Chronic nonadherence is the complete lack of adherence on the part of a patient to at least one aspect of their therapeutic regime for extended periods of time. Chronic nonadherence is similar to other forms of nonadherence in that it is a phenomena which is dangerous for patients, frustrating for practitioners, and costly to the health care system. However, unlike other forms of nonadherence, very little is known about this subject. In order to determine factors related to chronic nonadherence to a home exercise program, 15 male arthritis patients of varying ages underwent an in-depth structured interview. Eight of these patients were identified by the Arthritis Society as being chronic, treatment nonadherents. The other seven patients were randomly chosen from among the population of male arthritis patients in order to provide a comparison to the chronic nonadherent population. Ten variables were examined in this study in the hopes of determining factors related to chronic nonadherence. These variables were as follows: demographics, The Health Beliefs Model, patient's explanatory model, nature of the illness, satisfaction with practitioner attributes, shared responsibility, overall satisfaction, attitudes of significant others, use of unorthodox treatments, and problems with the home exercise program. Data analysis failed to produce any statistically significant findings, however the study did point to some interesting associations. One finding from this study is that nonadherence seems to be related to patient's Health Beliefs Models. Based on this finding the study then goes on to recommend an appropriate intervention which can be used by practitioners to enhance patient adherence. A second finding from this study is that a small number of the chronic nonadherent group were actually adherent to their home exercise programs. Several explanations have been provided as to how these patients might have been falsely labelled as chronic nonadherents. / Arts, Faculty of / Social Work, School of / Graduate

Mycolic acids, the characteristic, abundant waxes of the cell wall of Mycobacteria were purified by Counter Current Distribution (CCD) from alkaline methanolytic crude extracts of bacteria, aiming at investigating their role in eliciting immune responses. Crude mycobacterial cell-wall extracts were first made by saponification in potassium hydroxide methanol solution. Purification was then performed with CCD using a bi-phasic tricomponent system, consisting of double distilled deionized water (dddH2O), chloroform and methanol. Emulsions were formed in this system which in turn extended the purification time. The addition of a preliminary funnel extraction step, to reduce the saponified fatty acids in the crude extract, before CCD and the addition of NaCI as an emulsions breaker in the CCD solvent system, produced a high yield of pure mycolic acids. The purity of these mycolic acids were assessed using reversed-phase HPLC-analysis. This method proved not only to be applicable to purify mycolic acids from M. tuberculosis but was also applicable in purifying mycolic acids from other sources, such as M. vaccae. The immunogenic properties of the purified mycolic acids were confirmed in experiments in which they induced the formation of antibodies in Sprague-Dawley rats when immunized in Marcol 52 oil. The antibody response was monitored by ELISA after 3 months of repeated immunization every second week. A dose-related response was observed for the induction of antibodies specific for mycolic acids, immobilized on the ELISA plates. Mycolic acids also appeared to influence adjuvant arthritis. Pure mycolic acids, suspended in mineral oil were administered intradermally into Lewis rats one week before the intradermal administration of an arthritis-inducing dose of lyophilized M. tuberculosis H37Ra. Animals receiving Mycobacteria, but no mycolic acids treatment, developed severe symptoms of arthritis within two weeks after bacterial challenge. No arthritis symptoms were apparent in mycolic acids treated rats. Mycolic acids treatment alone, did not produce arthritis. Mycolic acids pre-treatment of M. tuberculosis H37Rv-infected mice, rendered tuberculosis susceptible Balb/c mice more resistant. This resistance was equivalent to that observed in tuberculosis resistant C57Bl/6 mice. Post-infection treatment of M. tuberculosis H37Rv-infected mice with MA had no effect. Resistance of C57Bl/6 mice is commonly associated with the expression of IL-12 and IFN-ã. The effect of mycolic acids in the spleens of M. tuberculosis-infected Balb/c mice was investigated. It was observed that there was no significant change on the THI and TH2 cytokines. The absence of mycolic acids-induced THI/TH2 cytokine bias implied that protection was not provided by the expression of IL-12 and IFN-ã in the spleen. These results support the hypothesis that mycolic acids are immunogenic in respect of being able to induce specific antibodies, to provide resistance against tuberculosis and to prevent the development of adjuvant arthritis. The mechanism by which mycolic acids perform these tasks is unknown, particularly in these rodent models, which differ from humans, in that they do not have the CD1b that presents mycolic acids in humans. Unravelling this mechanism, can possibly aid the development of a pharmaceutical formulation that introduces MA into the body to enhance resistance to TB and prevent arthritis as an associated side-reaction. / Dissertation (MSc)--University of Pretoria, 2010. / Biochemistry / unrestricted

