O HTLV-1 (Human T-Lymphotropic Virus) foi o primeiro retrovírus descoberto. Sua patogenia é relacionada à infecção das células T CD4+ e T CD8+ e sua disseminação depende da expansão clonal destas células. A imortalização celular e a resposta imune inflamatória direta contra o vírus levam os pacientes a desenvolverem a leucemia/ linfoma de células T do adulto (ATL) e paraparesia espástica tropical/mielopatia (TSP/HAM) respectivamente. Ainda que o vírus seja conhecido desde 1980, não existem trabalhos na literatura que evidenciem possíveis manifestações bucais associadas. Alguns estudos clínico-epidemiológicos, realizados em regiões altamente endêmicas para o vírus, apontam a possibilidade de associação entre o HTLV e a síndrome de Sjögren (SS). Este estudo objetivou conhecer melhor uma população HTLV+ identificando possíveis alterações estomatológicas. Foram avaliados 139 pacientes do Instituto de Infectologia Emilio Ribas, sendo que 112 (80,5%) eram HTLV-1+, 26 eram (18,7%) HTLV-2 + e 1 paciente era soropositivo para ambos os tipos virais. Entre os pacientes HTLV-1+, 88 (64,7%) eram assintomáticos e 48 (35,3%) apresentavam TSP/HAM. As alterações bucais mais freqüentes foram: xerostomia (26,5%), candidíase (25,4%), língua fissurada (22,1%) e língua depapilada (12,4%). Modelos de regressão logística multivariada confirmaram a TSP/HAM como um fator de risco independente para xerostomia (p=0,02), apresentando, pacientes TSP/HAM+, 3 vezes mais chances de desenvolver xerostomia quando comparados com pacientes sem TSP/HAM (OR=2,69; 95%IC=1,17-6,17). / HTLV-1 (human T-lymphotropic virus), the first retrovirus discovered, is associated with adult T cell leukemia/lymphoma (ATL) and tropical spastic paraparesis / HTLV associated myelopathy (TSP / HAM). Clinical studies and case reports in endemic areas showed the development of oral ALT and Sjögren`s syndrome in this patients. The aim of this study was to investigate the oral cavity of HTLV seropositive patients in São Paulo city. The present study was approved by the Institute of Infectious Diseases Emílio Ribas ethics committee. All patients answered a questionnaire designed for the study. Demographic and clinical data were recorded and then analyzed using Epi info (3.3.4 version) and SPSS Statistical Package for Social Sciences (v16.0). One hundred and thirty nine oral examinations were performed, 112 (80,5%) were HTLV-1 +, 26 were (18,7%) HTLV-2 + and one patient presented both types of HTLV. Sixty four (56,7%) were asymptomatic HTLV-1 seropositive patients, fourty nine (43,3%) patients were positive for HTLV-1 and TSP/HAM. HIV and HCV co-infection and comorbities were observed in 110 (79,1%) cases. Xerostomia (26,5%), candidosis (25,4%), oral fissured tongue (22,1%) and papillary atrophy of the tongue (12,4%) were the most prevalent oral manifestations found in these patients. Models of multivariate logistic regression confirmed the TSP / HAM as an independent risk factor for xerostomia (p = 0.02). Patients with TSP / HAM + were 3 times more likely to develop xerostomia when compared with patients without TSP / HAM (OR = 2.69, 95% CI = 1.17-6.17).

