p53 Mutation in histologically normal mucosa of the aero-digestive tract is not a marker of increased risk for second primary carcinoma in head and neck cancer patients.

Head and neck cancer patients are at high risk for developing second primary tumors. This is known as field cancerization of the aero-digestive tract. In a previous study, we showed that patients with multiple primary tumors were more likely to have p53 mutations in histologically normal mucosae than patients presenting with an isolated tumor. Based on this observation, we postulated that p53 mutations in normal tissue samples of patients bearing a single primary tumor could have a clinical value as a biomarker for the risk of developing second primary tumors. Thirty-five patients presenting with a single primary tumor were followed-up for a median of 51 months (range 1 month to 10.9 years) after biopsies of histologically normal squamous cell mucosa had been analyzed for p53 mutations with a yeast functional assay at the time of the primary tumor. During this follow-up, recurrences and non-sterilization of the primary tumor, occurrence of lymph node metastases, and of second primary tumors were evaluated. Sixteen (45.7%) patients were found to have p53 mutations in their normal squamous cell mucosa, and 19 (54.3%) patients showed no mutation. No relationship was found between p53 mutations and the occurrence of evaluated events during follow-up. Notably, the rate of second primary tumors was not associated with p53 mutations in the normal squamous mucosa. The correlation between p53 mutations in histologically normal mucosae and the incidence of second primary tumors is generally low. The benefit of analyzing p53 mutations in samples of normal squamous cell mucosa in every patient with a primary tumor of the head and neck is doubtful.

Topological origins of chromosomal territories.

Using freely jointed polymer model we compare equilibrium properties of crowded polymer chains whose segments are either permeable or not permeable for other segments to pass through. In particular, we addressed the question whether non-permeability of long chain molecules, in the absence of excluded volume effect, is sufficient to compartmentalize highly crowded polymer chains, similarly to what happens during formation of chromosomal territories in interphase nuclei. Our results indicate that even polymers without excluded volume compartmentalize and show strongly reduced intermingling when they are mutually non-permeable. Judging from the known fact that chromatin fibres originating from different chromosomes show very limited intermingling in interphase nuclei, we propose that regular chromatin fibres during chromosome decondensation can hardly serve as a substrate of cellular type II DNA topoisomerases.

