A olanzapina é um fármaco antipsicótico atípico utilizado no tratamento da esquizofrenia. Como efeitos adversos relacionados ao seu uso, encontram-se obesidade, hiperlipidemia, Diabetes Mellitus tipo II, entre outros. O presente trabalho avaliou os efeitos adversos passíveis de desenvolvimento em pacientes esquizofrênicos que fazem uso deste medicamento, avaliando o indivíduo antes de começar o tratamento, 30 e 60 dias após o início (T0, T1 e T2) através de dosagens antropométricas (peso, IMC, circunferência abdominal e porcentagens de tecido adiposo no organismo), hemodinâmicas (pressão arterial, frequência cardíaca), perfil lipídico (colesterol total, LDL-col, HDL-col e triglicérides), glicêmico (resistência à insulina HOMA-R, QUICKI e razão G/I; glicemia de jejum) e bioquímico (avaliação da função renal, hepática e dosagem de homocisteína, um marcador de risco cardiovascular). A olanzapina plasmática foi dosada nos mesmos tempos com intenção de se buscar uma correlação de dose-resposta (efeito adverso). A análise estatística foi realizada com auxílio dos \"softwares\" Graphpad Instat e Statgraphics, para o estudo e análise das médias (ANOVA), e análise de comparação múltipla entre os grupos (Tukey-Kramer). O nível de significância foi fixado em p<0,05. Para os grupos sem diferença estatística relevante, foram utilizadas técnicas de estatística descritiva para se observar diferenças mais sutis ou com relevância clínica. As altas concentrações plasmáticas encontradas não foram concordantes com os estudos prévios de outros autores, já que não foram mais propensos a desenvolver ganho de peso. Este efeito adverso foi encontrado no nosso grupo, porém sem apresentar uma correlação direta com a concentração plasmática. / The olanzapine is an atypical antipsychotic drug used to treat schizophrenia. The adverse effects related to its use are obesity, hyperlipidemia, diabetes mellitus type II and others. This study evaluated the adverse effects likely to develop in schizophrenia patients who use this drug, assessing the individual before starting treatment, 30 and 60 days after the start (T0, T1 and T2) by anthropometric measurements (weight, BMI , waist circumference and percentage of fat in the body), hemodynamic (blood pressure, heart rate), lipid profile (total cholesterol, LDL-col, col-HDL and triglycerides), glucose (insulin resistance - HOMA-R, QUICKI, G/I ratio and fasting plasma glucose) and biochemical (measurement of renal function, liver and determination of homocysteine, a marker of cardiovascular risk). The olanzapine plasma was measured at the same time looking for a dose-response (effect) correlation. Statistical analysis was performed using the \"software\" Statgraphics and GraphPad Instat for the study and analysis of means (ANOVA) and analysis of variance between groups (Tukey-Kramer). The significance level was set at p <0.05. For groups without statistical significant difference were used descriptive statistical techniques to observe more subtle differences or clinical relevance. The high plasma concentrations found were not consistent with previous studies of other authors, since there were more likely to develop weight gain. This adverse effect was found in our group, but without a direct correlation with plasma concentration.

Nos últimos anos, em áreas de produção de culturas transgênicas resistentes ao glyphosate, falhas no controle do capim-pé-de-galinha (Eleusine indica) são cada vez mais frequentes, estando provavelmente relacionadas ao uso indiscriminado do glyphosate e ao consequente aumento da pressão de seleção de biótipos de plantas daninhas resistentes a esse herbicida. Este trabalho teve como objetivo comparar a suscetibilidade de quatro populações de capim-pé-de-galinha ao herbicida glyphosate em diferentes estádios de desenvolvimento, bem como estudar a eficácia de herbicidas alternativos ao glyphosate no controle de plantas desta espécie na pré e pós-emergência das mesmas. Também foi objetivo deste trabalho estudar aspectos da biologia, tais como: crescimento, número de sementes produzidas por uma planta e influência da escarificação mecânica sobre a germinação do capim-pé-de- galinha. Foi verificado que existem diferenças na suscetibilidade das populações ao glyphosate, no qual a população denominada EIR2 proveniente de Primavera do Leste - MT foi a que necessitou de maiores doses para ser controlada, sendo caracterizada como um caso de resistência de nível baixo, pois a dose máxima de bula recomendada para a espécie é capaz de controlar todas as populações do estudo. Os herbicidas mais indicados para o controle de capim-pé-de-galinha na pré-emergência foram o flumioxazin, sulfentrazone, clomazone e trifluralina, apresentando maiores níveis de controle e efeito residual mais prolongado. O controle do capim-pé-de-galinha na pós-emergência inicial (2 a 3 perfilhos) e no estádio intermediário (6 a 8 perfilhos) foi eficiente com todos os herbicidas testados. No estádio mais avançado (10 a 12 perfilhos) o