Maladaptive exploratory behavior and neuropathology of the PS-1 P117L Alzheimer transgenic mice.

Patients with the early-onset Alzheimer's disease P117L mutation in the presenilin-1 gene (PS-1) present pathological hallmarks in the hippocampus, the frontal cortex and the basal ganglia. In the present work we determined by immunohistochemistry which brain regions were injured in the transgenic PS-1 P117L mice, in comparison to their littermates, the B6D2 mice. Furthermore, as these regions are involved in novelty detection, we investigated the behavior of these mice in tests for object and place novelty recognition. Limited numbers of senile plaques and neurofibrillary tangles were detected in aged PS-1 P117L mice in the CA1 only, indicating that the disease is restrained to an initial neuropathological stage. Western blots showed a change in PSD-95 expression (p=0.03), not in NR2A subunit, NR2B subunit and synaptophysin expressions in the frontal cortex, suggesting specific synaptic alterations. The behavioral tests repeatedly revealed, despite a non-significant preference for object or place novelty, maladaptive exploratory behavior of the PS-1 P117L mice in novel environmental conditions, not due to locomotor problems. These mice, unlike the B6D2 mice, were less inhibited to visit the center of the cages (p=0.01) and they continued to move excessively in the presence of a displaced object (p=0.021). Overall, the PS-1 P117L mice appear to be in an initial Alzheimer's disease-like neuropathological stage, and they showed a lack of reaction toward novel environmental conditions.

L'éthylglucuronide: un marquer de la consommation d'alcool [Ethyl glucuronide: a biomarker of alcohol consumption]

Excessive alcohol consumption represents a major risk factor for morbidity and mortality. It is therefore indispensable to be able to detect at-risk drinking. Ethyl glucuronide (EtG) is a specific marker of alcohol consumption. The determination of ethyl glucuronide in urine or blood can be used to prove recent driving under the influence of alcohol, even if ethanol is no longer detectable. The commercialization of an EtG specific immunological assay now allows to obtain preliminary results rapidly and easily with satisfying sensitivity. Moreover, the detection of ethyl glucuronide in hair offers the opportunity to evaluate an alcohol consumption over a long period. The EtG concentration in hair is in correlation with the amount of ingested alcohol. Thus, the analysis of ethyl glucuronide can be used to monitor abstinence, to detect alcohol relapse and to identify at-risk drinkers. However, a cut off allowing to detect chronic alcohol abuser reliably still does not exist. Therefore, it is recommended to perform the analysis of ethyl glucuronide in complement to the existing blood markers. A study financed by the Swiss Foundation for Alcohol Research is actually conducted by the West Switzerland University Center of Legal Medicine in order to establish an objective cut-off.

Evolution of a polymineralic mantle shear zone and the role of second phases in the localization of deformation

The influence of second phases (e.g., pyroxenes) on olivine grain size was studied by quantitative microfabric analyses of samples of the Hilti massif mantle shear zone (Semail ophiolite, Oman). The microstructures range from porphyroclastic tectonites to ultramylonites, from outside to the center of the shear zone. Starting at conditions of ridge-related flow, they formed under continuous cooling leading to progressive strain localization. The dependence of the average olivine grain size on the second-phase content can be split into a second-phase controlled and a dynamic recrystallization-controlled field. In the former, the olivine grain size is related to the ratio between the second-phase grain size and volume fraction (Zener parameter). In the latter, dynamic recrystallization manifested by a balance between grain growth and grain size reduction processes yields a stable olivine grain size. In both fields the average olivine and second-phase grain size decreases with decreasing temperature. Combining the microstructural information with deformation mechanism maps suggests that the porphyroclastic tectonites (similar to 1100 degrees C) and mylonites (similar to 800 degrees C) formed under the predominance of dislocation creep. Since olivine-rich layers are intercalated with layer parallel, polymineralic bands in the mylonites, nearly equiviscous conditions can be assumed. In the ultramylonites, diffusion creep represents the major deformation mechanism in the polymineralic layers. It is this switch in deformation mechanism from dislocation creep to diffusion creep that forces strain to localize in the fine-grained polymineralic domains at low temperatures (<similar to 700 degrees C), underlining the role of the second phases on strain localization in cooling mantle rocks.

