Cette thèse porte sur les convertisseurs des liaisons à courant continu (HVDC- High Voltage Direct Current). Une nouvelle méthodologie de synthèse des régulateurs des convertisseurs basée sur un modèle de commande a été développée. Ce dernier prend en considération non seulement les deux convertisseurs de la liaison HVDC mais aussi l'ensemble des principaux éléments impactant la stabilité transitoire du système électrique dans lequel la liaison est insérée. Une commande robuste coordonnée est proposée pour, à la fois, répondre au cahier des charges de la liaison et améliorer la stabilité de la zone AC voisine à la liaison. La coordination de la synthèse de régulateurs pour les convertisseurs se fait à deux niveaux : le premier concerne les deux stations de conversion d'une même liaison HVDC et un second consistant en la coordination de plusieurs liaisons HVDC. De plus, seules les mesures disponibles localement (i.e., au niveau des stations de conversion) sont utilisées. Ce nouveau cadre de commande est une alternative à la commande vectorielle classique. L'approche a été validée à la fois sur des benchmarks académiques et en grande taille sur des cas concrets de renforcement du réseau de transport européen. / This thesis focuses on the control of converters of high voltage direct current (HVDC) links. A new methodology of synthesis of the controllers of the HVDC converters based on a control model has been developed. The latter takes into consideration not only the two converters of HVDC link but all the main dynamics affecting the transient stability of the power system in which the link is inserted. In order to improve the stability of the AC zone neighboring the HVDC link, in addition to the local objectives like power and voltage control, a coordinated robust control is proposed. The coordination of the synthesis controllers for converters is done at two levels: the first one is the coordination of the two stations of an HVDC link the second is consisting on the coordination of several HVDC links. In addition, only measures available locally (i.e., at the converter stations) are used. This new control frame is an alternative to the conventional vector control. The approach was validated on both academic benchmark and a large-scale dynamic model of the whole European power system.

A Interconsulta Psiquiátrica é considerada uma área da Psiquiatria, que trabalha no Hospital Geral compondo uma equipe (Psiquiatria de Ligação) ou prestando seus serviços a uma equipe solicitante (Consultoria Psiquiátrica). O Serviço de Interconsulta em Psiquiatria (SIP) do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) teve início em março de 1978 e a Terapia Ocupacional passou a integrar esta equipe em 1999. O cotidiano hospitalar tem uma marca própria com obrigações como usar vestimentas, ter horários previamente estabelecidos para se alimentar, para cuidar de sua higiene e para receber visitas, inclusive dos familiares. Os terapeutas ocupacionais, como profissionais que lidam com o cotidiano do indivíduo, têm sido inseridos nas equipes multiprofissionais do Hospital Geral, contribuindo com seus conhecimentos teóricos e técnicos específicos para cuidar de pessoas hospitalizadas. Apesar das várias funções que a Terapia Ocupacional (TO) pode exercer no Serviço de Interconsulta, existe escassez de estudos publicados sobre o perfil sócio-demográfico dos pacientes atendidos, o que prejudica o planejamento de ações e o levantamento da necessidade de recursos humanos para aquele Serviço. O objetivo deste trabalho foi realizar um estudo retrospectivo dos Pedidos de Interconsulta (PIs) para a TO do Serviço de Interconsulta em Saúde Mental (SISMen) do HCFMRP - USP no período de janeiro de 2000 a dezembro de 2005. Os sujeitos foram os indivíduos que estiveram internados nas enfermarias do campus do hospital universitário e para quem foi solicitada a assistência do Serviço de TO naquele período, perfazendo um total de 633 pacientes e 709 PIs. Os dados foram coletados mediante consulta dos PIs e dos prontuários dos pacientes. A maioria dos sujeitos consultados foi do sexo feminino, com ensino fundamental incompleto e houve distribuição equilibrada entre os solteiros e casados. Quanto à idade e à situação laboral, a média de idade dos pacientes foi de 39,2 anos e a maioria deles