Surveillance active du cancer de la prostate [Active surveillance in prostate cancer].

Active surveillance in prostate cancer The spread of PSA in the screening of prostate cancer has almost doubled the incidence of this disease in the last twenty years. An improved understanding of the natural history of this cancer allows for risk stratification of the disease and to better predict insignificant prostate cancer. Active surveillance has recently been proposed as a new option to delay or avoid a radical treatment for patients with low-risk disease. The principle, results and future perspectives of this treatment modality are discussed in this review.

Epidemiology and prevention of cardiovascular disease in the Seychelles Islands (Indian Ocean)

This article presents selected findings and lessons from a cardiovascular research and prevention program initiated in 1989 in the Republic of Seychelles, a country in demographic and epidemiological transition. Rapid and sustained aging of the population (e.g., two-fold increase of people aged 30-39 from 1979 to 1995) implies, over the next few decades, further dramatic increase of the burden of chronic diseases, particularly cardiovascular disease (CVD). Epidemiological surveillance shows high age-specific rates of CVD (particularly stroke), high prevalence of peripheral atherosclerosis (plaques in carotid and femoral arteries), high prevalence of classical modifiable risk factors in the adult population (particularly hypertension), and substantial proportions of children with overweight. Stagnant life expectancy in men and an increase in women have been observed over the last two decades; this occurred despite largely improved health services and reduced infant mortality rates, and may reflect the large CVD burden found in middle-aged men (less so in middle-aged women). A national program of prevention of CVD has been initiated since 1991, which includes a mix of interventions to reduce risk factors in the general population and in high-risk individuals. Substantial research to back the prevention program indeed shows, at the moment, epidemiological patterns in Seychelles similar to those observed in Western countries (e.g., an association between peripheral atherosclerosis [as a proxy of CVD] and low density lipoprotein-cholesterol, smoking, diabetes, and [inversely] walking). This clearly supports the view that promotion of healthy lifestyles and control of conventional risk factors should be the main targets for CVD prevention and control.

Auditory spatial deficits following hemispheric lesions : dissociation of explicit and implicit processing

Les déficits auditifs spatiaux se produisent fréquemment après une lésion hémisphérique ; un précédent case report suggérait que la capacité explicite à reconnaître des positions sonores, comme dans la localisation des sons, peut être atteinte alors que l'utilisation implicite d'indices sonores pour la reconnaissance d'objets sonores dans un environnement bruyant reste préservée. En testant systématiquement des patients avec lésion hémisphérique inaugurale, nous avons montré que (1) l'utilisation explicite et/ou implicite des indices sonores peut être perturbée ; (2) la dissociation entre l'atteinte de l'utilisation explicite des indices sonores versus une préservation de l'utilisation implicite de ces indices est assez fréquente ; et (3) différents types de déficits dans la localisation des sons peuvent être associés avec une utilisation implicite préservée de ces indices sonores. Conceptuellement, la dissociation entre l'utilisation explicite et implicite de ces indices sonores peut illustrer la dichotomie des deux voies du système auditif. Nos résultats parlent en faveur d'une évaluation systématique des fonctions auditives spatiales dans un contexte clinique, surtout quand l'adaptation à un environnement sonore est en jeu. De plus, des études systématiques sont nécessaires afin de mettre en lien les troubles de l'utilisation explicite versus implicite de ces indices sonores avec les difficultés à effectuer les activités de la vie quotidienne, afin d'élaborer des stratégies de réhabilitation appropriées et afin de s'assurer jusqu'à quel point l'utilisation explicite et implicite des indices spatiaux peut être rééduquée à la suite d'un dommage cérébral.

Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe.

The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4-12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.

Surveillance for European bat lyssavirus in Swiss bats.

