Type 2 diabetes has reached epidemic proportions worldwide. The resulting increase in chronic and costly diabetes related complications has potentially catastrophic implications for healthcare systems, and economies and societies as a whole. One of the key pathological factors leading to type 2 diabetes is insulin resistance (IR), which is the reduced or impaired ability of the body to make use of available insulin to maintain normal blood glucose levels. Diagnosis of developing IR is possible up to 10 years before the diagnosis of type 2 diabetes, providing an invaluable opportunity to intervene and prevent or delay the onset of the disease. However, an accurate, yet simple, test to provide a widespread clinically feasible early diagnosis of IR is not yet available. Current clinically practicable tests cannot yield more than a crude surrogate metric that allows only a threshold-based assessment of an underlying disorder, and thus delay its diagnosis. This thesis develops, analyses and pilots a model-based insulin sensitivity test that is simple, short, physiological and cost efficient. It is thus useful in a practical clinical setting for wider clinical screening. The method incorporates physiological knowledge and modelling of glucose, insulin and C-peptide kinetics and their pharmaco-dynamics. The clinical protocol is designed to produce data from a dynamic perturbation of the metabolic system that enables a unique physiologically valid assessment of metabolic status. A combination of a-priori information and a convex integral-based identification method guarantee a unique, robust and automated identification of model parameters. In addition to a high resolution insulin sensitivity metric, the test also yields a clinically valuable and accurate assessment of pancreatic function, which is also a good indicator of the progression of the metabolic defect. The combination of these two diagnostic metrics allow a clinical assessment of a more complete picture of the overall metabolic dysfunction. This outcome can assist the clinician in providing an earlier and much improved diagnosis of insulin resistance and metabolic status and thus more optimised treatment options. Test protocol accuracy is first evaluated in Monte Carlo simulations and subsequently in a clinical pilot study. Both validations yield comparable results in repeatability and robustness. Repeatability and resolution of the test metrics are very high, particularly when compared to current clinical standard surrogate fasting or oral glucose tolerance assessments. Additionally, the model based insulin sensitivity metric is shown to be highly correlated to the highly complex, research focused gold standard euglycaemic clamp test. Various reduced sample and shortened protocols are also proposed to enable effective application of the test in a wider range of clinical and laboratory settings. Overall, test time can be as short as 30 minutes with no compromise in diagnostic performance. A suite of tests is thus created and made available to match varying clinical and research requirements in terms of accuracy, intensity and cost. Comparison between metrics obtained from all protocols is possible, as they measure the same underlying effects with identical model-based assumptions. Finally, the proposed insulin sensitivity test in all its forms is well suited for clinical use. The diagnostic value of the test can assist clinical diagnosis, improve treatment, and provide for higher resolution and earlier diagnosis than currently existing clinical and research standards. High risk populations can therefore be diagnosed much earlier and the onset of complications delayed. The net result will thus improve overall healthcare, reduce costs and save lives.

