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ID PMID Title PublicationDate abstract
20453443 Involvement of mast cells in systemic sclerosis. 2010 Systemic sclerosis is characterized by tissue fibrosis, obliterative microangiopathy and immune abnormalities. The etiology of SSc is largely unknown and is known to be resistant to existing corticosteroid and immunosuppressive drugs. Therefore, establishment of a treatment strategy especially for SSc patients with organ involvement is strongly desired. Mast cells are widely recognized as effector cells in allergic disorders and other IgE-mediated immune responses. However, recently, mast cells have become known to play a role in bridging innate immunity and adaptive immunity. Additionally, there is growing evidence of mast cell to be involved in pathogenesis of rheumatoid arthritis, and is expected as a novel therapeutic target. We describe here the role of mast cell in SSc pathology and suggest as a novel therapeutic target.
19751383 Musculoskeletal pain and sexual function in women. 2010 Feb INTRODUCTION: Sexual pain disorders refer to conditions of genital pain that interfere with intercourse. They often have a musculoskeletal component related to the pelvic floor and are included in the DSM-IV as sexual dysfunctions. Musculoskeletal pain (MP) that is not essentially genitally based often interferes with sex as well yet is not considered a distinct sexual dysfunction. MP is generally addressed by physiatrists, orthopedists, and rheumatologists who are not traditionally trained in sexual medicine, and therefore, the sexual concerns of women with MP often go unaddressed. AIM: The purposes of this review article were to describe how MP is perceived in the literature as affecting sexual function, illustrate how specific MP conditions prevalent in women may affect sexual function, and offer recommendations for clinical practice. METHODS: PubMed and Medline searches were performed using the keywords "musculoskeletal pain and sex,""lower back pain and sex,""arthritis and sex," and "fibromyalgia and sex". Main Outcome Measure. Review of the peer-reviewed literature. RESULTS: Most studies cite fatigue, medication, and relationship adjustment as affecting sexuality much as chronic illness does. While musculoskeletal contributors to genital sexual response and pain are considered relevant to sexual function, little is understood about how MP syndromes specifically affect sexual activity. CONCLUSION: Lack of mobility and MP can restrict intercourse and limit sexual activity, and gender differences are noted in response to pain. Sexual and relationship counseling should be offered as a component of rehabilitative treatment. Physical therapists are uniquely qualified to provide treatment to address functional activities of daily living, including sexual intercourse, and offer advice for modifications in positioning.
20412708 Rituximab in patients with rheumatoid arthritis and vasculitis-associated cutaneous ulcers 2010 Jan OBJECTIVES: To test the efficacy of treatment with rituximab in refractory rheumatoid vasculitis in patients with rheumatoid arthritis (RA). METHODS: Retrospective study of four female patients with histologically proven RA associated vasculitic cutaneous ulcers. All patients developed the lesions on long term treatment with methotrexate or leflunomide, and three of them with tumour necrosis factor alpha (TNF) blockers. All patients were refractory to prednisolone in the dosage between 0.5 and 1 mg/kg body weight for at least 4 weeks prior to rituximab. Rituximab were administered in two intravenous applications in the interval of 14 days accompanied by continued treatment with methotrexate or leflunomide and prednisolone. RESULTS: Three out of four patients achieved a rapid clinical remission of the lesions within 4 to 6 weeks after rituximab therapy continuing at least for four months with a successful corticoid reduction till prednisolone 10 mg a day. One patient showed no remission of the skin lesions accompanied by increasing levels for ESR and CRP. CONCLUSIONS: Rituximab treatment seems to be very effective in several cases of vasculitis-associated cutaneous ulcers in RA patients. However, the effectiveness of rituximab in cases with this indication remains to be shown in larger number of patients.