Pore-scale modeling of two-phase flow instabilities in porous media

Les problèmes d'écoulements multiphasiques en média poreux sont d'un grand intérêt pour de nombreuses applications scientifiques et techniques ; comme la séquestration de C02, l'extraction de pétrole et la dépollution des aquifères. La complexité intrinsèque des systèmes multiphasiques et l'hétérogénéité des formations géologiques sur des échelles multiples représentent un challenge majeur pour comprendre et modéliser les déplacements immiscibles dans les milieux poreux. Les descriptions à l'échelle supérieure basées sur la généralisation de l'équation de Darcy sont largement utilisées, mais ces méthodes sont sujettes à limitations pour les écoulements présentant de l'hystérèse. Les avancées récentes en terme de performances computationnelles et le développement de méthodes précises pour caractériser l'espace interstitiel ainsi que la distribution des phases ont favorisé l'utilisation de modèles qui permettent une résolution fine à l'échelle du pore. Ces modèles offrent un aperçu des caractéristiques de l'écoulement qui ne peuvent pas être facilement observées en laboratoire et peuvent être utilisé pour expliquer la différence entre les processus physiques et les modèles à l'échelle macroscopique existants. L'objet premier de la thèse se porte sur la simulation numérique directe : les équations de Navier-Stokes sont résolues dans l'espace interstitiel et la méthode du volume de fluide (VOF) est employée pour suivre l'évolution de l'interface. Dans VOF, la distribution des phases est décrite par une fonction fluide pour l'ensemble du domaine et des conditions aux bords particulières permettent la prise en compte des propriétés de mouillage du milieu poreux. Dans la première partie de la thèse, nous simulons le drainage dans une cellule Hele-Shaw 2D avec des obstacles cylindriques. Nous montrons que l'approche proposée est applicable même pour des ratios de densité et de viscosité très importants et permet de modéliser la transition entre déplacement stable et digitation visqueuse. Nous intéressons ensuite à l'interprétation de la pression capillaire à l'échelle macroscopique. Nous montrons que les techniques basées sur la moyenne spatiale de la pression présentent plusieurs limitations et sont imprécises en présence d'effets visqueux et de piégeage. Au contraire, une définition basée sur l'énergie permet de séparer les contributions capillaires des effets visqueux. La seconde partie de la thèse est consacrée à l'investigation des effets d'inertie associés aux reconfigurations irréversibles du ménisque causé par l'interface des instabilités. Comme prototype pour ces phénomènes, nous étudions d'abord la dynamique d'un ménisque dans un pore angulaire. Nous montrons que, dans un réseau de pores cubiques, les sauts et reconfigurations sont si fréquents que les effets d'inertie mènent à différentes configurations des fluides. A cause de la non-linéarité du problème, la distribution des fluides influence le travail des forces de pression, qui, à son tour, provoque une chute de pression dans la loi de Darcy. Cela suggère que ces phénomènes devraient être pris en compte lorsque que l'on décrit l'écoulement multiphasique en média poreux à l'échelle macroscopique. La dernière partie de la thèse s'attache à démontrer la validité de notre approche par une comparaison avec des expériences en laboratoire : un drainage instable dans un milieu poreux quasi 2D (une cellule Hele-Shaw avec des obstacles cylindriques). Plusieurs simulations sont tournées sous différentes conditions aux bords et en utilisant différents modèles (modèle intégré 2D et modèle 3D) afin de comparer certaines quantités macroscopiques avec les observations au laboratoire correspondantes. Malgré le challenge de modéliser des déplacements instables, où, par définition, de petites perturbations peuvent grandir sans fin, notre approche numérique apporte de résultats satisfaisants pour tous les cas étudiés. - Problems involving multiphase flow in porous media are of great interest in many scientific and engineering applications including Carbon Capture and Storage, oil recovery and groundwater remediation. The intrinsic complexity of multiphase systems and the multi scale heterogeneity of geological formations represent the major challenges to understand and model immiscible displacement in porous media. Upscaled descriptions based on generalization of Darcy's law are widely used, but they are subject to several limitations for flow that exhibit hysteric and history- dependent behaviors. Recent advances in high performance computing and the development of accurate methods to characterize pore space and phase distribution have fostered the use of models that allow sub-pore resolution. These models provide an insight on flow characteristics that cannot be easily achieved by laboratory experiments and can be used to explain the gap between physical processes and existing macro-scale models. We focus on direct numerical simulations: we solve the Navier-Stokes equations for mass and momentum conservation in the pore space and employ the Volume Of Fluid (VOF) method to track the evolution of the interface. In the VOF the distribution of the phases is described by a fluid function (whole-domain formulation) and special boundary conditions account for the wetting properties of the porous medium. In the first part of this thesis we simulate drainage in a 2-D Hele-Shaw cell filled with cylindrical obstacles. We show that the proposed approach can handle very large density and viscosity ratios and it is able to model the transition from stable displacement to viscous fingering. We then focus on the interpretation of the macroscopic capillary pressure showing that pressure average techniques are subject to several limitations and they are not accurate in presence of viscous effects and trapping. On the contrary an energy-based definition allows separating viscous and capillary contributions. In the second part of the thesis we investigate inertia effects associated with abrupt and irreversible reconfigurations of the menisci caused by interface instabilities. As a prototype of these phenomena we first consider the dynamics of a meniscus in an angular pore. We show that in a network of cubic pores, jumps and reconfigurations are so frequent that inertia effects lead to different fluid configurations. Due to the non-linearity of the problem, the distribution of the fluids influences the work done by pressure forces, which is in turn related to the pressure drop in Darcy's law. This suggests that these phenomena should be taken into account when upscaling multiphase flow in porous media. The last part of the thesis is devoted to proving the accuracy of the numerical approach by validation with experiments of unstable primary drainage in a quasi-2D porous medium (i.e., Hele-Shaw cell filled with cylindrical obstacles). We perform simulations under different boundary conditions and using different models (2-D integrated and full 3-D) and we compare several macroscopic quantities with the corresponding experiment. Despite the intrinsic challenges of modeling unstable displacement, where by definition small perturbations can grow without bounds, the numerical method gives satisfactory results for all the cases studied.

Subjective mental time: the functional architecture of projecting the self to past and future.

Abstract Human experience takes place in the line of mental time (MT) created through 'self-projection' of oneself to different time-points in the past or future. Here we manipulated self-projection in MT not only with respect to one's life events but also with respect to one's faces from different past and future time-points. Behavioural and event-related functional magnetic resonance imaging activity showed three independent effects characterized by (i) similarity between past recollection and future imagination, (ii) facilitation of judgements related to the future as compared with the past, and (iii) facilitation of judgements related to time-points distant from the present. These effects were found with respect to faces and events, and also suggest that brain mechanisms of MT are independent of whether actual life episodes have to be re-experienced or pre-experienced, recruiting a common cerebral network including the anteromedial temporal, posterior parietal, inferior frontal, temporo-parietal and insular cortices. These behavioural and neural data suggest that self-projection in time is a fundamental aspect of MT, relying on neural structures encoding memory, mental imagery and self.

Transient suppression of Shigella flexneri type 3 secretion by a protective O-antigen-specific monoclonal IgA.

Mucosal immunity to the enteric pathogen Shigella flexneri is mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag of S. flexneri serotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary for S. flexneri to gain entry into intestinal epithelial cells. IgAC5's effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5's effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag of S. flexneri partially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells. IMPORTANCE: Secretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by "immune exclusion," a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S-IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells.

