Cross-Cultural Adaptation and Validation of the Spinal Function Sort (SFS) for French- and German-Speaking Patients with Back Complaints

Aim: Functional subjective evaluation through questionnaire is fundamental, but not often realized in patients with back complaints, notably because of lack of validated tools, in accordance with recognized psychometric criteria. The Spinal Function Sort (SFS), developed according to actual standards, was only validated in English. The aim of this study is to translate, adapt and validate the French and German version of the SFS.Method and material: The translation and cross-cultural adaptation were performed following the methodology proposed by the American Association of Orthopedist Surgeon. A total of 344 patients, presenting varied back complaints (especially degenerative and traumatic), took part in this study in a tertiary French- (n=87; mean age 44y; 17 women) and German-speaking (n=257; mean age 41y; 53 women) center. Test-retest reliability was quantified using the intraclass correlation coefficient (ICC) and construct validity was assessed by estimating the Pearson's correlation with the SF-36 physical and mental scales, the Visual Analogue Scale for Pain Intensity (VAS), and subscales of the Hospital Anxiety and Depression Scale (HADS).Results: Respectively for the French and German version, ICC were 0.98 and 0.94. Correlations 0.63 and 0.67 with the SF-36 Physical Functioning subscale; 0.60 and 0.52 with the SF-36 Physical Summary Scale ; -0.33 and -0.51 with the VAS ; -0.08 and 0.25 with the SF-36 Mental Health scale; 0.01 and 0.28 with the SF-36 Mental Summary Scale; -0.26 and -0.42 with the HADS depression; -0.17 and -0.45 with the HADS anxiety.Discussion: For both the French and German version of the SFS, the reliability was excellent. Convergent construct validity with SF-36 physical scales is good, moderated with the VAS. We find out a low correlation with SF-36 mental scales (divergent construct validity). We find out a low correlation with HADS subscales in the French version, and a moderate one in the German version. Selection bias, chronicity of the complaints, as well as cultural differences could explain these results. In conclusion, both the French and German version of the SFS are valid and reliable for evaluation of perceived functional capacity for patients with back complaints.

Susceptibility and adaptation to human TRIM5α alleles at positive selected sites in HIV-1 capsid.

Numerous in vitro studies attribute to human TRIM5α some modest anti-HIV-1 activity and human population studies suggest some differential effect of TRIM5α polymorphisms on disease progression. If the activity of TRIM5α were relevant in vivo, it could result in positive selection on the viral capsid. To address this issue, we identified 10 positively selected sites in HIV-1 capsid from multiple viral strains and generated 17 clade B viruses carrying a minor (i.e. low frequency) residue or an alanine at those positions. All recombinant viruses were susceptible to the modest effect of common human TRIM5α and allelic variants R136Q, and H419Y; H43Y and G249D TRIM5α were generally inactive. Increased sensitivity to TRIM5α was observed for some capsid variants, suggesting that minor residues are selected against in human populations. On the other hand, the modest potency of human TRIM5α does not translate in escape mutations in the viral capsid.

Local adaptation maintains clinal variation in melanin-based coloration of European barn owls (Tyto alba).

Ecological parameters vary in space, and the resulting heterogeneity of selective forces can drive adaptive population divergence. Clinal variation represents a classical model to study the interplay of gene flow and selection in the dynamics of this local adaptation process. Although geographic variation in phenotypic traits in discrete populations could be remainders of past adaptation, maintenance of adaptive clinal variation requires recurrent selection. Clinal variation in genetically determined traits is generally attributed to adaptation of different genotypes to local conditions along an environmental gradient, although it can as well arise from neutral processes. Here, we investigated whether selection accounts for the strong clinal variation observed in a highly heritable pheomelanin-based color trait in the European barn owl by comparing spatial differentiation of color and of neutral genes among populations. Barn owl's coloration varies continuously from white in southwestern Europe to reddish-brown in northeastern Europe. A very low differentiation at neutral genetic markers suggests that substantial gene flow occurs among populations. The persistence of pronounced color differentiation despite this strong gene flow is consistent with the hypothesis that selection is the primary force maintaining color variation among European populations. Therefore, the color cline is most likely the result of local adaptation.

PROX1 Promotes Metabolic Adaptation and Fuels Outgrowth of Wnt(high) Metastatic Colon Cancer Cells.

