Le facteur pronostic majeur des cancers du col localement avancés (LACC) est le statut ganglionnaire lombo-aortique. Notre travail de thèse a été d'évaluer la lymphadénectomie lombo-aortique (qui représente la technique de référence pour obtenir cette information) à l'ère de la tomographie par émission de positron (TEP) et de la chirurgie par une seule incision (LESS). Les résultats publiés de cette thèse sont: la lymphadénectomie lombo-aortique extrapéritonéale par LESS est faisable. Nous en avons décrit et codifié la technique pour la première fois par une incision iliaque gauche unique ; cette technique que nous avons mise au point est sure, reproductible et équivalente sur le plan carcinologique et ergonomique à la laparoscopie conventionnelle ; la lymphadénectomie lombo-aortique de staging est indispensable dans les LACC compte tenu du taux de faux négatif du TEP-TDM retrouvé dans ce travail de thèse (12% s'élevant à 22 % en cas de fixations ganglionnaires pelviennes suspectes). Nous avons également démontré sur la plus large de la série de littérature que la lymphadénectomie lombo-aortique associée à l'extension des champs d'irradiation en lombo-aortique lors de la radio-chimiothérapie apporte aux patientes présentant des micrométastases une survie identique à celle des patientes négatives histologiquement au niveau lombo-aortique. En revanche, en cas d'atteinte macrométastatique le pronostic demeure péjoratif et nécessite de proposer d'autres options thérapeutiques / In locally advanced cervical cancer (LACC) the most important predictor of disease recurrence is para-aortic nodal status. The aim of our thesis was to evaluate the role of para-aortic lymphadenectomy (the current gold standard to assess para-aortic nodal status) in the era of positron emission tomography (PET) and single incision surgery (LESS). The published results of this thesis are: extraperitoneal para-aortic lymphadenectomy by LESS is feasible and we have described and codified the technique for the first time by a single left iliac incision; the technique we have developed is safe, reproducible and oncologically and ergonomically equivalent to conventional laparoscopy; para-aortic LAD staging is essential in LACC given the false negative rate of PET-CT found in this work (12% increasing to 22% if PET-CT reveals suspicious pelvic lymph nodes). We have also demonstrated, in the largest case series published to date, that para-aortic lymphadenectomy followed by chemoradiation including the pelvis and para-aortic lymph nodes for patients with micrometastatic para-aortic nodal involvement provides an overall survival that is identical to the overall survival of LACC with histologically negative para-aortic lymph nodes. However, in case of macrometastatic disease prognosis remains pejorative and requires other treatment options

INTRODUÇÃO - OBJETIVO: A vancomicina é um glicopeptídeo de primeira escolha largamente prescrito aos pacientes críticos no tratamento de infecções graves causadas por patógenos nosocomiais Gram-positivos susceptíveis. Os pacientes grandes queimados são considerados pacientes críticos pelas condições metabólicas e importantes alterações fisiopatológicas decorrentes do choque séptico que modificam a farmacocinética da vancomicina. Destaca-se, entretanto que nos pacientes críticos queimados pediátricos essa alteração ocorre em diferente proporção quando comparada aquela reportada para pacientes adultos. Assim sendo, a efetividade desse antimicrobiano é um desafio para a equipe clínica da terapia intensiva, uma vez que a dose empírica nesses pacientes tem fornecido concentrações inferiores às recomendadas, resultando em falha terapêutica pela falta de cobertura do antimicrobiano contra patógenos susceptíveis, CIM ≥1mg/L. O objetivo foi realizar o monitoramento das concentrações plasmáticas de vancomicina seguido da abordagem farmacocinética-farmacodinâmica (PK/PD) a fim de se avaliar a efetividade do regime empírico recomendado ao paciente crítico pediátrico e se realizar o ajuste de dose para erradicação dos patógenos. CASUÍSTICA E MÉTODOS: Incluíram-se 20 pacientes (14M/6F), função renal normal com média de idade 5,95 (4,5-7,4) anos, peso 25,2 (20,5-30)kg, superfície de área queimada total 31,1(25-37)%. Os acidentes foram causados pelo fogo/ combustão por álcool; registrou-se lesão inalatória (12/20) e uso de drogas vasoativas e ventilação mecânica em 13/20 pacientes. Os exames de rotina laboratorial foram realizados diariamente; antes do início da terapia antimicrobiana, colheram-se amostras de sangue no D0 para cultura e realização do teste de susceptibilidade. Os pacientes foram investigados em diferentes seguimentos durante o choque séptico; o regime de dose empírica recomendada pelo CCIH foi prescrito e 3-4 amostras seriadas de sangue (1,5 mL/cada) foram coletadas do CVC no intervalo de dose após a dose diária empírica recomendada e após a individualização da terapia medicamentosa. A quantificação de vancomicina plasmática foi realizada através da cromatografia líquida. Na modelagem PK utilizou-se o programa PK Solutions Noncompartmental Data Analysis versão 2.0. Na abordagem PK/PD e no tratamento estatístico aplicou-se o programa GraphPad Prisma v.5.0. Empregou-se a razão da área sob