era autônoma ou aposentada, seguida de dona de casa. Verificou-se que a Clínica Médica foi a responsável por mais do que um terço dos Pedidos de Interconsulta feitos para o Serviço de TO, seguida das clínicas Unidade Metabólica e Psiquiatria respectivamente; o tempo médio de internação dos pacientes encaminhados para esse Serviço foi de 51 dias, sendo que a média de internação no HCFMRP-USP foi de 6,4 dias. Consequentemente, o gasto desses pacientes variou entre uma e 2,4 vezes mais do que os pacientes internados nesta instituição. A taxa média de encaminhamento para a TO do SISMen foi de 0,5%, sendo que o motivo de solicitação mais freqüente esteve relacionado aos aspectos emocionais do indivíduo, seguido por fatores referentes à hospitalização. Estes dados, de modo geral, estão de acordo com a literatura nacional e internacional dos SIPs. Concluiu-se que há necessidade de um instrumento padronizado para avaliar a população atendida pelo Serviço de Interconsulta de TO e que alguns pontos merecem estudos mais detalhados como a possibilidade de existência de associações entre dados sócio-demográficos e clínicos e o encaminhamento dos pacientes para esse Serviço. / Consultation Liaison Psychiatric is considered to be an area of Psychiatry which is part of a General Hospital, involving a team (Liaison Psychiatry) or providing services to a team that requests them (Psychiatric Consultation). The Consultation Liaison Psychiatric Service (CLPS) of the University Hospital, Faculty of Medicine of Ribeirão Preto (HCFMRPUSP) was started in March 1978 and Occupational Therapy became part of this team in 1999. The daily hospital routine has specific rules such as wearing specific clothing and taking meals, caring for ones hygiene and receiving visits, including those of relatives, at pre-established times. Occupational therapists, as professionals who deal with the daily routine of an individual, have been inserted into the multiprofessional teams of the General Hospital, contributing their specific theoretical and technical knowledge to the care of hospitalized persons. Despite the various functions Occupational Therapy (OT) can perform in the CLPS, there is a scarcity of published studies on the sociodemographic profile of attended patients, impairing the planning of actions and the determination of the human resources needed for that Service. The objective of the present investigation was to conduct a retrospective study of the Requests of Consultation Liaison (RCLs) sent to the OT of the Service of The Consultation Liaison in Mental Health (SCLMH) of HCFMRP-USP during the period from January 2000 to December 2005. The subjects involved were the individuals who had been admitted to the wards of the University Hospital and for whom the assistance of the OT Service had been requested during that period, for a total of 633 patients and 709 RCLs. The data were collected from the RCLs and the medical records of the patients. Most of the subjects involved were women with incomplete elementary schooling, with a balanced distribution of single and married subjects. Mean patient age was 39.2 years and most patients were self-employed or retired, followed by the housewife category. Internal Medicine was responsible for more than one third of the RCLs sent to the OT Service, followed by the Metabolic Unit and Psychiatric clinics. The mean time of hospitalization of the patients referred to this Service was 51 days, with the mean duration of hospitalization at HCFMRPUSP being 6.4 days. Consequently, the expenses with these patients ranged from one to 2.4 times more than those for the patients hospitalized in this institution. The mean rate of referral to the OT of the SCLMH was 0.5%, with the most frequent reason for the request being related to the emotional aspects of the individual, followed by factors related to hospitalization. These data, in general, agree with the Brazilian and international literature about the CLPS. We conclude that there is the need for a standardized instrument for the evaluation of the population attended at the Consultation Liaison Service of OT and that some points need more detailed studies regarding the possibility of the existence of an association between sociodemographic and clinical data and the referral of these patients to the OT Service.

