Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
17353049 Decreased induction of IL-1beta in fibroblast-like synoviocytes: a possible regulatory mec 2007 May The response of fibroblast-like synoviocytes (FLS) to inflammatory stimuli was compared to their, respectively, derived dermal fibroblasts (DF) to determine whether regulatory controls exist within FLS to insure normal joint homeostasis. We further analyzed whether the loss of the normal regulatory controls present within the FLS could predispose to the development of non-rheumatic joint disease (non-RA). Primary fibroblast cell lines were generated from synovial and skin tissue from ten rheumatoid arthritis (RA) and ten non-RA patients. Cell lines were pulse labeled with [(35)S]-methionine and stimulated with TNFalpha or IL-1beta. Protein synthesis of IL-1beta, IL-6 and IL-8 was quantitated following immunoprecipitation. Gene expression was determined by Northern blot analysis. We noted, IL-1beta was minimally detected in FLS under nonstimulated conditions. In response to stimulation with IL-1beta or TNFalpha, production of IL-1beta was found to be 3.5 and 5-fold lower in FLS, respectively, when compared to DF from the same individual. In contrast, the production of IL-6 and IL-8 in FLS upon stimulation was 3-fold and 1.6-fold higher, respectively, than in DF. Furthermore, induced IL-1beta production in FLS, normalized relative to their, respectively, stimulated DF, was 2.5 times higher in non-RA versus RA-derived cells (p=0.032), an effect noted even after several passages of growth. Our data suggest that inductive expression of IL-1beta in FLS is under specific inhibitory control. Increased production of IL-1beta in FLS of susceptible individuals may lead to a higher risk of developing severe joint damage even in the absence of systemic inflammation.
17062431 A randomized, controlled study of a single intra-articular injection of etanercept or gluc 2006 Sep OBJECTIVE: Glucocorticosteroids are used successfully for both systemic and intra-articular treatment of arthritis. Inhibitors of tumour necrosis factor alpha (TNF-alpha) are effective when administered systemically and this study was performed to compare the effect of intra-articular injection of these two substances. DESIGN: A randomized, parallel-group, double-blind study with an independent observer. Thirty-eight patients with flare of arthritis in a single joint (wrist, elbow, or knee) were given intra-articular 25 mg etanercept or 40 mg methylprednisolone guided by ultrasound. The primary end-point was the 4-week change in pain in the target joint. The study complied with Good Clinical Practice (GCP) and the Consolidated Standards for Reporting of Trials (CONSORT) statement. RESULTS: At 4 weeks no difference in pain outcome between treatment groups was demonstrated by analysis of covariance (ANCOVA). Pain on the Visual Analogue Scale (VAS) for etanercept was baseline mean 40.9 (SD 19.6) mm, follow-up 32.7 (29.1) mm (p = 0.29), methylprednisolone baseline mean 47.1 (29.6) mm, follow-up 25.3 (24.7) mm (p<0.001). The investigator's evaluation was for etanercept baseline 30.6 (21.2) mm, follow-up 17.1 (15.5) mm (p = 0.054) and for methylprednisolone baseline 35.4 (26.4) mm, follow-up 11.9 (14.6) mm (p = 0.012). Joint swelling was for etanercept baseline 1.78 (0.73), follow-up 1.25 (0.77) (p = 0.015) and for methylprednisolone baseline 1.74 (0.73), follow-up 0.71 (0.77) (p<0.001). One serious adverse event was seen in a patient treated with methylprednisolone injection. CONCLUSION: Although no difference between groups was demonstrated, the within-group effect of methylprednisolone was more marked than that of etanercept. Injections with 25 mg etanercept were well tolerated. However, the cost of etanercept will presumably limit its use to patients with adverse reactions to steroid.