O HTLV-1 (Human T-Lymphotropic Virus) foi o primeiro retrovírus descoberto. Sua patogenia é relacionada à infecção das células T CD4+ e T CD8+ e sua disseminação depende da expansão clonal destas células. A imortalização celular e a resposta imune inflamatória direta contra o vírus levam os pacientes a desenvolverem a leucemia/ linfoma de células T do adulto (ATL) e paraparesia espástica tropical/mielopatia (TSP/HAM) respectivamente. Ainda que o vírus seja conhecido desde 1980, não existem trabalhos na literatura que evidenciem possíveis manifestações bucais associadas. Alguns estudos clínico-epidemiológicos, realizados em regiões altamente endêmicas para o vírus, apontam a possibilidade de associação entre o HTLV e a síndrome de Sjögren (SS). Este estudo objetivou conhecer melhor uma população HTLV+ identificando possíveis alterações estomatológicas. Foram avaliados 139 pacientes do Instituto de Infectologia Emilio Ribas, sendo que 112 (80,5%) eram HTLV-1+, 26 eram (18,7%) HTLV-2 + e 1 paciente era soropositivo para ambos os tipos virais. Entre os pacientes HTLV-1+, 88 (64,7%) eram assintomáticos e 48 (35,3%) apresentavam TSP/HAM. As alterações bucais mais freqüentes foram: xerostomia (26,5%), candidíase (25,4%), língua fissurada (22,1%) e língua depapilada (12,4%). Modelos de regressão logística multivariada confirmaram a TSP/HAM como um fator de risco independente para xerostomia (p=0,02), apresentando, pacientes TSP/HAM+, 3 vezes mais chances de desenvolver xerostomia quando comparados com pacientes sem TSP/HAM (OR=2,69; 95%IC=1,17-6,17). / HTLV-1 (human T-lymphotropic virus), the first retrovirus discovered, is associated with adult T cell leukemia/lymphoma (ATL) and tropical spastic paraparesis / HTLV associated myelopathy (TSP / HAM). Clinical studies and case reports in endemic areas showed the development of oral ALT and Sjögren`s syndrome in this patients. The aim of this study was to investigate the oral cavity of HTLV seropositive patients in São Paulo city. The present study was approved by the Institute of Infectious Diseases Emílio Ribas ethics committee. All patients answered a questionnaire designed for the study. Demographic and clinical data were recorded and then analyzed using Epi info (3.3.4 version) and SPSS Statistical Package for Social Sciences (v16.0). One hundred and thirty nine oral examinations were performed, 112 (80,5%) were HTLV-1 +, 26 were (18,7%) HTLV-2 + and one patient presented both types of HTLV. Sixty four (56,7%) were asymptomatic HTLV-1 seropositive patients, fourty nine (43,3%) patients were positive for HTLV-1 and TSP/HAM. HIV and HCV co-infection and comorbities were observed in 110 (79,1%) cases. Xerostomia (26,5%), candidosis (25,4%), oral fissured tongue (22,1%) and papillary atrophy of the tongue (12,4%) were the most prevalent oral manifestations found in these patients. Models of multivariate logistic regression confirmed the TSP / HAM as an independent risk factor for xerostomia (p = 0.02). Patients with TSP / HAM + were 3 times more likely to develop xerostomia when compared with patients without TSP / HAM (OR = 2.69, 95% CI = 1.17-6.17).

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<p>Model-Driven Engineering (MDE) leverages models to first-class status by shifting the focus of software development from coding to modeling. This thesis extends Antonio Cicchettis paper Difference Representation and Conflict Management in Model-Driven Engineering, adding concrete research corresponding to sequential composition.Differences between models can be displayed as deltas in a metamodel independent way. Working with these deltas, a need for sequential composites appears. This means, that several sequently deltas are marged together to a new delta. Since this delta contains a lot of unnecessary information, it needs to be optimized regarding to the minimal paradigm which is mentioned in the corresponding paper. This paper supplies the reader with a broad overview of the basic concepts, the difference representation and application including the metamodel independent approach, and finally a narrow examination of the research topic, including constraints, examples and implementation details.</p>

Model-Driven Engineering (MDE) leverages models to first-class status by shifting the focus of software development from coding to modeling. This thesis extends Antonio Cicchettis paper Difference Representation and Conflict Management in Model-Driven Engineering, adding concrete research corresponding to sequential composition.Differences between models can be displayed as deltas in a metamodel independent way. Working with these deltas, a need for sequential composites appears. This means, that several sequently deltas are marged together to a new delta. Since this delta contains a lot of unnecessary information, it needs to be optimized regarding to the minimal paradigm which is mentioned in the corresponding paper. This paper supplies the reader with a broad overview of the basic concepts, the difference representation and application including the metamodel independent approach, and finally a narrow examination of the research topic, including constraints, examples and implementation details.