Alps, genes, and chromosomes: their role in the formation of species in the Sorex araneus group (Mammalia, Insectivora), as inferred from two hybrid zones.

During the Pleistocene glaciations, the Alps were an efficient barrier to gene flow between isolated populations, often leading to allopatric speciation. Afterwards, the Alps strongly influenced the post-glacial recolonization of Europe and represent a major suture zone between differentiated populations. Two hybrid zones in the Swiss and French Alps between genetically and chromosomally well-differentiated species-the Valais shrew, Sorex antinorii, and the common shrew, S. araneus-were studied karyotypically and by analyzing the distribution of seven microsatellite loci. In the center of the Haslital hybrid zone the two species coexist over a distance of 900 m. Hybrid karyotypes, among them the most complex known in Sorex, are rare. F-statistics based on microsatellite data revealed a strong heterozygote deficit only in the center of the zone, due to the sympatric distribution of the two species with little hybridization between them. Structuring within the species (both F(IS) and F(ST)) was low. An hierarchical analysis showed a high level of interspecific differentiation. Results were compared with those previously reported in another hybrid zone located at Les Houches in the French Alps. Genetic structuring within and between species was comparable in both hybrid zones, although chromosomal incompatibilities are more important in Haslital, where a linkage block of the race-specific chromosomes should additionally impede gene flow. Evidence for a more restricted gene flow in Haslital comes from the genetically intermediate hybrid karyotypes, whereas in Les Houches, hybrid karyotypes are genetically identical to individuals of the pure karyotypic races. Genic and chromosomal introgression was observed in Les Houches, but not in Haslital. The possible influence of a river, separating the two species at Les Houches, on gene flow is discussed.

EADock : design of a new molecular docking algorithm and some of its applications