20422276 Why not treat human cancer with interleukin-1 blockade? 2010 Jun The clinical successes of targeting angiogenesis provide a basis for trials of interleukin-1 (IL-1) blockade and particularly anti-IL-1beta as an add-on therapy in human metastatic disease. In animal studies for over 20 years, IL-1 has been demonstrated to increase adherence of tumor cells to the endothelium in vitro, and administration of IL-1 to mice increases the number of metastatic colonies and tumor growth. Importantly, reducing endogenous IL-1 activity, particularly IL-1beta, with the naturally occurring IL-1 receptor antagonist (IL-1Ra) reduces both metastasis as well as tumor burden. Inhibition of IL-1 activity prevents in vivo blood vessel formation induced by products released from hypoxic macrophages or vascular endothelial cell growth factor itself. Mice deficient in IL-1beta do not form blood vessels in matrigels embedded with vascular endothelial cell growth factor or containing products of macrophages. Recombinant IL-1Ra (anakinra) has been administered to over 1,000 patients with septic shock resulting in a consistent reduction in all-cause 28-day mortality. Approved for treatment of rheumatoid arthritis, anakinra has a remarkable safety record. Anakinra resulted in decreased blood vessels in the pannus of affected joints in patients with rheumatoid arthritis. Neutralizing monoclonal antibodies to IL-1beta and a soluble receptor to IL-1 are approved for treating chronic inflammatory diseases. Given the availability of three therapeutic agents for limiting IL-1 activity, the safety of blocking IL-1, and the clear benefit of blocking IL-1 activity in animal models of metastasis and angiogenesis, clinical trials of IL-1 blockade should be initiated, particularly as an add-on therapy of patients receiving antiangiogenesis-based therapies.
19425902 Trends in RA patients' adherence to subcutaneous anti-TNF therapies and costs. 2009 Jun OBJECTIVE: To examine adherence to adalimumab (ADA) and etanercept (ETA) and health care costs in rheumatoid arthritis (RA) patients, and to explore the association between adherence, utilization and costs. RESEARCH DESIGN AND METHODS: Using administrative claims data from a large managed health care plan, RA patients treated with etanercept or adalimumab during the period from 01/01/2005 through 12/31/2005 were identified. The first dispensing date was defined as the index date. Patient adherence and costs were assessed during the 1 year post-index period. MAIN OUTCOME MEASURES: Nonadherence (medication possession ratio <80%) was modeled using logistic regression. Hazard ratios (HR) comparing time to discontinuation were estimated using Cox proportional hazard (PH) models. Propensity score matching with multivariate generalized linear modeling adjustment was done to assess cost difference between ADA and ETA. RESULTS: Of 3829 eligible RA patients, 1292 (765 existing, 527 naïve) and 2537 (1834 existing, 703 naïve) patients used ADA and ETA, respectively. Compared with ADA users, ETA users had longer average treatment duration (316 vs. 291 days; p < 0.0001). Unadjusted adherence rates for naïve and existing users were 63% and 70% (ADA), and 65% and 73% (ETA). Logistic regression analysis indicated that compared with ETA users, ADA users were more likely to be nonadherent (OR, naïve 1.24; existing; 1.25). Cox PH models indicated that existing ADA users were more likely to discontinue (HR = 1.11; p = 0.06) their medication than existing ETA users. Compared with ADA users, ETA users had significantly lower RA-related pharmacy costs (naïve: $10,892 vs. $12,534, p < 0.01; existing: $12,192 vs. $13,752, p < 0.01) and RA-related total costs (naïve: $11,976.42 vs. $13,511.99, p < 0.05; existing: $14,031 vs. $15,454, p < 0.05). CONCLUSIONS: ETA users had longer treatment duration, were more likely to adhere to their medication regimen and had lower RA-related pharmacy and RA-related total costs compared with ADA users. These findings must be considered within the limitations of this database analysis.