The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1(+) cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1(+) cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.

Risk and global change : developing scientific methods for advocacy and awareness raising

Les catastrophes sont souvent perçues comme des événements rapides et aléatoires. Si les déclencheurs peuvent être soudains, les catastrophes, elles, sont le résultat d'une accumulation des conséquences d'actions et de décisions inappropriées ainsi que du changement global. Pour modifier cette perception du risque, des outils de sensibilisation sont nécessaires. Des méthodes quantitatives ont été développées et ont permis d'identifier la distribution et les facteurs sous- jacents du risque.¦Le risque de catastrophes résulte de l'intersection entre aléas, exposition et vulnérabilité. La fréquence et l'intensité des aléas peuvent être influencées par le changement climatique ou le déclin des écosystèmes, la croissance démographique augmente l'exposition, alors que l'évolution du niveau de développement affecte la vulnérabilité. Chacune de ses composantes pouvant changer, le risque est dynamique et doit être réévalué périodiquement par les gouvernements, les assurances ou les agences de développement. Au niveau global, ces analyses sont souvent effectuées à l'aide de base de données sur les pertes enregistrées. Nos résultats montrent que celles-ci sont susceptibles d'être biaisées notamment par l'amélioration de l'accès à l'information. Elles ne sont pas exhaustives et ne donnent pas d'information sur l'exposition, l'intensité ou la vulnérabilité. Une nouvelle approche, indépendante des pertes reportées, est donc nécessaire.¦Les recherches présentées ici ont été mandatées par les Nations Unies et par des agences oeuvrant dans le développement et l'environnement (PNUD, l'UNISDR, la GTZ, le PNUE ou l'UICN). Ces organismes avaient besoin d'une évaluation quantitative sur les facteurs sous-jacents du risque, afin de sensibiliser les décideurs et pour la priorisation des projets de réduction des risques de désastres.¦La méthode est basée sur les systèmes d'information géographique, la télédétection, les bases de données et l'analyse statistique. Une importante quantité de données (1,7 Tb) et plusieurs milliers d'heures de calculs ont été nécessaires. Un modèle de risque global a été élaboré pour révéler la distribution des aléas, de l'exposition et des risques, ainsi que pour l'identification des facteurs de risque sous- jacent de plusieurs aléas (inondations, cyclones tropicaux, séismes et glissements de terrain). Deux indexes de risque multiples ont été générés pour comparer les pays. Les résultats incluent une évaluation du rôle de l'intensité de l'aléa, de l'exposition, de la pauvreté, de la gouvernance dans la configuration et les tendances du risque. Il apparaît que les facteurs de vulnérabilité changent en fonction du type d'aléa, et contrairement à l'exposition, leur poids décroît quand l'intensité augmente.¦Au niveau local, la méthode a été testée pour mettre en évidence l'influence du changement climatique et du déclin des écosystèmes sur l'aléa. Dans le nord du Pakistan, la déforestation induit une augmentation de la susceptibilité des glissements de terrain. Les recherches menées au Pérou (à base d'imagerie satellitaire et de collecte de données au sol) révèlent un retrait glaciaire rapide et donnent une évaluation du volume de glace restante ainsi que des scénarios sur l'évolution possible.¦Ces résultats ont été présentés à des publics différents, notamment en face de 160 gouvernements. Les résultats et les données générées sont accessibles en ligne (http://preview.grid.unep.ch). La méthode est flexible et facilement transposable à des échelles et problématiques différentes, offrant de bonnes perspectives pour l'adaptation à d'autres domaines de recherche.