Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 5 uppsatser.

Pacientes com doença reumática cardíaca (DRC) desenvolvem lesões valvares mediadas por linfócitos T CD4+, capazes de reconhecer cruzadamente proteínas cardíacas e estreptocócicas pelo mecanismo de mimetismo molecular. Neste trabalho empregamos uma biblioteca peptídica de Phage Display para identificar auto-antígenos cardíacos capazes de serem reconhecidos por duas linhagens intralesionais de linfócitos T e um clone derivado de uma das linhagens isolados de pacientes com DRC. A análise dos peptídeos dos fagos em banco de dados de proteínas revelou novos epitopos da miosina cardíaca, laminina, vimentina e outras proteínas coiled-coil, provavelmente involvidos no processo auto-imune da DRC. Outras moléculas inflamatórias como citocinas, integrinas e fatores de crescimento também foram identificadas / Rheumatic heart disease (RHD) patients develop valvar lesions with CD4+ T lymphocytes infiltrating the heart. Molecular mimicry between streptococcal and cardiac proteins recognized by these T cells may explain these auto-aggressive lesions. In the present work we used a Phage Display peptide library to identify cardiac antigens which could be recognized by two heart infiltrate T cell lines and by a T cell clone derived from one of the lines which were isolated from RHD patients. Using the protein data bank to analyse the phage peptides, we observed that many sequences showed homology with cardiac myosin, laminin, vimentin and other coiled-coil proteins, suggesting the involvement of these proteins in the autoimmune process of RHD. Other inflammatory molecules such as cytokines and integrins were also identified

Class of 2012 Abstract / Specific Aims: To evaluate the presence of statistical information from clinical studies in official product labeling specific for disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis. Methods: Data were abstracted from official product labeling DMARDs with FDA approval for treatment of rheumatoid arthritis. Each document was examined for the presence of statement regarding a priori type 1 error rate, p-values, and measures of variance. Medications were classified as either biologic or non-biologic. Main Results: A total of 14 DMARDs, 7 biologics (50%) and 7 non-biologics (50%), were found to be FDA approved for the treatment of rheumatoid arthritis. Primary outcomes consisted of American College of Rheumatology (ACR) response rates, radiographic changes, and health assessment questionnaire score (HAQ). Any measure of variance and the presence of a p-value were both found in six (43%) of the drug labels. Inclusion of p-values was found to be significantly greater in biologics compared to non-biologics for both ACR and radiographic results. Inclusion of variance was found to be significantly greater in biologics compared to non-biologics for radiographic changes only. No package inserts contained statements regarding the a priori type I error rate. Conclusions: Measures of variance are not frequently included in product labeling for either biologic or non-biologic DMARDs. However, inclusion of variance and p-values for ACR response rates and radiographic changes were more likely to be reported for biologics therapies as compared to non-biologics. A statement regarding Type 1 error rates were absent from labels regardless of outcome assessed.

Magister Scientiae (Physiotherapy) - MSc(Physio) / Rheumatic disease is estimated to be one of the most disabling diseases in South Africa and the world. The most common rheumatic diseases are osteoarthritis, fibromyalgia, rheumatoid arthritis, gout and systemic lupus erythematosus. The symptoms of the disease include pain, stiffness, swelling, decreased function. The patient’s functional abilities are severely affected by the pain which in turn, leads to poor quality of life and adverse stress. As a result patients who suffer with one or with a combination of rheumatic disease will experience pain, stress, decreased functional abilities and poor quality of life. The physical properties of water and the therapeutic effects of hydrotherapy, make hydrotherapy an effective form of exercise available to physiotherapists in the treatment of rheumatic disease. The aim of the current study was to determine the effects of a hydrotherapy intervention on the pain, stress, quality of life and functional abilities in patients with rheumatic disease. A quantitative and qualitative research design was employed to meet the objectives. The quantitative aspect involved an A-B-A design and the qualitative part of the study compromised indepth interviews which took place after the intervention. The instruments used were the WHOQOL-BREF instrument, the Visual Analogue Scale (VAS), the Weekly Stress Inventory-Short Form (WSI-SF) and the Health Assessment Questionnaire. (HAQ). The sample consisted of 19 patients who were diagnosed with one or a combination of rheumatic disease. The study was conducted at the hydrotherapy pool at Groote Schuur Hospital in Cape Town. Within the study sample, the majority of the participants were female (84%) with osteoarthritis being common among the participants (53%). The mean age was 60 years. The intervention had a significant impact on pain reduction (p = 0.0001), quality of life (p<0.05). However, the impact of hydrotherapy on stress and the social relationship domain in quality of life was inconclusive. It is thus evident from this study that hydrotherapy as a treatment modality for physiotherapists can be used to impact on the pain, quality of life and functional abilities in patients with rheumatic disease. iv Keywords