herbicida sethoxydim não controlou nenhuma das populações, não sendo indicado para plantas com mais de 6 perfilhos. Foram identificadas diferenças significativas entre o controle das populações com os inibidores da ACCase, sendo necessários outros estudos para confirmação da resistência a esses herbicidas. O capim-pé-de-galinha apresentou de maneira geral elevado acúmulo de matéria seca total, sendo considerado altamente competitivo. Foram encontradas diferenças entre o crescimento das populações, não havendo relação com a suscetibilidade diferencial ao glyphosate existente entre as mesmas. O perfilhamento iniciou-se aos 28 dias após a emergência (DAE), com um pico de crescimento dos 42 aos 63 DAE quando as plantas atingiram o ápice do acúmulo foliar e matéria seca, entrando posteriormente na senescência. O florescimento iniciou-se entre 42 e 49 DAE e perdurou até os 63 DAE. Uma planta da espécie Eleusine indica produziu em média 45000 sementes e não foram encontradas diferenças significativas na produção de sementes entre as populações. A escarificação mecânica das sementes acelerou o processo de germinação e aumentou a germinação final das populações de capim-pé-de-galinha. O mecanismo que confere a dormência física das sementes de capim-pé-de-galinha está relacionado com a impermeabilidade do tegumento. / Lately, in the areas of production of transgenic crops resistant to glyphosate failures in control of goosegrass has been reported frequently, probably by an intense using of glyphosate and consequent increasing in selection pressure of weeds resistant to glyphosate. For this reason this work was carried out in order to compare the susceptibility of four goosegrass populations to glyphosate in different stages of development, as well as studying the effectiveness of alternative herbicides to glyphosate in the control of such species in pre and post-emergence. It was also a goal of this work study biological aspects, such as growth, weed number produced by a plant and influence of mechanical scarification on the germination of the goosegrass. It was found that there are differences in the susceptibility of populations to glyphosate, in which EIR2 population from Primavera do Leste - MT was the one that required higher doses to be controlled, being characterized as a case of low-level resistance because of the maximum recommended dose is able to control all the populations studied. Herbicides the most suitable to control pre-emergence were flumioxazin, sulfentrazone, clomazone and trifluralin, with high levels of control were used a longer residual effect. The control of goosegrass in the early post-emergence (2-3 tillers) and the intermediate stage (6-8 tillers) was efficient with all the tested herbicides. In the most advanced stage (10 to 12 tillers) the herbicide sethoxydim did not control any of populations, was not were used suitable for plants with more than 6 tillers. Remarkable differences were identified between the control of populations with ACCase inhibitors. Other studies are necessary to confirm the resistance to these herbicides. The goosegrass showed high accumulation of total dry matter, being considered highly competitive. Some differences were found among the growth of the populations, with no relation to the differential susceptibility to glyphosate existing between them. The tillering began at 28 days after emergence (DAE), with a growth between of 42 to 63 DAE when the plants reached the apex of the leaf and dry matter accumulation, later entering senescence. The flowering started between 42 and 49 DAE and lasted until 63 DAE. A plant of Eleusine indica produced on average 45 000 seeds and there were no important differences between seed production among populations. Mechanical scarification of seeds accelerated the germination and increased the final germination populations of goosegrass. The mechanism that confers the physical dormancy of goosegrass seeds is related to the impermeability of the integument.

As radiações ionizantes (RI) são amplamente utilizadas na área médica, principalmente para diagnóstico e terapia. Uma vez que a exposição às radiações implica em sérias complicações para a saúde humana e para o meio ambiente, torna-se relevante a compreensão dos mecanismos moleculares que coordenam as respostas em diferentes tipos celulares, especialmente em células normais. A taxa de dose (TD) é um importante fator a ser considerado em radiobiologia, com base em alguns estudos sobre a sua influência nas respostas celulares. Nesse contexto, duas TD distintas (0,5 e 2,0Gy/min) foram testadas para verificar a influência da TD na expressão gênica e protéica em fibroblastos e linfócitos humanos. Fibroblastos primários em estado de confluência foram irradiados com 4Gy e linfócitos com 2 Gy, sob as TDs de 0,5 e 2,0 Gy/min. Em fibroblastos, o RNA foi coletado 6 h após a irradiação, tempo em que foram analisados os níveis de expressão gênica pelo método de microarranjos de cDNA e, para alguns genes