Scoliosis is defined as a patological curvature of spinal cord of more than 10ř in frontal plane which is combined with rotation of vertebral bodies and also with disruption of fyziological curvatures in sagittal plane. Idiopathic scoliosis is the most frequent type of this diagnosis. The thesis deals with overal issue of this disease, theories of etiology, incidence, classification, types of examination, possibilities of new testing and therapy. The practical part describes rasterstereographic DIERS Formetric III 4D testing and coparison with RTG examination. The study was carried out with 17 girls and 1 boy with idiopathic scoliosis 11 - 46ř at the age of 11 - 17 years. Results of this testing were statistically analysed. Best results were found out in measurements by automatically set range for a group of patients with Cobb angle ≤ 25ř - for 95% differences the limits of correspondance were ± 4ř, the average error was 0,3ř. For group of all patients the limits of correspondance were ± 14ř, the average error was 1,5ř. The results confirmed, that with an increase of Cobb ange a bigger error and systematic error appears.

Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Daniel Diviš Supervisors: Prof. Dr. Florence Apparailly, Directrice de Recherche Prof. PharmDr. Petr Pávek, Ph.D. (formal tutor) Title of diploma thesis: The role of miR-150 in the physiopathology of oligoarticular juvenile idiopathic arthritis Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatoid disease affecting children, and its pathological mechanisms are still poorly understood. Innate and adaptive immunity including myeloid cells play a major role in these processes. Epigenetic deregulations along with non-coding microRNAs have been reported in many inflammatory diseases. Moreover, preliminary results obtained by the research group of Prof. Florence Apparailly showed accumulation of intermediate monocytes along with the high expression of miR-150 in the synovial fluid of children affected by oligoarticular JIA. Based on these findings a hypothesis has been postulated suggesting that miR-150 could have a role in the pathogenesis of this disease and in the regulation of monocyte differentiation and function. To study the impact of miR-150 on monocytes from the peripheral blood of healthy donors, transfection experiments were performed to neutralize miR-150. The...

