Double gene deletion reveals the lack of cooperation between PPARalpha and PPARbeta in skeletal muscle.

The peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of most of the pathways linked to lipid metabolism. PPARalpha and PPARbeta isotypes are known to regulate muscle fatty acid oxidation and a reciprocal compensation of their function has been proposed. Herein, we investigated muscle contractile and metabolic phenotypes in PPARalpha-/-, PPARbeta-/-, and double PPARalpha-/- beta-/- mice. Heart and soleus muscle analyses show that the deletion of PPARalpha induces a decrease of the HAD activity (beta-oxidation) while soleus contractile phenotype remains unchanged. A PPARbeta deletion alone has no effect. However, these mild phenotypes are not due to a reciprocal compensation of PPARbeta and PPARalpha functions since double gene deletion PPARalpha-PPARbeta mostly reproduces the null PPARalpha-mediated reduced beta-oxidation, in addition to a shift from fast to slow fibers. In conclusion, PPARbeta is not required for maintaining skeletal muscle metabolic activity and does not compensate the lack of PPARalpha in PPARalpha null mice.

Complementarities between mathematical and computational modeling: the case of the repeated Prisoners' Dilemma

We study the properties of the well known Replicator Dynamics when applied to a finitely repeated version of the Prisoners' Dilemma game. We characterize the behavior of such dynamics under strongly simplifying assumptions (i.e. only 3 strategies are available) and show that the basin of attraction of defection shrinks as the number of repetitions increases. After discussing the difficulties involved in trying to relax the 'strongly simplifying assumptions' above, we approach the same model by means of simulations based on genetic algorithms. The resulting simulations describe a behavior of the system very close to the one predicted by the replicator dynamics without imposing any of the assumptions of the mathematical model. Our main conclusion is that mathematical and computational models are good complements for research in social sciences. Indeed, while computational models are extremely useful to extend the scope of the analysis to complex scenarios hard to analyze mathematically, formal models can be useful to verify and to explain the outcomes of computational models.

The correlation between inbreeding and fitness: does allele size matter?

The availability of highly polymorphic genetic markers, in particular microsatellites, has made it possible to test the effect of inbreeding on fitness in the field and in the absence of pedigree information. It has been suggested that the squared difference in allele size at a locus (d(2)) might be a better indicator of the level of inbreeding than is heterozygosity. Using an elegant new analytical model, Tsitrone et al. now put this idea to the test, and to rest.

