Assessing multiple sclerosis activity: is the in vitro production of tumor necrosis factor-alpha, interleukins 2, 6, 4, and 10, and immunoglobulin G of value?

Tumor necrosis factor (TNF) alpha, interleukins (IL) 2, 4, 6, and 10, and IgG oligoclonal bands (IgG OB) in vitro production was assessed, after whole-blood stimulation with lipopolysaccharide or concanavalin A, in 61 patients presenting with relapsing-remitting, relapsing-progressive, or chronic progressive multiple sclerosis. Multiple sclerosis patients were receiving no treatment or azathioprine (AZA), cyclosporin, cyclophosphamide, subcutaneous interferon (IFN) beta 1 a, or corticosteroids (CST). Statistical correlations significantly showed that: (a) AZA lowers TNF-alpha (P = 0.002) and increases IL-4 production (P = 0.0024), and IFN-beta 1 a increases TNF-alpha and decreases IL-4 levels; (b) CST has a negative effect on TNF-alpha, IL-6, and IL-4 synthesis; and (c) AZA, IFN-beta 1 a, and CST diminish IgG OB synthesis (P = 0.001). Although our study of the dynamics of TNF-alpha, IL-2, IL-4, IL-6, and IL-10 in vitro production generally found no statistically significant correlations (partly explained by the limited number of values in the various groups), IL-6 was shown to drop during the periods surrounding relapse (P = 0.05) in the absence of treatment, while TNF-alpha (P = 0.04) and IL-6 (P < 0.05) dropped before exacerbation in the presence of AZA. In vitro production of TNF-alpha was closely and positively correlated with that of IL-6, independently of clinical features. The enhanced production of IL-10 detected before or at relapse with AZA and IFN-beta 1 a (trends) may interfere with initiation of the immune reaction and with the development of new CNS lesions. Some discrepancies with previously published results stress the difficulties in studying the state of stimulation of different populations of leukocytes by using a variety of in vitro stimuli and in establishing a correlation between mRNA studies and the amount of final or active protein produced.

Role of genetic and social factors in modulating the efficiency of division of labour in social insects