3 Summary 3. 1 English The pharmaceutical industry has been facing several challenges during the last years, and the optimization of their drug discovery pipeline is believed to be the only viable solution. High-throughput techniques do participate actively to this optimization, especially when complemented by computational approaches aiming at rationalizing the enormous amount of information that they can produce. In siiico techniques, such as virtual screening or rational drug design, are now routinely used to guide drug discovery. Both heavily rely on the prediction of the molecular interaction (docking) occurring between drug-like molecules and a therapeutically relevant target. Several softwares are available to this end, but despite the very promising picture drawn in most benchmarks, they still hold several hidden weaknesses. As pointed out in several recent reviews, the docking problem is far from being solved, and there is now a need for methods able to identify binding modes with a high accuracy, which is essential to reliably compute the binding free energy of the ligand. This quantity is directly linked to its affinity and can be related to its biological activity. Accurate docking algorithms are thus critical for both the discovery and the rational optimization of new drugs. In this thesis, a new docking software aiming at this goal is presented, EADock. It uses a hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with .the CHARMM package for energy calculations and coordinate handling. A validation was carried out on 37 crystallized protein-ligand complexes featuring 11 different proteins. The search space was defined as a sphere of 15 R around the center of mass of the ligand position in the crystal structure, and conversely to other benchmarks, our algorithms was fed with optimized ligand positions up to 10 A root mean square deviation 2MSD) from the crystal structure. This validation illustrates the efficiency of our sampling heuristic, as correct binding modes, defined by a RMSD to the crystal structure lower than 2 A, were identified and ranked first for 68% of the complexes. The success rate increases to 78% when considering the five best-ranked clusters, and 92% when all clusters present in the last generation are taken into account. Most failures in this benchmark could be explained by the presence of crystal contacts in the experimental structure. EADock has been used to understand molecular interactions involved in the regulation of the Na,K ATPase, and in the activation of the nuclear hormone peroxisome proliferatoractivated receptors a (PPARa). It also helped to understand the action of common pollutants (phthalates) on PPARy, and the impact of biotransformations of the anticancer drug Imatinib (Gleevec®) on its binding mode to the Bcr-Abl tyrosine kinase. Finally, a fragment-based rational drug design approach using EADock was developed, and led to the successful design of new peptidic ligands for the a5ß1 integrin, and for the human PPARa. In both cases, the designed peptides presented activities comparable to that of well-established ligands such as the anticancer drug Cilengitide and Wy14,643, respectively. 3.2 French Les récentes difficultés de l'industrie pharmaceutique ne semblent pouvoir se résoudre que par l'optimisation de leur processus de développement de médicaments. Cette dernière implique de plus en plus. de techniques dites "haut-débit", particulièrement efficaces lorsqu'elles sont couplées aux outils informatiques permettant de gérer la masse de données produite. Désormais, les approches in silico telles que le criblage virtuel ou la conception rationnelle de nouvelles molécules sont utilisées couramment. Toutes deux reposent sur la capacité à prédire les détails de l'interaction moléculaire entre une molécule ressemblant à un principe actif (PA) et une protéine cible ayant un intérêt thérapeutique. Les comparatifs de logiciels s'attaquant à cette prédiction sont flatteurs, mais plusieurs problèmes subsistent. La littérature récente tend à remettre en cause leur fiabilité, affirmant l'émergence .d'un besoin pour des approches plus précises du mode d'interaction. Cette précision est essentielle au calcul de l'énergie libre de liaison, qui est directement liée à l'affinité du PA potentiel pour la protéine cible, et indirectement liée à son activité biologique. Une prédiction précise est d'une importance toute particulière pour la découverte et l'optimisation de nouvelles molécules actives. Cette thèse présente un nouveau logiciel, EADock, mettant en avant une telle précision. Cet algorithme évolutionnaire hybride utilise deux pressions de sélections, combinées à une gestion de la diversité sophistiquée. EADock repose sur CHARMM pour les calculs d'énergie et la gestion des coordonnées atomiques. Sa validation a été effectuée sur 37 complexes protéine-ligand cristallisés, incluant 11 protéines différentes. L'espace de recherche a été étendu à une sphère de 151 de rayon autour du centre de masse du ligand cristallisé, et contrairement aux comparatifs habituels, l'algorithme est parti de solutions optimisées présentant un RMSD jusqu'à 10 R par rapport à la structure cristalline. Cette validation a permis de mettre en évidence l'efficacité de notre heuristique de recherche car des modes d'interactions présentant un RMSD inférieur à 2 R par rapport à la structure cristalline ont été classés premier pour 68% des complexes. Lorsque les cinq meilleures solutions sont prises en compte, le taux de succès grimpe à 78%, et 92% lorsque la totalité de la dernière génération est prise en compte. La plupart des erreurs de prédiction sont imputables à la présence de contacts cristallins. Depuis, EADock a été utilisé pour comprendre les mécanismes moléculaires impliqués dans la régulation de la Na,K ATPase et dans l'activation du peroxisome proliferatoractivated receptor a (PPARa). Il a également permis de décrire l'interaction de polluants couramment rencontrés sur PPARy, ainsi que l'influence de la métabolisation de l'Imatinib (PA anticancéreux) sur la fixation à la kinase Bcr-Abl. Une approche basée sur la prédiction des interactions de fragments moléculaires avec protéine cible est également proposée. Elle a permis la découverte de nouveaux ligands peptidiques de PPARa et de l'intégrine a5ß1. Dans les deux cas, l'activité de ces nouveaux peptides est comparable à celles de ligands bien établis, comme le Wy14,643 pour le premier, et le Cilengitide (PA anticancéreux) pour la seconde.

Effects of computing parameters and measurement locations on the estimation of 3D NPS in non-stationary MDCT images.