19180502 Expression, regulation, and signaling of the pattern-recognition receptor nucleotide-bindi 2009 Feb OBJECTIVE: Since pattern-recognition receptors (PRRs), in particular Toll-like receptors (TLRs), were found to be overexpressed in the synovium of rheumatoid arthritis (RA) patients and to play a role in the production of disease-relevant molecules, we sought to determine the expression, regulation, and function of the PRR nucleotide-binding oligomerization domain 2 (NOD-2) in RA. METHODS: Expression of NOD-2 in synovial tissues was analyzed by immunohistochemistry. Expression and induction of NOD-2 in RA synovial fibroblasts (RASFs) were measured by conventional and real-time polymerase chain reaction (PCR) analyses. Levels of interleukin-6 (IL-6) and IL-8 were measured by enzyme-linked immunosorbent assay (ELISA) and expression of matrix metalloproteinases (MMPs) by ELISA and/or real-time PCR. NOD-2 expression was silenced with small interfering RNA. Western blotting with antibodies against phosphorylated and total p38, JNK, and ERK, as well as inhibitors of p38, JNK, and ERK was performed. Activation of NF-kappaB was measured by electrophoretic mobility shift assay. RESULTS: NOD-2 was expressed by fibroblasts and macrophages in the synovium of RA patients, predominantly at sites of invasion into articular cartilage. In cultured RASFs, no basal expression of messenger RNA for NOD-2 was detectable, but was induced by poly(I-C), lipopolysaccharide, and tumor necrosis factor alpha. After up-regulation of NOD-2 by TLR ligands, its ligand muramyl dipeptide (MDP) increased the expression of IL-6 and IL-8 via p38 and NF-kappaB. Stimulation with MDP further induced the expression of MMP-1, MMP-3, and MMP-13. CONCLUSION: Not only TLRs, but also the PRR NOD-2 is expressed in the synovium of RA patients, and activation of NOD-2 acts synergistically with TLRs in the production of proinflammatory and destructive mediators. Therefore, NOD-2 might contribute to the initiation and perpetuation of chronic, destructive inflammation in RA.
20094744 Serum hyaluronic acid levels do not explain morning stiffness in patients with fibromyalgi 2010 May To investigate the serum levels of hyaluronic acid (HA) in Korean female patients with fibromyalgia (FM) and correlate these levels with variables of disease severity including morning stiffness, we measured HA serum levels in 69 FM patients, 72 rheumatoid arthritis (RA) patients, and 71 healthy controls by enzyme-linked binding protein assay. The serum levels of HA in FM patients did not differ from those in the age-matched controls, whereas HA levels were significantly higher in RA patients than in FM patients and controls (both P < 0.001). With a cut-off value of 75 ng/mL, the prevalence of seropositivity was higher in RA patients (59.7%) than in FM patients (26.1%) or controls (14.1%; both P < 0.001). There were no differences in seropositivity between FM patients and controls, or between FM patients with severe symptoms and those with mild symptoms. The HA levels in FM patients were significantly correlated with age, age at diagnosis, age at symptom development, disease duration, symptom duration, and level of education. There were no correlations between HA levels and morning stiffness, tender point counts and scores, or Fibromyalgia Impact Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory scores. In our patients, the serum HA levels were not increased and did not reflect disease severity. These results suggest that serum HA is not a useful laboratory marker for diagnosis and assessment of FM.
19095472 Resistin is elevated following traumatic joint injury and causes matrix degradation and re 2009 May OBJECTIVE: Resistin is a secreted factor that is elevated in rheumatoid arthritis (RA) and believed to drive joint inflammation in vivo. This study was undertaken to determine if resistin is present in the joint following joint injury and to elucidate the role of resistin in cartilage degradation. METHODS: The level of resistin was measured in paired synovial fluid (SF) and serum samples from patients following joint injury (anterior cruciate ligament, ACL or meniscus tear). Localization of resistin was visualized by immunohistochemistry of synovial tissue and cartilage from healthy and OA donors. Mouse and human cartilage cultures were used to assess the effect of resistin on cartilage metabolism. RESULTS: In trauma patients, resistin levels declined with increasing time post injury. The resistin levels were highest in samples collected up to 1 week following traumatic injury (SF: 2980 pg/ml, serum: 7901 pg/ml) and lowest in samples collected 6-26 years post injury (SF: 686 pg/ml, serum: 5682 pg/ml). Resistin was shown to be expressed in macrophage-like cells in both healthy and OA synovial tissue. Treatment of mouse cartilage cultures with recombinant resistin led to a dose dependent loss of proteoglycan and induction of inflammatory cytokine and PGE(2) production. Recombinant resistin inhibited proteoglycan synthesis in human cartilage explants. CONCLUSION: Resistin is elevated both systemically and locally in the weeks immediately following joint injury and has a direct effect on cartilage matrix turnover and cytokine production. Resistin may play a role in the early stages of trauma-induced OA and may represent a new therapeutic target to slow joint destruction in OA.