de reparo do DNA e algumas proteínas (H2AX, PCNA e FEN1) a expressão foi analisada por qPCR e Western blot, respectivamente, em ambos os tipos celulares, 2 e 6 h após a irradiação. A análise de expressão gênica por microarranjos de cDNA efetuada pelo programa SAM revelou 94 genes (FDR < 0.05) induzidos sob a TD de 0,5 Gy/min. Os principais processos biológicos associados aos genes modulados foram metabolismo, reparo do DNA, apoptose e resposta ao estresse. Por outro lado, 34 genes foram modulados nas células irradiadas sob a taxa de dose de 2,0 Gy/min. Nesta TD, os processos biológicos de maior importância foram: metabolismo, reparo do DNA, replicação, resposta ao estresse e apoptose. Na análise por qPCR, alguns genes de reparo (ERCC1, ERCC3 (ou XPB), XPF, XPA, FEN1) e ATM (sensor de dano) apresentaram uma ampla diferença na modulação gênica detectada em resposta à variação na TD, principalmente nos fibroblastos analisados 2 h após a irradiação. Entretanto, essa diferença foi menor nos linfócitos. Em linfócitos houve um maior número de genes do NER reprimidos relativamente aos fibroblastos, principalmente quando se consideram as células analisadas 2 h após a irradiação, sugerindo que em linfócitos irradiados sob a menor TD, outras vias alternativas de reparo do DNA podem ter ocorrido, possivelmente para lesões do tipo quebra dupla, que são eficientemente induzidas por 2 Gy. A análise protéica de expressão da proteína PCNA indicou que esta se mostrou reprimida nos fibroblastos irradiados com a maior TD, enquanto que a expressão de H2AX nos linfócitos diminuiu 6 h após a irradiação. A proteína PCNA apresentou potencial como um bom indicador dos efeitos de diferentes TDs em fibroblastos irradiados. Em conjunto, os resultados do presente trabalho mostraram uma ampla variedade de processos biológicos envolvidos na resposta ao estresse gerado pela irradiação sob duas diferentes TDs em células humanas (linfócitos e fibroblastos) demonstrando que a TD realmente é capaz de influenciar as respostas celulares em nível transcricional e protéico, o que ainda não foi descrito na literatura. Assim, os resultados constituem informações relevantes que podem contribuir para o esclarecimento das respostas moleculares e vias de sinalização em células normais irradiadas. / Ionizing radiation (IR) has been widely applied in medicine, mainly in diagnosis and therapy purposes. Considering that the exposure to radiation lead to serious complications to human health and environment, it has been relevant to study molecular mechanisms underlying cell responses to gamma-rays in different cell types, especially in normal cells. In radiobiology, dose rate (DR) is an important factor to be taken in account, on the basis of previous results in the literature. In this context, two distinct DR (0.5 and 2.0Gy/min.) were tested aiming to verify the influence of DR on profiles of gene and protein expression displayed by human fibroblasts and lymphocytes. Confluent primary fibroblasts were irradiated with 4Gy and lymphocytes with 2 Gy of -rays, doses delivered at 0.5 and 2.0 Gy/min. RNA was extracted at 6 h post-irradiation for the expression analysis by the cDNA array method in fibroblasts. Few DNA repair genes and proteins (H2AX, PCNA and FEN1) were analyzed by qPCR and Western blot, respectively, in both cell types, at two time-points (2 and 6 h post-irradiation). Results on gene expression were analyzed by the SAM method, which indicated 94 up-regulated genes (False discovery rate < 0.05) at 0.5 Gy/min. The most significant biological processes associated with modulated genes were metabolism, DNA repair, apoptosis signaling and stress response. On the other hand, 34 genes were modulated in cells irradiated at 2.0 Gy/min. (4 up-regulated and 30 down-regulated genes). For such DR, the major biological processes were metabolism, DNA repair, replication, stress response and apoptosis. By using qPCR method, some DNA repair genes (ERCC1, ERCC3 (or XPB), XPF, XPA, FEN1) and ATM (damage sensor) were studied. A wide difference in gene modulation was detected in response to different DR, mainly for fibroblasts analyzed at 2 h post-irradiation. However, this difference was slight in lymphocytes, suggesting that other alternative repair pathways could occurr in irradiated lymphocytes under low TD, possibly in consequence of DNA lesions such as double strand breaks, which are efficiently induced by 2 Gy. Interestingly, the expression of PCNA was down-regulated in fibroblasts irradiated at 2.0 Gy/min, while the expression of H2AX in lymphocytes decreased at both DR 6 h post-irradiation, These findings indicated several biological processes involved in stress responses generated by irradiation at two different DR in human cells. Actually, DR influenced cellular responses at transcriptional and protein levels. These data obtained at molecular level provide relevant information towards clarifying the mechanisms underlying cellular responses displayed by irradiated- normal cells.

