The host response toward biomaterial component of tissue-engineered devices has been extensively investigated. The objective of this research was to understand the response of dendritic cells (DCs) to different biomaterials upon contact and identify biomaterials suitable for use in tissue engineering constructs for rheumatoid arthritis (RA) applications. Differential levels of functional DC maturation were observed depending on the type of biomaterial in 2-dimensional films or 3-dimensional scaffolds used to treat immature DCs; Poly(lactic-co-glycolic acid) (PLGA) or chitosan supported higher levels of DC maturation, as compared to immature DCs. Alginate supported moderate levels of DC maturation. Agarose did not support DC maturation whereas hyaluronic acid inhibited DC maturation. Further, these DCs treated with different biomaterials induced differential phenotype and polarization of autologous T cells upon co-culture of DCs and T cells; DCs treated with PLGA induced T helper type I with immunogenic response while DCs treated with agarose did T helper type II with tolerogenic response. Effect of different biomaterials (PLGA and agarose) was assessed in vivo upon implantation of them into the knee joint of RA-induced rabbit. Total leukocyte concentrations in the peripheral blood or in the joint lavage of the left knees (untreated control) were observed in differential levels depending on the biomaterial implant, possibly due to the systemic circulation of the peripheral blood. Furthermore, cartilage and bone healing progression was differentially observed in the osteochondral defect of the knee joint of RA-induced rabbit, depending on type of biomaterial scaffold implanted into the defect. Collectively, these results demonstrate the multifunctional impacts of inherently different biomaterials on in vitro immunomodulation of phenotype and polarization of DCs and autologous T cells. Furthermore, taken together with these immunomodulatory impacts of biomaterials, in vivo effects of different biomaterial scaffolds on RA environment shown in this study can suggest the criteria of selection and design of biomaterials for orthopedic tissue engineering, which may ultimately be best integrated into the diseased cartilage and bone.

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 5 uppsatser.

In this paper, a rheumatoid arthritis (RA) medicine clinical dataset with an ordinal response is selected to study this new medicine. In the dataset, there are four features, sex, age,treatment, and preliminary. Sex is a binary categorical variable with 1 indicates male, and 0 indicates female. Age is the numerical age of the patients. And treatment is a binary categorical variable with 1 indicates has RA, and 0 indicates does not have RA. And preliminary is a five class categorical variable indicates the patient’s RA severity status before taking the medication. The response Y is 5 class ordinal variable shows the severity of patient’s RA severity after taking the medication. The primary aim of this study is to determine what factors play a significant role in determine the response after taking the medicine. First, cumulative logistic regression is applied to the dataset to examine the effect of various factors on ordinal response. Secondly, the ordinal response is categorized into two classes. Then logistic regression is conducted to the RA dataset to see if the variable selection would be different. Moreover, the shrinkage methods, elastic net and lasso are used to make a variable selection on the RA dataset of two-class response for the purpose of adding penalization to increase the model’s robustness.The four model results were compared at the end of the paper. From the comparison result, logistic regression has a better performance on variable selection than the other three approaches based on P-value.

No description available.

The effect of synovial membrane products and mechanical pressure upon the metabolism of articular cartilage proteoglycans has been studied in vitro. The degradation of cartilage proteoglycans was studied in an organ culture system and measured as the release of [35S ] sulphate from prelabelled cartilage. The effect of synovial membrane products upon the synthesis of proteoglycans was studied in a chondrocyte monolayer system and the effect of mechanical pressure upon the synthesis of proteoglycans in an organ culture system. In both types of experiments [35S] sulphate was used as precursor. The findings may be summarized as follows 1 Conditioned synovial medium (control-SM) enhanced the degradation and reduced the synthesis of cartilage proteoglycans. In addition the degradation was further enhanced when the synovial tissue had been cultured in the presence of dextran sulphate. 2 Conditioned medium from synovial tissue cultured in the presence of indo-methacin (indo-SM), significantly reduced the synthesis of cartilage proteoglycans in chondrocyte cultures and reduced, although non-significantly, the degradation of proteoglycans in whole cartilage cultures. 3 Addition o f the prostaglandins E1 or E2 (PGE1 or PGE2 ) together with indo-SM to the cartilage cultures greatly enhanced cartilage degradation whereas the addition of PGE1 or PGE2 together with control-SM had no effect compared with that of control-SM alone. 4 Conditioned medium from synovial tissue cultured in the presence of low doses of glucocorticoids reduced cartilage degradation compared with control-SM. However, addition of control-SM together w ith low concentrations of glucocorticoids to the cartilage cultures significantly enhanced cartilage degradation. 5 Conditioned medium from synovial tissue cultured with actinomycin D or cycloheximide did not enhance cartilage degradation compared with cartilage cultured alone. 6 A continuous pressure of approximately 30 kgfcm-2 on cultures of cartilage reduced both the synthesis and the degradation o f cartilage proteoglycans. Although it is difficult to extrapolate from the in vitro to the in vivo situation, it is proposed that some factor(s) from the synovial membrane have the capacity to enhance the degradation and reduce the synthesis o f articular cartilage proteoglycans. From these experiments it cannot be completely excluded that treatm ent of arthritic joints with non-steroidal or streroidal anti-inflammatory drugs may result under certain conditions in enhanced joint damage. It is also suggested that under certain conditions the metabolism o f cartilage proteoglycans could be directly affected by mechanical stress. / <p>Diss. Umeå, Umeå universitet, 1982, härtill 6 uppsatser</p> / digitalisering@umu