a curva (ASCss0-24) e concentração inibitória mínima superior a 400 (ASCss0-24/CIM>400) como índice preditivo de efetividade recomendada para o antimicrobiano. Aplicou-se estatística paramétrica com relação aos dados demográficos e laboratoriais, e estatística não paramétrica com relação à dose, concentração plasmática, área sob a curva, constantes farmacocinéticas e efetividade do antimicrobiano. Aplicaram-se nesse estudo os testes paramétricos (ANOVA e Teste T de Student) e não paramétricos (Wilcoxon e Mann Whitney) no programa GraphPad Prisma v.5.0., e o nível de alfa igual ou inferior a 0,05 (P<0,05) foi considerado na significância estatística. RESULTADOS: A dose empírica de vancomicina foi 50 (44-51) mg/kg dia, mediana (quartis, IQ25-75) mostrou que o alvo foi atingido para 85% (17/20) dos pacientes apenas contra cepas sensíveis (CIM&≤1mg/L), ficando desta forma todos os pacientes desprotegidos contra cepas CIM >1mg/L (CIM: 2-4 mg/L). Então, registrou-se alteração de conduta médica relativa à prescrição com aumento da dose diária de vancomicina 94 (85-104) mg/Kg. Esse aumento se mostrou significativo com relação a dose inicial empírica, p<0,05. Após nova estabilização pela terapia dose ajustada, e coletas de sangue no platô, o alvo PK/PD foi alcançado para todos os pacientes, contra patógenos CIM 1mg/L. Entretanto, apenas 5/20 pacientes alcançaram o alvo PK/PD contra cepas susceptíveis CIM: 2mg/L, sendo que nenhum paciente se mostrou coberto contra cepas CIM 4mg/L. CONCLUSÃO: O regime empírico de dose recomendado para a vancomicina não se mostrou efetivo contra os patógenos sensíveis isolados. Concluindo, o controle terapêutico, estudo da farmacocinética e abordagem PK/PD realizado em tempo real possibilitou a alteração precoce de prescrição da vancomicina nos pacientes pediátricos grandes queimados de forma a otimizar a terapia antimicrobiana e o controle das infecções causadas por patógenos hospitalares susceptíveis (CIM ≥1mg/L). / INTRODUCTION- OBJECTIVE: Vancomycin is a first choice glycopeptide largely prescribed to critically ill adult or pediatric patients under therapy of severe infections caused by gram-positive susceptible nosocomial strains. Burn patients have metabolic conditions that change the pharmacokinetics of vancomycin in the treatment of severe infections. Pediatric patients are even more complicated because pharmacokinetic changes are quite different compared to adults, then effective vancomycin dose regimen is a challenge to clinic staff, once the initial dose recommended cannot reach the target against MIC ≥ 1 mg/L strains. Then therapeutic fail with impact on desired outcome. Therefore the rational of study was to apply therapeutic drug plasma monitoring (TDM) in order to identify the pharmacokinetic changes that occur in paediatric burns through PK/PD approach to perform in a real time the dose adjustment required. METHODS - CASUISTRY: Twenty septic burn pediatric patients was investigated after the admission in the Intensive Care Unit of Burns (ICBU) Plastic Surgery Division of HCFMUSP. Vancomycin empiric dose regimen recommended was prescribed 500mg every 6 hours, and patients received one hour drug infusion. Blood sampling was performed after drug infusion at time dose interval (1.5 mL/tube, sodium EDTA): 2nd or 3rd h, 4th, and before the next dose. Vancomycin was quantified by liquid chromatography (LC). Pharmacokinetics was investigated on the basis on one compartment open model by Noncompartmental Data Analysis PK Solutions v 2.0, software. PK/PD approach was based on the ratio of area under the plasma concentration - time curve (AUCss0-24) and the minimum inhibitory concentration (MIC) performed by GraphPad Prism v 5.0 software. The predictive index of drug effectiveness recommended was ASCss0-24/CIM>400. Statistics also was performed through by GraphPad Prism v 5.0 software by application of parametric tests to demographic data and also to laboratorial data (ANOVA, Student T test). Nonparametric statistics was applied related to dose, drug plasma measurements and AUC, kinetic data, data related to drug effectiveness (Mann Whitney). Statistical significant difference was considered, alpha lower than 0,05 (P<0,05). RESULTS -CONCLUSION: It was shown that the therapeutic target was reached to 85% (17/20) patients with the empiric daily dose of vancomycin (44-51) mg/kg, median (quartiles, IQ25-75) only for susceptible strains (MIC≤1mg/L). Then, changes of the prescription occurred in a real time and the daily dose was increased to 94 (85-104) mg/kg, p<0.05. New blood sampling was done at the steady state for TDM, PK and PK/PD approach and the target was reached for all patients MIC 1 mg/L strains; while the target was reached only 5/20 patients against MIC: 2mg/L susceptible strains, and none patient reached the target against MIC 4mg/L strains. It was shown that the drug effectiveness wasn\'t guaranteed by the vancomycin dose regimen recommended for the treatment of sepsis caused by nosocomial MIC≥1mg/L strains. In conclusion, TDM, pharmacokinetic study and PK/PD approach must be considered important tools do change vancomycin prescription in a real time in order to optimize the antimicrobial treatment of septic shock caused by nosocomial pathogens.