Most countries in Western Europe are currently free of rabies in terrestrial mammals. Nevertheless, rabies remains a residual risk to public health due to the natural circulation of bat-specific viruses, such as European bat lyssaviruses (EBLVs). European bat lyssavirus types 1 and 2 (EBLV-1 and EBLV-2) are widely distributed throughout Europe, but little is known of their true prevalence and epidemiology. We report that only three out of 837 brains taken from bats submitted to the Swiss Rabies Centre between 1976 and 2009 were found by immunofluorescence (FAT) to be positive for EBLVs. All three positive cases were in Myotis daubentoni, from 1992, 1993 and 2002. In addition to this passive surveillance, we undertook a targeted survey in 2009, aimed at detecting lyssaviruses in live bats in Switzerland. A total of 237 bats of the species M. daubentoni, Myotis myotis, Eptesicus serotinus and Nyctalus noctula were captured at different sites in western Switzerland. Oropharyngeal swabs and blood from each individual were analysed by RT-PCR and rapid fluorescent focus inhibition test (RFFIT), respectively. RNA corresponding to EBLV-2 was detected from oropharyngeal swabs of a single M. daubentoni bat, but no infectious virus was found. Molecular phylogenetic analysis revealed that the corresponding sequence was closely related to the other EBLV-2 sequences identified in previous rabies isolates from Swiss bats (particularly to that found at Geneva in 2002). Three M. daubentoni bats were found to be seropositive by RFFIT. In conclusion, even though the prevalence is low in Switzerland, continuous management and surveillance are required to assess the potential risk to public health.

Factors Affecting Audit Quality in the 2007 UK Regulatory Environment: Perceptions of Chief Financial Officers, Audit Committee Chairs and Audit Engagement Partners

In line with global changes, the UK regulatory regime for audit and corporate governance has changed significantly since the Enron scandal, with an increased role for audit committees and independent inspection of audit firms. UK listed company chief financial officers (CFOs), audit committee chairs (ACCs) and audit partners (APs) were surveyed in 2007 to obtain views on the impact of 36 economic and regulatory factors on audit quality. 498 usable responses were received, representing a response rate of 36%. All groups rated various audit committee interactions with auditors among the factors most enhancing audit quality. Exploratory factor analysis reduces the 36 factors to nine uncorrelated dimensions. In order of extraction, these are: economic risk; audit committee activities; risk of regulatory action; audit firm ethics; economic independence of auditor; audit partner rotation; risk of client loss; audit firm size; and, lastly, International Standards on Auditing (ISAs) and audit inspection. In addition to the activities of the audit committee, risk factors for the auditor (both economic and certain regulatory risks) are believed to most enhance audit quality. However, ISAs and the audit inspection regime, aspects of the ‘standards-surveillance compliance’ regulatory system, are viewed as less effective. Respondents commented that aspects of the changed regime are largely process and compliance driven, with high costs for limited benefits, supporting psychological bias regulation theory that claims there is overconfidence that a useful regulatory intervention exists.

Optimisation of antiretroviral therapy : pharmacokinetic and pharmacogenetic approaches