Secretory IgA: an actor of the interplay between the commensal flora and the intestinal immune system?

In the gastro-intestinal tract,Peyers patches have been describedas a major inductive site for mucosalsecretory IgA (SIgA) responses directedagainst pathogens. The classicalview is that SIgAserves as the firstline of defense against microorganismsby agglutining potential invadersand faciliting their clearance byperistaltic and mucociliary movements,a mechanism called immuneexclusion. Our laboratory has shownthat SIgA is not only able to be"retrotransported" into Peyers patchesvia the associated M cells, but also todeliver sizeable cargos in the form ofSIgA-based immune complexes, resultingin the onset of non-inflammatorytype of responses. Such a novelfunction raises the question of thepossible role of mucosal SIgA in theinterplay with commensal bacteriaand the contribution of the antibody inbacterial homeostasis. To address thisquestion, Lactobacillus rhamnosus(LPR) was administered into a mouseligated loop comprising a Peyerspatch, in association or not with SIgA.The fate of fluorescently labelled bacteriawas followed by laser scanningconfocal microscopy at different incubationtimes. After 2 hours of incubationin the loop, LPR bacteria arefound more abundantly in thesubepithelial dome (SED) regionwhen they are coated with SIgA thanLPR administered alone despite theyare absent from neighboring villi.Herein, it is shown that this mechanismof entry involves M cells inPeyers pathes. After their sampling byM cells, bacteria are engulfed by thedendritic cells of the subjacent SEDregion. Interestingly, LPR bacteriaare found coated by the endogenousnatural SIgA present in mice intestinalsecretions, confirming the requirementof SIgA for this type of entry.The subsequent effect on the maturationof dendritic cells after interactionwith LPR was investigated in vitroin presence or not of SIgA by measuringthe expression of CD40, CD80and CD86 surface markers with flowcytometry analyses. Results show thatDCs respond in the same way in presenceof SIgA than with LPR bacteriaalone, indicating that SIgA does notmodulate the interaction betweenDCs and bacteria in this context. Thiswork gives new evidences about theinvolvement of SIgA in the mechanismby which the intestinal immunesystem permanently checks the contentof the intestine.

Detecting, quantifying and adjusting for publication bias in meta-analyses: protocol of a systematic review on methods.

BACKGROUND: Health professionals and policymakers aspire to make healthcare decisions based on the entire relevant research evidence. This, however, can rarely be achieved because a considerable amount of research findings are not published, especially in case of 'negative' results - a phenomenon widely recognized as publication bias. Different methods of detecting, quantifying and adjusting for publication bias in meta-analyses have been described in the literature, such as graphical approaches and formal statistical tests to detect publication bias, and statistical approaches to modify effect sizes to adjust a pooled estimate when the presence of publication bias is suspected. An up-to-date systematic review of the existing methods is lacking. METHODS/DESIGN: The objectives of this systematic review are as follows:âeuro¢ To systematically review methodological articles which focus on non-publication of studies and to describe methods of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses.âeuro¢ To appraise strengths and weaknesses of methods, the resources they require, and the conditions under which the method could be used, based on findings of included studies.We will systematically search Web of Science, Medline, and the Cochrane Library for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses. A dedicated data extraction form is developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article. As this will be a qualitative systematic review, data reporting will involve a descriptive summary. DISCUSSION: Results are expected to be publicly available in mid 2013. This systematic review together with the results of other systematic reviews of the OPEN project (To Overcome Failure to Publish Negative Findings) will serve as a basis for the development of future policies and guidelines regarding the assessment and handling of publication bias in meta-analyses.

Superior diagnostic performance of perfusion-cardiovascular magnetic resonance versus SPECT to detect coronary artery disease: The secondary endpoints of the multicenter multivendor MR-IMPACT II (Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary Artery Disease Trial).