Made available in DSpace on 2016-04-27T14:31:21Z (GMT). No. of bitstreams: 1 Valdenice Minatel Melo de Cerqueira.pdf: 4853814 bytes, checksum: 9f1ec9cc78787554a18c679826fce57d (MD5) Previous issue date: 2014-02-26 / This narrative-based work is attached to the line of research known as New Technologies in Education of Education Program: Curriculum from PUC - SP. This is a descriptive and qualitative-related study that evolved from the implementation of Dante Tablet program in Dante Alighieri School between 2011 and 2012. The overall objective of this work is to observe, describe and analyze the actions employed in the implementation of a program intended for the integration of information, communication, mobile and digital technologies into the curriculum of a school of basic education, while identifying the resiliencies arisen concerning this implementation. For this, we carried out analyses on documents that reveal the history and routine of the mentioned school, among them records of the institution s foundation, its Internal Regulations, accounts of meetings for training teachers, reports of students and teachers steering committees, notes of teaching practices, and questionnaires for teachers of tenth-grade secondary school and students of the Student Steering Committee. The journey to Paradise of the poet Dante Alighieri, described in the book "The Divine Comedy", was used as a metaphor of the methodological process. As to the narrative that supports this work, its development was conducted in a spiral manner, from the concept of Valente s spiral learning. In this paper, the idea of resilience, taken from Simpson and Tavares studies, refers to actions that provide the ability to overcome difficulties and adversities. In addition to these authors, the theoretical framework also comprehends Almeida with regard to issues on curriculum web and Freire over his view on education as an intervention in the world that enables change and transformation. Throughout the work, we identified four resilient actions that were predominant for the maintenance of Dante Tablet program, which are: the creation of the Student Steering Committee; the amplified use of Virtual Learning Environment (MOODLE); the identification, encouragement and enhancement of successful practices that favored aspects of students and teachers authorship; and the provision of a high-quality connection to the Internet, which allows activities involving since the simple ones, such as searching and selecting information, until those that promote students authorship and co-authorship as well as, in a collaborative way, the production and organization of knowledge through cloud computing. The verification of these actions was possible through some indicators that, established by Fullan, are called in this research vectors namely, need, clarity, complexity and quality. In addition to the identification of those resilient actions, another finding of this work was that the process of integration of digital technologies into curriculum should be designed and effected from a deep reflection and a broad dialogue, with the participation of each individual involved in the pedagogical task (in particular, teachers, students and administrators) so as to approach the subject from the perspective of a shared management of web curriculum, prioritizing an online integration of people, ideas, knowledge and cultures. Finally, the expectation is that this work can contribute to the debate on integration of mobile digital technologies into the curriculum within the Brazilian basic education / A presente investigação de natureza narrativa integra-se na linha de pesquisa das Novas Tecnologias em Educação do Programa Educação: Currículo da PUC-SP. Trata-se de um estudo descritivo, de natureza qualitativa, e que se desenvolveu a partir da implantação do programa Dante Tablet no Colégio Dante Alighieri entre os anos de 2011 e 2012. O objetivo geral da pesquisa é observar, descrever e analisar as ações empregadas na implantação de um programa de integração das tecnologias digitais móveis da informação e comunicação (TDM) ao currículo de uma escola de educação básica, identificando as resiliências surgidas nesse processo. Para tanto, foram feitas análises de documentos que deixam transparecer a história e o cotidiano do referido colégio, entre os quais: relatos sobre a fundação do colégio, Regimento Interno, atas de reuniões dos comitês de gestão (docente e discente), apontamentos de práticas pedagógicas dos professores, além de questionários para professores das 1ª séries do Ensino Médio e alunos do Comitê Gestor Discente. A viagem rumo ao Paraíso do poeta Dante Alighieri, descrita na obra A Divina Comédia , foi utilizada como metáfora do processo metodológico. Relativamente à narrativa que sustenta esta tese, seu desenvolvimento foi