This thesis focused on the proximal factors associated with PFP, particularly, on hip muscle function. The overall purpose of this thesis was to elaborate a test, reliable and valid, for evaluating hip muscle function in females with PFP and that could be easily be used in the clinic. To reach this purpose, three sections have been considered:• Section 1 presented the results of a systematic review with meta-analysis entitled “Strength and endurance in females with patellofemoral pain”. This systematic review provided strong evidence that females with PFP have significant isometric strength deficit in hip abduction, extension, and external rotation when compared with healthy controls. Moderate evidence was obtained concerning isometric strength deficit in flexion. There was no evidence that females with PFP have strength deficits in adduction and internal rotation. Moderate evidence was found for isokinetic deficit in abduction and conflicting evidence for a deficit in rotation and extension. When compared with the uninjured limb, moderate evidence was found for a strength deficit in abduction, conflicting evidence for deficiencies in extension and external rotation strength and no evidence for internal rotation, adduction and flexion strength deficiencies. Finally, conflicting evidence was found for a decrease in hip muscular endurance.• Section 2 elaborated two clinical tests for the assessment of hip abductor endurance. After a preliminary phase, the hip abductor isometric endurance test was selected. The test-retest reliability and the validity were determined in healthy females and we concluded that the test could be recommended for clinicians.• Section 3 determined the applicability of the hip abductor isometric endurance test in females with PFP. We assessed the test-retest reliability of the hip abductor isometric endurance test in females with PFP and we compared holding time during the test between females with and without PFP. In this chapter, we chose also to use two others clinical tests, evaluating trunk extensor and ankle plantar flexor endurance, to compare females with and without PFP. We reported that females with PFP exhibited significantly lower hip abductor, trunk extensor and ankle plantar flexor endurance than healthy controls and we concluded that the hip abductor isometric endurance test could be recommended for the examination of patients with PFP. / Doctorat en Sciences de la motricité / info:eu-repo/semantics/nonPublished

La rosacée est une maladie inflammatoire chronique de la peau qui affecte presque exclusivement la peau faciale centrale. Actuellement, la morbidité de la rosacée en Chine augmente. Chaque signe clinique de la rosacée est lié à la pathogenèse de cette maladie cutanée dont la physiopathologie très complexe, implique différents types cellulaires et molécules de la peau et divers sous-types. Selon ces résultats, nous avons pu évaluer le rôle de la barrière cutanée et des microorganismes dans la rosacée. Le premier objectif de cette thèse était de déterminer si un microbiote cutané altéré est le résultat d'une pathophysiologie sous-jacente. Nous avons également comparé la rosacée chez des patients chinois et français en évaluant la fonction de la barrière cutanée. Ces tests aideront au choix de la thérapie la plus adaptée pour traiter des patients atteints de rosacée. A travers ces 4 années de recherche de thèse, nous avons montré que : • La biopsie standard de la surface de la peau est une bonne méthode pratique en clinique pour mesurer la densité de Demodex Folliculorum chez les patients atteints de rosacée et d'acné. Le RCM peut être un meilleur choix que le SSSB en raison de son exactitude, de son exhaustivité et de sa procédure indolore non invasive in vivo. RCM semble être plus sensible que son prédécesseur. D'après les résultats de l'analyse du nombre de Demodex dans les lésions de patients atteints de PPR, nous avons constaté que ce nombre est beaucoup plus élevé à Besançon qu'à Shanghai. Les caractéristiques physiologiques de la rosacée sont fortement associées aux interactions entre l'hôte et les micro-organismes, et nos données indiquent l'importance de la colonisation bactérienne. Dans la pathogenèse de la rosacée, il est donc souhaitable de prendre en compte l'altération du microbiote cutané et des réponses immunitaires.La MRC peut détecter dans la peau sensible et la rosacée, les structures endommagées par l'épidermolyse du patient, y compris la parakératose, le désordre en nid d'abeille. Elle pourrait être utilisée comme nouvelle méthode auxiliaire de détection et de diagnostic.l est important de prendre en compte l'association des microorganismes, des paramètres biophysiques de la peau, du microenvironnement et de la barrière cutanée, y compris les barrières physiques, chimiques et microbiennes, même dans la peau normale, dans la conception des produits de soins de la peau et des médicaments antimicrobiens / Rosacea is a common chronic inflammatory skin disease that almost exclusively affects the central facial skin. In these years, the morbidity ofrosacea in China has increased significantly. Each clinical signs of rosacea are related by the pathogenesis of this skin disease, and its pathophysiology is very complex, involving various cell types and molecules in the skin, and various subtypes. According these viewpoints, we chose the ERT and PPR patients, and focused on the microorganism and skin barrier to know more about the pathogenesis of rosacea. The first objective of this thesis was to know more about that