ABSTRACT: BACKGROUND: Perfusion-cardiovascular magnetic resonance (CMR) is generally accepted as an alternative to SPECT to assess myocardial ischemia non-invasively. However its performance vs gated-SPECT and in sub-populations is not fully established. The goal was to compare in a multicenter setting the diagnostic performance of perfusion-CMR and gated-SPECT for the detection of CAD in various populations using conventional x-ray coronary angiography (CXA) as the standard of reference. METHODS: In 33 centers (in US and Europe) 533 patients, eligible for CXA or SPECT, were enrolled in this multivendor trial. SPECT and CXA were performed within 4 weeks before or after CMR in all patients. Prevalence of CAD in the sample was 49% and 515 patients received MR contrast medium. Drop-out rates for CMR and SPECT were 5.6% and 3.7%, respectively (ns). The study was powered for the primary endpoint of non-inferiority of CMR vs SPECT for both, sensitivity and specificity for the detection of CAD (using a single-threshold reading), the results for the primary endpoint were reported elsewhere. In this article secondary endpoints are presented, i.e. the diagnostic performance of CMR versus SPECT in subpopulations such as multi-vessel disease (MVD), in men, in women, and in patients without prior myocardial infarction (MI). For diagnostic performance assessment the area under the receiver-operator-characteristics-curve (AUC) was calculated. Readers were blinded versus clinical data, CXA, and imaging results. RESULTS: The diagnostic performance (= area under ROC = AUC) of CMR was superior to SPECT (p = 0.0004, n = 425) and to gated-SPECT (p = 0.018, n = 253). CMR performed better than SPECT in MVD (p = 0.003 vs all SPECT, p = 0.04 vs gated-SPECT), in men (p = 0.004, n = 313) and in women (p = 0.03, n = 112) as well as in the non-infarct patients (p = 0.005, n = 186 in 1-3 vessel disease and p = 0.015, n = 140 in MVD). CONCLUSION: In this large multicenter, multivendor study the diagnostic performance of perfusion-CMR to detect CAD was superior to perfusion SPECT in the entire population and in sub-groups. Perfusion-CMR can be recommended as an alternative for SPECT imaging. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT00977093.

The role of PLK-1 in asynchronous cell division of two-cell stage "C. elegans" embryos

Summary Acquisition of lineage-specific cell cycle duration is an important feature of metazoan development. In Caenorhabditis a/egans, differences in cell cycle duration are already apparent in two-cell stage embryos, when the larger anterior blastomere AB divides before the smaller posterior blastomere P1. This time difference is under the control of anterior-posterior (A-P) polarity cues set by the PAR proteins. The mechanism by which these cues regulate the cell cycle machinery differentially in AB and P1 are incompletely understood. Previous work established that retardation of P1 cell division is due in part to preferential activation of an ATL1/CHK-1 dependent checkpoint in P1 but how the remaining time difference is controlled was not known at the onset of my work. The principal line of work in this thesis established that differential timing relies also on a mechanism that promotes mitosis onset preferentially in AB. The polo-like kinase PLK-1, a positive regulator of mitotic entry, is distributed in an asymmetric manner in two-cell stage embryos, with more protein present in AB than in P1. We find that PLK-1 asymmetry is regulated by anterior-posterior (A-P) polarity cues through preferential protein retention in the embryo anterior. Importantly, mild inactivation of plk-1 by RNAi delays entry into mitosis in P1 but not in AB, in a manner that is independent of ATL-1/CHK-1. Together, these findings favor a model in which differential timing of mitotic entry in C. elegans embryos relies on two complementary mechanisms: ATL-1/CHK-1 dependent preferential retardation in P1 and PLK-1 dependent preferential promotion in AB, which together couple polarity cues and cell cycle progression during early development. Besides analyzing PLK-1 asymmetry and its role in differential timing of two-cells stage embryos, we also characterized t2190, a mutant that exhibits reduced differential timing between AB and P1. We found this mutant to be a new allele of par-1. Additionally, we analyzed the role of NMY-2 in regulating the asynchrony of two-cell stage embryos, which may be uncoupled from its role in A-P polarity establishment and carried out a preliminary analysis of the mechanism underlying CDC-25 asymmetry between AB and P,. Overall, our works bring new insights into the mechanism controlling cell cycle progression in early C. elegans embryos. As most of the players important in C. elegans are conserved in other organisms, analogous mechanisms may be utilized in polarized cells of other species. Résumé Au cours du développement, les processus de division cellulaire sont régulés dans l'espace et le temps afin d'aboutir à la formation d'un organisme fonctionnel. Chez les Métazoaires, l'un des mécanismes de contrôle s'effectue au niveau de la durée du cycle cellulaire, celle-ci étant specifiée selon la lignée cellulaire. L'embryon du nématode Caenorhabditis elegans apparaît comme un excellent modèle d'étude de la régulation temporelle du cycle cellulaire. En effet, suite à la première division du zygote, l'embryon est alors composé de deux cellules de taille et d'identité différentes, appelées blastomères AB et P1. Ces deux cellules vont ensuite se diviser de manière asynchrone, le grand blastomère antérieur AB se divisant plus rapidement que le petit blastomère postérieur P1. Cette asynchronie de division est sous le contrôle des protéines PAR qui sont impliquées dans l'établissement de l'axe antéro-postérieur de l'embryon. A ce jour, les mécanismes moléculaires gouvernant ce processus d'asynchronie ne sont que partiellement compris. Des études menées précédemment ont établit que le retard de division observé dans le petit blastomère postérieur P1 était dû, en partie, à l'activation préférentielle dans cette cellule de ATL-1/CHK-1, protéines contrôlant la réponse à des erreurs dans le processus de réplication de l'ADN. L'analyse des autres mécanismes responsables de la différence temporelle d'entrée en mitose des deux cellules a été entreprise au cours de cette thèse. Nous avons considéré la possibilité que l'asynchronie de division était du à l'entrée préférentielle en mitose du grand blastomère AB. Nous avons établi que la protéine kinase PLK-1 (polo-like kinase 1), impliquée dans la régulation positive de la mitose, était distribuée de manière asymétrique dans l'embryon deux cellules. PLK-1 est en effet enrichi dans le blastomère AB. Cette localisation asymétrique de PLK-1 est sous le contrôle des protéines PAR et semble établie via une rétention de PLK-1 dans la cellule AB. Par ailleurs, nous avons démontré que l'inactivation partielle de plk-7 par interférence à ARN (RNAi) conduit à un délai de l'entrée en mitose de la cellule P1 spécifiquement, indépendamment des protéines régulatrices ATL-1/CHK-1. En conclusion, nous proposons un modèle de régulation temporelle de l'entrée en mitose dans l'embryon deux cellules de C. elegans basé sur deux mécanismes complémentaires. Le premier implique l'activation préférentielle des protéines ATL-1/CHK-1, et conduit à un retard d'entrée en mitose spécifiquement dans la cellule P1. Le second est basé sur la localisation asymétrique de la protéine kinase PLK-1 dans la cellule AB et induit une entrée précoce en mitose de cette cellule. Par ailleurs, nous avons étudié un mutant appelé t2190 qui réduit la différence temporelle d'entrée en mitose entre les cellules AB et P1. Nous avons démontré que ce mutant correspondait à un nouvel allèle du Bene par-1. De plus, nous avons analysé le rôle de NMY-2, une protéine myosine qui agit comme moteur moléculaire sur les filaments d'active; dans la régulation de l'asynchronie de division des blastomères AB et P1, indépendamment de sa fonction dans l'établissement de l'axe antéro-postérieur. Par ailleurs, nous avons commencé l'étude du mécanisme moléculaire régulant la localisation asymétrique entre les cellules AB et P1 de la protéine phosphatase CDC25, qui est également un important régulateur de l'entrée en mitose. En conclusion, ce travail de thèse a permis une meilleure compréhension des mécanismes gouvernant la progression du cycle cellulaire dans l'embryon précoce de C. elegans. Etant donné que la plupart des protéines impliquées dans ces processus sont conservées chez d'autres organismes multicellulaires, il apparaît probable que les mécanismes moléculaires révélés dans cette étude soit aussi utilisés chez ceux-ci.