Les progrès de la thérapie antirétrovirale ont transformé l'infection par le VIH d'une condition inévitablement fatale à une maladie chronique. En dépit de ce succès, l'échec thérapeutique et la toxicité médicamenteuse restent fréquents. Une réponse inadéquate au traitement est clairement multifactorielle et une individualisation de la posologie des médicaments qui se baserait sur les facteurs démographiques et génétiques des patients et sur les taux sanguins totaux, libres et/ou cellulaires des médicaments pourrait améliorer à la fois l'efficacité et la tolérance de la thérapie, cette dernière étant certainement un enjeu majeur pour un traitement qui se prend à vie.L'objectif global de cette thèse était de mieux comprendre les facteurs pharmacocinétiques (PK) et pharmacogénétiques (PG) influençant l'exposition aux médicaments antirétroviraux (ARVs) nous offrant ainsi une base rationnelle pour l'optimisation du traitement antiviral et pour l'ajustement posologique des médicaments chez les patients VIH-positifs. Une thérapie antirétrovirale adaptée au patient est susceptible d'augmenter la probabilité d'efficacité et de tolérance à ce traitement, permettant ainsi une meilleure compliance à long terme, et réduisant le risque d'émergence de résistance et d'échec thérapeutique.A cet effet, des méthodes de quantification des concentrations plasmatiques totales, libres et cellulaires des ARVs ainsi que de certains de leurs métabolites ont été développées et validées en utilisant la chromatographie liquide coupée à la spectrométrie de masse en tandem. Ces méthodes ont été appliquées pour la surveillance des taux d'ARVs dans diverses populations de patients HIV-positifs. Une étude clinique a été initiée dans le cadre de l'étude VIH Suisse de cohorte mère-enfant afin de déterminer si la grossesse influence la cinétique des ARVs. Les concentrations totales et libres du lopînavir, de l'atazanavir et de la névirapine ont été déterminées chez les femmes enceintes suivies pendant leur grossesse, et celles-ci ont été trouvées non influencées de manière cliniquement significative par la grossesse. Un ajustement posologique de ces ARVs n'est donc pas nécessaire chez les femmes enceintes. Lors d'une petite étude chez des patients HIV- positifs expérimentés, la corrélation entre l'exposition cellulaire et plasmatique des nouveaux ARVs, notamment le raltégravir, a été déterminée. Une bonne corrélation a été obtenue entre taux plasmatiques et cellulaires de raltégravir, suggérant que la surveillance des taux totaux est un substitut satisfaisant. Cependant, une importante variabilité inter¬patient a été observée dans les ratios d'accumulation cellulaire du raltégravir, ce qui devrait encourager des investigations supplémentaires chez les patients en échec sous ce traitement. L'efficacité du suivi thérapeutique des médicaments (TDM) pour l'adaptation des taux d'efavirenz chez des patients avec des concentrations au-dessus de la cible thérapeutique recommandée a été évaluée lors d'une étude prospective. L'adaptation des doses d'efavirenz basée sur le TDM s'est montrée efficace et sûre, soutenant l'utilisation du TDM chez les patients avec concentrations hors cible thérapeutique. L'impact des polymorphismes génétiques des cytochromes P450 (CYP) 2B6, 2A6 et 3A4/5 sur la pharmacocinétique de l'efavirenz et de ces métabolites a été étudié : un modèle de PK de population intégrant les covariats génétiques et démographiques a été construit. Les variations génétiques fonctionnelles dans les voies de métabolisation principales (CYP2B6) et accessoires {CYP2A6et 3A4/S) de l'efavirenz ont un impact sur sa disposition, et peuvent mener à des expositions extrêmes au médicament. Un? ajustement des doses guidé par le TDM est donc recommandé chez ces patients, en accord avec les polymorphismes génétiques.Ainsi, nous avons démonté qu'en utilisant une approche globale tenant compte à la fois des facteurs PK et PG influençant l'exposition aux ARVs chez les patients infectés, il est possible, si nécessaire, d'individualiser la thérapie antirétrovirale dans des situations diverses. L'optimisation du traitement antirétroviral contribue vraisemblablement à une meilleure efficacité thérapeutique à iong terme tout en réduisant la survenue d'effets indésirables.Résumé grand publicOptimisation de la thérapie antirétrovirale: approches pharmacocinétiques et pharmacogénétiquesLes progrès effectués dans le traitement de l'infection par le virus de llmmunodéficienoe humaine acquise (VIH) ont permis de transformer une affection mortelle en une maladie chronique traitable avec des médicaments de plus en plus efficaces. Malgré ce succès, un certain nombre de patients ne répondent pas de façon optimale à leur traitement etyou souffrent d'effets indésirables médicamenteux entraînant de fréquentes modifications dans leur thérapie. Il a été possible de mettre en évidence que l'efficacité d'un traitement antirétroviral est dans la plupart des cas corrélée aux concentrations de médicaments mesurées dans le sang des patients. Cependant, le virus se réplique dans la cellule, et seule la fraction des médicaments non liée aux protéines du plasma sanguin peut entrer dans la cellule et exercer l'activité antirétrovirale au niveau cellulaire. Il existe par ailleurs une importante variabilité des concentrations sanguines de médicament chez des patients prenant pourtant la même dose de médicament. Cette variabilité peut être due à des facteurs démographiques et/ou génétiques susceptibles d'influencer la réponse au traitement antirétroviral.Cette thèse a eu pour objectif de mieux comprendre les facteurs pharmacologiques et génétiques influençant l'efficacité et ta toxicité des médicaments antirétroviraux, dans le but d'individualiser la thérapie antivirale et d'améliorer le suivi des patients HIV-positifs.A cet effet, des méthodes de dosage très sensibles ont été développées