The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of chronic muscle diseases with frequent extramuscular organ involvement that contributes to serious prognosis. The presence of autoantibodies and composition of muscle infiltrates both support autoimmune nature of the disease and pathogenic role of B lymphocytes. Besides the traditional diagnostic subgroups, autoantibody characterised phenotype subsets have been identified with presumed similar pathogenic mechanisms. The best known is the antisynthetase syndrome which is characterised by presence of myositis, antisynthetase autoantibodies (with anti-Jo-1 being the most frequent), interstitial lung disease and other extramuscular manifestations. BAFF (B cell-Activating Factor of the TNF Family) is a key factor in B cell homeostasis modulation. In high levels, it allows survival of autoreactive B cell clones and thus participates in the pathogenesis of autoimmune diseases. Its expression is induced by type I interferons (IFN-1). The aim of the PhD thesis was to explore the role of BAFF in pathogenesis of IIMs by analysis of its serum levels, the receptors for BAFF in muscle tissue, their associations to IFN-1 and expression of BAFF gene mRNA transcription variants in peripheral blood cells. Further aspect was to study a possible...

Introduction: The inflammation plays the essential role in the bone loss in juvenile idiopathic arthritis (JIA). Proinflammatory cytokines and also glucocorticoids (GCs) may activate bone resorption by osteoclasts. Simultaneously, bone formation can be attenuated, especially by inhibitors of proteins, which control the osteoblast differentiation. The aim was to verify the hypothesis that in patients with highly active JIA, reduction of bone formation via Wingless (Wnt) proteins inhibitors - Dickkopf 1 (Dkk-1) and sclerostin could be found. Except the densitometry measurements of bone and lean mass, we assessed markers of disease activity, bone metabolism and remodeling in young adult patients with JIA before and during 2 years of anti TNFα (tumour necrosis factor α) treatment, which decreases disease activity. Results: In patients with JIA before antiTNFα treatment, bone mineral density (BMD, g/cmš) was significantly reduced compared to controls. Values of BMD and body composition in JIA significantly depended on disease duration and GCs treatment. Serum concentration of sclerostin was significantly elevated in JIA compared to values in healthy controls. Values of the other monitored markers did not differ between JIA and controls. In patients with JIA, Dkk-1 correlated positively with C-reactive...

INTRODUÇÃO: A urticária crônica igmaidiopática (UCI) é uma doença desencadeada pela desgranulação de basófilos e mastócitos com consequente liberação de histamina, sendo que o perfil imunológico nesta doença não é bem estabelecido. As estatinas, inibidores da 3-hidroxi-3-metilglutaril coenzima A redutase, apresentam efeitos antiinflamatórios e imunomodulatórios. O efeito desta droga tem sido estudado em muitas doenças inflamatórias crônicas, incluindo doenças autoimunes, mas não existem evidências na UCI. OBJETIVOS: O objetivo deste estudo foi analisar o efeito das estatinas na resposta imune e sua a influência na expressão de genes regulatórios e relacionados com a resposta inflamatória. MÉTODOS: A resposta limfoproliferativa a mitógenos e antígeno-específica de 22 pacientes com UCI e 41 controles na presença de estatinas (0,25-25 µM) foi analisada pela incorporação de timidina após 3 ou 6 dias de cultura. A progressão do ciclo celular e apoptose foi realizada pela incorporação de bromodeoxiuridina (Brdu) ao DNA após estímulo por PHA ou PWM e analisada por citometria de fluxo. A secreção de citocinas foi quantificada por ELISA e a expressão de mRNA de fatores regulatórios e pró-inflamatórios quantificados por real-time PCR. RESULTADOS: Os resultados evidenciaram que as estatinas em elevadas concentrações são capazes de inibir a capacidade mitogênica das células T e B seja dos indivíduos saudáveis ou de pacientes com UCI. A inibição da proliferação celular mediada pelas estatinas foi decorrente ao bloqueio na etapa inicial do ciclo celular (Fase G0/1), o que impediu o prosseguimento para outras fases do ciclo (S e G2/M). A diminuição da resposta proliferativa em resposta a um mitógeno como a PHA resultou na inibição da ativação celular pela estatina e a significante redução na produção de citocinas como IFN-?, IL-10, IL-17A e IL-5. Em contraste, o efeito modulatório das estatinas ao estímulo com LPS inibiu a produção de TNF-? e MIP-1? pelas células dos controles, mas não influenciou na produção de citocinas pró-inflamatórias pelas CMN dos pacientes com UCI. Somente a incubação prévia das células com as drogas, em alta concentração (25µM), foi possível verificar a modulação negativa na produção de IL-6 e MIP1-? para ambos os grupos, mas não para o TNF-? para os pacientes. A sinvastatina foi capaz exercer efeito modulatório mais pronunciado que a lovastatina na produção de citocinas induzidas por LPS. Os resultados evidenciaram que os pacientes com UCI possuem uma diminuição da expressão da enzima IDO e aumento de SOCS3 nas CMN. A sinvastina não altera esse perfil e previne a expressão de fatores inflamatórios como RORC?t e NALP3 inflamassomas. CONCLUSÕES: Em conjunto, os resultados sugerem um desequilíbrio dos mecanismos regulatórios que poderiam contribuir com a cronicidade e o perfil inflamatório na UCI. As estatinas apresentam maior efeito antiinflamatório que pró-inflamatório, sugerindo ter potencial clínico para o tratamento de doenças crônicas como a UCI. / INTRODUCTION: Chronic Idiopathic Urticaria (CIU) is a disease triggered by degranulation of basophils and mast cells with consequent histamine release and the CIU immunological profile is not well established. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also display a broad immunomodulatory property. Statins have been studied in several chronic inflammatory diseases, including autoimmune disorders, but there are no evidences in CIU disease. OBJECTIVES: The aim of this study was to verify the effect of statins the immune response, and the expression of genes related to regulatory and inflammatory response focusing in CIU patients and healthy controls (HC). METHODS: Lymphoproliferative response to mitogens or recall antigens of 22 patients with CIU and 41 HC with statins (0,25-25µM) was analyzed by timidine incorporation after 3 or 6 days of cell cultures. Cell cycle progression and apoptosis were assessed by bromodeoxyiridine (BrDU) incorporation to DNA upon PHA or PWM stimulus by flow cytometry. Cytokines secretion was measured by ELISA and mRNA of regulatory and proinflammatory genes were analyzed by quantitative real-time PCR. RESULTS: The results showed that high concentrations of statins can inhibit the mitogenic capacity of T and B cells of HC or CIU patients. The inhibition of cell proliferation mediated by statins was due to blockage in the initial phase of the cell cycle (G0/1), which prevented progress to cycle phases (S and G2/M). The decreased proliferative response in response to PHA mediated by statin resulted in a significant inhibition of IFN-?, IL-10, IL-17A and IL-5 secretion levels. Statin effect in response to LPS showed inhibition of TNF-? and MIP-1? secretion by cells from HC, but did not influence the production by PBMC of CIU. It was necessary the pre-incubation of cells with drugs at high concentration (25µM) to verify the negative modulation of IL-6 and MIP1-? secretion in both groups, except for TNF-? in CIU. Simvastatin was able to exert more pronounced modulatory effect than lovastatin in cytokine production induced by LPS. Furthermore, CIU patients have a decreased expression of the enzyme IDO and increased of SOCS3 in PBMC, which were not modified by simvastatin, whereas prevented the upregulation of proinflammatory factor as RORC?t and NALP3 inflammasomes. CONCLUSIONS: Altogether, the results evidenced an imbalance of regulatory mechanisms that could contribute to chronic evolution and inflammatory profile in CIU. Statins exhibited more anti-inflammatory effects than proinflammatory, suggesting a potential clinical role for treatment in chronic diseases as CIU.

A osteoporose é uma doença de alta prevalência na população geral, e a ocorrência de fraturas se associa a grande morbi-mortalidade e impacto econômico. Na maioria dos indivíduos afetados, a osteoporose tem etiologia multifatorial, com herdabilidade estimada entre 50 e 85%, atribuível a um conjunto de variantes genéticas de pequeno efeito individual. Raramente, há casos de osteoporose associada a síndromes monogênicas, decorrentes de defeitos genéticos de grande impacto. Postula-se que indivíduos com quadros extremos de osteoporose não sindrômica possam ter causa genética mono- ou oligogênica, atribuível a variantes de impacto intermediário sobre o fenótipo, ainda pouco reconhecidas. Nos últimos anos, o avanço das tecnologias de sequenciamento permitiu o reconhecimento de novos genes associados à fragilidade óssea e atualmente possibilita a análise simultânea de múltiplos genes. Neste contexto, os objetivos deste projeto de pesquisa foram: 1) buscar genes candidatos para fragilidade óssea previamente associados a doenças Mendelianas com alto impacto na resistência óssea, fenótipos extremos de osteoporose e estudos de associação genética em escala genômica (GWAS) para osteoporose; e 2) pesquisar a presença de variantes alélicas patogênicas nestes genes candidatos em indivíduos com osteoporose grave, familiar ou idiopática. A partir de revisão sistemática, 128 genes candidatos foram selecionados para compor um painel de sequenciamento paralelo em larga escala. O sequenciamento incluiu todos os éxons e 25 pares de bases das junções íntron-éxon. Foram consideradas variantes genéticas de interesse aquelas raras (frequência alélica < 1%) e com predição de alto impacto sobre a proteína codificada. Trinta e sete indivíduos (7 famílias e 21 casos isolados) foram selecionados seguindo critérios clínicos, laboratoriais e densitométricos restritivos, excluindo-se pacientes com causas secundárias de osteoporose. A coorte foi composta por homens em 54%, a mediana de idade ao diagnóstico foi 44 anos e 86% tinham histórico