20374389 Tubercular pyomyositis in a case of rheumatoid arthritis being treated with infliximab. 2010 Feb 1 A 55-year-old woman with rheumatoid arthritis having 4 months previously received two doses of infliximab, presented with fever, hypotension and swelling of right thigh posterolaterally. CT-guided aspiration was performed from the right thigh and revealed acid-fast bacilli (AFB) +++ and mycobacterial culture grew Mycobacterium tuberculosis. The patient improved on anti-tubercular treatment.
19714646 Liver X receptor agonism promotes articular inflammation in murine collagen-induced arthri 2009 Sep OBJECTIVE: Liver X receptors (LXRs) have previously been implicated in the regulation of inflammation and have, in general, been ascribed an antiinflammatory role. This study was therefore undertaken to explore the biologic mechanisms of LXRs in vivo and in vitro in an experimental inflammatory arthritis model. METHODS: Male DBA/1 mice were immunized with type II collagen and treated from an early or established stage of arthritis with 2 different concentrations of the LXR agonists T1317 and GW3965 or vehicle control. The mice were monitored for articular inflammation and cartilage degradation by scoring for clinical signs of arthritis, histologic examination of the joints, and analysis of serum cytokine and antibody levels. In vitro, primary human monocytes and T cells were cultured in the presence of GW3965 or T1317, and the concentrations of proinflammatory cytokines were measured by multiplex assay. RESULTS: Contrary to expectations, LXR agonism with the use of 2 discrete, specific molecular entities led to substantial exacerbation of articular inflammation and cartilage destruction in this murine collagen-induced arthritis model. This was associated ex vivo with elevated cytokine expression, with enhanced Th1 and Th17 cellular responses, and with elevated collagen-specific autoantibody production. In vitro, LXR agonists, in concert with lipopolysaccharide, promoted cytokine and chemokine release from human monocytes, and similar effects were observed in a T cell-macrophage coculture model that closely recapitulates the pathways that drive synovial cytokine release. CONCLUSION: Since LXRs are present in rheumatoid arthritis (RA) synovium, these results suggest that LXR-mediated pathways could exacerbate the chronic inflammatory response typical of RA.
19346219 Mesenchymal stem cells in rheumatoid synovium: enumeration and functional assessment in re 2010 Feb OBJECTIVE: Achieving joint regeneration in rheumatoid arthritis (RA) represents a future challenge. Autologous synovial mesenchymal stem cells (MSCs) could be therapeutically exploited. However, the inflammatory milieu in the RA synovium could adversely affect endogenous MSC function. To test this hypothesis, the frequency and multipotency of RA synovial MSCs was evaluated in relation to existing synovial inflammation. METHODS: Synovial inflammation was measured using the arthroscopic visual analogue score (VAS) and further validated using immunohistochemistry and flow cytometry. Highly proliferative clonogenic in vivo MSCs were enumerated following fluorescence-activated cell sorting and expansion for 20 population doublings. MSC multipotency was quantified following standard in vitro culture expansion and trilineage differentiation assays. Real-time PCR, flow cytometry and ELISA were used to evaluate pro- and anti-chondrogenic molecules in standard polyclonal synovial MSCs. RESULTS: The arthroscopic VAS significantly correlated with synovial macrophage infiltration. In RA, synovial MSC chondrogenesis was inhibited in direct relation to VAS (r = -0.777, p<0.05) and reduced compared with control osteoarthritis (OA)-MSCs (p<0.05). In vivo, MSCs resided in the synovial fibroblastic/stromal fraction (CD45(-)CD31(-)) and were reduced in frequency in relation to VAS (r = -0.695, p<0.05). In RA-MSCs, CD44 levels correlated negatively with inflammation and positively with chondrogenesis (r = -0.830 and r = 0.865, respectively). Cytokine production and Sox9 expression was similar in RA-MSCs and OA-MSCs. CONCLUSIONS: There is a negative relationship between synovial MSC chondrogenic and clonogenic capacities and the magnitude of synovitis in RA. Effective suppression of joint inflammation is therefore necessary for the development of autologous MSC treatments aimed at cartilage regeneration in RA.