pour permettre la quantification des médicaments antirétroviraux dans le sang et les cellules. Ces méthodes analytiques ont été appliquées dans le cadre de diverses études cliniques réalisées avec des patients. Une des études cliniques a recherché s'il y avait un impact des changements physiologiques liés à la grossesse sur les concentrations des médicaments antirétroviraux. Nous avons ainsi pu démontrer que la grossesse n'influençait pas de façon cliniquement significative le devenir des médicaments antirétroviraux chez les femmes enceintes HIV- positives. La posologie de médicaments ne devrait donc pas être modifiée dans cette population de patientes. Par ailleurs, d'autres études ont portés sur les variations génétiques des patients influençant l'activité enzymatique des protéines impliquées dans le métabolisme des médicaments antirétroviraux. Nous avons également étudié l'utilité d'une surveillance des concentrations de médicament (suivi thérapeutique) dans le sang des patients pour l'individualisation des traitements antiviraux. Il a été possible de mettre en évidence des relations significatives entre l'exposition aux médicaments antirétroviraux et l'existence chez les patients de certaines variations génétiques. Nos analyses ont également permis d'étudier les relations entre les concentrations dans le sang des patients et les taux mesurés dans les cellules où le virus HIV se réplique. De plus, la mesure des taux sanguins de médicaments antirétroviraux et leur interprétation a permis d'ajuster la posologie de médicaments chez les patients de façon efficace et sûre.Ainsi, la complémentarité des connaissances pharmacologiques, génétiques et virales s'inscrit dans l'optique d'une stratégie globale de prise en charge du patient et vise à l'individualisation de la thérapie antirétrovirale en fonction des caractéristiques propres de chaque individu. Cette approche contribue ainsi à l'optimisation du traitement antirétroviral dans la perspective d'un succès du traitement à long terme tout en réduisant la probabilité des effets indésirables rencontrés. - The improvement in antirétroviral therapy has transformed HIV infection from an inevitably fatal condition to a chronic, manageable disease. However, treatment failure and drug toxicity are frequent. Inadequate response to treatment is clearly multifactorial and, therefore, dosage individualisation based on demographic factors, genetic markers and measurement of total, free and/or cellular drug level may increase both drug efficacy and tolerability. Drug tolerability is certainly a major issue for a treatment that must be taken indefinitely.The global objective of this thesis aimed at increasing our current understanding of pharmacokinetic (PK) and pharmacogenetic (PG) factors influencing the exposition to antirétroviral drugs (ARVs) in HIV-positive patients. In turn, this should provide us with a rational basis for antiviral treatment optimisation and drug dosage adjustment in HIV- positive patients. Patient's tailored antirétroviral regimen is likely to enhance treatment effectiveness and tolerability, enabling a better compliance over time, and hence reducing the probability of emergence of viral resistance and treatment failure.To that endeavour, analytical methods for the measurement of total plasma, free and cellular concentrations of ARVs and some of their metabolites have been developed and validated using liquid chromatography coupled with tandem mass spectrometry. These assays have been applied for the monitoring of ARVs levels in various populations of HIV- positive patients. A clinical study has been initiated within the frame of the Mother and Child Swiss HIV Cohort Study to determine whether pregnancy influences the exposition to ARVs. Free and total plasma concentrations of lopinavir, atazanavir and nevirapine have been determined in pregnant women followed during the course of pregnancy, and were found not influenced to a clinically significant extent by pregnancy. Dosage adjustment for these drugs is therefore not required in pregnant women. In a study in treatment- experienced HIV-positive patients, the correlation between cellular and total plasma exposure to new antirétroviral drugs, notably the HIV integrase inhibitor raltegravir, has been determined. A good correlation was obtained between total and cellular levels of raltegravir, suggesting that monitoring of total levels are a satisfactory. However, significant inter-patient variability was observed in raltegravir cell accumulation which should prompt further investigations in patients failing under an integrase inhibitor-based regimen. The effectiveness of therapeutic drug monitoring (TDM) to guide efavirenz dose reduction in patients having concentrations above the recommended therapeutic range was evaluated in a prospective study. TDM-guided dosage adjustment of efavirenz was found feasible and safe, supporting the use of TDM in patients with efavirenz concentrations above therapeutic target. The impact of genetic polymorphisms of cytochromes P450 (CYP) 2B6, 2A6 and 3A4/5 on the PK of efavirenz and its metabolites was studied: a population PK model was built integrating both genetic and demographic covariates. Functional genetic variations in main (CYP2B6) and accessory (2A6, 3A4/5) metabolic pathways of efavirenz have an impact on efavirenz disposition, and may lead to extreme drug exposures. Dosage adjustment guided by TDM is thus required in those patients, according to the pharmacogenetic polymorphism.Thus, we have demonstrated, using a comprehensive approach taking into account both PK and PG factors influencing ARVs exposure in HIV-infected patients, the feasibility of individualising antirétroviral therapy in various situations. Antiviral treatment optimisation is likely to increase long-term treatment success while reducing the occurrence of adverse drug reactions.