INTRODUÇÃO: A presença de rugas na face devido à hipercinese muscular é comum nas regiões frontal, glabelar e peri-orbitárias. São descritos diversos métodos para o tratamento das rugas de expressão, como a dermoabrasão, a ablação a laser, o laser não ablativo, preenchimentos, cirurgia e aplicações de toxina botulínica. O tratamento das rugas da face com toxina botulínica tipo A é método consagrado, porém são pouco definidos os efeitos a longo prazo. Este estudo retrospectivo teve como objetivo avaliar as rugas das regiões frontal e glabelar da face em pacientes submetidas a aplicações seriadas da toxina botulínica tipo A com finalidade estética, analisando os intervalos entre as aplicações e as doses utilizadas. MÉTODOS: Foram analisadas 24 pacientes do sexo feminino, submetidas entre 5 a 7 aplicações da toxina botulínica tipo A, no período de julho de 1997 a junho de 2006. O tempo médio de acompanhamento foi de 42,2 (± 4,0) meses e o intervalo médio entre as aplicações de 8 (± 0,51) meses. A idade média observada de início da aplicação foi de 48,0 (± 3,0) anos, e da última aplicação foi de 51,6 (± 3,0) anos. Foram métodos de avaliação a análise da documentação fotográfica de antes da primeira e antes da última aplicação, sendo as rugas frontais e glabelares avaliadas segundo escala padronizada, e dados colhidos dos prontuários. RESULTADOS: A longo prazo, verificou-se: 1) amenização das rugas estáticas da região frontal em 62,5% das pacientes e em 37,5% tais rugas se mantiveram inalteradas; 2) amenização das rugas estáticas da região glabelar em 47,2% das pacientes, em 50% tais rugas se mantiveram inalteradas e em 2,8% verificou-se pouca acentuação; 3) amenização das rugas dinâmicas da região frontal em 84,7% das pacientes e em 15,3% tais rugas se mantiveram inalteradas; 4) amenização das rugas dinâmicas da região glabelar (corrugadores) em 63,9% das pacientes, em 26,4% tais rugas se mantiveram inalteradas e em 9,7% verificou-se pouca acentuação. 5) amenização das rugas dinâmicas da região glabelar (prócero) em 57% das pacientes, em 32% tais rugas se mantiveram inalteradas e em 11% verificou-se pouca acentuação. A média da dose total de toxina botulínica utilizada por sessão no presente estudo foi de 43,83 ± 1,25 U, e a dose total cumulativa foi de 272,08 ± 20,42 U. CONCLUSÕES: No longo prazo, existe maior porcentagem de pacientes com amenização ou aspecto inalterado das rugas estáticas e dinâmicas das regiões frontal e glabelar da face em relação a pacientes com acentuação das mesmas. Não houve variação estatisticamente significativa das médias dos intervalos entre as aplicações. A dose total de toxina botulínica aumentou de forma estatisticamente significativa até a terceira aplicação, mantendo-se sem variação significativa a partir de então. / INTRODUCTION: The presence of wrinkles on the face due to the over activity of muscles is rather common on the frontal, glabellar, and periocular regions. A number of methods for the treatment of face lines, such as skin abrasion, laser resurfacing, fillers, surgery and botulinum toxin A have been described. The treatment of facial rhytids with botulinum toxin A is widely used. However, its long term effects are not well defined. This retrospective study assesses the rhytids of both the frontal and glabellar regions of the face on patients submitted to multiple botulinum toxin A applications for aesthetic use, analyzing intervals between applications and dosages. METHODS: 24 female patients who had undergone 5 to 7 botulinum toxin A applications from July, 1997 to June, 2006 were studied. The mean time of follow up was 42.2 (± 4.0) months and the mean interval between applications was 8 (± 0.51) months. The mean age of the patients at the beginning of application was 48.0 (± 3.0) years old, and 51.6 (± 3.0) years old at the last application. The evaluation was carried through the analysis of photographic documentation from before the first and last applications, and both frontal and glabellar rhytids were evaluated according to standardized scale, as well as data collected from patients charts. RESULTS: the long term analysis demonstrated that: 1) improvement of the static rhytids of the frontal region in 62,5% of patients and such rhytids remained unaltered in 37.5% of the patients; 2) improvement of the static rhytids of the glabellar region in 47.2% of the patients, they remained unaltered in 50% of the patients and there was a slight worsening in 2.8% of the patients; 3) improvement of the dynamic rhytids of the frontal region in 84.7% of patients, and they remained unaltered in 15.3% of the patients; 4) improvement of the dynamic rhytids of the glabellar region (corrugator) in 63.9% of the patients, they remained unaltered in 26.4% of the patients and there was a slight worsening in 9.7% of the patients; 5) improvement of the dynamic rhytids of the glabellar region (procerus) in 57% of the patients, they remained unaltered in 32% and there was a slight worsening in 11% of the patients. The mean total dosage of botulinum toxin A used per session in this study was 43.83 ± 1.25 U, and the total cumulative dosage was 272.08 ± 20.42 U. CONCLUSIONS: In the long run, a higher percentage of patients showed improvement or unaltered aspect of their static and dynamic rhytids of the frontal and glabellar regions of the face, when compared to the patients that showed worsening. There was no variation of the mean intervals between the applications. The total dosage of botulinum toxin was significantly increased up to the third application, and kept stable in the following sessions.