Introdução: A Artrite Idiopática Juvenil (AIJ) inicia-se principalmente no intervalo etário de oito a catorze anos, podendo estar associada a déficit de crescimento e atraso puberal. O estadiamento de Tanner e a avaliação ultrassonográfica da pelve podem detectar atrasos no desenvolvimento puberal. Objetivos: Comparar a maturação sexual das meninas com AIJ a controles saudáveis, por meio da avaliação clínica dos estágios de Tanner e dos parâmetros da ultrassonografia (US) pélvica e relacionar esses achados aos níveis de hormônios sexuais e fatores relacionados à doença. Comparar, também, os dados antropométricos e a idade da menarca entre os dois grupos e relacioná-los a fatores de risco ligados à AIJ. Delineamento: Estudo transversal com grupo controle Metodologia: O estudo foi realizado com 44 meninas com AIJ e 59 controles com idades entre seis e dezoito anos incompletos, sem uso de glicocorticoides há no mínimo seis meses e sem outras doenças crônicas concomitantes. O diagnóstico de AIJ foi realizado de acordo com critérios da Liga Internacional das Associações de Reumatologia (ILAR). Foi realizada avaliação antropométrica, e a maturação sexual foi avaliada por meio dos estádios de Tanner. A US pélvica abdominal foi utilizada para avaliar as medidas do útero dos ovários e o índice de pulsatilidade das artérias uterinas (IP). Foram medidos níveis hormonais de FSH, LH, estrógeno, progesterona e IGF-1 nas meninas com AIJ. Resultados: Os parâmetros da US pélvica foram correlacionados aos estágios de Tanner no grupo controle (p <0,001). Todas as medidas de útero e ovários foram menores nas meninas com AIJ quando comparadas ao grupo controle. A média do IP das artérias uterinas foi maior nas meninas com AIJ. Estratificando-se por idade, o volume do útero foi menor nas meninas com AIJ na faixa etária de 10-11 anos (p < 0,004) e 14-15 anos (p=0,042), e a relação corpo/cérvice AP foi menor no intervalo de 10-11 anos (p=0,007). Os níveis de LH e estradiol foram fortemente relacionados ao aumento dos órgãos pélvicos (p<0,001) e inversamente com IP médio das artérias uterinas (p<0.01). O escore z do IMC e da estatura foi menor nas meninas com AIJ em relação ao grupo controle (p=0,032 e p=0,041 respectivamente). As meninas com AIJ poliarticular e com maior dose cumulativa de glicocorticoide apresentaram a maior chance de ter baixa estatura. Não houve diferença entre os grupos AIJ e controles com relação à idade da menarca. A altura final e a diferença entre essa altura e a altura-alvo familiar não foi diferente entre as meninas com AIJ e as do grupo controle. Conclusão: Nosso estudo mostrou que, mesmo sem uso de glicocorticoide há mais de seis meses, as crianças com formas mais graves de AIJ e que necessitaram de doses maiores de glicocorticoide estão mais suscetíveis ao retardo no crescimento e atraso no início da puberdade. A US pélvica demonstrou ser um exame sensível para avaliação da maturação sexual de meninas, identificando atrasos nas meninas com AIJ não percebidas por meio da avaliação clínica pelos estágios de Tanner. / Introduction: Juvenile Idiopathic Arthritis (JIA) manifests at the 8 to 14-year age span and is often associated with growth deficit and puberty delay. Tanner staging and pelvic ultrasonography (US) can be used to detect pubertal delays. Objectives: To compare sexual maturation in JIA girls and healthy controls (HC) by clinical evaluation with Tanner stages and pelvic US parameters and to correlate these findings with sexual hormone levels and disease related factors. Additionally, to compare anthropometric data and menarche age between groups and to correlate such findings with disease related risk factors in JIA patients. Study design: Cross-sectional study. Methods: 44 JIA and 59 healthy girls, aged six to 18 years, free of steroid use in the last six months and with no concomitant chronic diseases were included the study. JIA was diagnosed after the International League of the Rheumatology Associations (ILAR) criteria. Anthropometric and sexual development evaluations by Tanner staging were performed Pelvic US was performed to measure uterus, endometrial thickness, ovaries and uterine artery pulsatility index. Sexual hormone levels were measured in JIA girls. Results: Pelvic US parameters correlated with Tanner stages in HC (p <0.001). All uterine and ovarian measurements were smaller in JIA girls than in HC. Mean uterine artery PI was greater in JIA girls. Uterine volume was smaller in JIA girls at the 10 to 11 (P=0.004) and 14 to 15 year (p=0.042) age strata and the anteroposterior body cervix ratio was smaller in JIA girls the 10 to 11 year stratum (p=0.007). LH and estradiol levels were strongly correlated with pelvic organ size. (P<0.001) and inversely correlated with mean uterine artery PI (p<0.01) BMI and height for age z scores were smaller in JIA girls than in HC. Polyarticular JIA girls and those that had received greater steroid doses had the largest chance to have short stature. There was no difference between JIA girls and HC regarding menarche age. Final height and the final height/target height difference was not different between JIA girls and HC. Conclusion: The current study showed that JIA girls from the most severe subtypes and those that had received the largest steroid cumulative doses were more susceptible to growth and puberty delays, even six months after drug withdrawal. Pelvic US was a sensitive tool in detecting sexual development in girls, being able to identify puberty delays, unsuspected by Tanner stage evaluation.