20181277 c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role i 2010 INTRODUCTION: Tyrosine kinases are key mediators of multiple signaling pathways implicated in rheumatoid arthritis (RA). We previously demonstrated that imatinib mesylate--a Food and Drug Administration (FDA)-approved, antineoplastic drug that potently inhibits the tyrosine kinases Abl, c-Kit, platelet-derived growth factor receptor (PDGFR), and c-Fms--ameliorates murine autoimmune arthritis. However, which of the imatinib-targeted kinases is the principal culprit in disease pathogenesis remains unknown. Here we examine the role of c-Fms in autoimmune arthritis. METHODS: We tested the therapeutic efficacy of orally administered imatinib or GW2580, a small molecule that specifically inhibits c-Fms, in three mouse models of RA: collagen-induced arthritis (CIA), anti-collagen antibody-induced arthritis (CAIA), and K/BxN serum transfer-induced arthritis (K/BxN). Efficacy was evaluated by visual scoring of arthritis severity, paw thickness measurements, and histological analysis. We assessed the in vivo effects of imatinib and GW2580 on macrophage infiltration of synovial joints in CIA, and their in vitro effects on macrophage and osteoclast differentiation, and on osteoclast-mediated bone resorption. Further, we determined the effects of imatinib and GW2580 on the ability of macrophage colony-stimulating factor (M-CSF; the ligand for c-Fms) to prime bone marrow-derived macrophages to produce tumor necrosis factor (TNF) upon subsequent Fc receptor ligation. Finally, we measured M-CSF levels in synovial fluid from patients with RA, osteoarthritis (OA), or psoriatic arthritis (PsA), and levels of total and phosphorylated c-Fms in synovial tissue from patients with RA. RESULTS: GW2580 was as efficacious as imatinib in reducing arthritis severity in CIA, CAIA, and K/BxN models of RA. Specific inhibition of c-Fms abrogated (i) infiltration of macrophages into synovial joints of arthritic mice; (ii) differentiation of monocytes into macrophages and osteoclasts; (iii) osteoclast-mediated bone resorption; and (iv) priming of macrophages to produce TNF upon Fc receptor stimulation, an important trigger of synovitis in RA. Expression and activation of c-Fms in RA synovium were high, and levels of M-CSF were higher in RA synovial fluid than in OA or PsA synovial fluid. CONCLUSIONS: These results suggest that c-Fms plays a central role in the pathogenesis of RA by mediating the differentiation and priming of monocyte lineage cells. Therapeutic targeting of c-Fms could provide benefit in RA.
20112358 Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of 2010 Feb OBJECTIVE: Interleukin-27 (IL-27) has stimulatory and regulatory immune functions and is expressed in rheumatoid arthritis (RA) synovium. This study was undertaken to investigate the effects of IL-27 on human osteoclastogenesis, to determine whether IL-27 can stimulate or attenuate the osteoclast-mediated bone resorption that is a hallmark of RA. METHODS: Osteoclasts were generated from blood-derived human CD14+ cells. The effects of IL-27 on osteoclast formation were evaluated by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells and measuring the expression of osteoclast-related genes. The induction of nuclear factor of activated T cells c1 (NFATc1) and the activation of signaling pathways downstream of RANK were measured by immunoblotting. The expression of key molecules implicated in osteoclastogenesis (NFATc1, RANK, costimulatory receptors, and immunoreceptor tyrosine-based activation motif-harboring adaptor proteins) was measured by real-time reverse transcription-polymerase chain reaction. Murine osteoclast precursors obtained from mouse bone marrow and synovial fluid macrophages derived from RA patients were also tested for their responsiveness to IL-27. RESULTS: IL-27 inhibited human osteoclastogenesis, suppressed the induction of NFATc1, down-regulated the expression of RANK and triggering receptor expressed on myeloid cells 2 (TREM-2), and inhibited RANKL-mediated activation of ERK, p38, and NF-kappaB in osteoclast precursors. Synovial fluid macrophages from RA patients were refractory to the effects of IL-27. In contrast to the findings in humans, IL-27 only moderately suppressed murine osteoclastogenesis, and this was likely attributable to low expression of the IL-27 receptor subunit WSX-1 on murine osteoclast precursors. CONCLUSION: IL-27 inhibits human osteoclastogenesis by a direct mechanism that suppresses the responses of osteoclast precursors to RANKL. These findings suggest that, in addition to its well-known antiinflammatory effects, IL-27 plays a homeostatic role in restraining bone erosion. This homeostatic function is compromised under conditions of chronic inflammation such as in RA synovitis.