Cross-talk between glutamate and potassium regulation at the astrocyte membrane

Astrocytes play a central role in the brain by regulating glutamate and extracellular potassium concentrations ([K+]0), both released by neurons into the extracellular space during neuronal activity. Glutamate uptake is driven by the inwardly directed sodium gradient across the astrocyte membrane and involves the influx of three sodium ions and one proton and the efflux of one K+ ion per glutamate molecule. The glutamate transport induced rise in intracellular sodium stimulates the Na+/K+-ATPase which leads to significant energetic costs in astrocytes. To evaluate how these two fundamental functions of astrocytes, namely glutamate transport and K+ buffering, which are directly associated with neuronal activity, coexist and if they influence each other, in this thesis work we examined different cellular parameters of astrocytes. We therefore investigated the impact of altered [K+]0 on glutamate transporter activity. To assess this question we measured intracellular sodium fluctuations in mouse primary cultured astrocytes using dynamic fluorescence imaging. We found that glutamate uptake was tightly modulated both in amplitude and kinetics by [K+]0. Elevated [K+]0 strongly decreased glutamate transporter activity, with significant consequences on the cells energy metabolism. To ultimately evaluate potential effects of [K+]0 and glutamate on the astrocyte mitochondrial energy production we extended these studies by investigating their impact on the cytosolic and mitochondrial pH. We found that both [K+],, and glutamate strongly influenced cytosolic and mitochondrial pH, but in opposite directions. The effect of a simultaneous application of K+ and glutamate, however, did not fit with the arithmetical sum of each individual effects, suggesting that an additional non¬linear process is involved. We also investigated the impact of [K+]0 and glutamate transport, respectively, on intracellular potassium concentrations ([K+]0 in cultured astrocytes by characterizing and applying a newly developed Insensitive fluorescent dye. We observed that [K+]i followed [K+]0 changes in a nearly proportional way and that glutamate superfusion caused a reversible, glutamate-concentration dependent drop of [K+],, Our study shows the powerful influence of [K+]u on glutamate capture. These findings have strong implications for our understanding of the tightly regulated interplay between astrocytes and neurons in situations where [K+]0 undergoes large activity-dependent fluctuations. However, depending on the extent of K+ versus glutamate extracellular rise, energy metabolism in astrocytes will be differently regulated. Moreover, the novel insights obtained during this thesis work help understanding some of the underlying processes that prevail in certain pathologies of central nervous system, such as epilepsy and stroke. These results will possibly provide a basis for the development of novel therapeutic strategies. -- Les astrocytes jouent un rôle central dans le cerveau en régulant les concentrations de potassium (K+) et de glutamate, qui sont relâchés par les neurones dans l'espace extracellulaire lorsque ceux- ci sont actifs. La capture par les astrocytes du glutamate est un processus secondairement actif qui implique l'influx d'ions sodium (Na+) et d'un proton, ainsi que l'efflux d'ions K+, ce processus entraîne un coût métabolique important. Nous avons évalué comment ces fonctions fondamentales des astrocytes, la régulation du glutamate et du K+ extracellulaire, qui sont directement associés à l'activité neuronale, coexistent et si elles interagissent, en examinant différents paramètres cellulaires. Dans ce projet de thèse nous avons évalué l'impact des modifications de la concentration de potassium extracellulaire ([K+],,) sur le transport du glutamate. Nous avons mesuré le transport du glutamate par le biais des fluctuations internes de Na+ grâce à un colorant fluorescent en utilisant de l'imagerie à fluorescence dynamique sur des cultures primaires d'astrocytes. Nous avons trouvé que la capture du glutamate était étroitement régulée par [K+]0 aussi bien dans son amplitude que dans sa cinétique. Par la suite, nous avons porté notre attention sur l'impact de [K+]0 et du glutamate sur le pH cytosolique et mitochondrial de l'astrocyte dans le but, in fine, d'évaluer les effets potentiels sur la production d'énergie par la mitochondrie. Nous avons trouvé qu'autant le K+ que le glutamate, de manière individuelle, influençaient fortement le pH, cependant dans des directions opposées. Leurs effets individuels, ne peuvent toutefois pas être additionnés ce qui suggère qu'un processus additionnel non-linéaire est impliqué. En appliquant une nouvelle approche pour suivre et quantifier la concentration intracellulaire de potassium ([K+]0 par imagerie à fluorescence, nous avons observé que [K+]i suivait les changements de [K+]0 de manière quasiment proportionnelle et que la superfusion de glutamate induisait un décroissement rapide et réversible de [K+]i, qui dépend de la concentration de glutamate. Notre étude démontre l'influence de [K+]0 sur la capture du glutamate. Ces résultats permettent d'améliorer notre compréhension de l'interaction entre astrocytes et neurones dans des situations où [K+]0 fluctue en fonction de l'activité neuronale. Cependant, en fonction de l'importance de l'augmentation extracellulaire du K+ versus le glutamate, le métabolisme énergétique des astrocytes va être régulé de manière différente. De plus, les informations nouvelles que nous avons obtenues durant ce travail de thèse nous aident à comprendre quelques- uns des processus sous-jacents qui prévalent dans certaines pathologies du système nerveux central, comme par exemple l'épilepsie ou l'accident vasculaire cérébral. Ces informations pourront être importantes à intégrer dans la cadre du développement de nouvelles stratégies thérapeutiques.

Same wording, distinct concepts? Testing differences between expectancies and motives in a mediation model of alcohol outcomes.

Per definition, alcohol expectancies (after alcohol I expect X), and drinking motives (I drink to achieve X) are conceptually distinct constructs. Theorists have argued that motives mediate the association between expectancies and drinking outcomes. Yet, given the use of different instruments, do these constructs remain distinct when assessment items are matched? The present study tested to what extent motives mediated the link between expectancies and alcohol outcomes when identical items were used, first as expectancies and then as motives. A linear structural equation model was estimated based on a national representative sample of 5,779 alcohol-using students in Switzerland (mean age = 15.2 years). The results showed that expectancies explained up to 38% of the variance in motives. Together with motives, they explained up to 48% of the variance in alcohol outcomes (volume, 5+ drinking, and problems). In 10 of 12 outcomes, there was a significant mediated effect that was often higher than the direct expectancy effect. For coping, the expectancy effect was close to zero, indicating the strongest form of mediation. In only one case (conformity and 5+ drinking), there was a direct expectancy effect but no mediation. To conclude, the study demonstrates that motives are distinct from expectancies even when identical items are used. Motives are more proximally related to different alcohol outcomes, often mediating the effects of expectancies. Consequently, the effectiveness of interventions, particularly those aimed at coping drinkers, should be improved through a shift in focus from expectancies to drinking motives.