Summary : Division of labour is one of the most fascinating aspects of social insects. The efficient allocation of individuals to a multitude of different tasks requires a dynamic adjustment in response to the demands of a changing environment. A considerable number of theoretical models have focussed on identifying the mechanisms allowing colonies to perform efficient task allocation. The large majority of these models are built on the observation that individuals in a colony vary in their propensity (response threshold) to perform different tasks. Since individuals with a low threshold for a given task stimulus are more likely to perform that task than individuals with a high threshold, infra-colony variation in individual thresholds results in colony division of labour. These theoretical models suggest that variation in individual thresholds is affected by the within-colony genetic diversity. However, the models have not considered the genetic architecture underlying the individual response thresholds. This is important because a better understanding of division of labour requires determining how genotypic variation relates to differences in infra-colony response threshold distributions. In this thesis, we investigated the combined influence on task allocation efficiency of both, the within-colony genetic variability (stemming from variation in the number of matings by queens) and the number of genes underlying the response thresholds. We used an agent-based simulator to model a situation where workers in a colony had to perform either a regulatory task (where the amount of a given food item in the colony had to be maintained within predefined bounds) or a foraging task (where the quantity of a second type of food item collected had to be the highest possible). The performance of colonies was a function of workers being able to perform both tasks efficiently. To study the effect of within-colony genetic diversity, we compared the performance of colonies with queens mated with varying number of males. On the other hand, the influence of genetic architecture was investigated by varying the number of loci underlying the response threshold of the foraging and regulatory tasks. Artificial evolution was used to evolve the allelic values underlying the tasks thresholds. The results revealed that multiple matings always translated into higher colony performance, whatever the number of loci encoding the thresholds of the regulatory and foraging tasks. However, the beneficial effect of additional matings was particularly important when the genetic architecture of queens comprised one or few genes for the foraging task's threshold. By contrast, higher number of genes encoding the foraging task reduced colony performance with the detrimental effect being stronger when queens had mated with several males. Finally, the number of genes determining the threshold for the regulatory task only had a minor but incremental effect on colony performance. Overall, our numerical experiments indicate the importance of considering the effects of queen mating frequency, genetic architecture underlying task thresholds and the type of task performed when investigating the factors regulating the efficiency of division of labour in social insects. In this thesis we also investigate the task allocation efficiency of response threshold models and compare them with neural networks. While response threshold models are widely used amongst theoretical biologists interested in division of labour in social insects, our simulation reveals that they perform poorly compared to a neural network model. A major shortcoming of response thresholds is that they fail at one of the most crucial requirement of division of labour, the ability of individuals in a colony to efficiently switch between tasks under varying environmental conditions. Moreover, the intrinsic properties of the threshold models are that they lead to a large proportion of idle workers. Our results highlight these limitations of the response threshold models and provide an adequate substitute. Altogether, the experiments presented in this thesis provide novel contributions to the understanding of how division of labour in social insects is influenced by queen mating frequency and genetic architecture underlying worker task thresholds. Moreover, the thesis also provides a novel model of the mechanisms underlying worker task allocation that maybe more generally applicable than the widely used response threshold models. Resumé : La répartition du travail est l'un des aspects les plus fascinants des insectes vivant en société. Une allocation efficace de la multitude de différentes tâches entre individus demande un ajustement dynamique afin de répondre aux exigences d'un environnement en constant changement. Un nombre considérable de modèles théoriques se sont attachés à identifier les mécanismes permettant aux colonies d'effectuer une allocation efficace des tâches. La grande majorité des ces modèles sont basés sur le constat que les individus d'une même colonie diffèrent dans leur propension (inclination à répondre) à effectuer différentes tâches. Etant donné que les individus possédant un faible seuil de réponse à un stimulus associé à une tâche donnée sont plus disposés à effectuer cette dernière que les individus possédant un seuil élevé, les différences de seuils parmi les individus vivant au sein d'une même colonie mènent à une certaine répartition du travail. Ces modèles théoriques suggèrent que la variation des seuils des individus est affectée par la diversité génétique propre à la colonie. Cependant, ces modèles ne considèrent pas la structure génétique qui est à la base des seuils de réponse individuels. Ceci est très important car une meilleure compréhension de la répartition du travail requière de déterminer de quelle manière les variations génotypiques sont associées aux différentes distributions de seuils de réponse à l'intérieur d'une même colonie. Dans le cadre de cette thèse, nous étudions l'influence combinée de la variabilité génétique d'une colonie (qui prend son origine dans la variation du nombre d'accouplements des reines) avec le nombre de gènes supportant les seuils de réponse, vis-à-vis de la performance de l'allocation des tâches. Nous avons utilisé un simulateur basé sur des agents pour modéliser une situation où les travailleurs d'une colonie devaient accomplir une tâche de régulation (1a quantité d'une nourriture donnée doit être maintenue à l'intérieur d'un certain intervalle) ou une tâche de recherche de nourriture (la quantité d'une certaine nourriture doit être accumulée autant que possible). Dans ce contexte, 'efficacité des colonies tient en partie des travailleurs qui sont capable d'effectuer les deux tâches de manière efficace. Pour étudier l'effet de la diversité génétique d'une colonie, nous comparons l'efficacité des colonies possédant des reines qui s'accouplent avec un nombre variant de mâles. D'autre part, l'influence de la structure génétique a été étudiée en variant le nombre de loci à la base du seuil de réponse des deux tâches de régulation et de recherche de nourriture. Une évolution artificielle a été réalisée pour évoluer les valeurs alléliques qui sont à l'origine de ces seuils de réponse. Les résultats ont révélé que de nombreux accouplements se traduisaient toujours en une plus grande performance de la colonie, quelque soit le nombre de loci encodant les seuils des tâches de régulation et de recherche de nourriture. Cependant, les effets bénéfiques d'accouplements additionnels ont été particulièrement important lorsque la structure génétique des reines comprenait un ou quelques gènes pour le seuil de réponse pour la tâche de recherche de nourriture. D'autre part, un nombre plus élevé de gènes encodant la tâche de recherche de nourriture a diminué la performance de la colonie avec un effet nuisible d'autant plus fort lorsque les reines s'accouplent avec plusieurs mâles. Finalement, le nombre de gènes déterminant le seuil pour la tâche de régulation eu seulement un effet mineur mais incrémental sur la performance de la colonie. Pour conclure, nos expériences numériques révèlent l'importance de considérer les effets associés à la fréquence d'accouplement des reines, à la structure génétique qui est à l'origine des seuils de réponse pour les tâches ainsi qu'au type de tâche effectué au moment d'étudier les facteurs qui régulent l'efficacité de la répartition du travail chez les insectes vivant en communauté. Dans cette thèse, nous étudions l'efficacité de l'allocation des tâches des modèles prenant en compte des seuils de réponses, et les comparons à des réseaux de neurones. Alors que les modèles basés sur des seuils de réponse sont couramment utilisés parmi les biologistes intéressés par la répartition des tâches chez les insectes vivant en société, notre simulation montre qu'ils se révèlent peu efficace comparé à un modèle faisant usage de réseaux de neurones. Un point faible majeur des seuils de réponse est qu'ils échouent sur un point crucial nécessaire à la répartition des tâches, la capacité des individus d'une colonie à commuter efficacement entre des tâches soumises à des conditions environnementales changeantes. De plus, les propriétés intrinsèques des modèles basés sur l'utilisation de seuils conduisent à de larges populations de travailleurs inactifs. Nos résultats mettent en évidence les limites de ces modèles basés sur l'utilisation de seuils et fournissent un substitut adéquat. Ensemble, les expériences présentées dans cette thèse fournissent de nouvelles contributions pour comprendre comment la répartition du travail chez les insectes vivant en société est influencée par la fréquence d'accouplements des reines ainsi que par la structure génétique qui est à l'origine, pour un travailleur, du seuil de réponse pour une tâche. De plus, cette thèse fournit également un nouveau modèle décrivant les mécanismes qui sont à l'origine de l'allocation des tâches entre travailleurs, mécanismes qui peuvent être appliqué de manière plus générale que ceux couramment utilisés et basés sur des seuils de réponse.