Diploma thesis focuses on main forms of ATL and BTL communication and describes the most important factors of creating a successful ad-campaign. It's importance is ilustrated on three real examples.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19626号 / 医博第4133号 / 新制||医||1016(附属図書館) / 32662 / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 清水 章, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20977号 / 医博第4323号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小柳 義夫, 教授 小川 誠司, 教授 朝長 啓造 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

HTLV-1 et HTLV-2 sont des virus provoquant des infections persistantes. Après une période de latence clinique de plusieurs décennies, 2 à 5 % des individus infectés par HTLV-1 développent des pathologies comme la leucémie à cellules T de l’adulte (ATL) ou la paraparésie spastique tropicale/myélopathie associée à HTLV-1 (TSP/HAM). Malgré une forte homologie avec HTLV-1 dans son organisation génomique et sa séquence nucléotidique, l'infection par HTLV-2 n'est pas associée à des désordres hématologiques. L’interféron α (IFN-α) est un acteur majeur de la réponse immunitaire innée de l’hôte. Le rôle de la réponse IFN-α au cours d'une infection par HTLV-1 et notamment dans le développement de l'ATL reste peu documenté et controversé. Mon travail de thèse a consisté à caractériser le rôle de l'IFN-αsur l'infection par HTLV-1 en comparaison de l'infection par HTLV-2. Nous avons montré que l'infection de novo de lymphocytes T par HTLV-1 ou HTLV-2 était inhibée par l'IFN-α. Cette inhibition repose sur l'activation (phosphorylation) de la protéine PKR par l'IFN-α qui réprime les étapes tardives du cycle viral. D'autre part, nous avons étudié le rôle de la protéine ADAR1-p150 dont l'expression est aussi induite par l'IFN-α. La protéine ADAR-1-p150 est surexprimée dans les lymphocytes primaires activés et dans des lymphocytes infectés par HTLV-1 ou HTLV-2. Nous avons montré que la protéine ADAR-1-p150 contrecarrait l'effet inhibiteur de l'IFN-α sur le cycle d'HTLV-1 et d'HTLV-2, grâce à sa capacité à inhiber l'activation de PKR. Ces résultats suggèrent qu'un équilibre entre l'expression de ces 2 protéines peut influer sur le déroulement de l'infection par HTLV-1 ou HTLV-2. Enfin, nous avons observé que l'IFN-α n'avait pas d'effet sur des cellules déjà infectées par HTLV-1 contrairement à HTLV-2 qui reste partiellement sensible à cette cytokine. Un rôle différent de l'IFN-α sur HTLV-1 et HTLV-2 pourrait être à l'origine de la différence de pathogénicité entre les deux virus. / HTLV-1 and HTLV-2 viruses are responsible for life-long infections. After a long latency period, 2 to 5 % of HTLV-1 infected people develop diseases such as Adult T cell leukemia (ATL) or Tropical Spastic Paraparesis/HTLV-1 associated Myelopathy (TSP/HAM). Although both viruses are very similar in their genomic organization and in their nucleotide sequence, HTLV-2 has not been associated to any malignant hematological disorders. Interferon α (IFN-α) plays a major role in host innate immune response. The role of IFN-α during HTLV-1 infection and ATL onset has poorly been investigated and results are controversial. My project was aimed at characterizing the role of IFN-α in HTLV-1 infection compared to HTLV-2 infection. We showed that IFN-α inhibits HTLV-1 and HTLV-2 de novo infection in T-cells. This inhibition is mediated through PKR activation (phosphorylation) that prevents the latest steps of the viral cycle. We also studied the effect of ADAR-1-p150 whose expression is also induced by IFN-α. We showed that ADAR-1-p150 counteracts the inhibitory effect of IFN-α on HTLV-1 and HTLV-2 cycles, through inhibition of PKR activation. These results suggest that a balance between ADAR-1-p150 and PKR expression could influence HTLV-1 and HTLV-2 infection. Furthermore we observed that IFN-α has no effect on HTLV-1 infected cells whereas HTLV-2 infected cells are still sensitive to the cytokine. A different effect of IFN-α on HTLV-1 and HTLV-2 could be involved in the distinct pathological outcomes of HTLV-1 or HTLV-2 infection.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-15T19:10:27Z No. of bitstreams: 1 Isabela Archanjo Nunea. Analise dos níveis...2013pdf.pdf: 2339102 bytes, checksum: 867cc830f16593d9b7dad5bc1ec36aec (MD5) / Made available in DSpace on 2013-10-15T19:10:27Z (GMT). No. of bitstreams: 1 Isabela Archanjo Nunea. Analise dos níveis...2013pdf.pdf: 2339102 bytes, checksum: 867cc830f16593d9b7dad5bc1ec36aec (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / A Leucemia/Linfoma de células T do adulto (Adult T-cell leukemia - ATL) é uma neoplasia humana agressiva das células T CD4+ e que foi associada ao retrovírus HTLV-1. A diversidade das manifestações clínicas da ATL determinou a subdivisão desta neoplasia em cinco formas clínicas: aguda, linfoma, tumoral primária de pele, crônica e smoldering. O HTLV-1 é capaz de estimular a proliferação das células infectadas através dos produtos de alguns genes virais, sendo esta uma das estratégias para aumentar a carga proviral (proviral load – PVL). Dentre eles, o gene viral tax e o gene HBZ (HTLV-1 basic leucine zipper factor) são apontados como os principais responsáveis pela oncogenicidade do