequence of few opportunities for practice in some departments. Aim: Our aim was to design a tool for pathologists to train in less common OT typing. Method and Results: Representative slides of 20 less common OT were scanned (Nano Zoomer Digital Hamamatsu®) and the diagnostic algorithm proposed by Young and Scully applied to each case (Young RH and Scully RE, Seminars in Diagnostic Pathology 2001, 18: 161-235) to include: recognition of morphological pattern(s); shortlisting of differential diagnosis; proposition of relevant immunohistochemical markers. The next steps of this project will be: evaluation of the tool in several post-graduate training centers in Europe and Québec; improvement of its design based on evaluation results; diffusion to a larger public. Discussion: In clinical medicine, solving many cases is recognized as of utmost importance for a novice to become an expert. This project relies on the virtual slides technology to provide pathologists with a learning tool aimed at increasing their skills in OT typing. After due evaluation, this model might be extended to other uncommon tumors.

Characterization of GLUT8 and GLUT9, two novel glucose transporter isoforms

Summary Prevalence of type 2 diabetes is increasing worldwide at alarming rates, probably secondarily to that of obesity. As type 2 diabetes is characterized by blood hyperglycemia, controlling glucose entry into tissues from the bloodstream is key to maintain glycemia within acceptable ranges. In this context, several glucose transporter isoforms have been cloned recently and some of them have appeared to play important regulatory roles. Better characterizing two of them (GLUT8 and GLUT9) was the purpose of my work. The first part of my work was focused on GLUT8, which is mainly expressed in the brain and is able to transport glucose with high affinity. GLUT8 is retained intracellularly at basal state depending on an N-terminal dileucine motif, thus implying that cell surface expression may be induced by extracellular triggers. In this regard, I was interested in better defining GLUT8 subcellular localization at basal state and in finding signals promoting its translocation, using an adenoviral vector expressing a myc epitope-tagged version of the transporter, thus allowing expression and detection of cell-surface GLUT8 in primary hippocampal neurons and PC 12 cells. This tool enabled me to found out that GLUT8 resides in a unique compartment different from lysosomes, endoplasmic reticulum, endosomes and the Golgi. In addition, absence of GLUT8 translocation following pharmacological activation of several signalling pathways suggests that GLUT8 does not ever translocate to the cell surface, but would rather fulfill its role in its unique intracellular compartment. The second part of my work was focused on GLUT9, which -contrarily to GLUT8 - is unable to transport glucose, but retains the ability to bind glucose-derived cross-linker molecules, thereby suggesting that it may be a glucose sensor rather than a true glucose transporter. The aim of the project was thus to define if GLUT9 triggers intracellular signals when activated. Therefore, adenoviral vectors expressing GLUTS were used to infect both ßpancreatic and liver-derived cell lines, as GLUTS is endogenously expressed in the liver. Comparison of gene expression between cells infected with the GLUTS-expressing adenovirus and cells infected with a GFP-expressing control adenovirus ended up in the identification of the transcription factor HNF4α as being upregulated in aGLUT9-dependent manner. Résumé La prévalence du diabète de type 2 augmente de façon alarmante dans le monde entier, probablement secondairement à celle de l'obésité. Le diabète de type 2 étant caractérisé par une glycémie sanguine élevée, l'entrée du glucose dans les tissus depuis la circulation sanguine constitue un point de contrôle important pour maintenir la glycémie à des valeurs acceptables. Dans ce contexte, plusieurs isoformes de transporteurs au glucose ont été clonées récemment et certaines d'entre elles sont apparues comme jouant d'importants rôles régulateurs. Mieux caractériser deux d'entre elles (GLUT8 et GLUT9) était le but de mon travail. La première partie de mon travail a été centrée sur GLUT8, qui est exprimé principalement dans le cerveau et qui peut transporter le glucose avec une haute affinité. GLUT8 est retenu intracellulairement à l'état basal de façon dépendante d'un motif dileucine N-terminal, ce qui implique que son expression à la surface cellulaire pourrait être induite par des stimuli extracellulaires. Dans cette optique, je me suis intéressé à mieux définir la localisation subcellulaire de GLUT8 à l'état basal et à trouver des signaux activant sa translocation, en utilisant comme outil un vecteur adénoviral exprimant une version marquée (tag myc) du transporteur, me permettant ainsi d'exprimer et de détecter GLUT8 à la surface cellulaire dans des neurones hippocampiques primaires et des cellules PC12. Cet outil m'a permis de montrer que GLUT8 réside dans un compartiment unique différent