Mon projet de thèse repose sur l'idée de l'optimisation du rapport bénéfice /risque (fonction d'utilité) des doses de traitements ciblés en oncologie en intégrant la notion de l'efficacité dans les essais de phase précoce plus que la toxicité. Ceci est réalisé par le choix d'un schéma d'administration/dose optimal en se basant sur la modélisation pharmacocinétique-pharmacodynamique (PK-PD). L'application pratique de ce concept fait l'objet de mon projet de thèse, qui se présente par un essai multiparamétrique de phase 1, dont l'objectif principal est d'évaluer la tolérance de l'association de deux agents anticancéreux, évérolimus et sorafenib, à différentes doses et selon différents schémas d'administration, chez des patients ayant un cancer solide métastatique. Dans ce contexte, un modèle mathématique, multi-échelle de translation destiné à quantifier les relations entre différentes doses, pharmacocinétique, pharmacodynamie des effets radiologiques et cliniques est développé pour explorer les intéractions PK-PD ; ce qui permettra ensuite de choisir le protocole d'administration optimal de cette association. Ceci demande une bonne maîtrise de l'approche de population, une méthodologie basée sur un modèle d'effet mixte non linéaire en utilisant le logiciel (NONMEM 7), qui sert à ajuster les modèles aux données ainsi que les analyses pharmacocinétiques des données / The development of everolimus and sorafenib combination was stopped by drug companies, due to the high toxicity index and the lack of a clear benefit/toxicity ratio to guide dose recommendations for a phase II trial.We designed the first multi-parameter phase I study (EVESOR), based on mathematical modeling of data provided from an adequately designed trial. We aimed to identify optimal doses and dosing schedules for the everolimus ands orafenib combination and maximize the simulated benefit/toxicity ratioThere is strong rationale to combine everolimus and sorafenib in treatment of solid tumor patients. Indeed these drugs block 2 important interacting signaling pathways involved in tumor growth: PI3K-AKT-mTor and RAS-RAF-ERK pathways. The determination of the best drug doses and dosing schedules of this combination is a challenge.The combination has been assessed in several phase 1 trials. Preliminary outcomes suggest promising efficacy but potential limiting toxicities such as hand foot syndrome and biological disorders. In these trials, the impact of administration sequences of one drug with respect to other one has not been assessed. Daily monotherapy regimens of both drugs were used. However sorafenib dosing schedule may impact on everolimus tumor delivery and thus on toxicity & efficacy. It should be possible to determine the optimized doses and dosing schedules of both drugs, which are able to maximize the benefit/toxicity ratio using modeling and simulation studies. Adequate data from a phase 1 trial designed with this objective are requiredMathematical modeling may be a promising tool for establishing the links between doses, dosing schedules, pharmacokinetics, pharmacodynamics, pharmacogenomics, radiological and clinical effects and for simulating the benefit/toxicity ratio induced by different doses and dosing schedules of drug combinations

L’uranium (U) et le fluor (F) sont des substances néphrotoxiques naturelles et anthropogéniques auxquelles la population peut être exposée quotidiennement. Cependant, leurs effets à faibles doses restent méconnus et des études précédentes suggèrent qu’une exposition chronique à de faibles doses pourrait induire une réponse adaptative (RA). Afin de mettre en évidence cette RA rénale in vivo, un protocole d’exposition prime à faibles doses suivie d’un traitement challenge néphrotoxique a été mis en place. Une première étude dose-réponse aiguë a permis de définir nos conditions challenge, avec des doses néphrotoxiques de 5 et 7.5 mg/kg d’U et de F, et un temps d’analyse de 72h post-injection. Pour l’étude de la RA, les souris ont été contaminées 6 mois via l’eau de boisson à des doses prime d’U (0, 10, 20 et 40 mg/L) ou de F (0, 15, 30 et 50 mg/L), puis traitées aux concentrations « challenge ». Une RA est observée aux doses respectives de 20 et 50 mg/L d’U et de F, avec un retour à la normale de l’expression et de la sécrétion de biomarqueurs de néphrotoxicité KIM-1 et CLU en comparaison aux animaux non pré-exposés. Une diminution de l’apoptose ou de l’expression in situ de VCAM est observée chez les animaux pré-exposés respectivement à 20 mg/L d’U ou à 50 mg/L de fluor, concentrations auxquelles la RA a été identifiée. L’autophagie, la réponse UPR et le recrutement de cellules inflammatoires sont des mécanismes induits par l’U alors que seule la réponse UPR est induite par le F. Cependant, nos résultats ne permettent pas de les identifier comme des mécanismes impliqués dans la RA, car ces derniers sont induits avec ou sans préexposition. En conclusion, cette étude montre l’existence d’une RA dans le cadre d’une exposition chronique à de faibles doses d’U ou de F chez la souris, avec l’induction de mécanismes adaptatifs tels que la régulation de l’apoptose et de l’inflammation. Ces résultats permettent de mieux appréhender les effets de faibles expositions chroniques chez l’Homme, et d’apporter de nouvelles connaissances pour la radioprotection de l’Homme. / Human population can be daily exposed to uranium (U) and fluoride (F) because of their natural and anthropogenic presence in the environment. Although U and F are known to be nephrotoxicant at high doses, their effects after low dose exposures are still unknown and previous studies suggested that chronic exposures to low doses of U or F could induce adaptive responses (AR). Therefore, a mouse in vivo study was designed and carried out to examine whether exposure to chronic low priming doses of U and F can induce AR in the kidney upon exposure to nephrotoxic challenge treatment. A pilot dose-response study allowed selecting the nephrotoxic challenge treatments (5 mg/kg U and 7.5 mg/kg F), with a time of analysis of 72h post treatment. To study the AR, mice were exposed through drinking water for 6 months to priming doses of U (10, 20 and 40 mg/L) or F (15, 30 and 50 mg/L), and subsequently challenged. An AR was observed at the doses of 20 mg/L U and 50 mg/L F, with a return to normal gene expression and urinary levels of nephrotoxicity biomarkers KIM 1 and CLU in comparison with the non-pre-exposed mice. Apoptosis was reduced in animals pre-exposed to 20 mg/L U and a decrease of VCAM in situ expression was observed in animals pre-exposed to 50 mg/L F. These concentrations correspond to the appearance of AR. The unfolded protein response (UPR), autophagy and inflammatory cell recruitment were the mechanisms induced by U whereas only UPR was induced by F. However, these mechanisms were induced in challenged animals irrespective of pre-exposure. Thus, our results do not allow us to identify these mechanisms as those involved in the AR. In summary, our data showed the existence of an AR to low doses of U and F delivered chronically to mice, with the induction of adaptive mechanisms such as apoptosis and inflammatory regulation. Results of this study allow for better understanding of the potential effects chronic low-dose exposures of U and F on human population, and provide new knowledge for informing the radioprotection system.