Human endogenous retroviruses are the remnants of ancient retroviral infections present within our genome. These molecular fossils show similarities with present day exogenous retroviruses but act as typical Mendelian elements that are passed vertically between generations. Despite being repeatedly linked to a number of autoimmune diseases and disorders, no conclusive proof has been identified. Rheumatoid arthritis (RA) is one such disease which has been associated with an increase in HERV expression, compared to controls. In order to elucidate a clear role for HERVs in RA pathogenesis, autoantigens implicated in disease pathogenesis were scanned for sequence homology to retroviral genes. Such epitopes would induce antibodies cross reactive with host proteins, resulting in disease. Short peptides mimicking these regions were synthesised and the prevalence of anti-HERV antibodies was determined in RA patients and disease controls. Additionally, a novel real-time Polymerase Chain Reaction (PCR) assay was developed to accurately quantify levels of HERV-K (HML-2) gag expression, relative to normalised levels of housekeeping gene expression. Both serological and molecular assays showed significant increases in HERV-K (HML-2) activity in RA patients compared to disease controls with CD4+ lymphocytes harbouring the highest activity. The real-time assay was also used to determine whether factors within the synovium could modulate HERVs, resulting in their upregulation. Exogenous viral protein expression and pro-inflammatory cytokines were shown to exert a significant modulatory effect over HERV-K (HML-2) transcription. From this data, it is clear that RA patients have increased levels of HERV-K (HML-2) gag activity compared to controls. Despite this it is likely that factors within the synovium such as exogenous viral expression and pro-inflammatory cytokines also influence HERV-K (HML-2) transcription possibly contributing to a role of bystander activation, i.e. being influenced by external factors, rather than actively contributing to disease processes. The exact role of HERVs in RA pathology remains elusive; however this research proposes several mechanisms by which HERV-K (HML-2) may contribute to disease.

Background: Inflammation is the natural reaction of the body to an antigen. In some conditions, this reaction continues even after the elimination of the antigen, entering a chronic stage; it targets normal cells of the body and causes extensive damage. Rheumatoid arthritis (RA) is such a condition. It associates with significant metabolic alterations that lead to changes in body composition and especially body fat (BF) increases. In the general population, increased body fat (i.e. obesity) associates with a number of health disorders such as systemic low grade inflammation and a significantly increased risk for cardiovascular disease (CVD). Both effects of obesity could have detrimental effects in RA. Increased inflammation could worsen disease activity while obesity could further increase the already high CVD risk in RA. However, obesity in RA has attracted minimal scientific attention. Aims: The present project aimed to: 1) assess whether the existing measures of adiposity are able to identify the changes in body composition of RA patients, 2) if necessary develop RA-specific measures of adiposity, 3) investigate the association of obesity with disease characteristics and CVD profile of the patients, 4) and identify factors that might affect body weight and composition in these patients. Methods: A total of 1167 volunteers were assessed. Of them 43 suffered from osteoarthritis and 82 were healthy controls. These, together with 516 RA patients were used in the first study. Their body mass index (BMI), BF, and disease characteristics were assessed. In the second, third, fourth and fifth studies a separate set of 400 RA patients was assessed. In addition to the above assessments, their cardiovascular profile and more detailed disease characteristics were obtained. For the final study, 126 RA patients were assessed for all the above and also data on their physical activity levels and their diet were collected. Results: Assessments of adiposity for the general population are not valid for RA patients. Thus, we proposed RA-specific measures of adiposity. These are able to better identify RA patients with increased BF. We were also able to find associations between obesity and disease activity. Both underweight and obese RA patients had more active disease compared to normal-weight patients. Obese patients had significantly worse CVD profile compared to normal-weight. The newly devised measures of adiposity were able to identify those at increased risk. However, not all obese individuals were unhealthy and not all normal-weight healthy. Among our patients we were able to identify subtypes of obesity with distinct phenotypic characteristics that warrant special attention. Finally, we were able to identify factors that influence body weight and composition. Cigarette smoking protected against obesity while its cessation associated with increased adiposity. Physical activity was also found to be protective against obesity while diet or inflammation of the disease failed to produce any significant results. Conclusions: Obesity is a significant threat to the health of RA patients. The measures of adiposity developed herein should be used to identify obese RA patients. Physical activity seems like the sole mode for effective weight management in this population. Health and exercise professionals should actively encourage their patients to exercise as much as they can. This study has created more questions than it answered; further research in the association of obesity and inflammation, as well as in ways to treat it, is essential.