The goal of this study was to investigate the impact of computing parameters and the location of volumes of interest (VOI) on the calculation of 3D noise power spectrum (NPS) in order to determine an optimal set of computing parameters and propose a robust method for evaluating the noise properties of imaging systems. Noise stationarity in noise volumes acquired with a water phantom on a 128-MDCT and a 320-MDCT scanner were analyzed in the spatial domain in order to define locally stationary VOIs. The influence of the computing parameters in the 3D NPS measurement: the sampling distances bx,y,z and the VOI lengths Lx,y,z, the number of VOIs NVOI and the structured noise were investigated to minimize measurement errors. The effect of the VOI locations on the NPS was also investigated. Results showed that the noise (standard deviation) varies more in the r-direction (phantom radius) than z-direction plane. A 25 × 25 × 40 mm(3) VOI associated with DFOV = 200 mm (Lx,y,z = 64, bx,y = 0.391 mm with 512 × 512 matrix) and a first-order detrending method to reduce structured noise led to an accurate NPS estimation. NPS estimated from off centered small VOIs had a directional dependency contrary to NPS obtained from large VOIs located in the center of the volume or from small VOIs located on a concentric circle. This showed that the VOI size and location play a major role in the determination of NPS when images are not stationary. This study emphasizes the need for consistent measurement methods to assess and compare image quality in CT.

Low utilization of health care services following screening for hypertension in Dar es Salaam (Tanzania): a prospective population-based study.

BACKGROUND: Drug therapy in high-risk individuals has been advocated as an important strategy to reduce cardiovascular disease in low income countries. We determined, in a low-income urban population, the proportion of persons who utilized health services after having been diagnosed as hypertensive and advised to seek health care for further hypertension management. METHODS: A population-based survey of 9254 persons aged 25-64 years was conducted in Dar es Salaam. Among the 540 persons with high blood pressure (defined here as BP >or= 160/95 mmHg) at the initial contact, 253 (47%) had high BP on a 4th visit 45 days later. Among them, 208 were untreated and advised to attend health care in a health center of their choice for further management of their hypertension. One year later, 161 were seen again and asked about their use of health services during the interval. RESULTS: Among the 161 hypertensive persons advised to seek health care, 34% reported to have attended a formal health care provider during the 12-month interval (63% public facility; 30% private; 7% both). Antihypertensive treatment was taken by 34% at some point of time (suggesting poor uptake of health services) and 3% at the end of the 12-month follow-up (suggesting poor long-term compliance). Health services utilization tended to be associated with older age, previous history of high BP, being overweight and non-smoking, but not with education or wealth. Lack of symptoms and cost of treatment were the reasons reported most often for not attending health care. CONCLUSION: Low utilization of health services after hypertension screening suggests a small impact of a patient-centered screen-and-treat strategy in this low-income population. These findings emphasize the need to identify and address barriers to health care utilization for non-communicable diseases in this setting and, indirectly, the importance of public health measures for primary prevention of these diseases.

Colloid cysts of the third ventricle: correlation of MR and CT findings with histology and chemical analysis.

Eight patients with colloid cysts of the third ventricle were examined with CT and MR. In six, surgical resection was performed and the material was subjected to histologic evaluation; the concentrations of trace elements were determined by particle-induced X-ray emission. Stereotaxic aspiration was performed in two. The investigation showed that colloid cysts are often iso- or hypodense relative to brain on CT (5/8), but sometimes have a center of increased density. Increased density did not correlate with increased concentration of calcium or other metals but did not correlate with high cholesterol content. Colloid cysts appear more heterogeneous on MR (6/8) than on CT (3/8), despite a homogeneous appearance at histology. High signal on short TR/TE sequences is correlated with a high cholesterol content. A marked shortening of the T2 relaxation time is often noticed in the central part of the cyst. Analysis of trace elements showed that this phenomenon is not related to the presence of metals with paramagnetic effects. Our analysis of the contents of colloid cysts does not support the theory that differing metallic concentrations are responsible for differences in MR signal intensity or CT density. We did find that increased CT density and high MR signal correlated with high cholesterol content.

Coordination pattern adaptability: energy cost of degenerate behaviors.