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease that cause various inflammatory conditions in the body. The pathogenesis of this disease is yet unknown, and the diversity within the patients bring on major obstacle to clinical research for specific diagnostic markers. As a biomarker of SLE, both Interferon Regulatory Factor-5 (IRF5) and Microparticles (MP) have been suggested. Recently a study demonstrated higher concentration of IRF5+ MP in a small number of SLE patients compared to controls.  Aim: The purpose of this study was to validate and analyze IRF5+ MPs in a larger number of SLE patients and compare the results to known SLE subgroup based on IRF5 concentration.  Materials and methods: Totally 50 plasma samples from a larger cohort of SLE-patients (n=35) was analyzed together with population-based controls(n=15). Three different antibodies (in-house and commercial) were used for detection of IRF5+ MP with flow cytometry. Students t-test was used to investigate significant differences between SLE subgroup, controls and compared to the previous values. Results and Conclusion: The concentration of IRF5+ MP in SLE subgroup was significantly higher compared to controls (p&lt;0,05). However, there were no correlations between our results and the values from the previous study, suggesting that both methods measure various forms of IRF5. These results imply that IRF5+ MP could be a possible biomarker for pathogenesis in SLE, but further studies are needed for a better understanding of IRF5, as well as of MP.

La cardiopathie rhumatismale (CR) demeure la première cause de cardiopathie acquise chez les enfants et les jeunes adultes à travers le Monde. L'essor de l'échographie cardiaque comme outils de dépistage dans les zones endémiques pose de nouvelles questions. Trois études indépendantes ont été menées en Nouvelle Calédonie dans le cadre de la thèse de 2011 à 2013: " L'étude de cohorte rétrospective en population a évalué une campagne de dépistage national de la CR par échocardiographie visant à inclure tous les enfants scolarisés en classe de CM1 sur l'île de 2008 à 2011. Les méthodes diagnostiques complexes utilisées en recherche ne peuvent être transposées en campagnes de dépistage écho-guidées à l'échelle nationale en raison du nombre élevé d'enfants (~25%) sans diagnostic final. Le pronostic de la CR asymptomatique dépistée par échographie est bénin à moyen terme, quoique les lésions échographiques persistent dans la majorité des cas. Environ 13% des enfants initialement sains présentent des anomalies échocardiographiques à 2 ans de suivi. " Une étude prospective en population a exploré des méthodes simplifiées de dépistage à l'aide de l'échoscopie cardiaque avec des appareils de poche par du personnel paramédical. La sensibilité et la spécificité de cette approche permet de dépister ~80% des cas, avec une sensibilité de ~90% dans le cadre de CR certaine, seul cas de figure où un traitement est nécessaire. " Une cohorte hospitalière contemporaine de patients admis à l'unique centre du pays a permis d'apporter des données épidémiologiques de la CR symptomatique, et d'identifier les facteurs associés à la survenue d'événements cardiovasculaires. Le diagnostic y est encore souvent porté à un stade tardif, révélé par des complications (~25%). Le taux de survie à 8 ans de la CR symptomatique sans complication initiale est élevé (~98%) mais l’incidence annuelle d’événements atteint 59‰ (95% CI 44.35-73.75). La sévérité de la CR au diagnostic (CR moyenne versus modérée HR 3.39 (0.95 – 12.12); CR sévère versus modérée HR 10.81 (3.11 – 37.62), p<0.001) et l’antibioprophylaxie (HR 0.27 (0.12-0.63), p=0.01) sont les deux facteurs associés à la survenue d’événements cardiovasculaires. / Rheumatic heart disease (RHD) remains the leading acquired heart disease in the young worldwide. The advent of echocardiography as a screening tool has raised new questions in the field. This thesis incorporated three studies to explore critical questions regarding the burden of asymptomatic and symptomatic RHD in New Caledonia (2011-2013): Retrospective population-based cohort study assessing the first nationwide echo-screening campaign targeting all children in 4th grade (2008-2011). Methods derived from research may not be applicable as a healthcare policy given the lack of completeness (~25%). Outcomes of children with asymptomatic RHD detected by echocardiography are benign although the majority of valve lesions persist with little clinical implications. RHD being a dynamic condition, 13% of children at high risk of RHD with normal baseline echocardiograms may present with mild echocardiographic lesions at 2 years follow-up. Prospective population-based study assessing sensitivity and specificity to detect asymptomatic RHD of a focused cardiac ultrasound (FCU) compared to echocardiography. FCU includes nurses after a short training scheme using pocket-echocardiographic machines and simplified criteria. Sensitivity and specificity for RHD detection was of ~80% and performed better (sensitivity ~90%) when restricted to definite RHD in which case treatment is recommended. Retrospective hospital-based cohort of patients admitted with symptomatic RHD. RHD remains prevalent and incident. Diagnosis if often made at an advanced stage (~25%). In patients with uncomplicated RHD, the survival rate was ~96% at 8 years with however an annual incidence of 59.05‰ (95% CI 44.35-73.75) major cardiovascular events. The severity of RHD at diagnosis (moderate vs. mild HR 3.39 (0.95 – 12.12); severe vs. mild RHD HR 10.81 (3.11 – 37.62), p<0.001), and ongoing secondary prophylaxis at follow-up (HR 0.27 (0.12-0.63), p=0.01) were the two most influential factors associated with major cardiovascular events.