conduzido de maneira espiralada, a partir do conceito de espiral de aprendizagem de Valente. A resiliência, neste trabalho, remete às ações que oferecem capacidade de superar dificuldades e transpor situações adversas, e foi estudada a partir de Simpson e Tavares. Além desses autores, o aporte teórico também referencia Almeida nas questões de web currículo e Freire na perspectiva da educação como intervenção no mundo, possibilitando mudanças e transformações. Ao longo do trabalho, identificaram-se quatro ações resilientes que foram preponderantes para a sustentação do programa Dante Tablet: a criação do Comitê Gestor Discente; a utilização ampliada do ambiente virtual de aprendizagem criado no MOODLE; a identificação e valorização de práticas exitosas que favoreceram aspectos relacionados com a autoria de alunos e professores; e a oferta de uma conexão de qualidade com a internet, que possibilitou a realização de atividades desde as mais simples, como a busca e seleção de informações, até aquelas que promovem a autoria dos alunos e, de forma colaborativa, a produção e a organização do conhecimento por meio de serviços nas nuvens. A identificação dessas ações se deu por meio de alguns indicadores que, estabelecidos a partir do trabalho de Fullan, são chamados nesta pesquisa de vetores a saber, necessidade, clareza, complexidade e qualidade. Em complemento à identificação das ações resilientes, constatou-se que o processo de integração das tecnologias digitais ao currículo deve ser pensado e efetivado a partir de uma reflexão, de um diálogo, com a participação de todos os sujeitos do ato pedagógico (em particular, professores, alunos e gestores) na perspectiva de uma gestão compartilhada, do web currículo, priorizando uma integração, em rede, de pessoas, ideias, conhecimentos e culturas. Finalmente, a expectativa é a de que este trabalho possa contribuir para a reflexão sobre integração das tecnologias digitais móveis ao currículo, no âmbito da educação básica brasileira

INTRODUÇÃO - OBJETIVO: A vancomicina é um glicopeptídeo de primeira escolha largamente prescrito aos pacientes críticos no tratamento de infecções graves causadas por patógenos nosocomiais Gram-positivos susceptíveis. Os pacientes grandes queimados são considerados pacientes críticos pelas condições metabólicas e importantes alterações fisiopatológicas decorrentes do choque séptico que modificam a farmacocinética da vancomicina. Destaca-se, entretanto que nos pacientes críticos queimados pediátricos essa alteração ocorre em diferente proporção quando comparada aquela reportada para pacientes adultos. Assim sendo, a efetividade desse antimicrobiano é um desafio para a equipe clínica da terapia intensiva, uma vez que a dose empírica nesses pacientes tem fornecido concentrações inferiores às recomendadas, resultando em falha terapêutica pela falta de cobertura do antimicrobiano contra patógenos susceptíveis, CIM ≥1mg/L. O objetivo foi realizar o monitoramento das concentrações plasmáticas de vancomicina seguido da abordagem farmacocinética-farmacodinâmica (PK/PD) a fim de se avaliar a efetividade do regime empírico recomendado ao paciente crítico pediátrico e se realizar o ajuste de dose para erradicação dos patógenos. CASUÍSTICA E MÉTODOS: Incluíram-se 20 pacientes (14M/6F), função renal normal com média de idade 5,95 (4,5-7,4) anos, peso 25,2 (20,5-30)kg, superfície de área queimada total 31,1(25-37)%. Os acidentes foram causados pelo fogo/ combustão por álcool; registrou-se lesão inalatória (12/20) e uso de drogas vasoativas e ventilação mecânica em 13/20 pacientes. Os exames de rotina laboratorial foram realizados diariamente; antes do início da terapia antimicrobiana, colheram-se amostras de sangue no D0 para cultura e realização do teste de susceptibilidade. Os pacientes foram investigados em diferentes seguimentos durante o choque séptico; o regime de dose empírica recomendada pelo CCIH foi prescrito e 3-4 amostras seriadas de sangue (1,5 mL/cada) foram coletadas do CVC no intervalo de dose após a dose diária empírica recomendada e após a individualização da terapia medicamentosa. A quantificação de vancomicina plasmática foi realizada através da cromatografia líquida. Na modelagem PK utilizou-se o programa PK Solutions Noncompartmental Data Analysis versão 2.0. Na abordagem PK/PD e no tratamento estatístico aplicou-se o programa GraphPad Prisma v.5.0. Empregou-se a razão da área sob a curva (ASCss0-24) e concentração inibitória mínima superior a 400 (ASCss0-24/CIM>400) como índice preditivo de efetividade recomendada para o antimicrobiano. Aplicou-se estatística paramétrica com relação aos dados demográficos e laboratoriais, e estatística não paramétrica com relação à dose, concentração plasmática, área sob a curva, constantes farmacocinéticas e efetividade do antimicrobiano. Aplicaram-se nesse