de fratura. Dentre os 28 casos índices, foram identificadas 33 variantes de interesse. Após análise de segregação familiar, foi possível excluir patogenicidade de cinco destas variantes, restando 28 variantes potencialmente patogênicas, presentes em 71% da coorte. Todas as variantes foram encontradas em heterozigose, sendo 26 variantes de ponto não-sinônimas, uma deleção de 9 pares de bases, e uma grande deleção envolvendo o único éxon codificador do gene candidato GPR68. Foi encontrada uma associação de variantes em genes diferentes em 21% da coorte, incluindo uma mulher jovem com osteoporose grave e variantes em WNT1, PLS3 e NOTCH2. A análise de segregação familiar neste caso sugeriu um efeito patogênico aditivo das variantes. Vinte e cinco porcento das variantes potencialmente patogênicas foram identificadas em genes candidatos bem estabelecidos (WNT1, PLS3, COL1A1, COL1A2), e 57% se localizam em novos genes candidatos identificados inicialmente por GWAS, como NBR1 e GPR68, também associados à alteração da remodelação óssea em modelos animais. Os resultados deste trabalho dão relevância a novos genes na fisiologia da resistência óssea e indicam um papel proeminente de interações digênicas/oligogênicas em casos de osteoporose grave, familiar ou idiopática. O reconhecimento de novas vias associadas à fragilidade óssea pode levar ao desenvolvimento de novos tratamentos, e a identificação de variantes patogênicas associadas à osteoporose pode, futuramente, permitir um manejo clínico personalizado de pacientes e seus familiares / Osteoporosis is a highly prevalent disorder resulting in fragility fractures and incurring in great morbi-mortality and economic burden. In most cases, osteoporosis has a multifactorial etiology, with an estimated heritability of 50-85% attributable to a combination of several low-impact genetic variants. Rarely, cases of syndromic osteoporosis due to high-impact genetic defects are seen. It is therefore hypothesized that severe/idiopathic cases of otherwise inconspicuous osteoporosis may have a monoor oligogenic etiology due to genetic variants with an intermediate effect. During the past years, advances in molecular sequencing have revealed novel candidate genes for bone fragility, and have enabled simultaneous sequencing of multiple genes. In this context, the objectives of this research project were: 1) to identify candidate genes for bone fragility, as previously reported in association to Mendelian disorders with high impact on bone resistance, idiopathic or familial osteoporosis, and genome-wide association studies (GWAS) for bone mineral density and fragility fractures; and 2) to perform molecular analysis of these candidate genes in patients with severe, familial or idiopathic osteoporosis. Through a systematic review, 128 candidate genes were identified and included in a panel for massively parallel sequencing. Coding regions and 25-bp boundaries were captured and sequenced. Rare variants (allele frequency < 1%), with a predicted high impact on protein function were initially selected as variants of interest. Thirty-seven subjects (21 sporadic cases and 7 families) were included according to stringent criteria based on clinical and densitometric evaluation, excluding individuals with secondary osteoporosis. Males represented 54% of the cohort, median age at diagnosis was 44 years, and 84% of subjects had a history of fractures. Thirtythree variants of interest were identified initially. After familial segregation analysis, 5 variants were considered as benign in regard to bone fragility, resulting in 28 potentially pathogenic variants, all heterozygous, present in 71% of the cohort. Of these variants, 26 were nonsynonymous, there was one 9-bp deletion and one large deletion involving the only coding exon of candidate gene GPR68. An association of two or more variants in different genes was present in 21% of the cohort, including a young woman with severe osteoporosis and variants in WNT1, PLS3 and NOTCH2. Familial segregation in this case suggested an additive pathogenic effect of these variants. Twenty-five percent of potentially pathogenic variants were identified in well-established candidate genes (WNT1, PLS3, COL1A1, COL1A2), and 57% located to novel candidate genes initially identified by GWAS, such as NBR1 and GPR68, which have been previously associated to changes in bone remodeling in mouse models. These results support the involvement of GWAS genes in the pathophysyiology of osteoporosis, and indicate a prominent role for digenic/oligogenic interactions in cases of severe, familial or idiopathic osteoporosis. Recognition of new molecular pathways in the determination of bone fragility may lead to the development of new drugs, and the identification of pathogenic variants associated to osteoporosis may allow individualized clinical management of patients and their relatives