whether the skin impaired microbiota is a response to changes in the skin microenvironment resulting from rosacea's underlying pathophysiology. And we also interested in the difference between the French rosacea patients and the Chinese patients in the skin barrier function. Another objective was to find the practical non-invasive testing technology to evaluate the rosacea patients'skin barrier damage condition and in the treatment efficacy. Through these testing, we could know more about the skin barrier situation of the patient, which will help us to choose the more suitable therapy approach for the long time treatment period for rosacea patients. Through these 4 years research of this thesis, we have shown that: Standardized Skin Surface Biopsy is a good practical method to measure Demodex Folliculorum density in rosacea and acne patients in clinical experience. RCM may be a better choice than SSSB because of its accuracy, completeness and as an in vivo noninvasive painless procedure. RCM appears to be a more sensitive method which could be used more in research or clinical studies or to follow up treatment or recurrence. According to the results of testing demodex number in les ions of PPR patients, we found that it was much higher in Besancon than Shanghai even ifwe used the same method. The physiological features of rosacea are strongly associated with the interactions between the host and microorganisms, and our data indicate the importance of the bacterial colonization balance on the skin surface. In the pathogenesis ofrosacea, we'd better to care more about the skin dysbiosis with the enhanced immunity responds. RCM can detect in sensitive skin and rosacea patient epidermal damaged structures, including parakeratosis, disarranged honeycomb pattern and reduced honeycomb pattern depth. lt could be used as a new kind of the new auxiliary method in the detection and diagnosis, providing the new mentality for the diagnosis and treatment. It is important that the association of microorganisms, skin biophysical parameters, microenvironment and skin barrier function including physical, chemical and microbial barriers even in normal skin, which is essential for designing skin care products and anti-microbial drugs

L'histologie tridimensionnelle (3D) est un nouvel outil avancé de cancérologie. L'ensemble du profil chimique et des caractéristiques physiologiques d'un tissu est essentiel pour comprendre la logique du développement d'une pathologie. Cependant, il n'existe aucune technique analytique, in vivo ou histologique, capable de découvrir de telles caractéristiques anormales et de fournir une distribution3D à une résolution microscopique. Nous présentons ici une méthode unique de microscopie infrarouge (IR) à haut débit combinant une correction d'image automatisée et une analyse ultérieure des données spectrales pour la reconstruction d'image 3D-IR. Nous avons effectué l'analyse spectrale d'un organe complet pour un petit modèle animal, un cerveau de souris avec une tumeur de gliome implantée. L'image 3D-IR est reconstruite à partir de 370 coupes de tissus consécutives et corrigée à l'aide du tomogramme à rayons X de l'organe pour une analyse quantitative précise du contenu chimique. Une matrice 3D de spectres IR 89 x 106 est générée, ce qui nous permet de séparer la masse tumorale des tissus cérébraux sains en fonction de divers paramètres anatomiques,chimiques et métaboliques. Nous démontrons pour la première fois que des paramètres métaboliques quantitatifs (glucose, glycogène et lactate) peuvent être extraits et reconstruits en 3D à partir des spectres IR pour la caractérisation du métabolisme cérébral / tumoral (évaluation de l'effet de Warburg dans les tumeurs). Notre méthode peut être davantage exploitée en recherchant l'ensemble du profil spectral, en distinguant différents points de repère anatomiques dans le cerveau.Nous le démontrons par la reconstruction du corps calleux et de la région des noyaux gris centraux du cerveau. / Three-dimensional (3D) histology is a new advanced tool for cancerology. The whole chemical profile and physiological characteristics of a tissue is essential to understand the rationale of pathology development. However, there is no analytical technique, in vivo or histological, that is able to discover such abnormal features and provide a 3D distribution at microscopic resolution.Here, we introduce a unique high- throughput infrared (IR) microscopy method that combines automated image correction and subsequent spectral data analysis for 3D-IR image reconstruction. I performed spectral analysis of a complete organ for a small animal model, a mouse brain with animplanted glioma tumor. The 3D-IR image is reconstructed from 370 consecutive tissue sectionsand corrected using the X-ray tomogram of the organ for an accurate quantitative analysis of thechemical content. A 3D matrix of 89 x 106 IR spectra is generated, allowing us to separate the tumor mass from healthy brain tissues based on various anatomical, chemical, and metabolic parameters. I demonstrate for the first time that quantitative metabolic parameters (glucose, glycogen and lactate) can be extracted and reconstructed in 3D from the IR spectra for the characterization of the brain vs. tumor metabolism (assessing the Warburg effect in tumors). Our method can be further exploited by searching for the whole spectral profile, discriminating different anatomical landmarks in the brain. I demonstrate this by the reconstruction of the corpus callosum and basal ganglia region of the brain.