des lysosomes, du réticulum endoplasmique, des endosomes, ainsi que du Golgi. De plus, l'absence de translocation de GLUT8 à la suite de l'activation pharmacologique de plusieurs voies de signalisation suggère que GLUT8 ne transloque jamais à la membrane plasmique, mais jouerait plutôt un rôle au sein même de son compartiment intracellulaire unique. La seconde partie de mon travail a été centrée sur GLUT9, lequel -contrairement à GLUT8 -est incapable de transporter le glucose, mais conserve la capacité de se lier à des molécules dérivées du glucose, suggérant que ce pourrait être un senseur de glucose plutôt qu'un vrai transporteur. Le but du projet a donc été de définir si GLUT9 active des signaux intracellulaires quand il est lui-même activé. Pour ce faire, des vecteurs adénoviraux exprimant GLUT9 ont été utilisés pour infecter des lignées cellulaires dérivées de cellules ßpancréatiques et d'hépatocytes, GLUT9 étant exprimé de façon endogène dans le foie. La comparaison de l'expression des gènes entre des cellules infectées avec l'adénovirus exprimant GLUT9 et un adénovirus contrôle exprimant la GFP a permis d'identifier le facteur de transcription HNF4α comme étant régulé de façon GLUT9-dépendante. Résumé tout public Il existe deux types bien distincts de diabète. Le diabète de type 1 constitue environ 10 des cas de diabète et se déclare généralement à l'enfance. Il est caractérisé par une incapacité du pancréas à sécréter une hormone, l'insuline, qui régule la concentration sanguine du glucose (glycémie). Il en résulte une hyperglycémie sévère qui, si le patient n'est pas traité à l'insuline, conduit à de graves dommages à divers organes, ce qui peut mener à la cécité, à la perte des membres inférieurs, ainsi qu'à l'insuffisance rénale. Le diabète de type 2 se déclare plus tard dans la vie. Il n'est pas causé par une déficience en insuline, mais plutôt par une incapacité de l'insuline à agir sur ses tissus cibles. Le nombre de cas de diabète de type 2 augmente de façon dramatique, probablement à la suite de l'augmentation des cas d'obésité, le surpoids chronique étant le principal facteur de risque de diabète. Chez l'individu sain, le glucose sanguin est transporté dans différents organes (foie, muscles, tissu adipeux,...) où il est utilisé comme source d'énergie. Chez le patient diabétique, le captage de glucose est altéré, expliquant ainsi l'hyperglycémie. Il est ainsi crucial d'étudier les mécanismes permettant ce captage. Ainsi, des protéines permettant l'entrée de glucose dans la cellule depuis le milieu extracellulaire ont été découvertes depuis une vingtaine d'années. La plupart d'entre elles appartiennent à une sous-famille de protéines nommée GLUT (pour "GLUcose Transporters") dont cinq membres ont été caractérisés et nommés selon l'ordre de leur découverte (GLUT1-5). Néanmoins, la suppression de ces protéines chez la souris par des techniques moléculaires n'affecte pas totalement le captage de glucose, suggérant ainsi que des transporteurs de glucose encore inconnus pourraient exister. De telles protéines ont été isolées ces dernières années et nommées selon l'ordre de leur découverte (GLUT6-14). Durant mon travail de thèse, je me suis intéressé à deux d'entre elles, GLUT8 et GLUT9, qui ont été découvertes précédemment dans le laboratoire. GLUT8 est exprimé principalement dans le cerveau. La protéine n'est pas exprimée à la surface de la cellule, mais est retenue à l'intérieur. Des mécanismes complexes doivent donc exister pour déplacer le transporteur à la surface cellulaire, afin qu'il puisse permettre l'entrée du glucose dans la cellule. Mon travail a consisté d'une part à définir où se trouve le transporteur à l'intérieur de la cellule, et d'autre part à comprendre les mécanismes capables de déplacer GLUT8 vers la surface cellulaire, en utilisant des neurones exprimant une version marquée du transporteur, permettant ainsi sa détection par des méthodes biochimiques. Cela m'a permis de montrer que GLUT8 est localisé dans une partie de la cellule encore non décrite à ce jour et qu'il n'est jamais déplacé à la surface cellulaire, ce qui suggère que le transporteur doit jouer un rôle à l'intérieur de la cellule et non à sa surface. GLUT9 est exprimé dans le foie et dans les reins. Il ressemble beaucoup à GLUT8, mais ne transporte pas le glucose, ce qui suggère que ce pourrait être un récepteur au glucose plutôt qu'un transporteur à proprement parler. Le but de mon travail a été de tester cette hypothèse, en comparant des cellules du foie exprimant GLUT9 avec d'autres n'exprimant pas la protéine. Par des méthodes d'analyses moléculaires, j'ai pu montrer que la présence de GLUT9 dans les cellules du foie augmente l'expression de HNF4α, une protéine connue pour réguler la sécrétion d'insuline dans le pancréas ainsi que la production de glucose dans le foie. Des expériences complémentaires seront nécessaires afin de mieux comprendre par quels mécanismes GLUT9 influence l'expression de HNF4α dans le foie, ainsi que de définir l'importance de GLUT9 dans la régulation de la glycémie chez l'animal entier.