La thérapie photodynamique (PDT) est une modalité de traitement du cancer qui utilise la combinaison d'un photosensibilisant, de la lumière et d'oxygène moléculaire. L'application de nanosubstances liposomales pour délivrer les photosensibilisants dans la tumeur est devenu un sujet important de la recherche en PDT.La présente étude porte sur les formulations liposomales conventionnelles et stériquement stabilisées de photosensibilisant mTHPC, Foslip® et Fospeg®, dans le but de déterminer les paramètres pour l'optimisation de la PDT liposomale. La caractérisation du comportement in vitro de la mTHPC liposomale a été étudiée, particulièrement sa localisation, l'état d'agrégation et les propriétés photophysiques des drogues dans les liposomes. Nous avons démontré l'état monomérique de la mTHPC dans les vésicules lipidiques et une localisation partielle du mTHPC dans Fospeg® dans la partie PEG des liposomes, alors que la majeure partie est liée à la bicouche lipidique. Nous avons ensuite étudié les cinétiques de relargage des drogues, le mode de liaison aux protéines et la destruction des liposomes dans le sérum. Dans ce but, une méthodologie basée sur la fluorescence pour estimer le relargage de la mTHPC à la fois in vitro et in vivo a été développée. Le relargage de la mTHPC des liposomes PEGylés a été retardé par rapport aux liposomes conventionnels et la destruction des liposomes a été considérablement diminuée. La connaissance de tous ces paramètres permet de mieux prédire le taux de relargage de la drogue, les paramètres pharmacologiques et l'effet tumoricide in vivo. Le traitement PDT pourrait être plus avantageux avec le Fospeg® comparé à la mTHPC incorporée dans les liposomes conventionnels / Photodynamic therapy (PDT) is a photochemical-based modality of cancer treatment that uses a combination of a photosensitizer, light and molecular oxygen. Application of liposomal nanocarriers to deliver photosensitizers to tumor targets has become a major direction of PDT research. The present study investigates conventional and sterically stabilized liposomal formulations of the photosensitizer mTHPC, Foslip® and Fospeg®, with a view to determine the parameters for optimizing liposomal PDT. The characterization of in vitro behaviour of liposomal mTHPC was conducted, with an emphasis on drug localization, aggregation state and photophysical properties of the compounds in liposomes. We demonstrated the monomeric state of mTHPC in lipid vesicles and a partial localisation of mTHPC in Fospeg® in a PEG shell, while the main part was bound to the lipid bilayer. We further studied the drug release kinetics and binding pattern to serum proteins and the destruction of liposomes in serum. With this aim, a fluorescence-based methodology of estimating mTHPC release both in vitro and in vivo was developed, as well as an in vitro assay to characterize liposome destruction. The release of mTHPC from PEGylated liposomes was delayed compared with conventional liposomes along with greatly diminished liposome destruction. Knowledge of these parameters allows to better predict the drug release rate, pharmacological parameters and in vivo tumoricidal effect. The PDT treatment could be more advantageous with Fospeg® compared to mTHPC embedded in conventional liposomes

La thérapie photodynamique (PDT) est un traitement minimalement invasif basé sur une approche photochimique. Ce traitement est prometteur en oncologie et pour d’autres pathologies. La plupart des drogues utilisées en PDT (photosensibilisateurs) y compris le PS de seconde génération, la méta-tétra (hydroxyphényl)chlorine (mTHPC), sont hautement hydrophobiques et nécessitent un système de transport. Pour améliorer la solubilité de la mTHPC et ses propriétés pharmacocinétiques, les dérivés des β-cyclodextrines (β-CDs) ont été proposés. L’étude présente a analysé l’effet des β-CDs sur le comportement de la mTHPC à différentes étapes de sa distribution in vitro et in vivo. L’interaction de la mTHPC avec les β-CDs conduit à la formation de complexes d’inclusion qui abolissent complètement son agrégation après introduction dans le sérum. Il a été démontré que les β-CDs ont un effet lié à la concentration sur le processus de distribution de la mTHPC dans le sérum sanguin et les cultures cellulaires in vitro. L’étude in vivo confirme le fait que l’utilisation de β-CDs permet de modifier les processus de distribution de la mTHPC chez les animaux porteurs de tumeurs, ce qui se traduit par un taux moins élevé d’accumulation du PS dans la peau et les muscles, ainsi qu’une accumulation plus élevée du PS dans la tumeur. En conclusion, l’application des dérivés β-CDs peut ouvrir de nouvelles possibilités pour modifier et contrôler la biodistribution et les pharmacocinétiques de la mTHPC au cours de la PDT / Photodynamic therapy (PDT) is a minimally invasive photochemical treatment with a promising clinical track record for oncological and some other diseases. Most PDT-drugs (photosensitizers) including a second-generation PS meta-tetra(hydroxyphenyl)chorin (mTHPC) are highly hydrophobic and require delivery systems. To improve mTHPC solubility and pharmacokinetic properties, β-cyclodextrins (β-CDs) derivatives were proposed. The present study investigates the effect of β-CDs on mTHPC behavior at various stages of its distribution in vitro and in vivo. Interaction of mTHPC with β-CDs leads to the formation of inclusion complexes that completely abolishes its aggregation after introduction into serum. It was demonstrated that the β-CDs have a concentration-dependent effect on the process of mTHPC distribution in blood serum and cellular cultures in vitro. In vivo study confirms the fact that the use of β-CDs allows modifying mTHPC distribution processes in tumor bearing animals that is reflected in the decreased level of PS accumulation in skin and muscles, as well as in the increased PS accumulation in tumor. In conclusion, application of β-CD derivatives can open up new possibilities to modify and control biodistribution and pharmacokinetics of mTHPC in the course of PDT