19387646 Long-term anti-tumour necrosis factor therapy reverses the progression of carotid intima-m 2009 Dec The objective of the study is to evaluate the effect of TNF inhibition on carotid thickness over a 2-year period. 144 women with RA diagnosed according to ACR criteria, without clinical evidence of cardiac and/or vascular disease were enrolled and compared with 78 matched controls. All patients received methotrexate (15–20 mg weekly) for 3 months. Responders (n = 79) continued to be treated with methotrexate, non-responders (n = 40) moved to methotrexate plus a TNF alpha antagonist. Echosonographic studies of carotids were obtained before and after 2-year follow-up. A significant decrease of ca-IMT was observed in anti-TNF-treated patients (P < 0.001); on the other hand, no significant variation of ca-IMT was observed after 2 years in MTX-treated patients. Our study indicates that anti-TNF blocking agents, but not methotrexate, are capable of reducing IMT of carotid arteries in female RA patients in a 2-year follow-up.
19678436 [The efficacy of the three available anti-tumour necrosis factor therapies in patients wit 2009 Jun 22 Absolute treatment efficacy (via number needed to treat) of rheumatoid arthritis for each of the three available anti tumour necrosis factor alpha inhibiting therapies. Our aim was to indirectly compare the long-term efficacy of the available anti-tumour necrosis factor (TNF) therapies in patients with established rheumatoid arthritis. The results indicate that the absolute efficacy associated with use of these anti-TNF therapies is equivalent if applied in equivalent dosages. In standard dosages, infliximab (3 mg/kg/eight weeks) is only half as effective as adalimumab (40 mg/two weeks) and etanercept (25 mg twice weekly).
20732652 Targeting the B cell in rheumatoid arthritis. 2010 Aug There has been renewed interest in the B cell as a target for the treatment of rheumatoid arthritis (RA) over the past decade. Efficacy with rituximab has been demonstrated in randomised clinical trials (RCTs) resulting in regulatory approval for patients failing tumour necrosis factor (TNF) inhibitors. Although the actual mechanism of action has not been clearly delineated, several molecules are under development to modify B cell number/function in hope of superior efficacy/safety or ease of administration. The safety of rituximab over the intermediate time point has been comparable to that seen with other biologic disease-modifying anti-rheumatic drugs (DMARDs). The recent report of cases of progressive multifocal leukoencephalopathy in three patients receiving rituximab for RA is a concern and, for now, limits rituximab to salvage therapy for the treatment-resistant patient. How this impacts on other B-cell inhibitors under development is not yet clear. Development of biomarkers that will assist our therapeutic decisions to enhance the benefit/risk ratio for our patients are needed as we move forward with further selective targeted therapies.
19083035 GPs as citizens' agents: prescription behavior and altruism. 2009 Oct To curb the heavily increasing drug budgets some Danish counties have introduced voluntary agreements between general practitioners (GPs) and health authorities. We extend the models of generic prescription by Hellerstein (Rand J Econ 29(1):108-136, 1998) and Lundin (J Health Econ 19:639-662, 2000) to allow for substitution between analogues and use difference-in-difference models to assess the effect on two drug groups (lipid-lowering and rheumatism drugs). For both drug groups we find evidence of a significant effect of the intervention. In the case of lipid-lowering drugs, we found a significant larger impact on GPs with low loyalty to the insurer and with indication of low prescription quality. In contrast we found that the intervention had a significantly lower impact on this group of GPs in the case of rheumatism drugs. We conclude that the effectiveness of the voluntary approach may partly be due to its indirect effect on GPs' altruistic motivation, which makes the GPs and the authorities collide in a common agency role.