A púrpura trombocitopênica idiopática (PTI) é uma patologia adquirida que leva à redução da contagem de plaquetas, mediada por mecanismo imunológico. O tratamento inicial é a corticoterapia e, se caracterizada a falência ou dependência desta, a esplenectomia é a segunda opção. Autores recomendam que a esplenectomia seja realizada antes de se completarem 12 meses do diagnóstico, apesar de estudos sugerirem que a resposta após este período é semelhante. Neste estudo, pesquisaram-se a eficácia da esplenectomia tardia, as complicações da manutenção da terapia imunossupressora e as complicações hemorrágicas na população com esplenectomia tardia. Analisaram-se prontuários de 39 pacientes com idade de 4 a 64 anos (mediana de 27 anos) ao diagnóstico, submetidos à esplenectomia como procedimento terapêutico de PTI. Classificaram-se as respostas à esplenectomia, observadas na última visita, após 6 meses da cirurgia, em resposta completa (RC) (mais de 150.000 plaquetas/ l) parcial (RP) (de 50.000 a 150.000 plaquetas/ l) ou sem resposta (SR) (menos de 50.000 plaquetas/ l ou necessidade de medicação para controle da PTI). No período anterior à esplenectomia, a prednisona causou efeitos colaterais em 18% dos pacientes. Uma paciente que utilizou azatioprina desenvolveu carcinoma ductal de mama. Outros efeitos colaterais da azatioprina, danazol, colchicina, levamisol e vincristina reverteram após a suspensão das drogas. Não houve mortalidade relacionada à PTI nem às esplenectomias, mas houve mais hemorragias graves (21%) no período pré-operatório. As esplenectomias foram realizadas após 1 a 174 meses (mediana 36 meses) do diagnóstico e a última visita ocorreu depois de 9 a 300 meses (mediana 25,5 meses) da cirurgia. As respostas finais à esplenectomia foram: 16 (44%) RC, 10 (28%) RP, 10 (28%) SR. A comparação entre as respostas dos pacientes que realizaram a esplenectomia antes e as dos que a realizaram após 36 meses não mostrou diferença significativa (p=0,687). A esplenectomia tardia tem eficácia, aferida pela soma das RC e RP, comparável à citada pela literatura. As medicações imunossupressoras produziram mais efeitos colaterais e ocorreram mais hemorragias graves do que as relatadas pela literatura. / Idiopathic thrombocytopenic purpura (ITP) is an acquired immunologic disorder associated with reduction of platelet count. The primary treatment is prednisone in the majority of cases, and if it fails or if there is a dependence of it, the splenectomy is performed. The surgery is usually indicated within 12 months after diagnosis because of presumed better results. Nevertheless, clinical studies suggest that splenectomy is effective when performed after this 12 months. In this study the hemorrhagic complications of ITP, the side effects of immunossupressive therapy during preoperative period and the efficacy and safety of the procedure were studied in a population with late splenectomy. Thirty nine patients were included with median age of 27 years (range 4 to 64 years) at the diagnosis of ITP. The response to splenectomy were classified as complete response (CR) (platelets counts above 150.000/ l), partial response (PR) (platelet counts of 50.000 to 150.000/ l), and no response (NR) (less than 50.000/ l or use of drugs to maintain platelet count). In the preoperative period, prednisone caused side effects in 18% of patients. One patient who received azathioprine had breast cancer. Other side effects of azathioprine, danazol, colchicin, levamisole and vincristine remitted after drugs withdrawal. The surgeries were performed after 1 to 174 months of diagnosis (median of 36 months). Of the 39 patients, 36 had assessment of response to splenectomy after 9 to 300 months: 16 patients had CR (44%), 10 PR (28%), and 10 NR (28%). The responses of the patients with period of diagnosis to splenectomy of 36 months or more were not different from the patients with this period of less than 36 months (p=0.687). During the preoperative period, 21% of patients had severe hemorrhagic complications of ITP, but there were no death caused by ITP or splenectomy. Although, the favorable response (sum of CR and PR) of late splenectomy was similar, there were more side effects of immunossupressive therapy and severe hemorrhagic complications than the reported in the literature. Splenectomy is a therapeutic option for immune thrombocytopenic purpura (ITP), usually recommend before 12 months after diagnosis. In this study, 39 patients were splenectomized 1 to 174 months (median of 36 months) after the hemorrages and more side effects of prednisone than reported in the literature, but there were death. The favorable responses of late splectomy were similar to the reported in the literature. the favorable responses of the group with period of ITP diagnosis to splenectomy of the 36 months or more were not different from the group with less than 36 months (p=0.687).