¦La caractérisation du risque au niveau global et l'identification du rôle des écosystèmes dans le risque de catastrophe est en plein développement. Ces recherches ont révélés de nombreux défis, certains ont été résolus, d'autres sont restés des limitations. Cependant, il apparaît clairement que le niveau de développement configure line grande partie des risques de catastrophes. La dynamique du risque est gouvernée principalement par le changement global.¦Disasters are often perceived as fast and random events. If the triggers may be sudden, disasters are the result of an accumulation of actions, consequences from inappropriate decisions and from global change. To modify this perception of risk, advocacy tools are needed. Quantitative methods have been developed to identify the distribution and the underlying factors of risk.¦Disaster risk is resulting from the intersection of hazards, exposure and vulnerability. The frequency and intensity of hazards can be influenced by climate change or by the decline of ecosystems. Population growth increases the exposure, while changes in the level of development affect the vulnerability. Given that each of its components may change, the risk is dynamic and should be reviewed periodically by governments, insurance companies or development agencies. At the global level, these analyses are often performed using databases on reported losses. Our results show that these are likely to be biased in particular by improvements in access to information. International losses databases are not exhaustive and do not give information on exposure, the intensity or vulnerability. A new approach, independent of reported losses, is necessary.¦The researches presented here have been mandated by the United Nations and agencies working in the development and the environment (UNDP, UNISDR, GTZ, UNEP and IUCN). These organizations needed a quantitative assessment of the underlying factors of risk, to raise awareness amongst policymakers and to prioritize disaster risk reduction projects.¦The method is based on geographic information systems, remote sensing, databases and statistical analysis. It required a large amount of data (1.7 Tb of data on both the physical environment and socio-economic parameters) and several thousand hours of processing were necessary. A comprehensive risk model was developed to reveal the distribution of hazards, exposure and risk, and to identify underlying risk factors. These were performed for several hazards (e.g. floods, tropical cyclones, earthquakes and landslides). Two different multiple risk indexes were generated to compare countries. The results include an evaluation of the role of the intensity of the hazard, exposure, poverty, governance in the pattern and trends of risk. It appears that the vulnerability factors change depending on the type of hazard, and contrary to the exposure, their weight decreases as the intensity increases.¦Locally, the method was tested to highlight the influence of climate change and the ecosystems decline on the hazard. In northern Pakistan, deforestation exacerbates the susceptibility of landslides. Researches in Peru (based on satellite imagery and ground data collection) revealed a rapid glacier retreat and give an assessment of the remaining ice volume as well as scenarios of possible evolution.¦These results were presented to different audiences, including in front of 160 governments. The results and data generated are made available online through an open source SDI (http://preview.grid.unep.ch). The method is flexible and easily transferable to different scales and issues, with good prospects for adaptation to other research areas. The risk characterization at a global level and identifying the role of ecosystems in disaster risk is booming. These researches have revealed many challenges, some were resolved, while others remained limitations. However, it is clear that the level of development, and more over, unsustainable development, configures a large part of disaster risk and that the dynamics of risk is primarily governed by global change.