The role of Malt1 proteolytic activity in T cell activation and lymphoma development

Abstract Long term contact with pathogens induces an adaptive immune response, which is mainly mediated by T and B cells. Antigen-induced activation of T and B cells is an important event, since it facilitates the transition of harmless, low proliferative lymphocytes into powerful and fast expanding cells, which can, if deregulated, be extremely harmful and dangerous for the human body. One of the most important events during lymphocyte activation is the induction of NF-xB activity, a transcription factor that controls not only cytokine secretion, but also lymphocyte proliferation and survival. Recent discoveries identified the CBM complex as the central regulator of NF-xB activity in lymphocytes. The CBM complex consists of the three proteins Carma1, Bcl10 and Malt1, in which Carma1 serves as recruitment platform of the complex and Bcl10 as an adaptor to recruit Malt1 to this platform. But exactly how Malt1 activates NF-x6 is still poorly understood. We discovered that Malt1 is a protease, which cleaves its interaction partner Bcl10 upon T and B cell stimulation. We mapped the Bcl10 cleavage site by single point mutations as well as by a proteomics approach, and used this knowledge to design a fluorogenic Malt1 reporter peptide. With this tool were we able to the first time demonstrate proteolytic activity of Malt1 in vitro, using recombinant Malt1, and in stimulated T cells. Based on similarities to a metacaspase, we designed a Malt1inhibitor, which allowed unto investigate the role of Malt1 activity in T cells. Malt1-inhibited T cells showed a clear defect in NF-xB activity, resulting in impaired IL-2 cytokine secretion levels. We also found a new unexpected role for Bcl10; the blockade of Bcl10 cleavage resulted in a strongly impaired capability of stimulated T cells to adhere to the extracellular matrix protein fibronectin. Because of the central position of the C8M complex, it is not surprising that different lymphomas show abnormal expressions of Carma1, Bcl10 and Malt1. We investigated the role of Malt1 proteolytic activity in the most aggressive subtype of diffuse large B cell lymphomas called ABC, which was described to depend on the expression of Carmal, and frequently carries oncogenic Carmal mutations. We found constitutive high Malt1 activity in all tested ABC cell lines visualized by detection of cleavage products of Malt1 substrates. With the use of the Malt1-inhibitor, we could demonstrate that Malt-inhibition in those cells had two effects. First, the tumor cell proliferation was decreased, most likely because of lower autocrine stimulation by cytokines. Second, we could sensitize the ABC cells towards cell death, which is most likely caused by reduced expression of prosurvival NF-xB target gens. Taken together, we identified Malt1 as a protease in T and B cells, demonstrated its importance for NF-xB signaling and its deregulation in a subtype of diffuse large B cell lymphoma. This could allow the development of a new generation of immunomodulatory and anti-cancer drugs. Résumé Un contact prolongé avec des pathogènes provoque une réponse immunitaire adaptative qui dépend principalement des cellules T et 8. L'activation des lymphocytes T et B, suite à la reconnaissance d'un antigène, est un événement important puisqu'il facilite la transition pour ces cellules d'un état de prolifération limitée et inoffensive à une prolifération soutenue et rapide. Lorsque ce mécanisme est déréglé ìl peut devenir extrêmement nuisible et dangereux pour le corps humain. Un des événement les plus importants lors de l'activation des lymphocytes est l'induction du facteur de transcription NFxB, qui organise la sécrétion de cytokines ainsi que la prolifération et la survie des lymphocytes. Le complexe CBM, composé des trois protéines Carmai, Bc110 et Malt1, a été récemment identifié comme un régulateur central de l'activité de NF-x8 dans les lymphocytes. Carma1 sert de plateforme de recrutement pour ce complexe alors que Bc110 permet d'amener Malt1 dans cette plateforme. Cependant, le rôle exact de Malt1 dans l'activation de NF-tcB reste encore mal compris. Nous avons découvert que Malt1 est une protéase qui clive son partenaire d'interaction BcI10 après stimulation des cellules T et B. Nous avons identifié le site de clivage de BcI10 par une série de mutations ponctuelles ainsi que par une approche protéomique, ce qui nous a permis de fabriquer un peptide reporteur fluorogénique pour mesurer l'activité de Malt1. Grâce à cet outil, nous avons démontré pour la première fois l'activité protéolytique de Malt1 in vitro à l'aide de protéines Malt1 recombinantes ainsi que dans des cellules T stimulées. La ressemblance de Malt1 avec une métacaspase nous a permis de synthétiser un inhibiteur de Malt1 et d'étudier ainsi le rôle de l'activité de Malt1 dans les cellules T. L'inhibition de Malt1 dans les cellules T a révélé un net défaut de l'activité de NF-x8, ayant pour effet une sécrétion réduite de la cytokine IL-2. Nous avons également découvert un rôle inattendu pour Bcl10: en effet, bloquer le clivage de Bcl10 diminue fortement la capacité d'adhésion des cellules T stimulées à la protéine fïbronectine, un composant de la matrice extracellulaire. En raison de la position centrale du complexe CBM, il n'est pas étonnant que le niveau d'expression de Carmai, Bcl10 et Malt1 soit anormal dans plusieurs types de lymphomes. Nous avons examiné le rôle de l'activité protéolytique de Malt1 dans le sous-type le plus agressif des lymphomes B diffus à grandes cellules, appelé sous-type ABC. Ce sous-type de lymphomes dépend de l'expression de Carmai et présente souvent des mutations oncogéniques de Carma1. Nous avons démontré que l'activité de Malt1 était constitutivement élevée dans toutes les lignées cellulaires de type ABC testées, en mettant en évidence la présence de produits de clivage de différents substrats de Malt1. Enfin, l'utilisation de l'inhibiteur de Malt1 nous a permis de démontrer que l'inhibition de Malt1 avait deux effets. Premièrement, une diminution de la prolifération des cellules tumorales, probablement dûe à leur stimulation autocrine par des cytokines fortement réduite. Deuxièmement, une sensibilisation des cellules de type ABC à ia mort cellulaire, vraisemblablement causée par l'expression diminuée de gènes de survie dépendants de NF-tcB. En résumé, nous avons identifié Malt1 comme une protéase dans les cellules T et B, nous avons mis en évidence son importance pour l'activation de NF-xB ainsi que les conséquences du dérèglement de l'activité de Malt1 dans un sous-type de lymphome B diffus à larges cellules. Notre étude ouvre ainsi la voie au développement d'une nouvelle génération de médicaments immunomodulateurs et anti-cancéreux.

Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland.

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant's and pregnant woman's best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant's clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infant's burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

Use of terrestrial laser scanning for the characterization of retrogressive landslides in sensitive clay and rotational landslides in river banks

Depuis plus de 10 ans les modèles numériques d'altitude (MNA) produits par technologie de « light detection and ranging » (« LIDAR ») ont fourni de nouveaux outils très utiles pour des études géomorphologiques, particulièrement dans le cas des glissements de terrain. Le balayage laser terrestre (« TLS ») permet une utilisation très souple. Le TLS peut être employé pour la surveillance ou dans des situations d'urgence qui nécessitent une acquisition rapide d'un MNA afin d'évaluer l'aléa. Au travers de trois exemples, nous démontrons l'utilité du TLS pour la quantification de volumes de glissements de terrain, la création de profils et l'analyse de séries temporelles. Ces études de cas sont des glissements de terrain situés dans les argiles sensibles de l'est du Canada (Québec, Canada) ou de petits glissements rotationnels dans les berges d'une rivière (Suisse).

New approaches for the control and eradication of schistosomiasis in Venezuela

Schistosomiasis in Americawith the exception of Brazil, behaves as a chronic mild disease with few clinical manifestations due to low parasite burden. These features restrict the clinical and parasitological diagnosis. The most commonly used stool examination method, Kato-Katz, becomes intensitive when the majority of individuals excrete less than 100 eggs/g of feces. In view that antigen-detecting techniques have not been able to reveal light infections, the antibody detecting assays remain as a very valuable diagnostic tool for epidemiological surveillance. The Venezuelan Schistosomiasis Research group (CECOICE) has designed a mass chemotherapy strategy based on sero-diagnosis. Since blood sampling is one of the important limitating factors for large seroepidemiological trials we developed a simple capillary technique that sucessfully overcomed most of the limitations of blood drawing. In this sense, ELISA seems to be the most adecuate test for epidemiological studies. Soluble egg Schistosoma mansoni antigen (SEA) has been largely used in Venezuela. The sensitivity ELISA-SEA in our hands is 90% moreover its specific reach 92% when populations from non-endemic areas but heavily infected with other intestinal parasites are analyzed. The Schistosomiasis Control Program is currently carrying out the surveillance of endemic areas using ELISA-SEA as the first screening method, followed by the Circumoval Precipitin test for validation assay. The results with these two serological techniques allowed us to defined the criteria of chemotherapy in populations of the endemic areas. On the search of better diagnostic technique, Alkaline Phosphatase Immunoenzyme Assay (APIA) is being evaluated in field surveys.