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-09-21T19:16:32Z No. of bitstreams: 1 antoniomarciolimaferrazjunior.pdf: 2504413 bytes, checksum: 0d6202735d7b0c962ea156685fdc2823 (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-09-26T20:27:53Z (GMT) No. of bitstreams: 1 antoniomarciolimaferrazjunior.pdf: 2504413 bytes, checksum: 0d6202735d7b0c962ea156685fdc2823 (MD5) / Made available in DSpace on 2016-09-26T20:27:53Z (GMT). No. of bitstreams: 1 antoniomarciolimaferrazjunior.pdf: 2504413 bytes, checksum: 0d6202735d7b0c962ea156685fdc2823 (MD5) Previous issue date: 2010-07-29 / Desordens temporomandibulares (DTM) são alterações desencadeadas por distúrbios articulares e/ou musculares na região orofacial caracterizadas por manifestarem dor e/ou disfunção. A artrite idiopática juvenil (AIJ) é uma doença crônica e sistêmica, que se inicia em crianças e adolescente menores de 16 anos de idade, sendo caracterizada por uma sinovite crônica nas articulações. Os objetivos da presente pesquisa foram avaliar a presença de DTM em pacientes com AIJ por meio da utilização dos Critérios de Diagnóstico para Pesquisa da Desordem Temporomandibular (RDC/TMD) e, posteriormente, correlacionar o diagnóstico clínico de DTM com os achados da Tomografia Computadorizada de Feixe Cônico (TCFC) e com a idade, gênero sexual, tempo do início dos sintomas, tempo de tratamento e subtipo da AIJ dos pacientes. Foram avaliados 15 pacientes (oito do gênero sexual masculino e sete do gênero feminino) com idade variando entre seis e 28 anos (média de 16,3 anos). Foram encontradas 25 (83,3%) articulações temporomandibulares (ATM) com diagnóstico clínico de DTM. Apesar das alterações articulares terem sido frequentes na avaliação por meio da TCFC (83,3%), apenas cinco (17,7%) ATM apresentaram um diagnóstico clínico de osteoartrite ou osteoartrose. Após análise estatística dos resultados, com nível de significância de 5% (p≤0,05), pôde-se sugerir que: o diagnóstico clínico de DTM e os achados da TCFC não tiveram correlação estatisticamente significante com o gênero sexual e com o subtipo da AIJ; um maior número de diagnósticos clínicos de DTM do lado direito aumentou a probabilidade de se encontrar um maior grau de DTM no lado esquerdo e quanto maior o tempo do início dos sintomas da AIJ, maior foi o grau de DTM e maior foi a probabilidade de se encontrar alterações tomográficas bilateralmente; um número maior de alterações tomográficas do lado direito aumentou a probabilidade de se encontrar um maior grau de alteração tomográfica no lado esquerdo; as ATM do lado esquerdo dos pacientes acometidos pela AIJ numa idade mais avançada, com um início dos sintomas tendo ocorrido há mais tempo e com um maior tempo de tratamento estavam relacionadas com um maior grau de alteração tomográfica; quando o início dos sintomas da AIJ ocorreu há mais de três anos, maior foi o grau de DTM (lado direito e esquerdo) e o grau de alteração tomográfica (lado esquerdo) e também foi maior a probabilidade de se encontrar diagnóstico de DTM e alterações tomográficas bilateralmente; quando a idade no 8 momento da avaliação foi superior a 16 anos, maior foi o grau de DTM e de alteração tomográfica encontrado (lado esquerdo). / Temporomandibular disorders (TMD) are alterations triggered by joint and/or muscle disorders in the orofacial region characterized by expressing pain or dysfunction. Juvenile idiopathic arthritis (JIA) is a chronic and systemic disease, which begins in children and adolescents under 16 years old and is characterized by a chronic synovitis in the joints. The objectives of this research were to evaluate the presence of TMD in patients with JIA using Research Diagnostic Criteria to Temporomandibular Disorders (RDC/TMD), and subsequently to correlate the clinical diagnosis of TMD with the findings of Cone Beam Computed Tomography (CBCT) and with the age, gender, time of symptoms onset, treatment time and subtype of JIA patients. Fifteen patients (eight male and seven females) aged between six and 28 years (mean age of 16.3 years) we evaluated. Twenty-five (83.3%) temporomandibular joints (TMJ) had clinical diagnosis of TMD. Despite joint alterations have been frequent in the evaluation by CBCT (83.3%), only five (17.7%) ATM had a clinical diagnosis of osteoarthritis or osteoarthrosis. After statistical analysis of the results, with significance level of 5% (p ≤ 0.05), it was suggested that: clinical diagnosis of TMD and the findings of TCFC had no statistically significant correlation with gender and subtype of JIA; a greater number of clinical diagnoses of TMD on the right-hand side increased the probability of finding a greater degree of TMD on the lef-hand side, and the longer the time from symptom onset JIA, the greater the degree of TMD and the probability of finding tomographic alterations on both sides; a greater number of tomographic alterations on the right-hand side increased the probability of finding a greater alteration degree on the left-hand side tomographic; the ATM on the left-hand side of patients affected by JIA at a later age, having the symptoms onset beginning longer ago and a longer duration of treatment were related to a greater degree of tomographic alterations; when the JIA symptoms onset began more than three years ago, the greater was the degree of TMD (righthand and left-hand side) and the degree of tomographic alteration (left side), also was greater the probability of finding TMD diagnosis and tomographic alterations on both sides; when the patients are older than 16 by the time of the evaluation, the greater the degree of TMD and alterations found tomographic (left-hand side).