The control of chronic pain in equines is growing up recent years in function of the highest performance required of the animals in the different sportive modalities and the new look for methodologies of combat to animal maltreatment. It is cited even, the economic potentialities in the economic chain of the equine breeding to stimulation of the development of new technologies and products. In attendance to these rules, the work presented here brings the evaluation of the effectiveness and clinical security of a injectable neurolytic formulation for perineural use in equines. This type of drug is not yet available in Brazilian market. The Injectable Neurolytic Suspension (SNI) was formulated with ethanol, triamcinolone and bupivacaine, aiming at to use to advantage the neurolytic effect of ethanol, with no collateral inflammatory reactions and painful in local injection. The evaluation of chemical stability was carried through the evaluation of the loss of weight of the samples, variation of pH, time of sedimentation after the agitation and development of chromatographic method for identification and simultaneous determination of bupivacaine and triamcinolone. The clinical test was carried through per 180 days in five horses, having approached two aspects: (a)evaluation of the effectiveness of the neurolytic action and pain suppression of the SNI, and (b)the eventual toxicity related to the composition. The lameness was induced in the horses through the development of horseshoes method, carrying later through perineural infiltration of 5 mL of SNI in each branch of the palmar nerves. The evaluation of the SNI toxicity was carried out monitoring of the hepatic, kidney and skeletal muscle functions, measuring the serum levels of alanina aminotransferase (ALT), aspartate aminotransferase (AST), creatinofosfokinase (CK), Gamaglutamiltransferase (GGT), Urea and Creatinine. The SNI presented satisfactory chemical stability in temperatures of 4ºC and 20ºC. The clinical test indicated abolition of podal pain in the horses from 96 hours of infiltration, with effect kept up to 180 days. The SNI did not caused hepatic, kidney and/or skeletal muscle toxicity. All the results lead to a very promissory drug to this specific market in Brazil. / O controle da dor crônica em eqüinos tem evoluído nos últimos anos em função da maior exigência esportiva dos animais nas diferentes modalidades e da implantação de metodologias de combate aos maus tratos. Cite-se ainda que as potencialidades econômicas geradas no círculo da eqüinocultura acabam por estimular o desenvolvimento de novas tecnologias e produtos. Em atendimento a estes preceitos, o trabalho aqui apresentado traz a avaliação da eficácia e segurança clínica de uma formulação neurolítica injetável para uso perineural em eqüinos, até o momento inexistente no mercado nacional. A Suspensão Neurolítica Injetável foi formulada com etanol, triancinolona e bupivacaína, visando aproveitar o efeito neurolítico do etanol, sem causar as reações inflamatórias e dolorosas locais causadas pelo mesmo. A avaliação de estabilidade química foi realizada através da avaliação da perda de peso das amostras, variação de pH, tempo de sedimentação após a agitação e desenvolvimento de método cromatográfico para identificação e determinação simultânea dos teores de Bupivacaína e Triancinolona. O teste clínico foi realizado por 180 dias em cinco equinos, abordando dois aspectos: avaliação da eficácia da ação neurolítica e abolição da dor da SNI; e a eventual toxicidade relacionada à composição. Para a indução de claudicação nos eqüinos, foi desenvolvido método através de ferraduras, realizando posteriormente a infiltração perineural de 5 mL de SNI em cada ramo dos nervos palmares. A avaliação de toxicidade da SNI realizou-se através de monitoração das funções hepática, renal e muscular após as infiltrações, mensurando os níveis séricos de Alanina Aminotransferase (ALT), Aspartato Aminotransferase (AST), Creatinofosfoquinase (CK), Gamaglutamiltransferase (GGT), Uréia e Creatinina. A SNI apresentou estabilidade química satisfatória em temperaturas de 4ºC e 20ºC. O teste clínico indicou abolição da dor podal nos animais a partir de 96 horas da infiltração, com efeito mantido até 180 dias. A SNI não demonstrou causar toxicidade hepática, renal e/ou muscular, evidenciando a potencialidade de transformação em produto comercial.