estudo os testes paramétricos (ANOVA e Teste T de Student) e não paramétricos (Wilcoxon e Mann Whitney) no programa GraphPad Prisma v.5.0., e o nível de alfa igual ou inferior a 0,05 (P<0,05) foi considerado na significância estatística. RESULTADOS: A dose empírica de vancomicina foi 50 (44-51) mg/kg dia, mediana (quartis, IQ25-75) mostrou que o alvo foi atingido para 85% (17/20) dos pacientes apenas contra cepas sensíveis (CIM&≤1mg/L), ficando desta forma todos os pacientes desprotegidos contra cepas CIM >1mg/L (CIM: 2-4 mg/L). Então, registrou-se alteração de conduta médica relativa à prescrição com aumento da dose diária de vancomicina 94 (85-104) mg/Kg. Esse aumento se mostrou significativo com relação a dose inicial empírica, p<0,05. Após nova estabilização pela terapia dose ajustada, e coletas de sangue no platô, o alvo PK/PD foi alcançado para todos os pacientes, contra patógenos CIM 1mg/L. Entretanto, apenas 5/20 pacientes alcançaram o alvo PK/PD contra cepas susceptíveis CIM: 2mg/L, sendo que nenhum paciente se mostrou coberto contra cepas CIM 4mg/L. CONCLUSÃO: O regime empírico de dose recomendado para a vancomicina não se mostrou efetivo contra os patógenos sensíveis isolados. Concluindo, o controle terapêutico, estudo da farmacocinética e abordagem PK/PD realizado em tempo real possibilitou a alteração precoce de prescrição da vancomicina nos pacientes pediátricos grandes queimados de forma a otimizar a terapia antimicrobiana e o controle das infecções causadas por patógenos hospitalares susceptíveis (CIM ≥1mg/L). / INTRODUCTION- OBJECTIVE: Vancomycin is a first choice glycopeptide largely prescribed to critically ill adult or pediatric patients under therapy of severe infections caused by gram-positive susceptible nosocomial strains. Burn patients have metabolic conditions that change the pharmacokinetics of vancomycin in the treatment of severe infections. Pediatric patients are even more complicated because pharmacokinetic changes are quite different compared to adults, then effective vancomycin dose regimen is a challenge to clinic staff, once the initial dose recommended cannot reach the target against MIC ≥ 1 mg/L strains. Then therapeutic fail with impact on desired outcome. Therefore the rational of study was to apply therapeutic drug plasma monitoring (TDM) in order to identify the pharmacokinetic changes that occur in paediatric burns through PK/PD approach to perform in a real time the dose adjustment required. METHODS - CASUISTRY: Twenty septic burn pediatric patients was investigated after the admission in the Intensive Care Unit of Burns (ICBU) Plastic Surgery Division of HCFMUSP. Vancomycin empiric dose regimen recommended was prescribed 500mg every 6 hours, and patients received one hour drug infusion. Blood sampling was performed after drug infusion at time dose interval (1.5 mL/tube, sodium EDTA): 2nd or 3rd h, 4th, and before the next dose. Vancomycin was quantified by liquid chromatography (LC). Pharmacokinetics was investigated on the basis on one compartment open model by Noncompartmental Data Analysis PK Solutions v 2.0, software. PK/PD approach was based on the ratio of area under the plasma concentration - time curve (AUCss0-24) and the minimum inhibitory concentration (MIC) performed by GraphPad Prism v 5.0 software. The predictive index of drug effectiveness recommended was ASCss0-24/CIM>400. Statistics also was performed through by GraphPad Prism v 5.0 software by application of parametric tests to demographic data and also to laboratorial data (ANOVA, Student T test). Nonparametric statistics was applied related to dose, drug plasma measurements and AUC, kinetic data, data related to drug effectiveness (Mann Whitney). Statistical significant difference was considered, alpha lower than 0,05 (P<0,05). RESULTS -CONCLUSION: It was shown that the therapeutic target was reached to 85% (17/20) patients with the empiric daily dose of vancomycin (44-51) mg/kg, median (quartiles, IQ25-75) only for susceptible strains (MIC≤1mg/L). Then, changes of the prescription occurred in a real time and the daily dose was increased to 94 (85-104) mg/kg, p<0.05. New blood sampling was done at the steady state for TDM, PK and PK/PD approach and the target was reached for all patients MIC 1 mg/L strains; while the target was reached only 5/20 patients against MIC: 2mg/L susceptible strains, and none patient reached the target against MIC 4mg/L strains. It was shown that the drug effectiveness wasn\'t guaranteed by the vancomycin dose regimen recommended for the treatment of sepsis caused by nosocomial MIC≥1mg/L strains. In conclusion, TDM, pharmacokinetic study and PK/PD approach must be considered important tools do change vancomycin prescription in a real time in order to optimize the antimicrobial treatment of septic shock caused by nosocomial pathogens.