Background: Dilated Cardiomyopathy (DCM) is the most common functional type of cardiomyopathy in children with significant morbidity and the leading indication for cardiac transplant over 5 years of age. Identification of baseline risk factors for failing medical management by etiologic grouping remain to be elucidated in a large populationbased study. The competing risk for heart death between all-cause mortality and heart transplantation is often overestimated in the literature and may obscure additional novel risk factors associated with poor clinical outcomes. Methods: The National Heart Lung and Blood Institute Pediatric Cardiomyopathy Registry collected longitudinal data from 1731 children with DCM in North America from 1990 to 2007. Composite endpoint (CEP) was the earlier occurrence of death or heart transplant. Univariate and multivariate predictors were identified from demographic and echocardiographic data (expressed as z-scores) collected within 30 days of diagnosis. A competing risk analysis was performed calculating cumulative incidence and identifying novel prognostic factors. All analyses were performed by etiologic group. Results: Multivariate Cox regression identified the highest mortality risk among children with idiopathic disease (N=1192, CEP: 41%) when diagnosed over age 6 years, and with congestive heart failure (CHF) and decreased left ventricular fractional shortening (FS). Risk factors for those with myocarditis (N=272, CEP: 26%) were older age, CHF, and increased left ventricular (LV) end-diastolic dimension (EDD); while for neuromuscular disease (N=139, CEP: 40%), it was a decreased FS and increased EDD. Only univariate predictors were identified for children with familial isolated cardiomyopathy (N=79, CEP: 44%) including: CHF, increased EDD, end-systolic dimension, or LV mass, and decreased FS or ejection fraction), while for children with inborn errors of metabolism (N=43, CEP: 33%) risk factors included: a positive family history of cardiomyopathy or genetic syndromes. The group of children with malformation syndromes (N=6, CEP: 50%) was not large enough to model. Comparison of cause-specific event rates between Kaplan-Meier and cumulative incidence demonstrated an overestimation with the former method. Competing risk multivariate regression showed similar models to those for CEP, with the following exceptions: for neuromuscular disease, an increased EDD had a larger hazard ratio for transplant than for death; for idiopathic disease, an increased EDD was associated with transplant, but not with death, and growth retardation (height-for-age zscore) was associated with death but not transplant. Conclusions: Within etiologic grouping, demographics and echocardiographic values at diagnosis have varying predictive value. Generally, the presence of symptomatic disease in the form of CHF, echocardiographic evidence of more severe DCM, and increased age were indicative of worse outcomes. These results help to validate those from conflicting studies; however, they suggest that etiology modifies the importance of particular factors. Analysis of competing risk provides an alternate interpretation of studies with composite endpoints and assists in the transfer of clinically relevant information. For children with idiopathic and neuromuscular disease, the degree of dilation had a differential effect that has gone unrecognized. The novel finding of reduced stature and its effect on mortality suggests a potential for treatment and mitigation of poor outcomes in idiopathic DCM. Both increased dilation and reduced stature could be used to improve the triage process and refer children to cardiac transplantation who otherwise might die prematurely and unnecessarily. Subsequent studies on the utility of these factors and their effect on improving survival are warranted.

Concerns, Desires and Expectations Of Surgery For Adolescent Idiopathic Scoliosis: A Comparison Of Patients’, Parents’ & Surgeons’ Perspectives. Master of Science, 2008 Unni G. Narayanan Department of Health Policy, Management & Evaluation University of Toronto ABSTRACT This study explored the concerns, desires (goals) and expectations of adolescents undergoing surgery for idiopathic scoliosis, and contrasted their priorities with those of their parents and surgeons. Parents were more concerned than their children about the consequences of scoliosis and of surgery. With the exception of improving physical appearance, surgeons' goals of surgery were different from those of either the patients or parents. There was little agreement among surgeons about the natural history of scoliosis, other goals of surgery and the likelihood of specific outcomes. Parents wanted and expected more from surgery than their children. Parents and patients had greater expectations of surgery than surgeons. Although adolescents had different priorities from their parents, parents were aware of these differences and reliably predicted their children’s priorities. These findings have important implications on shared decision-making and informed consent, and might contribute to better understanding and measurement of outcomes that matter to patients.

Aim: To describe the longitudinal active joint count (AJC) trajectories in juvenile idiopathic arthritis (JIA). Methods: A retrospective cohort study at two Canadian centres was performed. The longitudinal trajectories of AJC were described using latent growth curve modeling. The association of baseline characteristics stratified by trajectory group was examined by univariate methods. Results: Data were analyzed for 659 children diagnosed with JIA between 1990/03-2009/09. A maximum of 10 years of follow-up data were included in the analysis. Participants were classified into 5 statistically and clinically distinct AJC trajectories by latent GCM. Conclusions: Using a novel longitudinal statistical method we were able to classify patients with JIA based on their pattern of AJC over time. The trajectory classes need to be examined for their relationship to important genetic and biological predictors. Identification of patterns of disease course is important in working towards the development of a clinically relevant outcome-based classification system in JIA.