No description available.

Chronische Schmerzerkrankungen beeinflussen die Arbeitsfähigkeit deutlich. Ziel dieser systematischen Übersichtsarbeit ist es, arbeitsbezogene Studienendpunkte in randomisierten, placebokontrollierten Studien zu chronischen Schmerzerkrankungen und schmerzhaften rheumatologischen Erkrankungen zu analysieren. Datenbanktreffer einer Literaturrecherche in Medline (Pubmed) wurden als Abstracts gesichtet und potentiell relevante Studien danach im Volltext beurteilt. Die methodologische Studienqualität wurde mit der Oxford Quality Scale (OQS) bewertet. Verfügbare arbeitsbezogene und schmerzbezogene Endpunkte wurden in Meta-Analysen mit Hilfe von einem „fixed effect model“ oder einem „random effects model“ zusammengefasst. Lineare Regressionen zwischen arbeitsbezogenen Endpunkten und schmerzbezogenen Endpunkten wurden durchgeführt. Insgesamt 31 Publikationen mit einer Gesamtzahl von 11434 Patienten berichten über arbeitsbezogene Studienendpunkte; dies waren nur ungefähr 0,23% aller relevanten Publikationen. Eine Meta-Analyse aller arbeitsbezogenen Endpunkte, ohne Unterteilung nach vorgenommener Behandlung und der spezifischen vorliegenden Erkrankung, konnte einen allgemeinen Behandlungserfolg von 0,35, ausgedrückt als standardisierte Mittelwertsdifferenz (SMD), mit einem 95%-Konfidenzintervall (95%-KI) von 0,21 bis 0,50 beschreiben. Eine umfassende Meta-Analyse der Schmerzendpunkte derselben Studien ergab eine allgemeine Verbesserung bezüglich schmerzbezogener Endpunkte von 0,40, ausgedrückt als SMD (95%-KI: 0,25; 0,55). Weitere Meta-Analysen zeigten statistisch signifikante Verbesserungen in den Behandlungsgruppen für die folgenden Parameter: Beeinträchtigungen bei der Arbeit (0,62 Punkte auf einer 0- bis 10-Punkte-Skala; 95%-KI: 0,45; 0,79), Arbeitsproduktivität (SMD 0,53; 95%-KI: 0,18; 0,88), 30%ige Schmerzverbesserung relativ zu Studienbeginn (ausgedrückt als Verbesserung des relativen Risikos (RR) von 33%; 95%-KI: 15%; 53%) und 50%ige Schmerzverbesserung relativ zu Studienbeginn (RR 46%; 95%-KI: 22%; 74%), 20%iges (RR 184%; 95%-KI: 86%; 334%), 50%iges (RR 237%; 95%-KI: 84%; 715%) und 70%iges (RR 232%; 95%-KI: 65%; 571%) Ansprechen der Patienten bezogen auf die Kriterien des „American College of Rheumatology“ (ACR). Ergebnisse Arbeitsfehlzeiten und Beschäftigungsverhältnisse betreffend waren heterogen und nicht aussagekräftig. Lineare Regressionensanalysen von sowohl kontinuierlichen arbeitsbezogenen mit kontinuierlichen schmerzbezogenen Endpunkten, als auch von kontinuierlichen arbeitsbezogenen Endpunkten mit kategorischen schmerzbezogenen Ansprechraten, belegten einen statistisch signifikanten Zusammenhang. Abschließend kann berichtet werden, dass arbeitsbezogene Endpunkte nur sehr selten in placebokontrollierten Studien zu chronischen Schmerzerkrankungen untersucht wurden, und dass, wenn sie berichtet wurden, die Endpunkte und Berichterstattung heterogen waren. Es konnten wiederholt statistisch signifikante Behandlungseffekte für verschiedene arbeitsbezogene Endpunkte nachgewiesen werden. Weiterhin konnte gezeigt werden, dass eine starke lineare Relation zwischen arbeitsbezogenen Endpunkten und schmerzbezogenen Endpunkten vorliegt.