This study investigated behavioral adaptability, which could be defined as a blend between stability and flexibility of the limbs movement and their inter-limb coordination, when individuals received informational constraints. Seven expert breaststroke swimmers performed three 200-m in breaststroke at constant submaximal intensity. Each trial was performed randomly in a different coordination pattern: 'freely-chosen', 'maximal glide' and 'minimal glide'. Two underwater and four aerial cameras enabled 3D movement analysis in order to assess elbow and knee angles, elbow-knee pair coordination, intra-cyclic velocity variations of the center of mass, stroke rate and stroke length and inter-limb coordination. The energy cost of locomotion was calculated from gas exchanges and blood lactate concentration. The results showed significantly higher glide, intra-cyclic velocity variations and energy cost under 'maximal glide' compared to 'freely-chosen' instructional conditions, as well as higher reorganization of limb movement and inter-limb coordination (p<0.05). In the 'minimal glide' condition, the swimmers did not show significantly shorter glide and lower energy cost, but they exhibited significantly lower deceleration of the center of mass, as well as modified limb movement and inter-limb coordination (p<0.05). These results highlight that a variety of structural adaptations can functionally satisfy the task-goal.

Development of fluid conduits in the auriferous shear zones of the Hutti Gold Mine, India: evidence for spatially and temporally heterogeneous fluid flow

The gold mineralization of the Hutti Mine is hosted by nine parallel, N - S trending, steeply dipping, 2 - 10 m wide shear zones, that transect Archaean amphibolites. The shear zones were formed after peak metamorphism during retrograde ductile D, shearing in the lower amphibolite facies. They were reactivated in the lower to mid greenschist facies by brittle-ductile D-3 shearing and intense quartz veining. The development of a S-2-S-3 crenulation cleavage facilitates the discrimination between the two deformation events and contemporaneous alteration and gold mineralization. Ductile D, shearing is associated with a pervasively developed distal chlorite - sed cite alteration assemblage in the outer parts of the shear zones and the proximal biotite-plagioclase alteration in the center of the shear zones. D3 is characterized by development of the inner chlorite-K-feldspar alteration, which forms a centimeter-scale alteration halo surrounding the laminated quartz veins and replaces earlier biotite along S-3. The average size of the laminated vein systems is 30-50 m along strike as well as down-dip and 2-6 m in width. Mass balance calculations suggest strong metasomatic changes for the proximal biotite-plagioclase alteration yielding mass and volume increase of ca. 16% and 12%, respectively. The calculated mass and volume changes of the distal chlorite-sericite alteration (ca. 11%, ca. 8%) are lower. The decrease in 6180 values of the whole rock from around 7.5 parts per thousand for the host rocks to 6-7 parts per thousand for the distal chlorite-sericite and the proximal biotite-plagioclase alteration and around 5 parts per thousand for the inner chlorite-K-feldspar alteration suggests hydrothermal alteration during two-stage deformation and fluid flow. The ductile D-2 deformation in the lower amphibolite facies has provided grain scale porosities by microfracturing. The pervasive, steady-state fluid flow resulted in a disseminated style of gold-sulfide mineralization and a penetrative alteration of the host rocks. Alternating ductile and brittle D3 deformation during lower to mid greenschist facies conditions followed the fault-valve process. Ductile creep in the shear zones resulted in a low permeability environment leading to fluid pressure build-up. Strongly episodic fluid advection and mass transfer was controlled by repeated seismic fracturing during the formation of laminated quartz(-gold) veins. The limitation of quartz veins to the extent of earlier shear zones indicate the importance of preexisting anisotropies for fault-valve action and economic gold mineralization. (C) 2003 Elsevier B.V. All rights reserved.