Task-dependent influence of genetic architecture and mating frequency on division of labour in social insect societies.

Division of labour is one of the most prominent features of social insects. The efficient allocation of individuals to different tasks requires dynamic adjustment in response to environmental perturbations. Theoretical models suggest that the colony-level flexibility in responding to external changes and internal perturbation may depend on the within-colony genetic diversity, which is affected by the number of breeding individuals. However, these models have not considered the genetic architecture underlying the propensity of workers to perform the various tasks. Here, we investigated how both within-colony genetic variability (stemming from variation in the number of matings by queens) and the number of genes influencing the stimulus (threshold) for a given task at which workers begin to perform that task jointly influence task allocation efficiency. We used a numerical agent-based model to investigate the situation where workers had to perform either a regulatory task or a foraging task. One hundred generations of artificial selection in populations consisting of 500 colonies revealed that an increased number of matings always improved colony performance, whatever the number of loci encoding the thresholds of the regulatory and foraging tasks. However, the beneficial effect of additional matings was particularly important when the genetic architecture of queens comprised one or a few genes for the foraging task's threshold. By contrast, a higher number of genes encoding the foraging task reduced colony performance with the detrimental effect being stronger when queens had mated with several males. Finally, the number of genes encoding the threshold for the regulatory task only had a minor effect on colony performance. Overall, our numerical experiments support the importance of mating frequency on efficiency of division of labour and also reveal complex interactions between the number of matings and genetic architecture.