From geriatric service to primary care: a retrospective pharmaceutical analysis of the medical prescription

Introduction The population of elderly persons is increasing andnegative outcomes due to polymedication are frequent. Discrepanciesin information about medication are frequent when older persons aretransitioning from hospital to home, increasing the risk of hospitalreadmission. The aims of this study were a) to determine discrepanciesin medical regimen indicated in two official discharge documents(DS = discharge summary, DP=discharge prescription); b) to characterizethe pharmacotherapy prescribed in older patients dischargedfrom a geriatric service.Materials & Methods Elderly patients (N=230) discharged from thegeriatric service (CHUV, Lausanne) over a 6-month period (January toJune 2009) were selected. Community pharmacists compared DS andDP to identify discrepancies including (a) drugs' name; (b) schedule ofadministration, dosage, frequency, prn prescription, treatment durationand galenic formulation. Beers' criteria were applied to identifypotentially inappropriate drugs and a descriptive analysis of drug costs,prescription profiles and generics were also performed.Results On average, patients were 82 ± 7 years old and stayed23.0 ± 11.6 days in the geriatric service. The delay between the datesof patient's discharge with the DP and the sending of the DS to hisgeneral physician averaged 14.0 ± 7.5 days (range 1-55). The DPhad an average of 10.0 ± 3.3 drugs (range 2-19). 77% of patients hadat least one discrepancy. A drug was missing on the DS in 57.8% ofpatients and 19.6% had a missing prn prescription. Among the 2312drugs prescribed, 3% belonged to Beers' list. They were prescribed to61 patients (26.5%), with 6 patients cumulating two Beers' potentiallyinappropriate drugs in their treatment. Analgesics (85% of thepatients), anticoagulants (80%), mineral supplements (77%), laxatives(52%) and antihypertensives (46%) were the drug classes most frequentlyprescribed. Mean costs of treatment as per DP was160.4 ± 179.4 Euros. Generic prescription represented more than 5%of the costs for 3 therapeutic classes (cholesterol-lowering agents(64%), antihypertensives (50%) and antidepressants (47%)).Discussion & Conclusion The high discrepancy rate between medicationlisted in the DP and the DS highlights a need for safetyimprovement. Potential benefits are expected from reinforced pharmacist-physician collaboration in transition from hospital to primarycare. In addition, even though Beers' criteria are questionable, thedrugs prescribed in this already fragile population, and the potentialopportunities of economical optimizations, are advocating thedevelopment and the scientific evaluation of a structured advancedcollaborative pharmacy practice service. This foresees improvedeffectiveness, safety and efficiency in the medication management ofelderly persons.