Submitted by Hellen Luz (hellencrisluz@gmail.com) on 2017-08-10T18:18:49Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_PolimorfismosGenicosTipo.pdf: 1974852 bytes, checksum: aa3b04d35c7266ffc0e87975cc193ae5 (MD5) / Approved for entry into archive by Irvana Coutinho (irvana@ufpa.br) on 2017-08-11T13:15:55Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_PolimorfismosGenicosTipo.pdf: 1974852 bytes, checksum: aa3b04d35c7266ffc0e87975cc193ae5 (MD5) / Made available in DSpace on 2017-08-11T13:15:55Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_PolimorfismosGenicosTipo.pdf: 1974852 bytes, checksum: aa3b04d35c7266ffc0e87975cc193ae5 (MD5) Previous issue date: 2017-07-26 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A fisiopatologia da depressão ainda permanece não totalmente compreendida. E apesar das contribuições da hipótese monoaminérgica para a compreensão de parte dos aspectos neurobiológicos desse transtorno, surgiram estudos com o objetivo de investigar o papel da neuroinflamação, dos polimorfismos em genes que influenciam a atividade inflamatória e as funções dos receptores monoaminérgicos no desenvolvimento do transtorno depressivo maior (TDM). Contudo, são poucas as pesquisas que analisaram o papel de vias inflamatórias upstream (como o papel dos genes NFKB1 e PAR1, capazes de influenciar a transcrição gênica de citocinas pró-inflamatórias) e do polimorfismo do gene codificante do receptor alfa 2 adrenérgico (gene ADRA2B) em indivíduos com o diagnóstico de depressão. Portanto, o objetivo deste estudo foi analisar o papel dos polimorfismos do tipo INDEL dos genes NFKB1 (rs28362491), PAR1 (rs11267092) e ADRA2B (rs34667759) no desenvolvimento do transtorno depressivo maior. Doze pacientes com diagnóstico de TDM e 145 controles saudáveis tiveram amostras de sangue coletadas e os polimorfismos dos 3 genes foram genotipados por uma única reação multiplex. Os produtos do PCR multiplex foram separados por eletroforese capilar e os dados analisadas no software GeneMapper 3.7 (Applied Biosystems). Esta pesquisa encontrou uma associação estatisticamente significante entre a variável depressão e os portadores do genótipo Del/Del do gene ADRA2B (p = 0,002): esses indivíduos apresentaram uma chance 6,41 vezes maior de desenvolver depressão quando comparados aos portadores dos genótipos Del/Ins e Ins/Ins. Não houve significância estatística entre os polimorfismos INDEL dos genes NFKB1 e PAR1 e o fenótipo depressivo. Nossos resultados sugerem que o marcador INDEL do gene ADRA2B (rs34667759), especificamente o alelo deleção, seja um possível biomarcador genético de vulnerabilidade para o desenvolvimento do TDM. / The pathophysiology of depression still remains not fully understood. And despite the contributions of the monoaminergic hypothesis to the understanding of neurobiological aspects of this disorder, studies have been carried out to investigate the role of neuroinflammation, polymorphisms in genes that influence inflammatory activity and monoaminergic receptor functions in the development of major depressive disorder (MDD). However, few studies have analyzed the role of upstream inflammatory pathways (such as the role of NFKB1 and PAR1 genes, which are capable of influencing transcription of proinflammatory cytokines) and of the alpha 2 adrenergic receptor encoding gene's polymorphism (ADRA2B gene) in individuals diagnosed with depression. Therefore, the objective of this study was to analyze the role of the INDEL type polymorphisms of NFKB1 (rs28362491), PAR1 (rs11267092) e ADRA2B (rs34667759) genes in the development of major depressive disorder. Twelve patients diagnosed with MDD and 145 healthy controls had blood samples collected and the INDEL polymorphisms of these 3 genes were genotyped by a single multiplex reaction. The multiplex PCR products were separated by capillary electrophoresis and the data analyzed in GeneMapper 3.7 software (Applied Biosystems). This research found a statistically significant association between depression and Del/Del genotype of the ADRA2B gene (p = 0.002): these individuals presented a 6.41 times greater chance of developing depression when compared to Del/Ins and Ins/Ins genotypes. There was no statistical significance between the INDEL polymorphisms of NFKB1 and PAR1 genes and depressive phenotype. Our results suggest that the INDEL marker of the ADRA2B gene (rs34667759), specifically the deletion allele, is a possible genetic biomarker of vulnerability for the development of MDD.