Adaptation of canine distemper virus to canine footpad keratinocytes modifies polymerase activity and fusogenicity through amino acid substitutions in the P/V/C and H proteins.

The wild-type canine distemper virus (CDV) strain A75/17 induces a non-cytocidal infection in cultures of canine footpad keratinocytes (CFKs) but produces very little progeny virus. After only three passages in CFKs, the virus produced 100-fold more progeny and induced a limited cytopathic effect. Sequence analysis of the CFK-adapted virus revealed only three amino acid differences, of which one was located in each the P/V/C, M and H proteins. In order to assess which amino acid changes were responsible for the increase of infectious virus production and altered phenotype of infection, we generated a series of recombinant viruses. Their analysis showed that the altered P/V/C proteins were responsible for the higher levels of virus progeny formation and that the amino acid change in the cytoplasmic tail of the H protein was the major determinant of cytopathogenicity.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors.

Local adaptation and life history traits evolution in heterogeneous environment : an empirical example in the freshwater snail, Galba truncatula

Abstract: To understand the processes of evolution, biologists are interested in the ability of a population to respond to natural or artificial selection. The amount of genetic variation is often viewed as the main factor allowing a species to answer to selection. Many theories have thus focused on the maintenance of genetic variability. Ecologists and population geneticists have long-suspected that the structure of the environment is connected to the maintenance of diversity. Theorists have shown that diversity can be permanently and stably maintained in temporal and spatial varying environment in certain conditions. Moreover, varying environments have been also theoretically demonstrated to cause the evolution of divergent life history strategies in the different niches constituting the environment. Although there is a huge number of theoretical studies selection and on life history evolution in heterogeneous environments, there is a clear lack of empirical studies. The purpose of this thesis was to. empirically study the evolutionary consequences of a heterogeneous environment in a freshwater snail Galba truncatula. Indeed, G. truncatula lives in two habitat types according the water availability. First, it can be found in streams or ponds which never completely dry out: a permanent habitat. Second, G. truncatula can be found in pools that freeze during winter and dry during summer: a temporary habitat. Using a common garden approach, we empirically demonstrated local adaptation of G. truncatula to temporary and permanent habitats. We used at first a comparison of molecular (FST) vs. quantitative (QST) genetic differentiation between temporary and permanent habitats. To confirm the pattern QST> FST between habitats suggesting local adaptation, we then tested the desiccation resistance of individuals from temporary and permanent habitats. This study confirmed that drought resistance seemed to be the main factor selected between habitats, and life history traits linked to the desiccation resistance were thus found divergent between habitats. However, despite this evidence of selection acting on mean values of traits between habitats, drift was suggested to be the main factor responsible of variation in variances-covariances between populations. At last, we found life history traits variation of individuals in a heterogeneous environment varying in parasite prevalence. This thesis empirically demonstrated the importance of heterogeneous environments in local adaptation and life history evolution and suggested that more experimental studies are needed to investigate this topic. Résumé: Les biologistes se sont depuis toujours intéressés en l'aptitude d'une population à répondre à la sélection naturelle. Cette réponse dépend de la quantité de variabilité génétique présente dans cette population. Plus particulièrement, les théoriciens se sont penchés sur la question du maintient de la variabilité génétique au sein d'environnements hétérogènes. Ils ont alors démontré que, sous certaines conditions, la diversité génétique peut se maintenir de manière stable et permanente dans des environnements variant au niveau spatial et temporel. De plus, ces environments variables ont été démontrés comme responsable de divergence de traits d'histoire de vie au sein des différentes niches constituant l'environnement. Cependant, malgré ce nombre important d'études théoriques portant sur la sélection et l'évolution des traits d'histoire de vie en environnement hétérogène, les études empiriques sont plus rares. Le but de cette thèse était donc d'étudier les conséquences évolutives d'un environnement hétérogène chez un esgarcot d'eau douce Galba truncatula. En effet, G. truncatula est trouvé dans deux types d'habitats qui diffèrent par leur niveau d'eau. Le premier, l'habitat temporaire, est constitué de flaques d'eau qui peuvent s'assécher pendant l'été et geler pendant l'hiver. Le second, l'habitat permanent, correspond à des marres ou à des ruisseaux qui ont un niveau d'eau constant durant toute l'année. Utilisant une approche expérimentale de type "jardin commun", nous avons démontré l'adaptation locale des individus à leur type d'habitat, permanent ou temporaire. Nous avons utilisé l'approche Fsr/QsT qui compare la différentiation génétique moléculaire avec la différentiation génétique quantitative entre les 2 habitats. Le phénomène d'adapation locale démontré par QsT > FsT, a été testé experimentalement en mesurant la résistance à la dessiccation d'individus d'habitat temporaire et permanent. Cette étude confirma que la résistance à la sécheresse a été sélectionné entre habitats et que les traits responsables de cette resistance sont différents entre habitats. Cependant si la sélection agit sur la valeur moyenne des traits entre habitats, la dérive génétique semble être le responsable majeur de la différence de variances-covariances entre populations. Pour finir, une variation de traits d'histoire de vie a été trouvée au sein d'un environnement hétérogène constitué de populations variants au niveau de leur taux de parasitisme. Pour conclure, cette thèse a donc démontré l'importance d'un environnement hétérogène sur l'adaptation locale et l'évolution des traits d'histoire de vie et suggère que plus d'études empiriques sur le sujet sont nécessaires.

La dépression majeure en hôpital général: adaptation et mise en oeuvre de recommandations pour la pratique clinique [Major depression in the general hospital: adaptation and implementation of guidelines]

Major depression IMD) is highly prevalent in the general hospital and adds a considerable burden to affected patients, but remains under detected and under treated. In an attempt to improve this situation, existing guidelines on MD were retrieved, systematically evaluated with the instrument AGREE (Appraisal of guidelines for research and evaluation), and adapted to the needs of the general hospital. These guidelines were made available on intranet, and actively implemented in two wards, where their impact on clinical practice was evaluated.

Guideline adaptation: an approach to enhance efficiency in guideline development and improve utilisation.