Le paracétamol est sujet à controverse depuis sa découverte. Que ce soit son mécanisme d’action, ses effets indésirables ou son efficacité, de nombreuses études ont été réalisées et parfois se contredisent. Parfois critiqué pour son efficacité limitée, il n’a pourtant rien à envier aux autres antalgiques : il soulage les douleurs faibles à modérées sans effets indésirables aux doses thérapeutiques. Cela en fait un médicament de premier recours chez la femme enceinte, le nourrisson et l’enfant. D’après un rapport de l’ANSM, sur les 30 substances actives les plus vendues en France en 2013 (montant total 1,15 milliard de boîtes), le paracétamol domine très largement (plus de 500 millions de boîtes). C'est l’antalgique et l’antipyrétique le plus consommé au monde. La pharmacopée des antalgiques est vieillissante, l’évolution de l’arsenal thérapeutique depuis 50 ans est limitée. Ce constat amène à réévaluer les stratégies de recherche. Maintenant, notre intérêt serait de comprendre les mécanismes et les cibles de ces antalgiques afin de développer des analogues plus affins tout en limitant leurs effets indésirables. Basée cette stratégie, le paracétamol est un parfait candidat. En effet, son mécanisme d’action n’est pas parfaitement connu mais son efficacité n’est plus à prouver. L’objectif de ces travaux est d’élucider le mystère qui entoure son mécanisme d’action et de découvrir ses cibles. Les dernières études redéfinissent le paracétamol comme un précurseur métabolique à l’origine d’un dérivé lipidique actif, nommé AM404. Ce dernier serait synthétisé dans certaines régions cérébrales exprimant l’enzyme FAAH capable de catalyser cette réaction. Le mécanisme alors mis en jeu montre que le paracétamol, via l’AM404, activerait les récepteurs TRPV1 centraux et indirectement les récepteurs CB1 pour renforcer un mécanisme central d’atténuation de la douleur via les voies descendantes sérotoninergiques. Cependant, le noyau cérébral concerné et le mécanisme cellulaire mis en jeu demeurent inconnus. Des données comportementales associées à une étude d’imagerie fonctionnelle ont levé le voile sur plusieurs régions cérébrales potentiellement impliquées dans l’action du paracétamol, notamment la substance grise périaqueducale. Cette dernière a suscité notre intérêt, car ce noyau exprime à la fois la triade FAAH/TRPV1/CB1, mais aussi est un carrefour des voies descendantes sérotoninergiques. Une activation dans la substance grise périaqueducale des récepteurs TRPV1 et CB1 est à même de produire un effet antinociceptif dépendant de ces contrôles descendants. Ces travaux de thèse ont conduit à conforter que l’action antalgique du paracétamol implique un mécanisme supra-spinal dépendant de l’enzyme FAAH en condition pathologique. Plus précisément, nous avons étudié le rôle de la triade FAAH/TRPV1/CB1 au niveau de la SGPA. Nous avons découvert que le paracétamol interagissait avec une voie de signalisation cellulaire mGLUR5-PLC-DAGL responsable de la production de l’endocannabinoïde 2-AG. Ce mécanisme pourrait à la fois expliquer l’étroite collaboration existant entre les récepteurs TRPV1 et CB1 dans l’effet antalgique du paracétamol et le renforcement des voies descendantes sérotoninergiques. Le paracétamol est donc un promédicament dont l’action cérébrale recruterait un ensemble de systèmes complexes pour médier son effet antalgique. Ce mécanisme séduisant ouvre la piste à de nouveaux antalgiques toujours plus efficaces avec des effets indésirables moindres, à l’image du paracétamol. / Paracetamol is since its discovery controversial. Whether with respect to the mechanism of action, its side effects or effectiveness, many studies have been performed, at times contradictory. Sometimes criticized for its limited effectiveness, it has nothing to envy in contrast to other analgesics whose effectiveness are often associated with side effects. Paracetamol has proven itself to relieve low to moderate pain without side effects at therapeutic doses. This makes it drug of choice for pregnant women, infants and children. According to a report by the ANSM of the 30 top-selling active substances in France in 2013, with a total of 1.15 billion boxes, paracetamol largely dominates this ranking as its sales are over 500 million boxes. Thus it has become the analgesic and antipyretic most consumed in the world. Today, the pharmacopoeia of analgesics is outdated; evolution of the therapeutic arsenal for 50 years is limited with few major discoveries reported. This observation leads to the need to reassess research strategies to innovate new and more effective molecules. Until now, the aim was to focus on a few molecules with high therapeutic potential in order to optimize their effectiveness without understanding their mechanisms. Now our interest is to understand the mechanisms and targets of these analgesics in order to develop more comparable molecules while limiting their adverse effects. Based on this strategy, paracetamol is a perfect candidate. Indeed, its mechanism of action is not fully known, but its effectiveness is proven. The aim of this work is to elucidate the mystery surrounding its mechanism of action and discover its targets. The latest studies redefine paracetamol as a metabolic precursor to the origin of an active lipid derivative, called AM404. The latter is synthesized in certain