The Role of Transnational Elites in shaping the evolving Field of Internet Governance

La gouvernance de l'Internet est une thématique récente dans la politique mondiale. Néanmoins, elle est devenue au fil des années un enjeu économique et politique important. La question a même pris une importance particulière au cours des derniers mois en devenant un sujet d'actualité récurrent. Forte de ce constat, c ette recherche retrace l'histoire de la gouvernance de l'Internet depuis son émergence comme enjeu politique dans les années 1980 jusqu'à la fin du Sommet Mondial sur la Société de l'Information (SMSI) en 2005. Plutôt que de se focaliser sur l'une ou l'autre des institutions impliquées dans la régulation du réseau informatique mondial, cette recherche analyse l'émergence et l'évolution historique d'un espace de luttes rassemblant un nombre croissant d'acteurs différents. Cette évolution est décrite à travers le prisme de la relation dialectique entre élites et non-élites et de la lutte autour de la définition de la gouvernance de l'Internet. Cette thèse explore donc la question de comment les relations au sein des élites de la gouvernance de l'Internet et entre ces élites et les non-élites expliquent l'emergence, l'évolution et la structuration d'un champ relativement autonome de la politique mondiale centré sur la gouvernance de l'Internet. Contre les perspectives dominantes réaliste et libérales, cette recherche s'ancre dans une approche issue de la combinaison des traditions hétérodoxes en économie politique internationale et des apports de la sociologie politique internationale. Celle-ci s'articule autour des concepts de champ, d'élites et d'hégémonie. Le concept de champ, développé par Bourdieu inspire un nombre croissant d'études de la politique mondiale. Il permet à la fois une étude différenciée de la mondialisation et l'émergence d'espaces de lutte et de domination au niveau transnational. La sociologie des élites, elle, permet une approche pragmatique et centrée sur les acteurs des questions de pouvoir dans la mondialisation. Cette recherche utilise plus particulièrement le concept d'élite du pouvoir de Wright Mills pour étudier l'unification d'élites a priori différentes autour de projets communs. Enfin, cette étude reprend le concept néo-gramscien d'hégémonie afin d'étudier à la fois la stabilité relative du pouvoir d'une élite garantie par la dimension consensuelle de la domination, et les germes de changement contenus dans tout ordre international. A travers l'étude des documents produits au cours de la période étudiée et en s'appuyant sur la création de bases de données sur les réseaux d'acteurs, cette étude s'intéresse aux débats qui ont suivi la commercialisation du réseau au début des années 1990 et aux négociations lors du SMSI. La première période a abouti à la création de l'Internet Corporation for Assigned Names and Numbers (ICANN) en 1998. Cette création est le résultat de la recherche d'un consensus entre les discours dominants des années 1990. C'est également le fruit d'une coalition entre intérêts au sein d'une élite du pouvoir de la gouvernance de l'Internet. Cependant, cette institutionnalisation de l'Internet autour de l'ICANN excluait un certain nombre d'acteurs et de discours qui ont depuis tenté de renverser cet ordre. Le SMSI a été le cadre de la remise en cause du mode de gouvernance de l'Internet par les États exclus du système, des universitaires et certaines ONG et organisations internationales. C'est pourquoi le SMSI constitue la seconde période historique étudiée dans cette thèse. La confrontation lors du SMSI a donné lieu à une reconfiguration de l'élite du pouvoir de la gouvernance de l'Internet ainsi qu'à une redéfinition des frontières du champ. Un nouveau projet hégémonique a vu le jour autour d'éléments discursifs tels que le multipartenariat et autour d'insitutions telles que le Forum sur la Gouvernance de l'Internet. Le succès relatif de ce projet a permis une stabilité insitutionnelle inédite depuis la fin du SMSI et une acceptation du discours des élites par un grand nombre d'acteurs du champ. Ce n'est que récemment que cet ordre a été remis en cause par les pouvoirs émergents dans la gouvernance de l'Internet. Cette thèse cherche à contribuer au débat scientifique sur trois plans. Sur le plan théorique, elle contribue à l'essor d'un dialogue entre approches d'économie politique mondiale et de sociologie politique internationale afin d'étudier à la fois les dynamiques structurelles liées au processus de mondialisation et les pratiques localisées des acteurs dans un domaine précis. Elle insiste notamment sur l'apport de les notions de champ et d'élite du pouvoir et sur leur compatibilité avec les anlayses néo-gramsciennes de l'hégémonie. Sur le plan méthodologique, ce dialogue se traduit par une utilisation de méthodes sociologiques telles que l'anlyse de réseaux d'acteurs et de déclarations pour compléter l'analyse qualitative de documents. Enfin, sur le plan empirique, cette recherche offre une perspective originale sur la gouvernance de l'Internet en insistant sur sa dimension historique, en démontrant la fragilité du concept de gouvernance multipartenaire (multistakeholder) et en se focalisant sur les rapports de pouvoir et les liens entre gouvernance de l'Internet et mondialisation. - Internet governance is a recent issue in global politics. However, it gradually became a major political and economic issue. It recently became even more important and now appears regularly in the news. Against this background, this research outlines the history of Internet governance from its emergence as a political issue in the 1980s to the end of the World Summit on the Information Society (WSIS) in 2005. Rather than focusing on one or the other institution involved in Internet governance, this research analyses the emergence and historical evolution of a space of struggle affecting a growing number of different actors. This evolution is described through the analysis of the dialectical relation between elites and non-elites and through the struggle around the definition of Internet governance. The thesis explores the question of how the relations among the elites of Internet governance and between these elites and non-elites explain the emergence, the evolution, and the structuration of a relatively autonomous field of world politics centred around Internet governance. Against dominant realist and liberal perspectives, this research draws upon a cross-fertilisation of heterodox international political economy and international political sociology. This approach focuses on concepts such as field, elites and hegemony. The concept of field, as developed by Bourdieu, is increasingly used in International Relations to build a differentiated analysis of globalisation and to describe the emergence of transnational spaces of struggle and domination. Elite sociology allows for a pragmatic actor-centred analysis of the issue of power in the globalisation process. This research particularly draws on Wright Mill's concept of power elite in order to explore the unification of different elites around shared projects. Finally, this thesis uses the Neo-Gramscian concept of hegemony in order to study both the consensual dimension of domination and the prospect of change contained in any international order. Through the analysis of the documents produced within the analysed period, and through the creation of databases of networks of actors, this research focuses on the debates that followed the commercialisation of the Internet throughout the 1990s and during the WSIS. The first time period led to the creation of the Internet Corporation for Assigned Names and Numbers (ICANN) in 1998. This creation resulted from the consensus-building between the dominant discourses of the time. It also resulted from the coalition of interests among an emerging power elite. However, this institutionalisation of Internet governance around the ICANN excluded a number of actors and discourses that resisted this mode of governance. The WSIS became the institutional framework within which the governance system was questioned by some excluded states, scholars, NGOs and intergovernmental organisations. The confrontation between the power elite and counter-elites during the WSIS triggered a reconfiguration of the power elite as well as a re-definition of the boundaries of the field. A new hegemonic project emerged around discursive elements such as the idea of multistakeholderism and institutional elements such as the Internet Governance Forum. The relative success of the hegemonic project allowed for a certain stability within the field and an acceptance by most non-elites of the new order. It is only recently that this order began to be questioned by the emerging powers of Internet governance. This research provides three main contributions to the scientific debate. On the theoretical level, it contributes to the emergence of a dialogue between International Political Economy and International Political Sociology perspectives in order to analyse both the structural trends of the globalisation process and the located practices of actors in a given issue-area. It notably stresses the contribution of concepts such as field and power elite and their compatibility with a Neo-Gramscian framework to analyse hegemony. On the methodological level, this perspective relies on the use of mixed methods, combining qualitative content analysis with social network analysis of actors and statements. Finally, on the empirical level, this research provides an original perspective on Internet governance. It stresses the historical dimension of current Internet governance arrangements. It also criticise the notion of multistakeholde ism and focuses instead on the power dynamics and the relation between Internet governance and globalisation.

