京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20258号 / 医博第4217号 / 新制||医||1020(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 小西 靖彦, 教授 平家 俊男, 教授 中畑 龍俊 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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IntroductionChildren with juvenile idiopathic arthritis (JIA) are at risk of developing sight threatening JIAassociated uveitis (JIA-U). Swedish children with JIA are included in an ophthalmologicalscreening program, based on European studies, to ensure early detection and treatment of JIAU.AimThe aim of this study was to describe the prevalence, risk factors, clinical characteristics andassociated ocular complications of JIA-U and pharmacological therapy in a cohort of Swedishchildren with JIA. MethodsThe study was conducted as a retrospective review of medical records of children with JIAtreated at Örebro University Hospital, Sweden in 2010-2019, with a minimum of one year ofophthalmological follow-up.ResultsMedical records of 200 children with JIA were reviewed, of which 96 children were includedin the study. Uveitis was detected in 21/92 (22.8%) children. Boys developed uveitisproportionally more often than girls. JIA-U onset within the first four years after JIA diagnosisoccurred in 52.4% and onset occurred later in boys than in girls (p = 0.019). Oligoarthritis wasthe only significant risk factor for uveitis development (OR 3.111, 95% CI 1.029-9.409, p =0.044). Uveitis associated complications occurred in 7/21 (33.3%) children. ConclusionIn this regional cohort study, we found a higher prevalence of JIA-U, a higher proportion ofboys developing uveitis and a lower portion of children developing uveitis within the four yearsof high frequency screening compared to recent Swedish respectively European studies. Ourfindings indicated the need of future Swedish studies to revise and optimize the currentSwedish guidelines for ophthalmological JIA-U screening.

Indiana University-Purdue University Indianapolis (IUPUI) / Inflammation of the urethra—urethritis—is commonly diagnosed in men and women who have sexually transmitted infections (STI). Characteristic signs and symptoms of urethritis include urethral discharge and burning pain during urination (dysuria). However, these findings are non-specific and can be elicited by STI for which optimal treatment approaches differ. We wanted to investigate if immunoglobulins (antibodies) in the urine of men with acute urethritis could determine the etiologies of these cases. Previously, we conducted an observational case-control study of biological males to compare the urethral microbiota of participants with unambiguous, laboratory-confirmed urethritis (cases) and participants without urethral inflammation (controls). This revealed that nearly 2 in 5 men with nongonococcal urethritis tested negative for all common STI. We identified atypical urethral pathogens in approximately 1/3 of these STI-negative individuals using shotgun metagenomic sequencing. However, we did not detect microorganisms suspected to be urethral pathogens in the remaining 2/3 of STI-negative participants. We hypothesized that these men with “pathogen-negative” urethritis had persisting inflammation from a recent STI that already cleared spontaneously by the time of testing. We observed that urine IgA antibodies against Chlamydia trachomatis (Ctr) infectious particles were significantly more prevalent among men with pathogen-negative urethritis compared to controls. In contrast, we found that the prevalence of urine anti-Ctr IgA was similar between controls and urethritis cases with atypical infections. However, our efforts to detect antibodies against another common STI, Mycoplasma genitalium (Mgen), were complicated by low abundance in urine and the unexpected prevalence of Mgen-reactive antibodies among controls. Collectively, our results suggest that signs and symptoms of urethritis can continue after the causative STI(s) have been eliminated. Furthermore, male urine represents a practical, non-invasive source of pathogen-reactive antibodies that could be evaluated using point-of-care diagnostic tests to elucidate urethritis etiologies. Importantly, our results also suggest that sexual partners of men with pathogen-negative, nongonococcal urethritis are an unrecognized chlamydia reservoir. / 2024-05-22

Adolescent idiopathic scoliosis (AIS) is characterized by a three-dimensional curve within the spine thus creating asymmetries within the trunk. In addition to modifying the trunk geometry, these structural asymmetries change the location of the center of mass. Gait patterns in people with AIS may possibly be altered on the basis of these structural changes. The purpose of this study was to identify differences in gait kinematics and kinetics as well as left-right symmetry as a function of the severity of adolescent idiopathic scoliosis. Forty-five girls divided into a control group, a mild-to-moderate AIS group and a severe AIS group participated in data collection. Gait analysis included bilateral kinematic and kinetic measurements. The maximal joint ranges of motion at the ankle, knee, hip and trunk-pelvis were analyzed. Maxima and minima in the antero-posterior, medio-lateral and vertical components of ground reaction force (GRF) were compared between the three groups as well as the median frequencies obtained from a frequency spectrum analysis of GRF. A symmetry index was computed between the primary curve side and the contralateral side for each kinematic and kinetic variable. Both AIS groups differed from controls in their range of motion at the ankle and at the knee but for the AIS group with severe curves, this was also observed at the hip. Both local maxima in the vertical component and the maximum of the antero-posterior component of the ground reaction force were decreased while the local minimum of the vertical component and the antero-posterior component of GRF increased in the severe AIS group compared to the control group. Higher median frequency contents in the antero-posterior and vertical component of ground reaction force were found in the AIS groups than in controls. No difference in asymmetry was found in any of the variables between all groups. These results seem to indicate that severe AIS participants have a more altered gait pattern than the mild-to-moderate AIS group. Findings from this study point toward greater changes in kinematics and kinetics during stance between all AIS groups and the control group.

