L'électroconvulsivothérapie (ECT) est une réponse thérapeutique reconnue comme efficace face à la résistance et au délai d'action des agents pharmacologiques, pour les épisodes dépressifs majeurs. Bien que l'efficacité thérapeutique des ECT soit reconnue de tous, la connaissance incomplète des effets biologiques qui sous tendent l'effet thérapeutique contribue à discréditer ce soin. Les marqueurs biologiques ne sont pas facilement accessible chez l’Homme, il a donc été développé chez les rongeurs, l’équivalent des ECT : les stimulations électro-convulsives (ECS). A ce jour, les divers résultats provenant des études chez les animaux n’ont permis d’obtenir des conclusions claires, et ceci est majoritairement dû à l’utilisation d’animaux naïfs. Dans ce contexte, l'objectif du projet de thèse était d'analyser les effets biologiques et comportementaux des ECS répétées, modèle de l'électro convulsivothérapie, sur un modèle animal de troubles psychiatriques : la souris MAP6 KO. En effet, ces souris expriment constitutivement des altérations biologiques et comportementales assimilées à certains symptômes de la dépression. Nous avons montré qu’un traitement par ECS améliore certaines des altérations comportementales des souris MAP6 KO, avec un maintien dans le temps différent selon le comportement analysé. Au niveau biologique, le traitement par ECS n’induit pas de modification détectable de l’expression des protéines dans le cerveau, mais induit une augmentation de la neurogénèse adulte hippocampal, et plus particulièrement une augmentation du taux d'intégration des neurones néoformés. L'augmentation du nombre de nouveaux neurones survivants pourrait être favorisée par l’augmentation de la complexité de l’arborisation dendritique et de la densité synaptique. De plus nous observons une augmentation de la densité des épines dendritiques dans les neurones corticaux et une augmentation de l’expression du BDNF dans l’hippocampe. En conclusion, le projet de thèse montre que les ECS appliquées aux souris MAP6 KO-ont un effet important au niveau de la plasticité cérébrale et plus particulièrement au niveau de l’intégration des nouveaux neurones issus de la neurogénèse adulte hippocampique. / In Major depressive disorder, the electroconvulsive therapy (ECT) is recognized as an effective treatment to face drug-resistance and action latency of pharmacological agents. Although the therapeutic efficacy of ECT is internationally recognized, the ill-characterized biological effects of ECT contribute to discredit this treatment. Direct access of specific markers in human is not easy, prompting the development of the animal counterpart of ECT, the electro convulsive stimulations (ECS). To date, current results arising from ECS studies in animals remain not fully conclusive because mainly data have been obtained with unchallenged/naive animals. The objective of this project was to analyze the biological and behavioral effects of ECS treatment, on an animal model of psychiatric disorder: the MAP6-KO mice. Indeed MAP6-KO mice (also known as STOP KO mice) constitutively exhibit behavioural and biological features relevant to some aspects of major depressive disorder. We found that ECS treatment has an overall beneficial effect on several constitutive behavioural defects, displayed by MAP6 KO mice, with variable lasting times. At biological levels, ECS treatment did not induce detectable modification of brain proteins expression pattern, but induce an overall increase of hippocampal neurogenesis, and more particularly potentiate the survival rate of newborn neurons, probably through an increase dendritic complexity and dendritic spines density. We also found that ECS enhance dendritic spines density in vivo in cortical neurons and increase hippocampal levels of the trophic factor, BDNF. In summary our work provide evidence that ECS treatment when applied to MAP6 KO mice induces major neuronal plasticity events, the stronger being the increased integration rate of hippocampal new-born neurons.