Missing value imputation in longitudinal measures of alcohol consumption

Attrition in longitudinal studies can lead to biased results. The study is motivated by the unexpected observation that alcohol consumption decreased despite increased availability, which may be due to sample attrition of heavy drinkers. Several imputation methods have been proposed, but rarely compared in longitudinal studies of alcohol consumption. The imputation of consumption level measurements is computationally particularly challenging due to alcohol consumption being a semi-continuous variable (dichotomous drinking status and continuous volume among drinkers), and the non-normality of data in the continuous part. Data come from a longitudinal study in Denmark with four waves (2003-2006) and 1771 individuals at baseline. Five techniques for missing data are compared: Last value carried forward (LVCF) was used as a single, and Hotdeck, Heckman modelling, multivariate imputation by chained equations (MICE), and a Bayesian approach as multiple imputation methods. Predictive mean matching was used to account for non-normality, where instead of imputing regression estimates, "real" observed values from similar cases are imputed. Methods were also compared by means of a simulated dataset. The simulation showed that the Bayesian approach yielded the most unbiased estimates for imputation. The finding of no increase in consumption levels despite a higher availability remained unaltered. Copyright (C) 2011 John Wiley & Sons, Ltd.

Assessing the Relationship between the Baseline Value of a Continuous Variable and Subsequent Change over Time

Analyzing the relationship between the baseline value and subsequent change of a continuous variable is a frequent matter of inquiry in cohort studies. These analyses are surprisingly complex, particularly if only two waves of data are available. It is unclear for non-biostatisticians where the complexity of this analysis lies and which statistical method is adequate.With the help of simulated longitudinal data of body mass index in children,we review statistical methods for the analysis of the association between the baseline value and subsequent change, assuming linear growth with time. Key issues in such analyses are mathematical coupling, measurement error, variability of change between individuals, and regression to the mean. Ideally, it is better to rely on multiple repeated measurements at different times and a linear random effects model is a standard approach if more than two waves of data are available. If only two waves of data are available, our simulations show that Blomqvist's method - which consists in adjusting for measurement error variance the estimated regression coefficient of observed change on baseline value - provides accurate estimates. The adequacy of the methods to assess the relationship between the baseline value and subsequent change depends on the number of data waves, the availability of information on measurement error, and the variability of change between individuals.

Will climate change drive alien invasive plants into areas of high protection value? An improved model-based regional assessment to prioritise the management of invasions.

Species distribution models (SDMs) studies suggest that, without control measures, the distribution of many alien invasive plant species (AIS) will increase under climate and land-use changes. Due to limited resources and large areas colonised by invaders, management and monitoring resources must be prioritised. Choices depend on the conservation value of the invaded areas and can be guided by SDM predictions. Here, we use a hierarchical SDM framework, complemented by connectivity analysis of AIS distributions, to evaluate current and future conflicts between AIS and high conservation value areas. We illustrate the framework with three Australian wattle (Acacia) species and patterns of conservation value in Northern Portugal. Results show that protected areas will likely suffer higher pressure from all three Acacia species under future climatic conditions. Due to this higher predicted conflict in protected areas, management might be prioritised for Acacia dealbata and Acacia melanoxylon. Connectivity of AIS suitable areas inside protected areas is currently lower than across the full study area, but this would change under future environmental conditions. Coupled SDM and connectivity analysis can support resource prioritisation for anticipation and monitoring of AIS impacts. However, further tests of this framework over a wide range of regions and organisms are still required before wide application.

Extent of hypoattenuation on CT angiography source images in basilar artery occlusion: prognostic value in the Basilar Artery International Cooperation Study.