Withdrawal, "serosorting" and "strategic positioning": use of risk reduction strategies with casual sex partners in men who have sex with men (MSM) in Switzerland, 2007

Introduction: 1) Withdrawal before ejaculation, "serosorting" (to choose a partner of same serostatus) and "strategic positioning" (only insertive vs. only receptive role in anal sex according to serostatus) are known to be used by MSM as alternatives to condom use. 2) Despite their questionable levels of effectiveness they are collectively labelled as "risk reduction strategies" (RRS). Objectives: The aim of this study is to estimate the prevalence and factors related to RRS in men who report unprotected anal intercourse (UAI) with occasional partners in the last 12 months. Methods: 1) In 2007, a module on RRS was included in a repeated national survey conducted among readers of gay newspapers, members of gay organizations and visitors of gay websites (N=2953). 2) Using an anonymous self-completed questionnaire, participants were asked whether, with the aim of avoiding HIV infection, RRS were used with occasional partners. Analysis: 1) Prevalences were calculated in participants who reported UAI with occasional partners in the last 12 months (n=416). 2) A logistic regression was performed, using "at least one RRS" as dependent variable. Number of partners in the last 12 months, HIV-status and usual socio-demographic characteristics were used as independent factors. Result : 1) 70% (292/416) of the participants reporting UAI used at least one RRS when they had unprotected sex with casual partners in the last 12 months (Table 1). 2) Withrawal before ejaculation was the most frequently reported strategy, followed by serosorting and strategic positioning (Table 1). 3) Participants who reported at least one RRS were more likely to be over 30 years and to belong to a gay organisation. HIV-positive and non-tested participants were less likely to report RRS than HIV-negative participants (Table 2). Conclusions: 1) The majority of MSM who reported UAI in the last 12 months tried to reduce risk of HIV transmission by using specific strategies (withdrawal, serosorting, strategic positioning). It is not known, however, to what extent the use of these strategies was systematic. 2) It is necessary to provide MSM with balanced information on these strategies and their respective level of effectiveness. 3) It is important to monitor the use of RRS in HIV behavioural surveillance surveys in MSM.

La reconnaissance des objets sonores chez l'humain

Abstract : This thesis investigated the spatio-temporal brain mechanisms of three processes involved in recognizing environmental sounds produced by living (animal vocalisations) and man-made (manufactured) objects: their discrimination, their plasticity, and the involvement of action representations. Results showed rapid brain discrimination between these categories beginning at ~70ms. Then, beginning at ~150ms, effects of plasticity are observed, without any influence of the categories of sounds. Both of these processes of discrimination and repetition priming involved brain structures located in temporal and frontal lobes. Activation of brain areas BA21 and BA22 suggest an access to semantic representations and/or linked to object manipulation. To investigate the involvement of action representations in sound recognition, analyses were restricted to sounds produced by man-made objects. Results suggest an access to representations linked to action functionally related to sound rather than to representations linked to action that produced sound. These effects occurred at ~300ms post-stimulus onset and involved differential activity brain regions attributed to the mirror neuron system. These data are discussed in regard to motor preparation of actions functionally linked to sounds. Collectively these data showed a sequential progression of cerebral activity underlying the recognizing of environmental sounds. The processes occurred firstly in a shared network of brain areas before propagating elsewhere and/or leading to differential activity in these structures. Cerebral responses observed in this work allowed establishing a dynamic model of discrimination of sounds produced by living and man-made objects.

The geographic understanding of snail borne disease in endemic areas using satellite surveillance

The current status of research on use of earth observing satellite sensors and geographic ifnormation systems for control program management of schistosomiais and fascioliasis is reviewed.