Defining publication bias: protocol for a systematic review of highly cited articles and proposal for a new framework.

BACKGROUND: Selective publication of studies, which is commonly called publication bias, is widely recognized. Over the years a new nomenclature for other types of bias related to non-publication or distortion related to the dissemination of research findings has been developed. However, several of these different biases are often still summarized by the term 'publication bias'. METHODS/DESIGN: As part of the OPEN Project (To Overcome failure to Publish nEgative fiNdings) we will conduct a systematic review with the following objectives:- To systematically review highly cited articles that focus on non-publication of studies and to present the various definitions of biases related to the dissemination of research findings contained in the articles identified.- To develop and discuss a new framework on nomenclature of various aspects of distortion in the dissemination process that leads to public availability of research findings in an international group of experts in the context of the OPEN Project.We will systematically search Web of Knowledge for highly cited articles that provide a definition of biases related to the dissemination of research findings. A specifically designed data extraction form will be developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article.For the development of a new framework we will construct an initial table listing different levels and different hazards en route to making research findings public. An international group of experts will iteratively review the table and reflect on its content until no new insights emerge and consensus has been reached. DISCUSSION: Results are expected to be publicly available in mid-2013. This systematic review together with the results of other systematic reviews of the OPEN project will serve as a basis for the development of future policies and guidelines regarding the assessment and prevention of publication bias.