BACKGROUND: Developing and updating high-quality guidelines requires substantial time and resources. To reduce duplication of effort and enhance efficiency, we developed a process for guideline adaptation and assessed initial perceptions of its feasibility and usefulness. METHODS: Based on preliminary developments and empirical studies, a series of meetings with guideline experts were organised to define a process for guideline adaptation (ADAPTE) and to develop a manual and a toolkit made available on a website (http://www.adapte.org). Potential users, guideline developers and implementers, were invited to register and to complete a questionnaire evaluating their perception about the proposed process. RESULTS: The ADAPTE process consists of three phases (set-up, adaptation, finalisation), 9 modules and 24 steps. The adaptation phase involves identifying specific clinical questions, searching for, retrieving and assessing available guidelines, and preparing the draft adapted guideline. Among 330 registered individuals (46 countries), 144 completed the questionnaire. A majority found the ADAPTE process clear (78%), comprehensive (69%) and feasible (60%), and the manual useful (79%). However, 21% found the ADAPTE process complex. 44% feared that they will not find appropriate and high-quality source guidelines. DISCUSSION: A comprehensive framework for guideline adaptation has been developed to meet the challenges of timely guideline development and implementation. The ADAPTE process generated important interest among guideline developers and implementers. The majority perceived the ADAPTE process to be feasible, useful and leading to improved methodological rigour and guideline quality. However, some de novo development might be needed if no high quality guideline exists for a given topic.

Role of mutations in the phosphoprotein on RNA polymerase activity of canine distemper virus following cell culture adaptation

Abstract: The canine distemper virus A75/17 wild-type strain, which is unable to replicate in cell lines, was adapted to growth in Vero cells. Sequence comparison between the A75/17 and the Vero cell-adapted A75/17-V virus revealed 7 amino acid differences between the 2 viruses. Three of these were located in the matrix protein, three in the phosphoprotein also changing the V protein but not the C protein and one in the large protein. The phosphoprotein and the large protein constituted the viral RNA polymerase whose activity was studied by transfection experiments using a reverse genetic system with a plasmid encoding a minireplicon and expression plasmids encoding the nucleocapsid protein and the viral RNA polymerase subunits. Surprinsingly, the enzyme of A75/17 CDV was significantly more active in cell lines compared to the polymerase of A75/17-V CDV. The decrease in overall enzyme activity was found to be due to both decreased replication and transcription activity. This polymerase attenuation was confirmed in CHO cells infection stably expressing the dog SLAM receptor mainly found in dog's lymphoid organs and allowing both virus strains to enter these cells at the same efficiency. A75/17-V CDV replicated more slowly in CHODogSLAM cells than A75/17 CDV and syncytium formation was significantly decreased compared to A75/17 infected CHODogSLAM cells.. Cell culture adaptation lead to an attenuated virus strain both in vitro and in vivo with decreased polymerase activity and syncytium forming capability showing an important role of the polymerase in determining the phenoytpe of the virus. In addition, this reduced phenotype of A75/17-V CDV was shown to be due to the P mutations in the P protein only, showing an important function of the polycistronic P gene in the adaptation process. The role of the matrix protein was found not to have any effect on polymerase activity, however its participation in the adaptation process still needs to be elucidated. The accessory proteins V and C were shown to act on polymerase activity, but their functions in virus pathogenicity and in inhibiting the interferon system have not been studied in this thesis. The V proteins have an activating effect on the polymerase of both the A75/17 and the A75/17-V CDV strains. Although the C protein amino acid sequence was not changed during adaptation of wild-type canine distemper virus in Vero cells, the C protein was demonstrated to have opposite effects on polymerase activity of both virus strains suggesting a different interaction of the C protein with the proteins forming the polymerase complex, which could modulate polymeras activity. These effects were demonstrated by transfection experiments and studying recombinant viruses not expressing the C protein. Thus, the abrogation of the C protein decrease the activity of the wild-type polymerase. In contrast, the polymerase activity of the Vero cell- adapted virus is enhanced in the absence of the C protein and this has also been demonstrated with a recombinant virus, which grew faster in the first 48 hours of infection. Future studies will focus on the generation of recombinant wild-type viruses, which should be very helpful in understanding the molecular mechanisms underlying the adaptation process and the loss of pathogenicity.