Introdução: A estratificação de risco pré-operatória é elemento essencial para a decisão cirúrgica, assim foram desenvolvidos alguns sistemas de pontuações para predizer mortalidade após cirurgia cardíaca em adultos. O EuroSCORE (ES) é um dos mais difundidos mundialmente sendo considerado um bom preditor de mortalidade em pacientes que foram submetidos à cirurgia cardíaca e foi considerado um sistema de pontuação de fácil uso e boa aplicabilidade. Racional: O ES já é usado assistencialmente em nossa instituição, entretanto, não foi realizada uma validação local em uma coorte específica de portadores de valvopatias. Sabemos das importantes diferenças epidemiológicas entre nossa população e pacientes citados na literatura mundial. Objetivos: O objetivo desse estudo é validar o ES como ferramenta preditora de mortalidade após cirurgia valvar. Métodos: Foram incluídos no trabalho 540 pacientes portadores de Valvopatia, com indicação de substituição da função valvar. O período de inclusão foi de fevereiro a dezembro de 2009. Todos os pacientes tiveram o cálculo da mortalidade estimada, baseada no EuroSCORE no pré-operatório, foram seguidos até alta hospitalar ou 30 dias após cirurgia. A capacidade discriminativa do modelo foi calculada utilizando a área sobre a curva receiver operating Characteristic (ROC) e a para o cálculo calibração utilizou-se o teste de Hosmer-Lemeshow (H-L). Resultados: A média etária da população foi de 56 ± 12 anos, 50% do sexo feminino, com etiologia predominante de Doença reumática. As variáveis: endocardite infecciosa, hipertensão pulmonar e o histórico de cirurgia prévia foram mais prevalentes em nossa coorte quando comparada com o banco de dados original do ES. A mortalidade observada global foi de 16% (6% em cirurgias eletivas e 34% em cirurgia de emergência), já a mortalidade predita foi de 6.1%, 8.7% e 4.31% para ES aditivo, ES logístico e ESII, respectivamente. Na avaliação da capacidade discriminativa a área sobre a curva ROC (ASCR) foi considerada boa com valores de 0,81 ; 0,76 ; 0,76 respectivamente para ES II; ES aditivo e logístico. A calibração do modelo foi considerada ideal com P > 0,05 para os modelos de ES. Conclusão: Os modelos do ES foram validados como ferramentas preditoras de risco de mortalidade após cirurgia cardíaca valvar / Introduction: Preoperative risk stratification is essential for surgical decision, and some scoring systems have been developed to predict mortality after cardiac surgery in adults. The European System for Cardiac Operative Risk Evaluation (EuroSCORE), developed in European states, aims to predict 30-day mortality of patients undergoing cardiac surgery. Although already used in our institution we not been performed a local validation. We know the epidemiological difference between Brazilian and European population. Therefore, the aim of this study was to evaluate the validation of the EuroSCORE models in our institution. Methods: Between February 1st 2009 and December 30th 2009, a total of 540 consecutive patients with valvular heart disease and indication for surgical treatment were evaluated before and after this treatment. Patient demographics, risk factors, surgery details, length of hospital stay and 30-day mortality were collected. The EuroSCORE algorithms were calculated according to the published guidelines (http://www.euroscore.org) on the entire patient sample prior to the time of surgery. Performance of the models was assessed by comparing the observed and predicted mortality. The area under the receiver operating characteristic curve (AUCR) evaluated the predictive performance. The calibration was analyzed by Hosmer-Lemeshow goodness-of-fit statistic. Results: The mean age was 56±12 years and 50% of patients were female. The most common etiology of valvular heart disease was Rheumatic disease. Main differences between the present cohort and the original EuroSCORE cohort were: Age, gender, previous cardiac surgery, pulmonary hypertension and active endocarditis. The mean of Aditive and logistic EuroSCORE were 6 ± 3 and 8.66 ± 10.35 respectively. For EuroSCORE II the mean logistic value was 4.2 ± 5.95. Mortality rate of 16% (6% in elective surgery and 34 % in emergency/urgency surgery), with estimated mortalities according to additive, logistic EuroSCORE and EuroSCORE II of 6.1%, 8.7% and 4.31%, respectively. The AUC for additive EuroSCORE was 0.76, for logistic EuroSCORE 0.76, was lower than that for EuroSCORE II 0.81. Conclusion: EuroSCORE models demonstrated good discriminative capacity and calibration in these valvular heart disease patients undergoing cardiac surgery