regions of the brain expressing the FAAH enzyme capable of catalyzing this reaction. The mechanism thus put into play shows that paracetamol, via AM404, activates TRPV1 receptors and the central CB1 receptors indirectly to reinforce a central mechanism of pain relief via serotonergic descending pathways. However, the cerebral area concerned and the cellular mechanism involved remain unknown. Behavioral data associated with a functional imaging study unveiled several brain regions potentially involved in the action of paracetamol, including the periaqueductal gray matter. The latter sparked our interest for two reasons: one because it expresses the core triad FAAH/TRPV1/CB1; and two it also represents a crossroad of descending serotonergic pathways. Activation in the periaqueductal gray matter of the TRPV1 and CB1 receptors is adapted to produce an antinociceptive effect dependent on these descendant control systems. This work of this thesis has led to re-affirm that the analgesic action induced by paracetamol involves a supra-spinal mechanism dependent on the FAAH enzyme in pathological conditions. Specifically, we investigated the role of the triad FAAH/TRPV1/CB1 in the periaqueductal gray matter. We found that paracetamol interacted with the cell signaling pathway mGluR5-PLC-DAGL responsible for production of the endocannabinoid 2-AG. This mechanism can explain both the close collaboration between the TRPV1 and CB1 receptors in the analgesic effect of paracetamol and the reinforcing of serotonergic descending pathways. Paracetamol is thus a prodrug whose cerebral action involves a set of complex systems to mediate its analgesic effect. This attractive mechanism opens the track to new painkillers ever more effective with fewer side effects, reflected paracetamol mechanism.

Les améliorations dans les procédures cliniques de radiothérapie ont conduit à des taux de survie élevés. En conséquence, les effets secondaires possibles de la dose délivrée aux tissus sains sont devenus une préoccupation croissante pour les radiothérapeutes. L’estimation de la dose aux tissus sains, y compris à distance du volume-cible présente un intérêt clinique croissant pour évaluer le risque aux structures sensibles situées hors du champ d’irradiation. Nos travaux antérieurs se sont focalisés sur l’évaluation la dose à distance des faisceaux de photons. La dose à distance due aux faisceaux d’électrons n’a jamais été prise en compte, ce qui peut conduire à des sous-estimations des doses à distance lorsque le traitement est fait entièrement ou partiellement par les électrons. C’est la raison pour laquelle, une étude approfondie de la dose à distance des faisceaux d’électrons est devenue indispensable. Dans le présent travail de thèse, nous avons dans un premier temps réalisé une étude expérimentale décrivant la dose à distance des faisceaux d’électrons de haute énergie produits par différents accélérateurs linéaires, équipés de différents types d’applicateurs. Nous avons analysé l’influence de différents paramètres du faisceau sur la dose à distance dont l’énergie du faisceau, la taille et le type de l’applicateur, la distance à l’axe du faisceau ainsi que la profondeur dans l’eau. Nous avons séparé la dose à distance en deux composantes principales : la dose due aux photons de bremsstrahlung et la dose due aux électrons diffusés. Ensuite, nous avons développé un modèle pour le calcul de la composante de la dose due aux photons de bremsstrahlung en tout point dans le patient, et un modèle pour le calcul de la dose due aux électrons diffusés en dehors du champ d’irradiation. Enfin, nous avons évalué l’application de nos modèles de calcul de dose à distance dans une situation clinique réelles afin de démontrer l’intérêt clinique de notre modélisation, l’objectif étant de mettre un point à terme, un outil logiciel innovant répondant à la fois aux besoins de l’optimisation de la radiothérapie moderne et à ceux de l’épidémiologie de la dose comme facteur de risque d’effets iatrogènes. / The large improvements in the radiotherapy (RT) procedures have led to high survival rates. So the possible side late effects of the radiotherapy due to the doses deposited into the normal tissues have become a growing concern for the radio-oncologists. The assessment of the dose outside the radiation field presents an important clinical benefit for estimating the risk at sensible structures situated partially or entirely outside the radiation field, especially in pediatric, pregnant patients or the patients having cardiac implantable devices. More understanding of side effects of RT will require not only improved control of the high doses delivered to the target volumes, but also better knowledge of the unintended but unavoidable lower doses delivered out of the target. In this context, most studies on out-of-field dose estimation focus on photon beams. Nevertheless, electron beams are still an important component of RT, for treating superficial tumors (at depths < 5 cm). The out-of-field dose from electron beams has never been taken account, which causes an under estimation of this dose when the radiotherapy is done only or partly by the electrons. For this reason, a detailed investigation of the out-of-field dose from electron beams is essential for better estimation of the out-of-field dose regardless the radiotherapy