Clostridium difficile est une bactérie entéropathogène responsable de diarrhées nosocomiales post-antibiotiques et de colites pseudomembraneuses. Ces dernières années, l'incidence et la gravité des infections à C. difficile ont significativement augmenté en Amérique et en Europe. Cette évolution semble être liée à l'émergence puis à la dissémination très rapide d'un clone particulièrement virulent de PCR-ribotype 027. Les facteurs de virulence majeurs de C. difficile sont les toxines TcdA et TcdB qui sont responsables des lésions intestinales. Cependant, l’étape de colonisation de l’intestin par la bactérie est considérée comme un pré-requis à l’infection. Afin de mieux comprendre les mécanismes d’hypervirulence de la souche 027, nous nous sommes focalisés sur l’étude du processus de colonisation intestinal de cette souche en le comparant à celui de la souche non épidémique 630∆erm. Dans un premier temps, nous avons étudié le rôle de la protéine de liaison à la fibronectine FbpA. La caractérisation in vitro et in vivo d’un mutant d’inactivation de fbpA, nous a permis de montrer l’implication de cette protéine dans le processus de colonisation de la souche non épidémique 630∆erm. La difficulté à obtenir un mutant dans la souche épidémique 027 R20291 ne nous a pas permis de comparer les propriétés adhésives de FbpA entre les deux souches. Dans un deuxième temps, nous avons étudié les caractéristiques des protéines flagellaires FliC, FliD, FlgE et MotB. Nous avons montré que les flagelles agissent en tant qu’adhésines chez la souche 027 et que ce rôle est moins important chez la souche 630∆erm. Nous avons également montré que les flagelles sont impliqués dans des processus cellulaires autres que l’adhésion et la colonisation. Selon une étude transcriptomique d’un mutant ∆FliC de la souche 027 R20291, il s’est avéré que la flagelline est aussi impliquée dans la production de toxines, la sporulation et dans l’adaptation de la bactérie aux conditions de stress. Une étude complémentaire serait nécessaire afin de mieux comprendre le système de régulation qui régi ces différents processus cellulaires.Finalement, nous avons effectué une analyse transcriptomique de la cinétique de colonisation in vivo de la souche 027. L’étude a révélé l’expression précoce des gènes de toxines et de sporulation au cours du processus d’infection. Elle nous a également permis d’identifier des gènes spécifiques à la souche 027 qui sont exprimés lors du processus infectieux. Ces gènes pourraient éventuellement être impliqués dans la virulence de C. difficile 027 et pourraient constituer de nouvelles pistes d’étude. / Clostridium difficile is an enteropathogenic bacterium that causes post-antibiotic nosocomial diarrhea and pseudomembranous colitis. During the last decade, the incidence and the severity of C. difficile infections have significantly increased in America and Europe. This evolution seems to be related to the emergence and to the rapid dissemination of a particularly virulent clone of PCR-ribotype 027. The main virulence factors of C. difficile are the TcdA and TcdB cytotoxins which are responsible for intestinal lesions. However, the intestinal colonization by the bacterium is considered as an indispensible step for infection.To better understand the hypervirulence mechanisms of strain 027, we focused on the study of intestinal colonization process of this strain compared to the colonization process of the non-epidemic strain 630Δerm. First, we studied the role of the fibronectin binding protein FbpA. In vitro and in vivo characterization of a mutant FbpA showed the involvement of this protein in the colonization process of the non-epidemic strain 630Δerm. The difficulty of obtaining a mutant in the epidemic strain R20291 027 does not allow us to compare the adhesive properties of FbpA between the two strains.In a second step, we studied the characteristics of flagellar proteins FliC, FliD, FlgE and MotB. We showed that the flagella have a role in the adhesion and colonization of strain 027 and that this role is less important in strain 630Δerm. We also showed that flagella are involved in other cellular processes than adhesion and colonization. A transcriptomic study of a FliC mutant in 027 R20291 shows that flagellin is also involved in toxin production, sporulation and in the adaptation of bacteria to stress conditions. Further study should be performed to better understand the regulation system that governs these different cellular processes. Finally, we performed a transcriptomic analysis of the kinetic of in vivo colonization of the 027 R20291 strain. The study revealed a very early expression of toxin and sporulation genes during the first stages of the infection process. This analysis also allowed us to identify some genes, specific to 027 strains, which appeared regulated during the infection process. These genes could be involved in the virulence of C. difficile 027 strains and could provide new issues of study to better understand C. difficile virulence.