BACKGROUND AND PURPOSE: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) quantifies the extent of early ischemic changes in the posterior circulation with a 10-point grading system. We hypothesized that pc-ASPECTS applied to CT angiography source images predicts functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS). METHODS: BASICS was a prospective, observational registry of consecutive patients with acute symptomatic basilar artery occlusion. Functional outcome was assessed at 1 month. We applied pc-ASPECTS to CT angiography source images of patients with CT angiography for confirmation of basilar artery occlusion. We calculated unadjusted and adjusted risk ratios (RRs) of pc-ASPECTS dichotomized at ≥8 versus <8. Primary outcome measure was favorable outcome (modified Rankin Scale scores 0-3). Secondary outcome measures were mortality and functional independence (modified Rankin Scale scores 0-2). RESULTS: Of 158 patients included, 78 patients had a CT angiography source images pc-ASPECTS≥8. Patients with a pc-ASPECTS≥8 more often had a favorable outcome than patients with a pc-ASPECTS<8 (crude RR, 1.7; 95% CI, 0.98-3.0). After adjustment for age, baseline National Institutes of Health Stroke Scale score, and thrombolysis, pc-ASPECTS≥8 was not related to favorable outcome (RR, 1.3; 95% CI, 0.8-2.2), but it was related to reduced mortality (RR, 0.7; 95% CI, 0.5-0.98) and functional independence (RR, 2.0; 95% CI, 1.1-3.8). In post hoc analysis, pc-ASPECTS dichotomized at ≥6 versus <6 predicted a favorable outcome (adjusted RR, 3.1; 95% CI, 1.2-7.5). CONCLUSIONS: pc-ASPECTS on CT angiography source images independently predicted death and functional independence at 1 month in the CT angiography subgroup of patients in the BASICS registry.

Division of labour influences the rate of ageing in weaver ant workers.

The evolutionary theory of ageing predicts that the timing of senescence has been primarily shaped by the extrinsic mortality rate, which causes selection intensity to decline over time. One difficulty in testing the evolutionary theory of ageing is that extrinsic mortality risk is often confounded with body size and fecundity, which may also directly affect lifespan. Social insects with a pronounced division of labour between worker castes provide a unique opportunity to study the direct effect of extrinsic mortality on the evolution of ageing rates independently of body size, reproductive effort and genetic configuration. In the weaver ant, Oecophylla smaragdina, the major (large) workers perform the risky tasks outside the nest, while the minor (small) workers stay within the highly protected arboreal nest. Hence, this pronounced division of labour is associated with high differences in extrinsic mortality risks. The evolutionary theory of ageing predicts that the minor workers should have a longer intrinsic lifespan than the major workers. In line with this prediction, we found that in a protected environment the minor workers lived significantly longer than the major workers did. Hence, the ageing rate appears to have been moulded by variation in the extrinsic mortality rate independently of size, reproductive effort and genetic configuration.

Fracture vertébrate évaluée par ostéodensitométrie. Un nouveau facteur de risque pour la fracture [Vertebral fracture assessed by DXA: a new risk factor for fracture]

At the age of 50, a woman has a lifetime risk of more than 40% to present a vertebral fracture. More than 60% of vertebral fractures remain undiagnosed. As a consequence it is of major importance to develop screening strategies to detect these fractures. Vertebral fracture assessment (VFA) by DXA allows one to detect vertebral fracture from T4 to L4 using DXA devices, while performing also during the same visit the bone mineral density measurement. Such an approach should improve the evaluation of fracture risk and therapeutic indication. Compared to the standard X-ray assessment, VFA highly enables to detect moderate or severe vertebral fractures below T6.

Valeur ajoutée de la supervision du médecin-assistant par un médecin de famille dans une permanence [Added value of family practitioners' supervision of junior doctors in a walk-in clinic].

The pending workforce crisis in family medicine has triggered various initiatives. This article describes the PMU-FLON walk-in clinic, a project of the Institute of General Medicine University of Lausanne. The working conditions in this clinic are close to that of a family practice. Doctors in training are supervised by family doctors who work part-time in the clinic. The objective is to improve training in the various fields of family medicine, from technical skills (improving optimal use of diagnostic tools), to integrating patients' requests in a more global patient-centered approach. This new educational model allows doctors in training to benefit from the specific approaches of different trainers. It will contribute to promoting quality family medicine in the future.