Aim: To describe the longitudinal active joint count (AJC) trajectories in juvenile idiopathic arthritis (JIA). Methods: A retrospective cohort study at two Canadian centres was performed. The longitudinal trajectories of AJC were described using latent growth curve modeling. The association of baseline characteristics stratified by trajectory group was examined by univariate methods. Results: Data were analyzed for 659 children diagnosed with JIA between 1990/03-2009/09. A maximum of 10 years of follow-up data were included in the analysis. Participants were classified into 5 statistically and clinically distinct AJC trajectories by latent GCM. Conclusions: Using a novel longitudinal statistical method we were able to classify patients with JIA based on their pattern of AJC over time. The trajectory classes need to be examined for their relationship to important genetic and biological predictors. Identification of patterns of disease course is important in working towards the development of a clinically relevant outcome-based classification system in JIA.

Concerns, Desires and Expectations Of Surgery For Adolescent Idiopathic Scoliosis: A Comparison Of Patients’, Parents’ & Surgeons’ Perspectives. Master of Science, 2008 Unni G. Narayanan Department of Health Policy, Management & Evaluation University of Toronto ABSTRACT This study explored the concerns, desires (goals) and expectations of adolescents undergoing surgery for idiopathic scoliosis, and contrasted their priorities with those of their parents and surgeons. Parents were more concerned than their children about the consequences of scoliosis and of surgery. With the exception of improving physical appearance, surgeons' goals of surgery were different from those of either the patients or parents. There was little agreement among surgeons about the natural history of scoliosis, other goals of surgery and the likelihood of specific outcomes. Parents wanted and expected more from surgery than their children. Parents and patients had greater expectations of surgery than surgeons. Although adolescents had different priorities from their parents, parents were aware of these differences and reliably predicted their children’s priorities. These findings have important implications on shared decision-making and informed consent, and might contribute to better understanding and measurement of outcomes that matter to patients.

ROGDI, a novel gene, locates on human¡¦s chromosome 16p13.3. According to Gene Ontology Annotation database, ROGDI is related to hemopoiesis and positive regulation of cell proliferation. In order to investigate the function of this novel gene in pulmonary fibrosis, fibrotic models in vivo and in vitro were created. Mice which received single intra-tracheal bleomycin injection were sacrificed on various intervals. Rogdi and other pro-fibrotic mediators, including CCL2 and TGF-£]1, were up-regulated in the early phase(< 10 days). On contrary, the anti-fibrotic mediators IL-10, IFN-£^ and heme oxygenase(HO)-1 were up-regulated in the late phase(> 10 days). The precursor microRNA 21 (miR-21) was up-regulated as the fibrotic severity increased. The human embryonic fibroblasts(WI-38 cells) showed fibrogenic phenotype and up-regulation of precursor miR-21 and ROGDI after bleomycin treatment. Human embryonic fibroblasts transfected by coding sequence of ROGDI showed up-regulated precursor miR-21 and £\-SMA compared to those transfected by empty vectors after bleomycin treatment. Two signaling molecules related to positive regulation of cell proliferation, Akt and Erk, showed over-expressed after ROGDI transfection and bleomycin treatment compared to those with empty vector transfection. Our results imply that ROGDI is up-regulated in pulmonary fibrosis and turns fibroblasts into fibrogenic phenotype through positive regulation of miR-21. The increase of precursor, but not primary miR-21, after ROGDI transfection and bleomycin treatment indicates that ROGDI may regulate the TGF-£] signaling pathway in human embryonic fibroblasts. Our results support that ROGDI is a novel gene for pulmonary fibrosis and warrants for further investigation. £[

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