La voie de signalisation Sonic Hedgehog (Shh) joue un rôle fondamental au cours de l’embryogenèse pour la mise en place de nombreux tissus. Elle persiste à l’âge adulte et régulerait notamment le contrôle de fonctions cérébrales. Son activation requiert la liaison d’un peptide Shh sur le récepteur Patched (Ptc) qui réprime l’activité constitutive de Smoothened (Smo), un récepteur apparenté à la famille des récepteurs couplés aux protéines G (RCPG). Récemment, des essais cliniques pour le traitement de médulloblastomes et de diverses tumeurs solides chez l’Homme ont été menés avec des antagonistes de Smo. Cependant, ces molécules ont révélé des limitations à leur utilisation puisque des résistances au traitement sont apparues. Le travail de cette thèse a conduit au développement d’un modèle pharmacophorique des antagonistes de Smo qui a ensuite permis le criblage virtuel d’une banque de molécules et l’identification de nouvelles familles d’antagonistes de Smo. L’acylthiourée MRT-10 et l’acylurée MRT-14 ont été les deux premiers composés caractérisés. Des études de relations structure-activité ont permis l’identification d’une nouvelle famille d’inhibiteurs du récepteur Smo de haute affinité à laquelle l’acylguanidine MRT-83 appartient. Ce composé s’adapte parfaitement au modèle pharmacophorique des antagonistes de Smo. Les modifications structurales que MRT-83 présentes en comparaison avec les deux têtes de séries précédemment caractérisées sont à l’origine du gain d’activité de MRT-83 sur de nombreux tests cellulaires mettant en jeu l’activation de la voie Shh. Le composé MRT-83 inhibe la liaison de la BODIPY-cyclopamine sur le récepteur Smo humain et bloque la prolifération des précurseurs des cellules granulaires de rat avec une affinité de l’ordre du nanomolaire, comparable à celle des antagonistes de référence de Smo tels que le GDC-0449 et le LDE-225. Malgré l’homologie de séquence entre Smo et la famille des récepteurs Frizzled impliqués dans la signalisation Wnt, le composé MRT-83 ne présente aucun effet sur la voie Wnt. MRT-83 bloque la translocation de Smo dans le cil primaire induite par l’activation de la voie Shh dans les cellules NT2, une lignée issue d’un tératocarcinome humain, contrairement à l’antagoniste de Smo de référence, la cyclopamine qui induit l’adressage du récepteur dans le cil primaire. L’injection stéréotaxique dans le ventricule latéral de cerveau de souris adulte de MRT-83, contrairement à celle d’un composé de structure analogue, dépourvu d’activité sur Smo, inhibe l’expression des transcrits de Ptc induite par l’injection de Shh dans la zone sous-ventriculaire, l’une des deux principales aires de neurogenèse adulte. Ces résultats démontrent que les dérivés MRT bloquent également la signalisation Shh in vivo. Ainsi, les composés MRT-10, MRT-14, MRT-83 et les molécules de structure analogues caractérisées sont de puissants antagonistes de Smo. Ces molécules constituent de nouveaux outils pharmacologiques qui pourraient permettre d’améliorer notre compréhension des mécanismes moléculaires et biochimiques régulant la signalisation Hh et permettre le développement de nouvelles molécules en clinique pour le traitement des tumeurs Hh-dépendantes. / The Sonic Hedgehog (Shh) signaling pathway is implicated in multiple physiological responses including the control of brain functions. In mammals, the Shh pathway is expressed at the primary cilium and its activation requires the binding of a Shh peptide to the Patched (Ptc) receptor which represses the constitutive activity of Smoothened (Smo), a proposed member of the G-protein-coupled receptor (GPCR) family. Recently, clinical trials for treating medulloblastoma and various solid tumors in human have been conducted with Smo antagonists such as GDC-0449 or LDE-225. Such molecules may have some limitations leading to treatment