19134182 MegaSNPHunter: a learning approach to detect disease predisposition SNPs and high level in 2009 Jan 9 BACKGROUND: The interactions of multiple single nucleotide polymorphisms (SNPs) are highly hypothesized to affect an individual's susceptibility to complex diseases. Although many works have been done to identify and quantify the importance of multi-SNP interactions, few of them could handle the genome wide data due to the combinatorial explosive search space and the difficulty to statistically evaluate the high-order interactions given limited samples. RESULTS: Three comparative experiments are designed to evaluate the performance of MegaSNPHunter. The first experiment uses synthetic data generated on the basis of epistasis models. The second one uses a genome wide study on Parkinson disease (data acquired by using Illumina HumanHap300 SNP chips). The third one chooses the rheumatoid arthritis study from Wellcome Trust Case Control Consortium (WTCCC) using Affymetrix GeneChip 500K Mapping Array Set. MegaSNPHunter outperforms the best solution in this area and reports many potential interactions for the two real studies. CONCLUSION: The experimental results on both synthetic data and two real data sets demonstrate that our proposed approach outperforms the best solution that is currently available in handling large-scale SNP data both in terms of speed and in terms of detection of potential interactions that were not identified before. To our knowledge, MegaSNPHunter is the first approach that is capable of identifying the disease-associated SNP interactions from WTCCC studies and is promising for practical disease prognosis.
20016201 The diabetic antigen glutamic acid decarboxylase (GAD 65) in the human peripheral blood. 2010 BACKGROUND: Glutamic acid decarboxylase (GAD 65) is a diabetes-associated antigen which is generally considered to be strictly intracellular. In order to better understand autoimmunity, this study demonstrates the appearance of GAD 65 in the peripheral human blood and presents implications for the diagnosis and therapy of some autoimmune diseases. METHODS: The GAD 65 molecules are detected by their interaction with monoclonal antibodies labeled with dyes in an experimental setup with fluorescence correlation spectroscopy (FCS). These interactions result in changes in Brownian motion measured as fluorescence fluctuations. Sera from 153 patients with diabetes mellitus type 1 and controls were investigated. To enable the representation of the molecule as a model for further discussions, we present structural visualizations of its hydrophobic properties, leading to possible interactions with the cell membrane lipids and epitope locations. RESULTS: The GAD65 antigen could be measured with a sensitivity of 2.65 microg/ml in 'clean systems' resulting from spiking experiments and human sera. The GAD 65 antigen could be identified in 8 patient sera: 4 children with diabetes mellitus type 1 and 4 adults initially taken as controls but who retrospectively showed signs of autoimmunity. CONCLUSION: We conclude that these findings are of significance for the concept of autoimmunity, i.e. in an initial step the immune system is primed by its accessibility to GAD 65. Our experimental results may also be important for the therapy of diabetes mellitus type 1 and other autoimmune diseases by the passive administration of GAD 65 antibodies.
19742087 Pre-operative and intra-operative factors related to shoulder arthroplasty outcomes. 2009 The purpose of this study was to analyze pre-operative and intra-operative factors that affect the outcome of shoulder arthroplasty. We undertook a retrospective review of all shoulder arthroplasties performed at our institution between 1986 and 2003. Patients were contacted and outcomes were assessed using the Simple Shoulder Test and the Western Ontario Osteoarthritis of the Shoulder Index questionnaires. One hundred six patients (126 shoulders) participated in the study. The average length of follow-up was 6 years 9 months (range 2 to 20 years). Revision arthroplasty surgery and female gender were associated with worse outcomes. Age, the number of medical comorbidities, obesity, pre-operative range of motion, prior non-arthroplasty surgery, smoking, and alcohol abuse did not correlate with outcome. Patients who had shoulder arthroplasty for osteoarthritis had better outcome scores than those with rheumatoid arthritis. For intra-operative variables, significantly worse outcomes were found both with the use of hemiarthroplasty and in patients with a rotator cuff tear identified at the time of surgery. These findings may help to optimize patient and surgery selection in shoulder arthroplasty and assist in preoperative patient counseling.