Online teaching of inflammatory skin pathology by a French-speaking International University Network.

INTRODUCTION: Developments in technology, web-based teaching and whole slide imaging have broadened the teaching horizon in anatomic pathology. Creating online learning material including many types of media such as radiologic images, whole slides, videos, clinical and macroscopic photographs, is now accessible to most universities. Unfortunately, a major limiting factor to maintain and update the learning material is the amount of resources needed. In this perspective, a French-national university network was initiated in 2011 to build joint online teaching modules consisting of clinical cases and tests. The network has since expanded internationally to Québec, Switzerland and Ivory Coast. METHOD: One of the first steps of the project was to build a learning module on inflammatory skin pathology for interns and residents in pathology and dermatology. A pathology resident from Québec spent 6 weeks in France and Switzerland to develop the contents and build the module on an e-learning Moodle platform under the supervision of two dermatopathologists. The learning module contains text, interactive clinical cases, tests with feedback, virtual slides, images and clinical photographs. For that module, the virtual slides are decentralized in 2 universities (Bordeaux and Paris 7). Each university is responsible of its own slide scanning, image storage and online display with virtual slide viewers. RESULTS: The module on inflammatory skin pathology includes more than 50 web pages with French original content, tests and clinical cases, links to over 45 virtual images and more than 50 microscopic and clinical photographs. The whole learning module is being revised by four dermatopathologists and two senior pathologists. It will be accessible to interns and residents in the spring of 2014. The experience and knowledge gained from that work will be transferred to the next international resident whose work will be aimed at creating lung and breast pathology learning modules. CONCLUSION: The challenges of sustaining a project of this scope are numerous. The technical aspect of whole-slide imaging and storage needs to be developed by each university or group. The content needs to be regularly updated and its accuracy reviewed by experts in each individual domain. The learning modules also need to be promoted within the academic community to ensure maximal benefit for trainees. A collateral benefit of the project was the establishment of international partnerships between French-speaking universities and pathologists with the common goal of promoting pathology education through the use of multi-media technology including whole slide imaging.