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2017-05-17T15:37:54Z No. of bitstreams: 1 marianedemelomelquiadescardoso.pdf: 3228798 bytes, checksum: 2494751b6e0c186b89d6a664d39997d5 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-17T16:16:39Z (GMT) No. of bitstreams: 1 marianedemelomelquiadescardoso.pdf: 3228798 bytes, checksum: 2494751b6e0c186b89d6a664d39997d5 (MD5) / Made available in DSpace on 2017-05-17T16:16:39Z (GMT). No. of bitstreams: 1 marianedemelomelquiadescardoso.pdf: 3228798 bytes, checksum: 2494751b6e0c186b89d6a664d39997d5 (MD5) Previous issue date: 2010-07-29 / A Artrite Idiopática Juvenil (AIJ) é a doença reumatológica crônica da infância, responsável por limitações físicas, psicológicas e até sociais dos pacientes a curto e/ou longo prazo, sendo caracterizada por inflamação da sinóvia em uma ou mais articulações. A articulação temporomandibular (ATM), como qualquer outra articulação sinovial, pode ser um sítio para a artritre idiopática juvenil. A literatura relata uma alta prevalência de sinais e sintomas de desordens temporomandibulares (DTM) em pacientes com AIJ. Foram avaliadas as articulações temporomandibulares de 15 pacientes (30 articulações) com diagnostico de artrite idiopática juvenil por meio de tomografia computadorizada de feixe cônico com o objetivo de investigar alterações ósseas (aplainamento, erosão osteófito e esclerose). Dos pacientes avaliados, 13 possuíam pelo menos um dos tipos de alterações investigadas (87%) e apenas dois pacientes não apresentaram alterações registradas tomograficamente. Aplainamentos e osteófitos foram as alterações mais encontradas nos côndilos mandibulares (53,3%) e 43% dos complexos fossa/eminências articulares encontravam-se aplainadas. As alterações encontradas foram mais freqüentes do que a literatura relata e justifica-se pelo melhoramento da ferramenta de diagnostico – tomografia computadorizada de feixe cônico. / Juvenile Idiopathic Arthritis (JIA) is a chronic rheumatic disease of childhood, accounting for physical limitations, psychological, social and even the patients in the short and / or long term, and is characterized by inflammation of the synovium in one or more joints. The temporomandibular joint (TMJ), like other synovial joint may be a site for juvenile idiopathic arthritis. The literature reports a high prevalence of signs and symptoms of temporomandibular disorders (TMD) in patients with JIA. Were evaluated the temporomandibular joints of 15 patients (30 joints) with diagnosis of juvenile idiopathic arthritis using cone beam computed tomography in order to investigate bone changes (flattening, erosion, osteophytes and sclerosis). Among the patients, 13 had at least one of the types of alterations analyzed (87%) and only two patients showed no changes recorded tomographically. Flattening and osteophytes were the most found in the mandibular condyles and (53.3%) and 43.3% of the complexe fossa/articular eminences were flattened. The alterations were more frequent than the literature reports and are justified by the improvement of diagnostic tools - cone beam computed tomography.

Dreaming is a complex, multimodal and sequentially organized model of the waking world (Metzinger, 2003). Nightmares are a category of dreams involving threatening scenarios, anxiety and other negative emotions (Hartmann, 1998; Nielsen &amp; Levin, 2007). Dreams and nightmares are explored in this present thesis in the light of psychology and modern cognitive neuroscience as to their nature, function and neural correlates. The three main dream theories and their leading investigations are reviewed to evaluate their evidence and overall explanatory power to account for the function of dreams and nightmares. Random Activation Theories (RATs) claim dreams are biological epiphenomena and by-products of sleep underlying mechanisms (Crick &amp; Mitchison, 1983; Flanagan, 1995, 2000a, 2000b, Hobson &amp; McCarley, 1997). Mood regulation theories consider that the psychological function of dreams is to regulate mood and help with the adaptation of individuals to their current environment such as solving daily concerns and recovery after trauma exposure (Hartmann, 1996; Levin, 1998; Stickgold, 2008; Kramer, 1991a, 1991b, 2014). Threat Simulation Theories of dreams present the evolutionary function for dreaming as a simulating off-line model of the world used to rehearse threatening events encountered in the human ancestral environment (Revonsuo, 2000a). With the threat-simulation system, threats were likely to be recognized and avoidance skills developed to guarantee reproductive success. TST consider nightmares to reflect the threat-simulation system fully activated (Revonsuo, 2000a). Supported by a robust body of evidence TST is concluded to be the most plausible theory at the moment to account as a theoretical explanation of dreams and nightmares

La scoliose idiopathique de l’adolescence constitue la déformation tridimensionnelle de la colonne vertébrale la plus couramment rencontrée chez les adolescents. Cette condition a fait l’objet de plusieurs études quant à ses facteurs étiologiques, ses facteurs de risque de progression et ses approches thérapeutiques. Les études démontrent que l’étiologie de cette pathologie serait multifactorielle, regroupant entre autres des causes génétiques, hormonales, mécaniques et neuromusculaires. Malgré le fait qu’il soit difficile de prédire quelles sont les déformations qui progresseront, certains facteurs tels que l’âge et le sexe du patient, l’âge du début de la ménarche, le type et la sévérité de la déformation ainsi que la maturité osseuse (signe de Risser) ont fait l’objet de nombreuses études et représentent par le fait même des critères de référence utilisés pour estimer cette probabilité. La scoliose idiopathique a souvent été considérée comme une condition non douloureuse, faisant en sorte que peu d’études se sont arrêtées à évaluer les douleurs au dos chez les patients affligés de cette pathologie. On retrouve donc, au cours des vingt dernières années, seulement une dizaine d’études qui ont spécifiquement évalué ce phénomène. Parmi ces études, on note une grande hétérogénéité des facteurs d’inclusion, des définitions des douleurs au dos, de la période de prévalence et des instruments de mesure utilisés, rendant difficile la détermination de cette prévalence. Considérant la relation entre les douleurs exprimées chez les adolescents et celles chez les adultes, ainsi que les coûts sociétaux associés à ces douleurs, il serait important d’obtenir un portrait plus exact de l’ampleur de la douleur chez cette clientèle. ii Les objectifs généraux de cette thèse visaient à (objectif 1) mettre à jour les connaissances relatives à la prévalence des douleurs au dos chez les adolescents avec une scoliose idiopathique (SI), à (objectif 2) vérifier s’il existe une relation entre la sévérité de la déformation, sa localisation et la présence de douleurs au dos chez ces patients, à (objectif 3) valider à nouveau l’aspect psychométrique du questionnaire SRS-22fv et enfin à (objectif 4) explorer une possible