HTLV-1. Não está bem estabelecida a relação ente os níveis de carga proviral e os níveis de expressão dos genes virais tax e HBZ nas diferentes formas clínicas desta neoplasia. Foram descritos dois transcritos para o gene HBZ, o HBZ e o HBZ-SI. Este estudo teve como objetivo a análise da carga proviral e da expressão dos genes virais tax e HBZ nas diferentes manifestações da ATL. Foram incluídos no estudo 60 pacientes de ATL para a análise da carga proviral e destes, foi realizado a análise da expressão viral em 38 pacientes. Adicionalmente, foram incluídos 16 portadores assintomáticos adultos. A expressão dos genes tax e HBZ e a carga proviral foram quantificadas pela técnica de PCR em tempo real considerando para a carga proviral a região tax do provírus e utilizando a β-globina como gene de referência e para expressão viral foi utilizado a β-actina como gene de referência. A mediana da carga proviral na ATL foi maior do que nos portadores assintomáticos (p<0,001). Foi observada também uma correlação positiva entre a carga proviral e a linfocitose. As formas smoldering, linfoma e tumoral primária de pele apresentaram carga proviral similar a observada nos portadores assintomáticos. Na expressão dos genes viriais na ATL e em portadores assintomáticos a mediana do transcrito HBZ-SI foi maior em relação ao transcrito HBZ (p<0,0001 e p=0.003, respectivamente) e ao gene tax (p<0,0001 e p=0.003, respectivamente). Observou-se uma correlação positiva entre os níveis de expressão de todos os transcritos estudados. Os níveis de expressão do gene tax e do transcrito HBZ também correlacionaram positivamente com a carga proviral, enquanto que a expressão do transcrito HBZ-SI não correlacionou. Os portadores assintomáticos apresentaram níveis maiores de expressão destes transcritos por célula infetada que os pacientes com ATL com forma aguda. O gene HBZ, principalmente o transcrito HBZ-SI parece ter um papel mais importante que o gene tax na infecção pelo HTLV-1, independentemente da condição clínica. Os portadores assintomáticos parecem ter maior dependência da expressão destes transcritos para estimulação da proliferação celular e manutenção da carga proviral que as formas crônicas e agudas da ATL, que apresentam marcada linfocitose. Os níveis de expressão do transcrito HBZ-SI por célula infectada variam entre as diferentes formas clinicas da ATL. / Adult T-cell leukemia (ATL) is an aggressive neoplasm of human CD4+ T cells and was associated with the retrovirus HTLV-1. ATL has different clinical manifestations and hás been classified into five clinical types: acute, lymphoma, primary cutaneous tumoral, chronic and smoldering. The HTLV-1 is capable of stimulating of proliferation of infected cells through the products of some viral genes, this being one of strategies to increase the proviral load (PVL). Among them, the tax viral gene and the gene HBZ (HTLV-1 basic leucine zipper factor) are pointed as the main responsible for the oncogenicity of HTLV-1. Is not fully understood the relation between the levels of proviral load and the levels of expression of the viral genes tax and HBZ in different clinical type of this neoplasm. We describe two transcripts for the HBZ gene, the HBZ and HBZ-SI. The goal of this study was to analyze the proviral load and the expression of viral genes tax and HBZ in the different manifestations of ATL. Was included 60 patients for the proviral load analysis and these was performed the analysis of viral expression in 38 patients. Additionally, we included 16 asymptomatic adults. The expression of tax and HBZ genes and proviral load were quantified by PCR real time considering to proviral load the region tax of the provirus and using the β-globin gene as a reference gene and for the viral expression was used β-actin as a reference gene. The proviral load median on ATL was higher than in asymptomatic patients (p<0.001). It was also observed a positive correlation between the proviral load and lymphocytosis. The smoldering, lymphoma and primary cutaneous tumoral types showed similar proviral load to that observed in asymptomatic carriers. In the expression of viral genes in ATL and in asymptomatic carriers the median of transcript HBZ-SI was higher compared to the transcript HBZ (p<0.001 and p=0.0003, respectively) and the tax gene (p<0.001 and p=0.0003, respectively). There was a positive correlation between the expression levels of all the transcripts studied. The expression levels of the tax gene and the transcript HBZ also positively correlated with the proviral load whereas the expression of transcript HBZ-SI did not correlate. Asymptomatic carriers had higher levels of expression of these transcripts per cell infected that the ATL patients with acute type. The HBZ gene, mainly the transcript HBZ-SI seems to have a more important role than the tax gene in HTLV-1, regardless of the clinical condition. Asymptomatic carriers appear to have greater dependency of the expression of these transcripts for stimulation of cell proliferation and maintenance of the proviral load that the chronic and acute types of ATL, which have marked lymphocytosis. The expression levels of transcript HBZ-SI by infected cell vary between different clinical types of ATL.