resistance. In the present work, the development of a pharmacophoric model of Smo antagonists allowed a virtual screening strategy to identify novel Smo inhibitors. The acylthiourea MRT-10 and the acylurea MRT-14 were the two first leads identified. Structure-activity relationship experiments led to the discovery of new series of Smo inhibitors with high potency and to which the acylguanidine MRT-83 belongs. This inhibitor perfectly fits with the proposed pharmacophoric model for Smo antagonists. The discrete structural differences between MRT-83 and the original leads may account for the increased potency of MRT-83 observed in various in vitro Shh-based assays. MRT-83 inhibits BODIPY-cyclopamine binding to human Smo and Shh-mediated proliferation of rat granule cell proliferation with nanomolar potency similar to GDC-0449 or LDE-225. Despite significant homology of Smo with the Frizzled family of receptors which are involved in the Wnt signaling pathway, MRT-83 displays no significant effect on this pathway. MRT-83 blocks Smo translocation induced by Shh pathway activation to the primary cilia of NT2 cells that derive from a pluripotent testicular carcinoma whereas cyclopamine, a reference Smo antagonist, induces Smo accumulation of Smo signals at the primary cilium. Therefore, it might be anticipated that MRT-83, like GDC-0449 and LDE-225, interacts with Smo in a manner different from that of cyclopamine, suggesting that while their binding sites are overlapping, they are not identical. Stereotaxic injection of MRT-83 into the lateral ventricle of adult mice but not of a structurally-related compound inactive at Smo, abolished upregulation of Ptc transcription induced by Shh in the neighboring subventricular zone, one of the two main neurogenic areas of the adult brain. These data demonstrate that MRT derivatives efficiently antagonize Shh signaling in vivo. Thus, MRT-10, MRT-14, MRT-83 and structurally-related molecules are potent Smo antagonists. These compounds should be useful for clarifying the molecular and biochemical mechanisms underlying the resistance of Smo inhibitors in brain cancer cells and may help develop new therapies against Shh pathway-related brain diseases.

Introduction: An osteoporotic fracture affects every other woman and every fourth man in Sweden. To meet the needs, Örebro County implemented in 2007 a fracture liaison service(FLS) to identify, investigate and treat these patients. Aim: To evaluate the efficacy of the FLS in Örebro County by reporting the prevalence ofbone mineral density testing and anti-osteoporotic treatment initiation following a low traumafracture. Secondary aim was to evaluate adherence to treatment after 12 months. Methods: 1269 medical records were retrospectively examined for all patients, 50-85 yearsold, with a fractured wrist, upper arm, hip, pelvis or vertebra in Örebro County in 2016.Patient characteristics and continuation through the FLS was studied. Primary objectives wereall descriptive, but various subgroups were compared using chi-square and independent ttests.Limit of significance at p<0.05. Results: 738 patients were eligible for inclusion (mean age 71.00 (±9.16) years, 76.6%women). 391 (53.0%) were referred for investigation, of which 348 (89.0%) attended. 253(72.7%) of the measured patients had indication for treatment, later prescribed to 76.7% ofthese, mainly once weekly oral bisphosphonates (64.4%). Adherence after 12 months wasavailable for 176 patients, of which 119 (67.6%) were still persistent. Conclusion: The FLS in Örebro County seems to be in line with national and internationalcounterparts. Still, there is room for improvement. The major gap appears to be identificationand referral for investigation of patients at risk of osteoporosis. Once passed the identificationstep, the losses through the program are in much smaller proportions.