Le but de ces travaux est de proposer une contribution au recalage d'images TDM-TEP dans les régions thoraciques et abdominales. Notre méthodologie est fondée sur l'introduction de contraintes anatomiques au recalage non linéaire appliqué sur les intensités. Cette introduction est faite d'une manière explicite, en divisant la procédure en une phase d'initialisation recalant les structures segmentées dans les deux images, et une deuxième phase de recalage à niveaux de gris, raffinant l'étape précédente de l'algorithme. Les transformations sont modélisées dans les deux étapes à partir de Free Form Deformations (FFD). La segmentation est réalisée selon une procédure hiérarchique de reconnaissance de formes. La mesure fournie par le protocole d'évaluation que nous avons développé indique une erreur inférieure à 1cm pour les structures les plus significatives (poumons, foie, reins, coeur), sauf pour le stomach (erreur d'1.5cm).

Thesis (Ph.D. (Town and Regional Planning))--North-West University, Potchefstroom Campus, 2008.

Within the field of depression the “monoamine hypothesis” has been the leading theory to explain the biological basis of depression. This theory proposes that the biological basis of depression is due to a deficiency in one or more of three key neurotransmitter systems, namely noradrenaline, dopamine and serotonin which are thought to mediate the therapeutic actions of virtually every known antidepressant agent. Citalopram is a selective serotonin-reuptake inhibitor (SSRI) used for the treatment of depression and anxiety disorders. Citalopram is a racemic compound, in other words composed of a 50:50 mixture of two enantiomers (S-(+)-citalopram and R-(-)-citalopram) and with one of the enantiomers (S-(+)-citalopram) accounting for the inhibitory effect. At the time of introduction of citalopram the physician needed a therapeutic drug monitoring service to identify patients with interactions, compliance problems and for handling questions concerning polymorphic enzymes and drug metabolism. An achiral analytical separation method based on solid-phase extraction followed by high-performance liquid chromatography (HPLC) was developed for routine therapeutic drug monitoring (TDM) of citalopram and its two main demethylated metabolites. As the data available on citalopram were from achiral concentration determinations and to be able to further investigate citalopram enantiomers effects and distribution, a chiral method for separation of the enantiomers of citalopram and its demethylated metabolites was established. The advances within chiral separation techniques have made measurement of the concentrations of the individual enantiomers in biological fluids possible. The process behind enantioselective separation is however not fully understood and the mechanism behind the separation can be further scrutinized by the use of multivariate methods. A study of the optimization and characterization of the separation of the enantiomers of citalopram, desmethylcitalopram and didesmethylcitalopram on an acetylated ß-cyclodextrin column, by use of two different chemometric programs - response surface modelling and sequential optimization was performed. Sequential optimization can be a quicker mean of optimizing a chromatographic separation; response surface modelling, in addition to enabling optimization of the chromatographic process, also serves as a tool for learning more about the separation mechanism. Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent, despite the increasing use of citalopram in these age groups. A study was initiated to investigate adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites. The ratios between the S- and R-enantiomers of citalopram and didesmethylcitalopram were in agreement with studies involving older patients. The concentrations of the S-(+)- and R-(-) enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the polymorphic CYP2C19 enzyme. Even though the SSRIs are considered less toxic compared with older monoamine-active drugs like the tricyclic/tetracyclic antidepressants, the risk of developing serious side effects such as ECG abnormalities and convulsions has been seen for citalopram, when larger doses have been ingested. Furthermore, fatal overdoses have been reported where citalopram alone was the cause of death. Data on the toxicity of each of the enantiomers in humans have not been reported and no data on blood levels of the enantiomers in cases of intoxication have been presented. An investigation was initiated on forensic autopsy cases where citalopram had been found at the routine screening and these cases were further analysed with enantioselective analysis to determine the blood concentrations of the enantiomers of citalopram and metabolites. Furthermore the genotyping regarding the polymorphic enzymes CYP2D6 and CYP2C19 were performed. In 53 autopsy cases, we found increasing S/R ratios with increasing concentrations of citalopram. We found also that high citalopram S/R ratio were associated with high parent drug to metabolite ratio and may be an indicator of recent intake. Only 3.8 % were found to be poor metabolizers regarding CYP2D6 and for CYP2C19 no poor metabolizer was found. Enantioselective analysis of citalopram and its metabolites can provide valuable information about the time that has elapsed between intake and death. Genotyping can be of help in specific cases but the possibility of pharmacokinetic interactions is apparently a far greater problem than genetic enzyme deficiency. / On the day of the public defence the status of article IV was: Submitted.