Arterial endothelial cells (ECs) are subjected to pulsatile strain due to pressure changes in the cardiac cycle and this may play a significant role in vascular function in health and disease. Further, ECs differentially respond to different patterns of strain. There is much evidence that cyclic uniaxial strain results in a perpendicular orientation of ECs and their stress fibers, while no such alignment occurs in response to cyclic equaibiaxial stretch. It is unclear how cells and their stress fibers determine their specific response to particular spatiotemporal changes in the matrix, however. Given that ECs located at regions in the arterial tree prone to atherogenesis are non-aglined, while ECs in relatively healthy regions are oriented perpendicular to the principal direction of cyclic stretch, it is important to understand the mechanisms which regulate stretch-induced stress fiber alignment. The focus of this thesis was to develop realistic models to describe the dynamic changes in the organization of stress fibers in response to diverse spatiotemporal patterns of stretch. The model is based on the premise that stress fibers are pre-stressed at a ?homeostatic? level so that stress fibers are extended beyond their unloaded lengths, and that perturbation in stress fiber length from the homeostatic level destabilizes the stress fibers. A deterministic model described experimentally measured time courses of stress fiber reorientation perpendicular to the direction of cyclic uniaxial stretch, as well as the lack of alignment in response to equibiaxial stretch. In the case of cyclic simple elongation with transverse matrix contraction, stress fibers oriented in the direction of least perturbation in stretch. Model analysis indicated the need for a time-dependent stress fiber mechanical property, however. Thus, a stochastic model was developed that incorporated the concept that stress fibers tend to self-adjust to an equilibrium level of extension when they are perturbed from their unload lengths with the turnover of stress fibers. The stochastic model successfully described experimentally measured time courses of stress fiber reorganization over a range of frequencies. At a frequency of 1 Hz, stress fibers predominantly oriented perpendicular to stretch, while at 0.1 Hz the extent of stress fiber alignment was markedly reduced and at 0.01 Hz there was no alignment at all. Both the deterministic and stochastic models accurately described the relationship between stretch magnitude and the extent of stress fiber alignment in endothelial cells subjected to cyclic uniaxial stretch. Parameter sensitivity analyses for each model were used to demonstrate the effects of each parameter on the characteristics of the system response. In summary, the mathematical models were capable of describing stress fiber reorganization in response to diverse temporal and spatial patterns of stretch. These models provide a theoretical framework to elucidate the mechanisms by which adherent cells sense the characteristics of matrix deformation and describe a mechanism by which the cells can then adapt to such deformations to maintain mechanical homeostasis.

Introduction: Venous disease impairs the quality of life, necessitates time off work and causes venous ulcers. The focus of this thesis is to explore strategies to prevent chronic venous insufficiency (CVI) and venous ulceration. Aims 1. To identify a population at risk of developing venous ulcers 2. To study the pressure profile required by elastic stockings to halve transit venous time 3. To explore the role of compression following ankle fracture Methods: Data was collected from 231 patients with venous ulcers and age and sex matched 210 controls to identify risk factors for venous ulceration. Univariate and multivariate analysis of potential risk factors was undertaken to identify those that independently predict this risk. After identifying the population at risk, prophylactic strategies were developed. The effect of Engineered Compression Stockings (ECS) delivering 15mmHg, 25mmHg and 35mmHg pressure at the ankle on the calf venous transit time and volume was measured to determine the ideal pressure profile required to halve transit venous time, which should be appropriate for DVT prophylaxis. A dorsal foot vein was cannulated in 15 healthy volunteers with no venous disease. The transit time (secs) for ultrasound contrast from a foot vein to the popliteal vein was measured using duplex ultrasound. Calf volumes were recorded by water displacement. ECS delivering 25mmHg of pressure around the ankle were compared with no compression in a randomized controlled trial (RCT) in 90 patients within 72 hours of ankle fracture. Patients were randomised to either i) ECS and air-cast boot or ii) a liner and air-cast boot and were followed at 2, 4, 8, 12 weeks and 6 months. The primary outcome was functional recovery measured using the Olerud Molander Ankle Score (OMAS). Secondary outcomes were i) The American Orthopaedic Foot and Ankle Score (AOFAS), ii) SF12v2 Quality of Life score (QoL), iii) pain, and iv) frequency of DVT. Results The risk factors significantly associated with venous ulceration on multivariate analysis included a history of Deep Vein Thrombosis (DVT), phlebitis, hip replacement, poor mobility, weight/kg>100Kg, varicose veins (VV), family history of VV and weight (kg) between 75-100kg. A simple diagnostic scoring system was derived from this regression analysis with scores of . 3 predicting a 6.7% annual risk and of < 1 a 0.6% risk. Mean transit time without compression was 35, 32 and 33 secs while standing, sitting and lying. Transit time was consistently halved by ECS delivering 25mmHg to 14, 13 and 14 secs respectively (p<0.001). Mean leg volume whilst standing was reduced significantly from 3447ml with no ECS to 3259ml, 3161ml and 3067ml with ECS applying 15, 25 and 35mmHg respectively (p<0.001). ECS in ankle fracture patients reduced ankle swelling at all time points and significantly improved mean OMAS score at six months to 98 compared with 67 for the liner (p<0.001). AOFAS and SF12v2 scores were also significantly improved (p<0.001, p= 0.016). Of 86 patients with duplex imaging at four weeks, only five (12%) of the 43 ECS patients had a DVT compared with 10 (23%) of the 43 controls (p= 0.26). Conclusions: The risk score for venous ulcers will allow us to undertake RCTs on the prevention of leg ulceration. The pressure profile required to halve transit venous time is 25mmHg. The frequency of asymptomatic DVT following ankle fracture is sufficient to justify prophylaxis. Compression has a potential role in the management of ankle fractures by improving functional outcome and QoL. These studies facilitate research into the prevention of venous disease.