Comparison of central macular thickness (CMT) measurement between time domain and spectral domain (SD) optical coherence tomography (OCT) and reproducibility of SD OCT in active neovascular AMD

Purpose: To evaluate the reproducibility of Cirrus-SD OCT measurements and to compare central macular thickness (CMT) measurements between TD-Stratus and SD-Cirrus OCT in patients with active exudative AMD. Methods: Consecutive case series of patients with active exudative AMD seen in the Medical Retina Department. Patients underwent 1 scan with Stratus (macular thickness map protocol) and 5 scans with Cirrus (Macular Cube protocol) at the same visit by the same experienced examiner. To be included, patients best-corrected visual acuity (BCVA) had to be >20/200 while all scans had to be of sufficient quality, well-centered and at least one Cirrus scan with CMT >300 microns. The repeatability of the SD Cirrus was estimated by using all 5 CMT measurements and the mean of the Cirrus measurements was compared with the CMT obtained by TD Stratus. Results: Cirrus OCT demonstrated high intraobserver repeatability at the central foveal region (ICC 96%). The mean of the CMT measurements was 321microns for Stratus and 387 microns for Cirrus. The average difference was 65m (SD=30). The coefficient of concordance between Stratus and Cirrus CMT measurements was rho=0,749 with a high precision and a moderate accuracy. The equation of the line of regression between Stratus and meanCirrus is given by the following: M_stratus = 0,848 x m_cirrus - 4,496 (1).Conclusions: The Cirrus macular cube protocol allows reproducible CMT measurements in patients with active exudative AMD. In cases of upgrading from TD to SD use and vice versa, there is the possibility to predict the measurements by using the equation (1). These real life data and conclusions can help in improving our clinical management of patients with neovascular AMD.

Assessing catchment-scale erosion and yields of suspended solids from improved temperate grassland.

This paper quantifies the yields of suspended solids (SS) from a headwater catchment managed as improved temperate grassland, providing the first direct, catchment-scale evidence of the rates of erosion from this land-use in the UK and assessing the threat posed to aquatic ecosystems. High-resolution monitoring of catchment hydrology and the concentrations of SS and volatile organic matter (VOM) were carried out in the first-order channel of the Den Brook headwater catchment in Devon (UK) during the 2006-2007 hydrological season. The widely used 'rating curve' (discharge-concentration) approach was employed to estimate yields of SS, but as demonstrated by previous researchers, this study showed that discharge is a poor predictor of SS concentrations and therefore any yields estimated from this technique are likely to be highly uncertain. Nevertheless, for the purpose of providing estimates of yields that are comparable to previous studies on other land uses/sources, this technique was adopted albeit in an uncertainty-based framework. The findings suggest that contrary to the common perception, grasslands can be erosive landscapes with SS yields from this catchment estimated to be between 0.54 and 1.21 t ha(-1) y(-1). In terms of on-site erosion problems, this rate of erosion does not significantly exceed the commonly used 'tolerable' threshold in the UK ( approximately 1 t ha(-1) y(-1)). In terms of off-site erosion problems, it is argued here that the conventional expression of SS yield as a bulk annual figure has little relevance to the water quality and ecological status of surface waters and therefore an alternative technique (the concentration-frequency curve) is developed within this paper for the specific purpose of assessing the ecological threat posed by the delivery of SS into surface waters. This technique illustrates that concentrations of SS recorded at the catchment outlet frequently exceed the water quality guidelines, such as those of the EU Freshwater Fisheries Directive (78/659/EC), and pose a serious threat to aquatic organisms. It is suggested that failure to recognise improved temperate grasslands as a potential source of particulate material could result in the non-compliance of surface waters to water quality guidelines, deterioration of ecological status and failure of water quality remediation measures.

Amoebal pathogens as emerging causal agents of pneumonia.

Despite using modern microbiological diagnostic approaches, the aetiological agents of pneumonia remain unidentified in about 50% of cases. Some bacteria that grow poorly or not at all in axenic media used in routine clinical bacteriology laboratory but which can develop inside amoebae may be the agents of these lower respiratory tract infections (RTIs) of unexplained aetiology. Such amoebae-resisting bacteria, which coevolved with amoebae to resist their microbicidal machinery, may have developed virulence traits that help them survive within human macrophages, i.e. the first line of innate immune defence in the lung. We review here the current evidence for the emerging pathogenic role of various amoebae-resisting microorganisms as agents of RTIs in humans. Specifically, we discuss the emerging pathogenic roles of Legionella-like amoebal pathogens, novel Chlamydiae (Parachlamydia acanthamoebae, Simkania negevensis), waterborne mycobacteria and Bradyrhizobiaceae (Bosea and Afipia spp.).