prise en charge alternative des patients avec scoliose idiopathique de l’adolescence (SIA) exprimant des rachialgies. La première étude rétrospective que nous avons effectuée a permis d’évaluer de quelle façon les douleurs exprimées par plus de 300 patients étaient rapportées dans les dossiers et d’établir la prévalence de ces douleurs chez ces derniers. De plus, cette étude a évalué le type de prise en charge recommandée lorsque des douleurs étaient mentionnées au dossier. Cette étude a permis de confirmer que près de 50 % des patients avec SIA exprimaient de la douleur au dos et que la majorité de ces derniers (80 %) n’avaient aucune prise en charge de celle-ci. La deuxième étude prospective que nous avons réalisée a évalué les douleurs au dos chez plus de 500 adolescents avec scoliose idiopathique de l’adolescence. Plus de 68 % de ces patients rapportaient la présence de douleurs au dos. Pour les régions thoraciques et lombaires, les douleurs étaient positivement associées avec la sévérité de la scoliose, alors que le port du corset avait un effet modérateur sur la douleur. La troisième étude incluse dans la présente thèse visait à (objectif 3) vérifier la validité de contenu et de construit de la version canadienne-française du questionnaire SRS- 22, soit le SRS-22fv, rempli par les patients recrutés lors de la deuxième étude. Ce iii questionnaire est couramment rempli par les patients scoliotiques. Notre étude a bénéficié d’un échantillon de 352 patients qui ont entièrement répondu au questionnaire SRS-22fv. L’analyse découlant de notre étude nous a menés à produire une version abrégée du SRS-22 contenant 18 éléments, avec une meilleure consistance interne ainsi qu’une variance explicative supérieure, soit 63,3 % pour le SRS-18fv, comparativement à 47,4 % pour le SRS-22fv. La dernière étude que nous avons menée (objectif 4) met en lumière une option de prise en charge alternative des patients avec scoliose exprimant ou non des douleurs au dos. En effet, les manipulations vertébrales font partie des options de traitements couramment utilisées chez les adolescents sains. Une grande incertitude demeure toutefois quant à l’utilisation de cette approche thérapeutique chez les patients avec scoliose idiopathique de l’adolescence. Cette étude a permis de confirmer qu’il y a un manque de données probantes dans ce domaine. Les résultats de cette thèse permettent de mieux comprendre le phénomène de la douleur au dos chez les adolescents avec scoliose idiopathique. Ces douleurs semblent plus prévalentes qu’initialement estimées, et il s’avère qu’un lien semble probable entre l’intensité des douleurs ressenties et la localisation de la courbe, ainsi qu’avec la sévérité de la scoliose chez ces adolescents. / Adolescent idiopathic scoliosis is a three-dimensional spinal deformity. This pathology is the most common spinal deviation encountered in adolescents and has been thoroughly researched over the past few decades regarding its aetiological factors, its risk of progression and management. It is now commonly accepted that the aetiology of adolescent idiopathic scoliosis is multifactorial and includes, among other things, genetic, hormonal, mechanic, and neuromuscular factors. Though predicting which deviation will progress remain challenging, certain factors such as the age of the patient at presentation, its gender, bone maturity (Risser sign), menarchal status, and the severity of the spinal deformity are now widely accepted as factors that may provide some guidance to estimate this probability. Adolescent idiopathic scoliosis has often been considered as a non-painful pathology, and this is perhaps why researchers have failed to assess back pain in this population more systematically. Only a few studies have been published over the last two decades on this subject. Among those studies, inclusion criteria are widely heterogeneous, as is the working definition of back pain, how the prevalence period was estimated, and which outcome measure was relied upon to assess back pain in this population. Because of this, the determination of back pain prevalence in scoliosis patients remains challenging. Considering the relationship between adolescent and adult spinal pain, and the high societal cost associated with this condition, it would be appropriate to obtain a clearer picture of this condition in this population. v The primary objectives of this thesis were to (objectif 1) update the current knowledge of back pain prevalence in adolescent idiopathic scoliosis patients, to (objectif 2) ascertain if a relationship was present between the severity and localisation of the scoliosis and the back pain, too (objectif 3) reassess the psychometric properties of the SRS-22fv questionnaire, and to (objectif 4) explore an alternative back pain management for those patients. The first retrospective study included in this thesis assessed back pain prevalence in 300 adolescent idiopathic scoliosis patients. It also looked at how pain was reported and if pain management was recommended for patients reporting back pain. This study confirmed that back pain was a prevalent condition in this population and that in the vast majority of those reporting back pain, there was no kind of management recommended. The second prospective study assessed back pain prevalence in more than 500 adolescent idiopathic scoliosis patients. Point prevalence of back pain was close to 68 %. For the thoracic and lumbar regions, the pain was positively associated with the severity of the scoliosis and bracing, prescribed to stabilise or prevent the curve progression, had a protective effect. Data collected in the previous study were employed to validate the most commonly utilised outcome measure in adolescent idiopathic scoliosis, the SRS-22. The SRS-22 is a measurement instrument used to ascertain the quality of life and pain in scoliotic patients. The third article includes a report on analyses done regarding the validation of the SRS- 22fv. Complete data were available for 352 adolescents. The study demonstrated that a briefer version (18 items) had a better internal consistency and explained a greater proportion of the variance thus 63,3 % instead of 47,4 % for the SRS-22fv. vi The last study included in this thesis looked at an alternative treatment for the management scoliotic patients with or without back pain. This modality of spinal manipulation is a treatment that healthy adolescents commonly utilised. However, it was found that the rate of utilisation remains unclear within adolescent idiopathic scoliosis patients. A literature review revealed the need to have better-designed studies to assess the efficacy of spinal manipulation in this population adequately. The acquired knowledge throughout this thesis leads us to a better comprehension and understanding of back pain in adolescent idiopathic scoliosis patients. Back pain appears to be more prevalent than initially estimated and a relationship seems to be present between the level of pain intensity and the scoliosis localisation and severity in patients suffering from this pathology.