No description available.

No description available.

L’hypothalamus est une structure cérébrale ayant un rôle clé dans la régulation de la prise alimentaire. Parmi les différentes populations neuronales qui le composent, les neurones produisant la pro-opiomélanocortine (POMC) sont classiquement connus pour diminuer la prise alimentaire et le poids corporel via la libération de neuropeptides produits par le clivage de POMC. Notre étude, grâce à l’utilisation d’approches génétiques, pharmacologiques, électrophysiologiques et moléculaires, remet en question les notions classiques sur la fonction des neurones à POMC dans la balance énergétique, en démontrant qu’il existe deux sous-populations fonctionnellement distinctes de neurones à POMC, qui augmentent ou diminuent la prise alimentaire en fonction du neurotransmetteur qu’elles libèrent, l’acide γ-aminobutyrique (GABA) ou le glutamate. Une troisième population capable de produire aussi bien du GABA que du glutamate a également été identifiée. La régulation des neurones à POMC GABAergiques et glutamatergiques dépend de la voie de la cible de la rapamycine chez les mammifères (mTORC1), qui fonctionne comme un détecteur d’énergie cellulaire, et du système endocannabinoïde (ECS), qui régule la libération de neurotransmetteurs. De plus, nous avons également démontré, via l’utilisation de souris mutantes conditionnelles, l’importance de la protéine p62 ou séquestrome 1 (p62/SQSTM1), qui régule l’activité de mTORC1 et l’autophagie, dans les neurones à POMC dans la régulation de l’homéostasie énergétique. Nos données offrent un nouvel aperçu sur les mécanismes moléculaires impliqués dans la régulation de la balance énergétique. / The hypothalamus is a brain structure with a key role in the regulation of food intake. Among the different neuronal populations of which it is composed, pro-opiomelanocortin (POMC) neurons are classically known to decrease food intake and body weight through the release of neuropeptides produced by the cleavage of POMC. Our study, through the use of genetic, pharmacological, electrophysiological and molecular approaches, challenges conventional notions about POMC neuron function in energy balance by showing that there are two functionally distinct POMC neuronal sub-populations, which increase or decrease food intake depending on which neurotransmitter they release, γ-aminobutyric acid (GABA) or glutamate. A third population capable of producing both GABA and glutamate has also been identified. The regulation of POMC GABAergic and glutamatergic neurons depends on the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which functions as a cellular energy sensor, and the endocannabinoid system (ECS), which regulates neurotransmitters release. In addition, we have also demonstrated through the use of a conditional knockout mice, the importance of the protein p62 or sequestrome 1 (p62/SQSTM1), which regulates mTORC1 activity and autophagy, in POMC neurons for the regulation of energy homeostasis. Our data provide new insights on the molecular mechanisms involved in the regulation of energy balance.