La Tomographie par Emission de Positons (TEP) au Fluoro-déoxyglucose marqué au Fluor 18 (¹⁸F-FDG), analogue du glucose, permet d'obtenir une image de la consommation de glucose dans l'organisme. La plupart des foyers tumoraux présentant une consommation excessive de glucose, son utilisation en oncologie permet d'améliorer la prise en charge des patients en diminuant le temps nécessaire pour évaluer l'efficacité des traitements tels que la chimiothérapie et la radiothérapie. Mon projet de recherche visait à proposer et améliorer des méthodes de quantification en TEP au ¹⁸F-FDG afin de caractériser au mieux l'évolution métabolique des volumes tumoraux.De nombreux facteurs biaisent la quantification en TEP. Parmi eux, l'Effet de Volume Partiel (EVP) reste difficile à corriger, notamment à cause de la faible résolution spatiale des images TEP. Afin de déterminer l'impact de la correction de l'EVP sur l'évaluation des réponses des tumeurs, une étude sur données simulées par Monte Carlo a tout d'abord été effectuée. Cette étude a été complétée par l'analyse de données TEP/TDM (Tomodensitométrie) acquises chez 40 patients atteints de cancers colorectaux métastatiques (CCM), traités par chimiothérapie à l'Institut Jules Bordet (Bruxelles). L'analyse de 101 tumeurs a montré que les critères tels que le SUV, n'incluant pas de correction de l'EVP, et qui reflètent alors le volume tumoral et son activité, prédisaient mieux l'évolution tumorale que les critères corrigés de l'EVP. Compte tenus des résultats prometteurs récents de méthodes de caractérisation de l'hétérogénéité de la fixation du FDG dans les tumeurs, un second volet de notre travail a consisté à étudier l'intérêt de la prise en compte de la texture dans le cadre du suivi thérapeutique. L'application de l'analyse de texture aux cas de CCM étudiés précédemment n'a pas permis de démontrer une valeur ajoutée des indices de texture par rapport aux index quantitatifs couramment employés en clinique. Nous avons montré que cette conclusion s'expliquait en partie par la non-robustesse des indices de texture vis-à-vis des paramètres impliqués dans leur mesure. Nous avons enfin cherché à évaluer une méthode d'Analyse Factorielle de Séquences d'Images Médicales (AFSIM), appliquée au contexte du suivi thérapeutique, pour caractériser l'évolution tumorale tout au long du traitement. Cette étude a porté sur 9 séries de 4 à 6 examens TEP/TDM de patients traités par radiothérapie au Centre Hospitalier Universitaire Henri Becquerel de Rouen. Outre l'information visuelle globale apportée par cette méthode, l'analyse quantitative des résultats obtenus a permis de caractériser l'hétérogénéité de la réponse vue par l'AFSIM. L'échec des index classiques, provenant entre autres de leur incapacité à distinguer les processus inflammatoires de l'activité métabolique tumorale, a permis de monter la valeur ajoutée de l'AFSIM par rapport aux index tels que le SUV maximal ou moyen.

L'approche développée par l'équipe imXgam du CPPM a consisté à adapter la technologie des pixels hybrides XPAD à l'imagerie biomédicale. C'est dans cette optique qu'un micro tomodensitomètre PIXSCAN II basé sur la nouvelle génération de détecteurs à pixels hybrides appelés XPAD3 a été développé. Ce travail de thèse décrit la démarche engagée pour évaluer l'apport de la technologie à pixels hybrides en tomodensitométrie par rayons X en termes de contraste et de dose et pour explorer de nouvelles possibilités d'imagerie biomédicale à faible dose. L'évaluation des performances ainsi que la validation des résultats obtenus avec les données acquises avec le détecteur XPAD3 ont été comparées aux résultats obtenus avec la caméra CCD DALSA XR-4 similaire aux détecteurs utilisés dans la plupart des micro-TDM usuels. Le détecteur XPAD3 permet d'obtenir des images reconstruites d'une qualité satisfaisante et proche de celle des images de la caméra DALSA XR-4, mais avec une meilleure résolution spatiale. A faible dose, les images du détecteur XPAD3 sont de meilleure qualité que celles de la caméra CCD. Du point de vue de l'instrumentation, ce projet a prouvé le bon fonctionnement du dispositif PIXSCAN II pour la souris. Nous avons pu reproduire une qualité d'image semblable à celle obtenue avec un détecteur à intégration de charges de type caméra CCD. Pour améliorer les performances du détecteur XPAD3, il va falloir optimiser la stabilité des seuils et avoir des courbes de réponses des pixels en fonction de l'énergie assez homogènes en utilisant un capteur plus dense comme le CdTe par exemple.