Le contrôle post-transcriptionnel de l'expression des gènes représente un vaste ensemble de processus biologiques autour de la machinerie des ARNm, jouant un rôle majeur dans la création de la diversité du répertoire protéique. La dérégulation de ces processus, générant un phénotype altéré, pourrait contribuer à la progression tumorale dans les cancers du sein. Nos travaux se sont axés sur l'étude de l'épissage alternatif des pré-ARNm et la dérégulation de la machinerie de l'épissage dans la progression métastatique des cancers du sein. Dans un modèle murin de carcinome mammaire, nous avons identifié des variants d'épissage spécifiquement associés au potentiel métastatique. Dans une large cohorte de patientes, nous avons montré que l'expression de certains de ces variants dans des tumeurs est associée à un pronostic défavorable. Enfin, nous avons caractérisé le profil d'expression des protéines régulatrices de l'épissage dans plusieurs séries de cancer du sein. Cette étude offre de nouvelles connaissances et perspectives pour le développement de biomarqueurs de la progression tumorale. / Alternative RNA processing is a mechanism that plays a critical role for creation of protein diversity through selective inclusion or exclusion of RNA sequences during post-transcriptional control of gene expression. We hypothesized that alteration in this process might contribute greatly to tumour development and progression in breast cancer. The aim of our study was to identify and characterize defects in alternative splicing during breast tumour progression. In a murine model, we could identify specific mRNA splicing variants associated with metastatic development. In a large cohort of breast cancer patients, expression of a subset of these variants was correlated to poor prognosis. Finally, we characterised the expression profile of a large panel of proteins of the splicing machinery in breast cancer. Our study provides new insights in the understanding of mechanisms leading to tumour progression and perspectives for the development of new biomarkers and therapies.

A Interconsulta Psiquiátrica é considerada uma área da Psiquiatria, que trabalha no Hospital Geral compondo uma equipe (Psiquiatria de Ligação) ou prestando seus serviços a uma equipe solicitante (Consultoria Psiquiátrica). O Serviço de Interconsulta em Psiquiatria (SIP) do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) teve início em março de 1978 e a Terapia Ocupacional passou a integrar esta equipe em 1999. O cotidiano hospitalar tem uma marca própria com obrigações como usar vestimentas, ter horários previamente estabelecidos para se alimentar, para cuidar de sua higiene e para receber visitas, inclusive dos familiares. Os terapeutas ocupacionais, como profissionais que lidam com o cotidiano do indivíduo, têm sido inseridos nas equipes multiprofissionais do Hospital Geral, contribuindo com seus conhecimentos teóricos e técnicos específicos para cuidar de pessoas hospitalizadas. Apesar das várias funções que a Terapia Ocupacional (TO) pode exercer no Serviço de Interconsulta, existe escassez de estudos publicados sobre o perfil sócio-demográfico dos pacientes atendidos, o que prejudica o planejamento de ações e o levantamento da necessidade de recursos humanos para aquele Serviço. O objetivo deste trabalho foi realizar um estudo retrospectivo dos Pedidos de Interconsulta (PIs) para a TO do Serviço de Interconsulta em Saúde Mental (SISMen) do HCFMRP - USP no período de janeiro de 2000 a dezembro de 2005. Os sujeitos foram os indivíduos que estiveram internados nas enfermarias do campus do hospital universitário e para quem foi solicitada a assistência do Serviço de TO naquele período, perfazendo um total de 633 pacientes e 709 PIs. Os dados foram coletados mediante consulta dos PIs e dos prontuários dos pacientes. A maioria dos sujeitos consultados foi do sexo feminino, com ensino fundamental incompleto e houve distribuição equilibrada entre os solteiros e casados. Quanto à idade e à situação laboral, a média de idade dos pacientes foi de 39,2 anos e a maioria deles era autônoma ou aposentada, seguida de dona de casa. Verificou-se que a Clínica Médica foi a responsável por mais do que um terço dos Pedidos de Interconsulta feitos para o Serviço de TO, seguida das clínicas Unidade Metabólica e Psiquiatria respectivamente; o tempo médio de internação dos pacientes encaminhados para esse Serviço foi de 51 dias, sendo que a média de internação no HCFMRP-USP foi de 6,4 dias. Consequentemente, o gasto desses pacientes variou entre uma e 2,4 vezes mais do que os pacientes internados nesta instituição. A taxa média de encaminhamento para a TO do SISMen foi de 0,5%, sendo que o motivo de solicitação mais freqüente esteve relacionado aos aspectos emocionais do indivíduo, seguido por fatores referentes à hospitalização. Estes dados, de modo geral, estão de acordo com a literatura nacional e internacional dos SIPs. Concluiu-se que há necessidade de um instrumento padronizado para avaliar a população atendida pelo Serviço de Interconsulta de TO e que alguns pontos merecem estudos mais detalhados como a