Fog of War is a term for uncertainty in situational awareness. Fog of War is an essential part of a wargame which causes the participating units’ perception of the environment to be distorted and altered. Introducing a certain amount of uncertainty helps to better mimic the situation on the battlefield. Fog of War comes in multiple forms and levels, whereas the visual detection level is of primary interest for this thesis. Two forms of visual detection have been implemented to simulate a simple and advanced form of Fog of War. The simple level is based solely on the distance between two units, while the advanced level determines whether two units possess a clear line of sight between them, to decisively add realism to a played scenario. The two models were created based on the Entity Component System software architecture, and the maps used for the wargame were based on data from ArcGIS. Extensive testing of the two models, for different types of terrains, show good performance and computational efficiency, however with the expected caveat that flat landscape requires significantly more processing power and memory capacity than a hilly terrain. / Krigsdimma är en term för osäkerhet inom situationsmedvetenhet. Krigsdimma är en väsentlig del av ett krigsspel och medför att deltagande förbands uppfattning av miljön förvrängs och förändras samt att ett visst mått av osäkerhet introduceras för att bättre efterlikna situationen på slagfältet. Krigsdimma kommer i flera former och flera nivåer, där visuell detektering är av primärt intresse för denna avhandling. Två former av visuell detektering har implementerats för att simulera en enkel och en avancerad form av krigsdimma. Den enkla nivån bygger enbart på avståndet mellan två förband medan den avancerade nivån kan avgöra om två enheter i verkligheten har en fri siktlinje mellan sig, något som på ett avgörande sätt kan tillföra realism till ett spelat scenario. De två realiseringarna skapades baserat på en Entity Component System mjukvaruarkitektur, och kartorna som användes för krigsspelet baserade sig på data från ArcGIS. Omfattande tester av de två modellerna, för olika terrängtyper, visar på god funktion och beräkningseffektivitet, dock kräver flackt landskap betydligt mer processorkraft och minneskapacitet än kuperad terräng.

El presente estudio; descriptivo, no experimental y transversal, tiene como objetivo aportar conocimientos en relación a la evaluación del dolor miofascial, a través de la determinación del umbral de dolor a la presión de los músculos Masetero y Temporal en este tipo de pacientes, en sujetos sanos y la posible relación entre dichos umbrales y el género de los sujetos.

El estudio es descriptivo de tipo transversal, no experimental, abarcando una muestra de 1600 fichas clínicas de personas mayores de 15 años obtenidas mediante muestreo aleatorio simple en el CESFAM “Cristo Vive”. Los resultados indicaron que las EMERs más prevalentes, en el centro de salud en referencia, fueron el Lumbago no especificado con una prevalencia global de 10,25%; lesión de hombro no especificada (Hombro doloroso) 4,05% y Gonartrosis (osteoartrosis de rodilla) 2,56%. Las hipótesis planteadas (H1; H2; H3) resultaron rechazadas al no encontrarse una asociación estadística significativa (p>0.05) entre las variables involucradas, aceptando las hipótesis H0 correspondientes a cada una, de no relación entre las variables: EMER más prevalentes y nivel educacional. Los datos de prevalencia hallados en la muestra estudiada, fueron cercanos a la bibliografía revisada, en otros casos, la prevalencia fue menor que la esperada, probablemente a que se consideró solo el año 2004 como criterio de inclusión.

This thesis documents the modelling of generic Environmental Control System(ECS) of an aircraft in Modelica by utilizing components from free version of theTTECCS (Technical Thermodynamic Environmental Control and Cooling Systems) library. In doing so, components used for developing ECS from the TTECCS library are mathematically verified with theoretical formula in MATLAB. Selected components are investigated with valid input data to initialize the simulation and verify its behaviors with corresponding available data. Hereinafter, the object-oriented modelling method is used to integrate ECS components to develop a functional system. The main function of ECS is to regulate the pressure and temperature inside the cabin to accepted physiology flight safetylevels. Different types of ECS architecture are presented in this document. An ECS developed here is based on the bootstrap system and consists only one cooling unit comprised with the source, pipes, two heat exchanger, compressor, turbine, temper-ature control valve, pressure control valve, and sinks. Dry air(Ideal gas) is used as a medium in the system. Temperature drop along each component corresponds to available A320 cruise flight data in order to calculate the top level parameter and to initialize the components, subsequently an ECS system. Several systematized methods for Object-oriented modelling and system design were studied and steps are extracted accordingly that suits to initiate the procedurefor this project, which is also presented. Time domain simulation is performed inModelica and Dymola. A simplified control system is built to regulate the system, therefore restrained it as a future work to develop real in-flight condition control system of an ECS.Top level parameters were selected within valid customized ranges for developing a performance map of the components. After generating the map, optimal data from the map were taken to initialize final ECS. The simulation results of the final model is then compared to A320 flight data which is comparable in behavior; this was expected. Above all, simulation environment Modelica and free version of TTECCS library components are reliable to develop ECS in order to investigate ECS components behavior and predict cabin conditions before developing a prototype.