O Streptococcus pyogenes (Grupo A de Lancefield) é uma bactéria Gram positiva e beta-hemolítica, responsável por infecções, tais como Faringite, Sepse, Fasciíte Necrotizante e Síndrome do Choque Tóxico Estreptocócico. Indivíduos suscetíveis podem desenvolver sequela não supurativa auto-imune pós-estreptocócica, como a Febre Reumática, Doença Reumática Cardíaca e a Glomerulonefrite Aguda. A proteína M é o principal antígeno bacteriano. Consiste em aproximadamente 450 resíduos de aminoácidos dispostos em quatro regiões (A, B, C e D), contendo alguns blocos de repetições. As regiões C e D são conservadas e a N-terminal (regiões A e B) é polimórfica. Atualmente, existem mais de 250 genótipos de emm conhecidos em todo o mundo, de acordo com o Centers for Disease Control and Prevention. Há vários anos, o desenvolvimento de uma vacina contra S. pyogenes (StreptInCor - identificação médica) foi iniciado, com base na região conservada da proteína M, com o objetivo de proteger o indivíduo vacinado contra infecções estreptocócicas, sem causar reações autoimunes. No presente estudo foi analisada a capacidade \"in vitro\" de anticorpos anti-StreptInCor neutralizarem/opsonizarem as cepas de S. pyogenes mais freqüentes em São Paulo, através da análise do reconhecimento das cepas por soros de camundongos imunizados com StreptInCor. Também foi avaliada por Western blotting a presença de anticorpos de reação cruzada dirigidos ao tecido cardíaco valvular humano. Anticorpos anti-StreptInCor foram capazes de neutralizar/opsonizar, pelo menos, cinco diferentes cepas mostrando que a imunização com StreptInCor pode ser eficaz contra várias cepas de S. pyogenes, assim como prevenir a infecção e sequelas subsequentes, sem causar reações auto-imunes. / Streptococcus pyogenes (Group A) is a Gram positive and beta-hemolytic bacteria, responsible for infections such as Pharyngitis, Sepsis, Necrotizing Fasciitis and Streptococcal Toxic Shock Syndrome. Susceptible individuals may develop post-streptococcal non-suppurative autoimmune sequelae such as Rheumatic Fever, Rheumatic Heart Disease and Acute Glomerulonephritis. The M protein is the major bacterial antigen. It consists of approximately 450 amino acid residues arranged in four regions (A, B, C and D), containing some repeated blocks. C and D regions are conserved and the N-terminus (regions A and B) is polymorphic. Currently there are over 250 known emm genotypes worldwide, according to the Centers for Disease Control and Prevention. Several years ago the development of a vaccine against S. pyogenes (StreptInCor - medical identification) was initiated, based on the M protein conserved region, aiming to protect against streptococcal infections without causing autoimmune reactions. In the present study we analyzed the \"in vitro\" ability of anti-StreptInCor antibodies to neutralize/opsonize the most frequent S. pyogenes strains in Sao Paulo by examining the strains recognition by sera from StreptInCor immunized mice. We also evaluated the presence of cross reactive antibodies directed to the human heart valve tissue by Western blotting. Anti-StreptInCor antibodies were able to neutralize/opsonize at least 5 strains, showing that the immunization with StreptInCor can be effective against several S. pyogenes strains as well as preventing infection and subsequent sequelae, without causing autoimmune reactions.