A 3 year old Hispanic male presented with fevers, skin rash, left neck swelling and refusal to walk of several days duration. Physical exam revealed a febrile, fussy toddler with a tender, cystic lesion in the left submandibular region. Both ankles had tender cystic lesions on the lateral malleolar regions. Labs: WBC 33,000 with neutrophilia, bandemia, thrombocytosis, and increased ESR and CRP. MRI of the neck and ankles revealed cystic lymphatic malformations with no communication with the joints.ENT specialist was consulted and neck cystic lesion was aspirated to rule out a septic focus. Bone scan of the lower extremities ruled out infectious or malignant etiology. He was started on multiple antibiotics with a presumed diagnosis of sepsis. An ECHO on the 4th hospital day showed a pericardial effusion which required a pericardial window. He also developed bilateral pleural effusions which resolved with supportive treatment. Aspirates from the cystic lesions, pericardial fluid, blood and urine cultures were sterile. Even in the second week of hospital stay, he continued to spike high fevers (Tmax 107) with high white counts and left shift inspite of treatment with antibiotics. A diagnosis of systemic onset juvenile idiopathic arthritis (SOJIA) was made with input from rheumatologist. Antibiotics were discontinued and steroids were started with good response. Cystic lesions were treated with percutaneous sclerotherapy with doxycycline. He was discharged home on oral steroids, NSAID’s and weekly methotrexate. Etanercept was added to decrease dependence on oral steroids. He remains in good health 2 years since initial presentation. Discussion: A febrile toddler who refuses to walk is a common clinical presentation in pediatrics. Differential diagnosis of such a patient includes osteomyelitis, septic arthritis, acute rheumatic fever, leukemia and non-accidental trauma. The presence of systemic extra-articular symptoms as in our patient must alert the pediatrician to systemic onset juvenile rheumatoid arthritis (SOJIA). It accounts for 10-20% of all juvenile idiopathic arthritis (JIA) patients with an incidence of 0.4-0.8 per 100,000. SOJIA differs from other conditions in its multisystem involvement. Clinical features like pleurisy, pericarditis, spiking fevers, hepatosplenomegaly and lymphadenopathy overshadow the joint symptoms. The joint involvement may be completely absent or may be a late clinical feature. These patients have leukocytosis, thrombocytosis and high inflammatory markers simulating a septic focus. In our patient, the accurate diagnosis was complicated by the confounding presence of multiple cystic lymphatic lesions. Treatment of SOJIA is challenging. Oral steroids, NSAID’s, methotrexate, etanercept and the newer anakinra have been used with varying success. Our case underlines the importance of considering a diagnosis of systemic onset JIA in a febrile toddler even in the absence of overt joint involvement.