possibilidade de existência de associações entre dados sócio-demográficos e clínicos e o encaminhamento dos pacientes para esse Serviço. / Consultation Liaison Psychiatric is considered to be an area of Psychiatry which is part of a General Hospital, involving a team (Liaison Psychiatry) or providing services to a team that requests them (Psychiatric Consultation). The Consultation Liaison Psychiatric Service (CLPS) of the University Hospital, Faculty of Medicine of Ribeirão Preto (HCFMRPUSP) was started in March 1978 and Occupational Therapy became part of this team in 1999. The daily hospital routine has specific rules such as wearing specific clothing and taking meals, caring for ones hygiene and receiving visits, including those of relatives, at pre-established times. Occupational therapists, as professionals who deal with the daily routine of an individual, have been inserted into the multiprofessional teams of the General Hospital, contributing their specific theoretical and technical knowledge to the care of hospitalized persons. Despite the various functions Occupational Therapy (OT) can perform in the CLPS, there is a scarcity of published studies on the sociodemographic profile of attended patients, impairing the planning of actions and the determination of the human resources needed for that Service. The objective of the present investigation was to conduct a retrospective study of the Requests of Consultation Liaison (RCLs) sent to the OT of the Service of The Consultation Liaison in Mental Health (SCLMH) of HCFMRP-USP during the period from January 2000 to December 2005. The subjects involved were the individuals who had been admitted to the wards of the University Hospital and for whom the assistance of the OT Service had been requested during that period, for a total of 633 patients and 709 RCLs. The data were collected from the RCLs and the medical records of the patients. Most of the subjects involved were women with incomplete elementary schooling, with a balanced distribution of single and married subjects. Mean patient age was 39.2 years and most patients were self-employed or retired, followed by the housewife category. Internal Medicine was responsible for more than one third of the RCLs sent to the OT Service, followed by the Metabolic Unit and Psychiatric clinics. The mean time of hospitalization of the patients referred to this Service was 51 days, with the mean duration of hospitalization at HCFMRPUSP being 6.4 days. Consequently, the expenses with these patients ranged from one to 2.4 times more than those for the patients hospitalized in this institution. The mean rate of referral to the OT of the SCLMH was 0.5%, with the most frequent reason for the request being related to the emotional aspects of the individual, followed by factors related to hospitalization. These data, in general, agree with the Brazilian and international literature about the CLPS. We conclude that there is the need for a standardized instrument for the evaluation of the population attended at the Consultation Liaison Service of OT and that some points need more detailed studies regarding the possibility of the existence of an association between sociodemographic and clinical data and the referral of these patients to the OT Service.

Au cours de ces travaux de thèse, nous avons exploré de nouvelles applications des proazaphosphatranes et de leurs dérivés, en particulier leur confinement dans une cage moléculaire. Dans la première partie, une bibliographie présente la littérature concernant (i) la découverte et les applications de proazaphosphatranes, (ii) les catalyseurs confinés dans des cages covalentes et (iii) la liaison halogène - une interaction non covalente émergente-. Par la suite, l’utilisation de proazaphosphatranes comme organocatalyseur très efficace pour la réaction de Strecker est décrit. Ensuite, un système FLP (paire de Lewis frustrée) comprenant un proazaphosphatrane encagé comme base de Lewis et du TiCl4 comme acide de Lewis a été utilisé pour catalyser la réaction de MBH (Morita-Baylis-Hillman). Finalement, un azaphosphatrane chloré a été synthétisé, et ses propriétés de reconnaissance vis à vis de différents anions halogénures, par liaison halogène, a été étudié. / In this dissertation, our goal is to explore new applications of proazaphosphatranes and their derivatives, especially in a confined space. In the first part, a comprehensive literature review regarding 1) discovery and application of proazaphosphatranes, 2) confined covalent cages based organo- and metal-catalysts, and 3) halogen bonding – an emergent noncovalent interaction has been demonstrated. Subsequently, proazaphosphatrane as highly efficient organocatalyst for the Strecker reaction is discussed. And a FLP (frustrated Lewis pair) system comprising an encaged proazaphosphatrane as Lewis base and TiCl4 as Lewis acid for MBH (Morita–Baylis–Hillman) reaction is reported. In the end, chlorinated azaphosphatrane is synthesized and studied in the recognition of different halide anions by halogen bonding, exhibiting a preferable affinity for chloride over bromide and iodide.