A comparison of injuries among children and adult football (soccer) players

Football is a universal and an affordable game but we need to minimize the incidence of accidents among the increasing number of young football players. Our 11 year retrospective epidemiological study (1990-2000) of football injuries in children (N= 1000) was compared with those of adult players in the 2006 European Championship. This comparative study confirmed that the anatomical, biomechanical and biological conditions differ between adults and children and that they warrant particular attention to protect the latter vulnerable group against bone avulsions, overuse pathologies and fatigue-fractures. Injuries were shown to increase significantly with age up to 16 years (P=0.005). Children suffer mainly from contusions, fractures and sprain injuries. Head injuries were more common in boys (P=0.070), while girls were more prone to sprains. The types of injuries differ between adults and children (sprain versus fractures), the anatomical location of injuries is different (lower limbs in adults, lower and upper limbs in children), the circumstances of the injuries are different (contact in adults versus non-contact in children), and teenage girls have different types of injuries than teenage boys. An increased incidence of injuries is due to changes in the position of the center of gravity and in the morphotype during rapid growth. For these reasons it is mandatory to adapt the training to the age and sex of the players. It is unsafe to train children the same way as adults. The height, the weight and the speed of growth must be taken into account by the multidisciplinary team when organising the training programmes. -- Le football fait partie des sports les plus pratiqués au monde en raison de sa popularité et de son accessibilité économ ique. L'incidence des blessures liées à cette pratique doit être diminuée surtout chez les jeunes joueurs en raison de la croissance exponentielle du nombre de joueurs féminins et masculins. Une étude épidémiologique rétrospective sur 11 ans (1990-2000) a été réalisée chez les enfants victimes de blessures liées au football (N==1000), puis a été comparée aux données recueillies de l'UEFA lors d'un Championnat Européen en 2006 sur les lésions des joueurs adultes. Cette étude comparative confirme que les structures anatomiques, biologiques et les tensions biomécaniques chez l'enfant diffèrent de celles de l'adulte. Les enfants ont un risque plus élevé de souffrir d'avulsion osseuse et de fractures de fatigue que les adultes. Les blessures augmentent significativement avec l'âge jusqu'à 16 ans (P==0,005). Les traumatismes crâniens sont plus fréquents chez les garçons tandis que les entorses sont plus à risque chez les filles. Les adultes font plus souvent des entorses tandis que les enfants font plus de fractures. La localisation anatomique diffère également entre ces deux groupes (les membres inférieurs chez l'adulte et les membres inférieurs et supérieurs chez l'enfant). La circonstance des blessures diffère également (choc avec un autre joueur chez l'adulte et des blessures sans contact chez l'enfant). Chez les adolescents, les blessures des filles diffèrent de celles des garçons. L'augmentation chez les enfants de cette incidence est liée au déplacement lors de la croissance du centre de gravité, avec une maladresse accrue lors des phases de croissance. Pour toutes ces raisons, il est justifié d'adapter les entraînements de football en fonction de l'âge, du sexe et du morphotype. L'entrainement des enfants doit être différent de celui des adultes. Le poids, la taille et la vitesse de croissance doit être prise en compte dans des structures multidisciplinaires afin de permettre une meilleure longévité sportive des jeunes joueurs de football.

Impact of the Femoral Head Position on Moment Arms in Total Hip Arthroplasty: A Parametric Finite Element Study.

BACKGROUND: Although the importance of accurate femoral reconstruction to achieve a good functional outcome is well documented, quantitative data on the effects of a displacement of the femoral center of rotation on moment arms are scarce. The purpose of this study was to calculate moment arms after nonanatomical femoral reconstruction. METHODS: Finite element models of 15 patients including the pelvis, the femur, and the gluteal muscles were developed. Moment arms were calculated within the native anatomy and compared to distinct displacement of the femoral center of rotation (leg lengthening of 10 mm, loss of femoral offset of 20%, anteversion ±10°, and fixed anteversion at 15°). Calculations were performed within the range of motion observed during a normal gait cycle. RESULTS: Although with all evaluated displacements of the femoral center of rotation, the abductor moment arm remained positive, some fibers initially contributing to extension became antagonists (flexors) and vice versa. A loss of 20% of femoral offset led to an average decrease of 15% of abductor moment. Femoral lengthening and changes in femoral anteversion (±10°, fixed at 15°) led to minimal changes in abductor moment arms (maximum change of 5%). Native femoral anteversion correlated with the changes in moment arms induced by the 5 variations of reconstruction. CONCLUSION: Accurate reconstruction of offset is important to maintaining abductor moment arms, while changes of femoral rotation had minimal effects. Patients with larger native femoral anteversion appear to be more susceptible to femoral head displacements.