Juvenile idiopathic arthritis (JIA) is a chronic systemic inflammatory disease in childhood with unknown etiology. Previous studies have demonstrated an important role for CD4+ T helper cells. The aim of the present study was to investigate the T cell phenotype and cytokine profile in children with JIA with focus on disease activity. T cells from peripheral blood mononuclear cells of 84 children with JIA and 40 age-matched healthy donors (HD) were analyzed by flowcytometry. T cells from JIA patients were less differentiated with higher numbers of naïve T cells compared to HD. Cytokine profile analysis revealed a reduced intracellular Th1- and Th2-specific cytokine production. Significantly higher levels of RORуt expression, the most important transcription factor of Th17 cells, were found during acute disease flare. Moreover, IL-17 production was significantly higher in patients with active disease compared to patients in remission. Furthermore, stimulation experiments with CCR6+CD4+ T cells, which we could identify as IL-17 producing cells, revealed distinct plasticity. Polarization of isolated CCR6+ cells into Th17, Th1 or regulatory T cells, respectively, was achieved using specific cytokines. Interestingly, the potential to polarize differed in JIA patients and healthy donors. T cells from JIA patients showed a more stable Th17 phenotype and restricted switching to Th1 or Treg. These results suggest a predominant Th17 phenotype of T cells in JIA patients. During disease flares, RORуt seems to be an important factor leading to Th17 polarization. An opposing modulation of Th1, Th2 or Treg was not found. In conclusion, a Th17 phenotype dominates during disease flares in JIA and underlines the role of inflammatory T cells in the etiopathogenesis of JIA. IL-17, CCR6 and RORуt, Th17-specific factors, may be interesting targets for novel therapeutic approaches in JIA. / Die Juvenile idiopathische Arthritis (JIA) ist ein chronisch entzündliches Krankheitsbild des Kindesalters mit ungeklärter Ursache. Eine ätiopathogenetische Beteiligung des Immunsystems und im speziellen der T-Zellen ist wahrscheinlich. Die vorliegende durchflusszytometrische Untersuchung umfasst die Daten von 84 JIA Patienten und 40 altersgleichen Kontrollprobanden und vergleicht die Ergebnisse im transversalen sowie longitudinalen Studiendesign. Die Phänotypisierung der Lymphozyten zeigte im Vergleich zu gesunden Kontrollprobanden eine abweichende Verteilung der T-Helferzell-Subpopulationen. Die CD4 positiven T-Helferzellen der JIA Patienten setzen sich aus einer Anzahl proportional verminderter differenzierter Zellen und vermehrter naiver Zellen zusammen. Im Zytokinprofil wurde eine reduzierte Th1- sowie Th2-Antwort beobachtet. In allen T-Zell-Subpopulationen der JIA Patienten fand sich RORуt, der Transkiptionsfaktor der Th17-Differenzierung, hochreguliert. Im klinischen Schub der Arthritis zeigte sich eine signifikant erhöhte RORуt-Expression sowie eine vermehrte IL-17 Produktion. Die IL-17 produzierenden Zellen zeigten u.a. einen regulatorischen Phänotyp. Bei den Stimulationsversuchen von CCR6+ Zellen, die wir als IL-17 produzierende Zellen definieren konnten, wurde eine ausgeprägte Plastizität beobachtet. Mit spezifischen Zytokinstimuli wurden die IL-17 produzierenden Zellen vermehrt zu Th17, Th1 oder regulatorischen T-Zellen polarisiert. Die Polarisierbarkeit unterschied sich zwischen JIA Patienten und Kontrollprobanden. Die CCR6+ Zellen der JIA Patienten zeigten im Vergleich zu den Kontrollprobanden ausgeprägte Polarisierungstendenzen zum Th17-Phänotyp und ließen sich nur gering in Th1 oder Treg konvertieren. Die Ergebnisse unserer Untersuchung lassen auf eine Dominanz im Th17-Differenzierungsweg schließen. Der Transkriptionsfaktor RORуt scheint vor allem im akuten Krankheitsschub zu prädominieren und die Th17-Differenzierung zu steuern. Eine Gegenregulation von Th1- und Th2-Zellen fehlt. Zusammenfassend ergeben sich Hinweise darauf, dass Th17-Zellen eine bedeutende Rolle in der Pathogenese der Juvenilen idiopathischen Arthritis spielen. In wieweit man IL-17, den CCR6-Rezeptor oder den Transkriptionsfaktor RORуt als Angriffsziel von krankheitsmodifizierenden Therapeutika nutzen kann, muss in weiteren Studien untersucht werden. Ebenso gilt es herauszufinden, ob die forcierte Polarisierung in Richtung regulatorische T-Zellen oder gegenregulatorisch aktive Th1 und Th2 Zellen eine Therapiestrategie darstellt.