Abstract The etiology of juvenile idiopathic arthritis (JIA) is still unknown but genetic and enviromental factors play role in the pathogenesis. The aim of the study was to detect endoscopic and immunohistological changes in the gut in JIA compared with the controls and potential correlation of mucosal immunological activation with clinical activity of JIA. JIA patients (n=26) and negative controls (n=71) suffering from gastrointestinal symptoms without significant gastrointestinal disease were recruited for the study. Positive controls were patients with cows milk protein sensitive enteropathy (n=24). The intraepithelial lymphocytes counts, cytotoxic (granzyme A, B) and gamma/delta T-cell count and HLA-DR antigens were evaluated by using immunohistochemistry and messenger RNA expression levels of important immune mediators were assessed with real time PCR (RT-PCR) from fresh frozen intestinal mucosal samples. In JIA compared with negative controls, there was increased presence of lymphonodular hyperplasia and expression of HLA-DR antigens in abnormal mucosal cites, in crypts of the ileum. These changes were correlating with activity of JIA. In JIA compared with negative controls, there were found elevated granzyme B but decreased cytoprotective heat shock protein expression. The mRNA expression levels of anti- inflammatory mediators like TGFβ, IL10 and transcriptor factor of regulatory T-cells FOXP3, inversely correlated with activity of JIA. In conclusion, patients with JIA suffering from gastrointestinal symptoms display evidence of intestinal mucosal immune activation and there is an association between levels of mucosal immune alteration and clinical activity of JIA. These findings support the hypothesis that there is a link between the intestinal immune system and pathogenesis of juvenile idiopathic arthritis. In order to confirm these findings, more extensive series of JIA patients without gastrointestinal symptoms needs to be examined. / Tiivistelmä Lastenreuman tautimekanismi on tuntematon. Geneettiset ominaisuudet ja ympäristötekijät ovat yhteydessä taudin syntyyn. Tutkimuksen tavoitteena oli selvittää, onko suolen limakalvolla endoskooppisia tai immunohistologisia muutoksia enemmän lastenreumassa kuin kontrolleilla, ja että liittyvätkö muutokset niveltaudin aktiivisuuteen. Tutkimukseen otettiin 26 suolioireista lastenreumapotilasta, 76 verrokkia joilla ei ollut autoimmuunisairautta sekä 24 viivästynyttä maitoallergiaa sairastavaa lasta, joille tehtiin suolen tähystystutkimus. Ohutsuolinäytteistä arvioitiin immunohistologisesti solunsisäisten lymfosyyttien, gamma/delta-positiivisten lymfosyyttien sekä sytotoksisten (grantsyymi-A ja -B) lymfosyyttien määrä. Lisäksi määritettiin immunohistologisesti ohutsuolen limakalvon epiteelisolujen HLA-DR- antigeenien ja epiteelisolua suojaavien lämpöshokkiproteiinien ilmenemistä sekä käänteis-PCR-menetelmällä keskeisten välttäjäaineiden lähetti-RNA-tasoja. Tutkimuksessa lastenreumaa sairastavilla esiintyi enemmän suolen imukudoskertymää (lymfonodulaarinen hyperplasia) negatiiviseen verrokkiryhmään nähden sekä HLA-DR antigeenejä epätyypillisellä alueella ohutsuolen loppuosan limakalvon kryptassa. Nämä löydökset olivat yhteydessä lastenreuman aktiivisuuteen. Lastenreumassa oli verrokkeja enemmän sytotoksisia lymfosyyttejä ja vähemmän lämpöshokkiproteiineja. Tulehdusta suojaavat lähetti- RNA-tasot korreloivat käänteisesti lastenreumataudin aktiivisuuteen. Väitöstutkimuksen suolioireisilla lastenreumapotilailla oli suolen limakalvolla muutoksia, jotka sopivat poikkeavaan antigeenien käsittelyyn. Nämä löydökset tukevat hypoteesia, että lastenreumassa suolen limakalvon immunologinen aktivaatio on yhteydessä taudin puhkeamiseen. Jotta tulokset voisi yleistää, tarvittaisiin jatkotutkimus, joka on tehty suolioireettomilla lastenreumapotilailla ja riittävällä otoskoolla.