type. In this thesis, we have experimentally evaluated the out-of-field doses in high-energy electron beams for three linear accelerators equipped with different electron applicator types used in daily practice. The dependence of this dose on different parameters, such as the applicator size, the electron beam energy, the depth, and the off-axis distance have been investigated. The scattered electrons component and the bremsstrahlung photons component have been separated by a semi-experimental method. We have developed a multi-source model based on existing multi-scattering models for calculating the bremsstrahlung dose distribution at any point in the patient inside and outside the radiation field. We have also analytically calculated the scattered electrons dose distribution outside the radiation field. These two models permit to calculate the total out-of-field dose from electron beams anywhere in the patient. Finally, we have evaluated the application of our models of dose calculation in a real clinical situation in order to validate our software, the aim being to set up an innovative software tool, meeting both the needs of radiotherapy and epidemiology of the dose as a risk factor for iatrogenic effects

L'arthrose est une maladie dégénérative de l'articulation qui provoque des douleurs, une raideur et une diminution de mobilité. La quantification de l’interligne articulaire est la mesure qui permet de diagnostiquer la maladie et de suivre son évolution. A ce jour, la radiographie conventionnelle est la méthode de référence pour ce diagnostic et ce suivi. Néanmoins, l'articulation du genou et ses modifications structurales sont trop complexes pour permettre un diagnostic à un stade précoce à partir de simples images 2D. Une des pistes prometteuses de la recherche sur le diagnostic précoce est l’exploitation de l’information 3D de l’interligne. C’est dans ce contexte que s’inscrit cette thèse qui a pour but la segmentation et la quantification 3D de l’interligne articulaire afin d’atteindre l’objectif du diagnostic précoce de l’arthrose de genou. Au cours de cette thèse nous avons développé une méthode de quantification semi-automatique de l’interligne articulaire. La cartographie 3D des distances générée a permis de caractériser la morphologie de l’espace articulaire sur des images haute résolution 3D. Pour atteindre l’objectif de quantification à basse dose, deux approches ont été explorées. La première consistait à proposer une approche de segmentation 3D du volume osseux à partir d’un faible nombre de projections. La deuxième approche consiste à réaliser la quantification 3D de l’interligne sur des images issus d’un scanner basse dose obtenue à l’aide d’autres algorithmes mis en œuvre par les partenaires du projet VOXELO. La segmentation de l’interligne a été dans ce cas utilisée comme un critère de qualité de la reconstruction selon ces différents algorithmes.Afin de tester la robustesse de notre approche, nous avons utilisé des images haute résolution selon 2 types de géométrie du faisceau ou des images à faible dose et également sur des images scanner clinique in vivo. Ceci nous permet de conclure que la méthode de quantification de l’interligne que nous avons développé en 3D est potentiellement applicable sur des images provenant de différents appareils de scanner. Cet outil sera potentiellement utile pour détecter les stades précoces et suivre la progression de l'arthrose en clinique. / Osteoarthritis (OA) is a degenerative joint disease that causes pain, stiffness and decrease mobility. Knee OA presents the greatest morbidity. The main characteristic of OA is the cartilage loss inducing joint space narrowing. Usually, the diagnosis and progression of OA is monitored by the joint space measurement. Actually, conventional radiography is the reference method for the diagnosis and monitoring. However, the knee joint and structural changes are too complex to be assessed from simple 2D images especially at early stage. A promising research into early diagnosis is the use of 3D. The objective of our thesis is to provide a tool for a 3D quantification of joint space in order to achieve the goal of early diagnosis of knee osteoarthritis. In this thesis we have developed a semi-automatic method for the quantification of joint space. The 3D map generated allowed us to characterize the morphology of the joint space widths on 3D high resolution images.To achieve the goal of low-dose quantification, two approaches have been explored. The first was to provide a 3D segmentation method for bone extraction from a limited number of projections. The second approach is to perform the 3D quantification from a low dose scan obtained using other algorithms implemented by our partners of VOXELO project. The segmentation of the joint space was used as a quality criterion according to these different algorithms.To test the robustness of our approach, we used high-resolution images with different geometry acquisition types and low-dose images. We have also done a test on clinical CT images in vivo. This allows us to conclude that the method we developed is potentially applicable to images from different scanner devices. This tool can be used for detecting the early stages and track the progress of the clinical osteoarthritis

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