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Macrophages are an important cell type well known for its’ role in the immune system. Macrophages have two hematopoietic sources; they can be derived from hematopoietic stem cell (HSC) progenitors or erythro-myeloid progenitors (EMP). Synovial macrophages exist within the normal healthy joint, but the current origins and functions of these cells are unclear, including those involved in inflammatory arthritis (IA). To explore the origins of the synovial macrophages we utilized both cell lineage-tracing models and an arthritic model, K/BxN mice serum transfer arthritis (STA). We used Flt3Cre;Rosa26LSL-YFP mice to label HSC-derived cells and Cx3cr1CreERT2;Rosa26LSL-tdTomato and CSF1rmericremer;Rosa26LSL-tdTomato mice to label EMP-derived cells. Our histological data showed a unique population of EMP derived synovial tissue resident macrophages that was present in mice at ages E16.5 and P0 (neonate). Additionally, we found that HSC-derived cells do not significantly contribute to synovial macrophage populations throughout development. Interestingly, in arthritic conditions, we detected a dramatic increase in HSC-derived synovial macrophages in the inflamed synovium. Using macrophage markers F4/80 and CD68 we were able to fluorescently label and identify three different subtypes of synovial macrophages that exist within the joint in both homeostatic and arthritic conditions. Although further studies need to be completed, we have taken a pivotal step towards characterizing synovial macrophages in healthy and arthritic mice.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Psychiatry Johannesburg, 2012 / Background: Rheumatoid Arthritis (RA) is a chronic auto-immune musculoskeletal disorder of unknown aetiology that can result in physical disability, chronic pain and impaired quality of life. RA is associated with an increased prevalence of depression. The presence of depression in RA is reported to be associated with pain, functional disability, high disease activity and mortality. This study aims to determine the prevalence of depressive symptoms in a cohort of Black South African patients attending a Rheumatology outpatient clinic at a public health center. It also aims to determine the association and correlation between the presence of depressive symptoms and the sociodemographic profile and RA clinical characteristics of the study population. Methodology: The study was conducted in a Rheumatology out patient clinic. The study sample consisted of 100 systematically selected participants of Black race. The participants completed the disability questionnaire (HAQ-DI), Visual Analogue Scales (VAS) for pain, fatigue and disease activity; and the depression and tension subscales of the Arthritis Impact Measurement Scale (AIMS). The MADRS was then administered to assess depressive symptoms. Study participants were clinically assessed for disability, joint status and disease activity. Data was analyzed using the SAS version 9.1 statistical program. Results: The majority of the sample was female (85%) and unmarried (66%). The prevalence of current depression was 13.2%, although a further 22.2% of the sample was already stable on antidepressant treatment. The mean RA disease duration was 12.5 ± 9.2 years. No significant associations were found between the presence of depression and the sociodemographic variables. MADRS scores were significantly associated and correlated with disability (p = 0.002, r = 0.30); fatigue (p = <0.001, r = 0.43); disease activity (p = 0.001, r = 0.32); AIMS-D (p < 0.001, r = 0.40) and AIMS-T (p < 0.001, r = 0.35). Upon adjusting for age and clinical status, significant associations remained with MADRS scores and all five above-mentioned RA variables although correlations weakened slightly. Conclusions: Co morbid depression is prevalent in South African Black patients with RA. In order to improve clinical outcomes in RA, depression must be actively sought and effectively managed.

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Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-01

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