An audit of diagnostic reference levels in interventional cardiology and radiology: are there differences between academic and non-academic centres?

A wide variation in patient exposure has been observed in interventional radiology and cardiology. The purpose of this study was to investigate the patient dose from fluoroscopy-guided procedures performed in non-academic centres when compared with academic centres. Four procedures (coronary angiography, percutaneous coronary intervention, angiography of the lower limbs and percutaneous transluminal angioplasty of the lower limbs) were evaluated. Data on the dose-area product, fluoroscopy time and number of images for 1000 procedures were obtained from 23 non-academic centres and compared with data from 5 academic centres. No differences were found for cardiology procedures performed in non-academic centres versus academic ones. However, significantly lower doses were delivered to patients for procedures of the lower limbs when they were performed in non-academic centres. This may be due to more complex procedures performed in the academic centres. Comparison between the centres showed a great variation in the patient dose for these lower limb procedures.

Genetic Data Showing Evolutionary Links between Leishmania and Endotrypanum

Striking similarities at the morphological, molecular and biological levels exist between many trypanosomatids isolated from sylvatic insects and/or vertebrate reservoir hosts that make the identification of medically important parasites demanding. Some molecular data have pointed to the relationship between some Leishmania species and Endotrypanum, which has an important epidemiological significance and can be helpful to understand the evolution of those parasites. In this study, we have demonstrated a close genetic relationship between Endotrypanum and two new leishmanial species, L. (V.) colombiensis and L. (V.) equatorensis. We have used (a) numerical zymotaxonomy and (b) the variability of the internal transcribed spacers of the rRNA genes to examine relationships in this group. The evolutionary trees obtained revealed high genetic similarity between L. (V.) colombiensis, L. (V.) equatorensis and Endotrypanum, forming a tight cluster of parasites. Based on further results of (c) minicircle kDNA heterogeneity analysis and (d) measurement of the sialidase activity these parasites were also grouped together.

Interrelationship between Ectoparasites and Wild Rodents from Tijucas do Sul, State of Paraná, Brazil

Sixteen species of ectoparasites were collected from 50 wild rodents, from August 1990 to August 1991, in an area of Araucaria augustifolia forest, in the municipality of Tijucas do Sul, State of Paraná, Brazil. Ectoparasites infested 98% of the rodents, with the highest indices of infestation found in the dry-cool season. Species that occurred in single or multiple infestations were recorded. Ectoparasite/host associations were significant (p<0.01) for Gigantolaelaps wolffsohni/Oryzomys nigripes, Polygenis pradoi/Oxymycterus sp. and Amblyopinus sp./Oxymycterus sp. The following represent new host records: Polygenis (Polygenis) tripus from Akodon serrensis and Hoplopleura sciuricola from Sciurus aestuans. New geographic records are given for two species of flea and one sucking lice.

Prosodic differences between Germans and German-speaking Swiss in L2

Cette recherche étudie dans quelle mesure l'origine géographique d'un locuteur influence son accent dans une langue étrangère. L'anglais et le français parlés par des Allemands et des Suisses alémaniques sont examinés à travers une expérience de perception et d'analyses phonétiques. L'expérience de perception démontre que les participants sont bien capables d'indiquer si une phrase est lue par un Allemand ou un Suisse alémanique; les participants de langue maternelle allemande y réussissent le mieux. L'analyse prosodique permet d'observer de nettes différences entre les deux groupes de locuteurs. Dans la lecture des phrases françaises, les Suisses alémaniques ont tendance à accentuer la première syllabe des mots, en montant avec leur intonation et en prolongeant la durée des voyelles. Les Allemands, en revanche, accentuent par une intonation fortement montante la dernière syllabe des mots.

Pharmacokinetic interaction between methotrexate and chloral hydrate.

We report the case of a drug interaction between methotrexate (MTX) and chloral hydrate (CH) observed in a child treated for acute leukemia. Significantly slower MTX clearance and increased MTX exposure occurred on the first three courses of a high-dose chemotherapy when co-administered with CH despite normal renal function, adequate hydration, and alkalinization. Mean MTX area under the curve associated with CH administration was 1,134 µmol hours/L, compared to 608 µmol hours/L after discontinuation of CH. This interaction possibly resulted from a competition between anionic CH metabolites and MTX for renal tubular excretion.