Introducing blended learning into a Master Program in Nursing Sciences: a first exploration of a holistic evaluation framework

This contribution presents the first stage of a project to assist the transition of a traditional to a blended program in higher nursing education. We shall describe the goals and context of this project, present the evaluation framework, discuss some early results and then discuss the usefulness of the first version of the evaluation framework.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Contribution of isotope ratio mass spectrometry to the investigation of improvised explosives: isotopic study of black powders ans ammonium nitrates

The establishment of legislative rules about explosives in the eighties has reduced the illicit use of military and civilian explosives. However, bomb-makers have rapidly taken advantage of substances easily accessible and intended for licit uses to produce their own explosives. This change in strategy has given rise to an increase of improvised explosive charges, which is moreover assisted by the ease of implementation of the recipes, widely available through open sources. While the nature of the explosive charges has evolved, instrumental methods currently used in routine, although more sensitive than before, have a limited power of discrimination and allow mostly the determination of the chemical nature of the substance. Isotope ratio mass spectrometry (IRMS) has been applied to a wide range of forensic materials. Conclusions drawn from the majority of the studies stress its high power of discrimination. Preliminary studies conducted so far on the isotopic analysis of intact explosives (pre-blast) have shown that samples with the same chemical composition and coming from different sources could be differentiated. The measurement of stable isotope ratios appears therefore as a new and remarkable analytical tool for the discrimination or the identification of a substance with a definite source. However, much research is still needed to assess the validity of the results in order to use them either in an operational prospect or in court. Through the isotopic study of black powders and ammonium nitrates, this research aims at evaluating the contribution of isotope ratio mass spectrometry to the investigation of explosives, both from a pre-blast and from a post-blast approach. More specifically, the goal of the research is to provide additional elements necessary to a valid interpretation of the results, when used in explosives investigation. This work includes a fundamental study on the variability of the isotopic profile of black powder and ammonium nitrate in both space and time. On one hand, the inter-variability between manufacturers and, particularly, the intra-variability within a manufacturer has been studied. On the other hand, the stability of the isotopic profile over time has been evaluated through the aging of these substances exposed to different environmental conditions. The second part of this project considers the applicability of this high-precision technology to traces and residues of explosives, taking account of the characteristics specific to the field, including their sampling, a probable isotopic fractionation during the explosion, and the interferences with the matrix of the site.

Development of a harmonised method for the profiling of amphetamine

Résumé : Cette thèse de doctorat est le fruit d'un projet de recherche européen financé par le quatrième programme cadre de la Commission Européenne (DG XII, Standards, Measurement and Testing). Ce projet, dénommé SMT-CT98-2277, a été financé pour la partie suisse par l'Office Fédéral de l'Education et de la Science (OFES, Berne, Suisse). Le but de ce projet était de développer une méthode harmonisée et collaborativement testée pour le profilage des impuretés de l'amphétamine illicite par chromatographie capillaire en phase gazeuse. Le travail a été divisé en sept phases majeures qui concernaient la synthèse de l'amphétamine, l'identification d'impuretés, l'optimisation de la préparation de l'échantillon et du système chromatographique, la variabilité des résultats, l'investigation de méthodes mathématiques pour la classification et la comparaison de profils et finalement l'application de la méthode à des réels échantillons illicites. La méthode résultant de ce travail n'a pas seulement montré que les données étaient interchangeables entre laboratoires mais aussi qu'elle était supérieure en de nombreux points aux méthodes préalablement publiées dans la littérature scientifique. Abstract : This Ph.D. thesis was carried out in parallel to an European project funded by the fourth framework program of the European Commission (DG XII, Standards, Measurement and Testing). This project, named SMT-CT98-2277 was funded, for the Swiss part, by the Federal Office of Education and Science (OFES, Bern, Switzerland). The aim of the project was to develop a harmonised, collaboratively tested method for the impurity profiling of illicit amphetamine by capillary gas chromatography. The work was divided into seven main tasks which deal with the synthesis of amphetamine, identification of impurities, optimization of sample preparation and of the chromatographic system, variability of the results, investigation of numerical methods for the classification and comparison of profiles and finally application of the methodology to real illicit samples. The resulting method has not only shown to produce interchangeable data between different laboratories but was also found to be superior in many aspects to previously published methods.