published_or_final_version / Social Work / Master / Master of Social Work

Rheumatoid arthritis (RA) is a progressive autoimmune disorder of joints that is associated with high health care costs and yet lacks guidance on how early to initiate biologic disease-modifying antirheumatic drugs (DMARDs), a class of medications that is the major cost driver in RA management. The main purpose of this study was to examine patient socio-demographics, medication use patterns, and clinical characteristics associated with initiation of biologic DMARDs. This was a retrospective study using Texas Medicaid prescription and medical claims database during the study period of July 1, 2003 – December 31, 2010. Patients (18 – 63 years) with an RA diagnosis (ICD-9-CM code 714.xx), no non-biologic DMARD or biologic DMARD use during the pre-index period, and a minimum of 2 prescription claims for the same non-biologic DMARD during the post-index period were included in the study. The primary study outcomes were time to initiation of biologic DMARDs and likelihood of initiating biologic DMARDs. There was a total of 2,714 subjects included in the study. The majority had claims for pain medications (92.4%), glucocorticoids (64.9%), and non-biologic DMARD monotherapy (86.4%); while 24.3% initiated on biologic DMARDs and 58.9% had a Charlson Comorbidity Index (CCI) score=1. Compared to time to initiation (days) of biologic DMARDs for methotrexate (539.7±276.9) users, it was longer for sulfasalazine (670.2±167.8) and hydroxychloroquine (680.2±158.7) users and similar to leflunomide users (541.6±286.5; p<0.0001). There were no significant differences in time to initiation between non-biologic DMARD mono vs. dual therapy. Younger age, glucocorticoid use, methotrexate user (vs. sulfasalazine, hydroxychloroquine users), and non-biologic DMARD monotherapy user (vs. dual therapy user) were significantly associated with higher likelihood to initiate biologic DMARDs. In conclusion, age, glucocorticoid use, non-biologic DMARD type and therapy were significant factors associated with initiation of biologic DMARDs. Healthcare providers and Texas Medicaid should recognize these potential driving factors and take efforts to achieve optimal therapy for RA patients through thorough RA medication evaluation, well-structured RA monitoring programs, and patient education. / text

A series of five individual studies explored: (1) Whether a treatment focus emphasizing active anger expression would alter the subject's awareness of and ability to express anger and (2) Whether such a treatment focus would alter the subject's experience of illness in the form of her report of pain and stiffness as "better", "the same", or "worse" than yesterday's experience. The treatment strategy utilized general Gestalt principles and was further focused on specific techniques of Anger Therapy as an agent of change. Evaluation of outcome in this time-lagged multiple baseline design viewed the overall process from the beginning of a baseline observation period through a maximum of one week following the conclusion of the last six weekly treatment sessions; daily measurement of the process of change during treatment; and clinical description of the subjects and of the treatment process itself. The overall process was formally assessed in pre and post treatment testing which included the Novaco Anger Inventory, Buss-Durkee Hostility Inventory, Marlowe-Crowne Social Desirability Scale, and FIRO-B. Daily telephone interview measured the frequency of anger awareness, anger expression; and ratings of anger intensity, overall daily mood, pain, and stiffness. Information from the treatment process was integrated with that obtained from other sources in discussing the outcome for each subject. It was concluded that intense anger expression appeared to effect temporary or transitory improvement in pain; that there was a relationship between each subject's perceived daily anger intensity and pain which appeared consistent for all subjects studied; and that issues of need for approval and control appeared related to anger awareness and expression as measured by the psychometrics utilized. These were recommended as potentially fruitful areas of future investigation. Background data revealed striking similarities in birth order and parenting practices which seemed worthy of further study as well.