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Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal. / Le but de cette étude est d'évaluer les caractéristiques associées à la mobilité de la colonne vertébrale chez les patients ayant une scoliose idiopathique. Selon les études antérieures, une augmentation de la flexibilité et de la mobilité de la colonne vertébrale serait reliée à une courbure scoliotique. Une meilleure compréhension de ce phénomène serait utile à révolution et au traitement de cette maladie. De plus, la caractérisation des mouvements normaux pourrait servir d'indicateur complémentaire au pronostique. Cette étude porte sur l'évaluation de la mobilité de la colonne vertébrale chez les patients scoliotiques. Les résultats ont été comparés à ceux de sujets témoins normaux afin d'établir s'il existe une relation entre la mobilité de la colonne vertébrale et certaines variables biodémographiques. Soixante-cinq adolescents ayant une scoliose idiopathique ont constitué le groupe patient alors que des sujets (13 garçons et 7 filles) d'âge comparable formaient le groupe témoin. Les patients avaient un âge moyen de 14 ans et n avaient pas été opères' à la colonne vertébrale bien qu' une scoliose était présente. Tous les sujets ont été mesurés et évalués à la clinique de scoliose de l' hôpital Sainte-Justine. L'âge, la hauteur et le poids ont été mesurés. Les mesures de la mobilité ont été effectuées dans les trois plans à l'aide d'un inclinomètre. Un test-t de Student et une analyse de régression multiple ont été utilisées pour déterminer la présence de différences significatives entre les deux groupes et l'importance relative des variables biodémographiques sur la mobilité de la colonne vertébrale. Une valeur de p < 0.001 pour le test-t et de p < 0.05 pour les corrélations et les régressions multiples ont été arbitrairement choisies. La mobilité de la colonne vertébrale du groupe sujets était significativement différente de celle du groupe témoin. Elle était plus petite chez les 'atients dans les plans sagittal et transverse, un résultat qui n'appuie pas l'hypothèse d'une flexibilité excessive chez les patients scoliotiques. Très peu de corrélation a été trouvée entre les différentes variables biodémographiques et plus particulièrement avec l'angle de Cobb qui indique la sévérité des courbures. L'implication clinique de ce travail porte sur l'importance possible de maintenir une amplitude normale de mouvement dans les régions thoraco-lombaire. / The primary purpose of this study was to evaluate the characteristics of spinal mobility in adolescent idiopathic scoliosis. Earlier studies have indicated that an increase in flexibility and spinal mobility may be of importance in producing deviation of spine. Knowledge of the effect of adolescent idiopathic scoliosis on spinal mobility could be useful in the evaluation and treatment of the disease. Furthermore, characterization of the abnormal motion may be of prognostic value. This study focused on the assessment of spinal mobility in adolescent idiopathic scoliosis as compared to that of normal subjects and tried to establish a relationship between the likely spinal mobility differences and some biodemographic variables. Sixty five girls with progressive adolescent idiopathic scoliosis formed the patient group while 20 age-matched controls (13 boys and 7 girls) with normal spine comprised the able-bodied group. The scoliofcic patients were girls with a mean age of 14 years, and all had combined thoracic and lumbar nonoperated curves. All subjects were measured and evaluated in the scoliosis clinic of Sainte-Justine Hospital. Age, height, and weight were determined. Measurements of the mobility were done in three planes with an inclinometer. Student t-test technique and multivariate regression analysis were used to determine the significant differences between the two groups and the relative importance of the biodemographic variables on spinal mobility with a p value of 0.001 for t-test and 0.05 for correlation and mutivariate regression. Spinal mobility of the patient group was found to be significantly different from those of normals. Spinal mobility was more restricted among scoliotic patients in the sagittal and transverse planes, a finding which does not support the hypothesis of excessive flexibility of the spine in idiopathic scoliosis. Very little correlation could be detected between biodemographic variables, and specially the Cobb angle which measured severity of curves even though the spinal mobility was reduced in scoliotic patients. The clinical implication of this work may be that preservation of a normal range of motion in the thoracolumbar spine should be one of the aims of treatment.

Circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) are sensitive markers of cardiovascular damage and repair, respectively. The aim of this thesis was to advance the state of knowledge regarding CECs and EPCs, and the factors affecting their concentrations, in children and adolescents. The first and second studies demonstrated that CECs and EPCs were similar when participants were split by sex, chronological age (8-10 vs. 14-16 years), and biological age (≤ -1 vs. ≥ +1 year from peak height velocity). Moreover, CECs, but not EPCs, were positively associated with aerobic fitness and negatively related to daily moderate-to-vigorous physical activity. Neither CECs nor EPCs were related to level of adiposity. Although there was a large degree of inter-individual variability in both cell types, most of our data were clustered towards one end of the reported range. These observations highlighted the need to examine these cells in children with chronic conditions associated with an increased risk of poor cardiovascular health. Therefore, CECs and EPCs were examined at rest and in response to acute exercise in juvenile idiopathic arthritis (JIA) and healthy controls. Resting levels of CECs and EPCs were similar in both groups, which may be attributable to the low disease activity in the participants with JIA. High intensity, intermittent exercise (HIIE) and moderate intensity, continuous exercise (MICE) had no effect on CECs in both groups. Conversely, MICE led to a robust increase in EPCs in healthy controls; no such change was observed in youth with JIA. This thesis represents the first comprehensive assessment of CECs and EPCs in the context of fitness, physical activity, and acute exercise in children and adolescents. Future research should examine the function and fate of these cells in youth, as well as the potential mechanisms underlying the blunted EPC response to exercise in JIA. / Thesis / Doctor of Philosophy (PhD) / Fitness and physical activity are critical for maintaining and improving cardiovascular health in children and adults. We don’t know exactly how they do this but the evidence in adults suggests it may be related to rare cells in the blood involved in repairing damaged blood vessels. The main objective of this thesis was to learn more about these cells, called circulating endothelial cells and endothelial progenitor cells, in children. We found that only circulating endothelial cells were related to fitness and physical activity. We also found that endothelial progenitor cells increased when healthy children performed 60 minutes of cycling. On the other hand, these cells did not change when children with juvenile idiopathic arthritis performed the same exercise. More research is needed to determine exactly why these cells responded to exercise in healthy but not sick children, and to help us identify the optimal exercise to improve these cells in youth.