CleanEx: a database of heterogeneous gene expression data based on a consistent gene nomenclature and linked to an improved annotation system

Résumé: L'automatisation du séquençage et de l'annotation des génomes, ainsi que l'application à large échelle de méthodes de mesure de l'expression génique, génèrent une quantité phénoménale de données pour des organismes modèles tels que l'homme ou la souris. Dans ce déluge de données, il devient très difficile d'obtenir des informations spécifiques à un organisme ou à un gène, et une telle recherche aboutit fréquemment à des réponses fragmentées, voir incomplètes. La création d'une base de données capable de gérer et d'intégrer aussi bien les données génomiques que les données transcriptomiques peut grandement améliorer la vitesse de recherche ainsi que la qualité des résultats obtenus, en permettant une comparaison directe de mesures d'expression des gènes provenant d'expériences réalisées grâce à des techniques différentes. L'objectif principal de ce projet, appelé CleanEx, est de fournir un accès direct aux données d'expression publiques par le biais de noms de gènes officiels, et de représenter des données d'expression produites selon des protocoles différents de manière à faciliter une analyse générale et une comparaison entre plusieurs jeux de données. Une mise à jour cohérente et régulière de la nomenclature des gènes est assurée en associant chaque expérience d'expression de gène à un identificateur permanent de la séquence-cible, donnant une description physique de la population d'ARN visée par l'expérience. Ces identificateurs sont ensuite associés à intervalles réguliers aux catalogues, en constante évolution, des gènes d'organismes modèles. Cette procédure automatique de traçage se fonde en partie sur des ressources externes d'information génomique, telles que UniGene et RefSeq. La partie centrale de CleanEx consiste en un index de gènes établi de manière hebdomadaire et qui contient les liens à toutes les données publiques d'expression déjà incorporées au système. En outre, la base de données des séquences-cible fournit un lien sur le gène correspondant ainsi qu'un contrôle de qualité de ce lien pour différents types de ressources expérimentales, telles que des clones ou des sondes Affymetrix. Le système de recherche en ligne de CleanEx offre un accès aux entrées individuelles ainsi qu'à des outils d'analyse croisée de jeux de donnnées. Ces outils se sont avérés très efficaces dans le cadre de la comparaison de l'expression de gènes, ainsi que, dans une certaine mesure, dans la détection d'une variation de cette expression liée au phénomène d'épissage alternatif. Les fichiers et les outils de CleanEx sont accessibles en ligne (http://www.cleanex.isb-sib.ch/). Abstract: The automatic genome sequencing and annotation, as well as the large-scale gene expression measurements methods, generate a massive amount of data for model organisms. Searching for genespecific or organism-specific information througout all the different databases has become a very difficult task, and often results in fragmented and unrelated answers. The generation of a database which will federate and integrate genomic and transcriptomic data together will greatly improve the search speed as well as the quality of the results by allowing a direct comparison of expression results obtained by different techniques. The main goal of this project, called the CleanEx database, is thus to provide access to public gene expression data via unique gene names and to represent heterogeneous expression data produced by different technologies in a way that facilitates joint analysis and crossdataset comparisons. A consistent and uptodate gene nomenclature is achieved by associating each single gene expression experiment with a permanent target identifier consisting of a physical description of the targeted RNA population or the hybridization reagent used. These targets are then mapped at regular intervals to the growing and evolving catalogues of genes from model organisms, such as human and mouse. The completely automatic mapping procedure relies partly on external genome information resources such as UniGene and RefSeq. The central part of CleanEx is a weekly built gene index containing crossreferences to all public expression data already incorporated into the system. In addition, the expression target database of CleanEx provides gene mapping and quality control information for various types of experimental resources, such as cDNA clones or Affymetrix probe sets. The Affymetrix mapping files are accessible as text files, for further use in external applications, and as individual entries, via the webbased interfaces . The CleanEx webbased query interfaces offer access to individual entries via text string searches or quantitative expression criteria, as well as crossdataset analysis tools, and crosschip gene comparison. These tools have proven to be very efficient in expression data comparison and even, to a certain extent, in detection of differentially expressed splice variants. The CleanEx flat files and tools are available online at: http://www.cleanex.isbsib. ch/.