18056393 Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and de 2007 Dec 15 T lymphocytes expressing the chemokine receptors, CCR2, CCR5, CXCR3, and CXCR6 are increased in inflamed tissues in rheumatoid arthritis. The role of CXCR3 in autoimmune arthritis induced in Lewis rats was investigated. CXCR3+ T cells migrated 2- to 3-fold more than CXCR3- T cells to inflamed joints in arthritic animals. CXCR3-expressing in vivo Ag-activated T lymphoblasts and in vitro-activated lymph node cells from arthritic animals were strongly recruited to the arthritic joints, and treatment with anti-CXCR3 mAb significantly inhibited this T cell recruitment by 40-60%. Immune T cells from the spleen and lymph nodes of actively immunized arthritic donors adoptively transferred arthritis to naive rats. Treatment with anti-CXCR3 mAb delayed the onset of arthritis and significantly reduced the severity of joint inflammation with a >50% decrease in the clinical arthritis score. Blockade of CXCR3 also significantly reduced the weight loss in the arthritic animals and inhibited neutrophil accumulation in the joints by 50-60%. There was a marked reduction in the leukocyte infiltration of the synovium in the presence of CXCR3 blockade and a decrease in the loss of articular cartilage of the joints. In conclusion, CXCR3 on T cells has an essential role in T cell recruitment to inflamed joints and the development of joint inflammation in adjuvant arthritis.
18774002 C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus e 2008 Sep 15 Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.
16759146 Immunosuppressive activity of deer antler extracts of Cervus korean TEMMINCK var. mantchur 2006 Mar Unossified horn or pilose antler cut from deer, which belong to the Cervidae generally is termed Nokyong. Nokyong is one of the most famous Korean traditional medicines and has been considered to possess sexual-reinforcing and antiaging actions. In this study, water extract of deer antler extract (DAA) prepared from the growing antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe was used to investigate the efficacy of the DAA on the development of type II collagen (CII)-induced arthritis (CIA) in rats. Male rats were immunized with an emulsion of 200 microg of CII and complete Freund's adjuvant (CFA). The rats then were administered by injection a suspension of DAA or phosphate-buffered saline. The effect of DAA on cellular responses to CII was examined. The injection of DAA suppressed the CII-specific secretion of interferon (IFN)-gamma from splenocytes ex vivo. The influence of DAA also was evaluated on the incidence and development of arthritis in rat CIA. Rats were immunized twice at a 3-wk interval with bovine CII, with DAA being given by injection once a d for 14 d with four different regimens. A 14-d course of DAA treatment at a daily dose of 100 microg/kg, which began on the d of the first CII immunization, suppressed the development of arthritis, as well as antibody formation and delayed-type hypersensitivity to CII. Treatment with DAA resulted in inhibition of development of arthritis and immune responses to CII.
18457983 Auto-antibodies do not influence development of atherosclerotic plaques in rheumatoid arth 2008 Jul BACKGROUND: Many questions remain unanswered about premature atherosclerosis in rheumatoid arthritis (RA). Besides inflammation, some studies have suggested the role of autoantibodies on its pathogenesis. OBJECTIVE: The aim of this study was to investigate the presence of antibodies against phospholipids, beta2-glycoprotein1 (beta2-gp1), lipoprotein lipase, and heat shock proteins (Hsp) in RA patients and to evaluate their possible association with subclinical carotid atherosclerosis. METHODS: Seventy-one RA patients and 53 age- and sex-matched controls were selected to perform anticardiolipin antibodies (aCL) (IgG and IgM), anti-beta2-gp1 (IgG, IgM, and IgA), anti-lipoprotein lipase (anti-LPL), anti-Hsp 60, and anti-Hsp 65 by ELISA tests. Intima-medial thickness (IMT) of common carotid and presence of plaques were assessed by high-resolution B-mode ultrasonography. Exclusion criteria were smoking, diabetes, and arterial hypertension. Lipoproteins, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fibrinogen levels, as well as health assessment questionnaire (HAQ) and disease activity score (DAS) 28 were also evaluated. RESULTS: Age (48.93+/-12.31 vs. 45.37+/-9.37 years; p=0.20) and body mass index (BMI) (p=0.69) were similar in RA and controls, as well as female gender (p=0.56). The mean IMT was similar between RA and controls (0.721+/-0.16 vs. 0.667+/-0.14 mm, p=0.07) but the frequency of plaques was higher in RA (14.1% vs. 1.9%; p=0.02). In RA patients, IMT measurements did not differ according to the presence or absence of these antibodies: IgG aCL (0.62+/-0.64 vs. 0.72+/-0.17 mm, p=0.24), IgM aCL (0.65+/-0.79 vs. 0.73+/-0.17 mm, p=0.33), anti-Hsp 60 (0.78+/-0.20 vs. 0.71+/-0.16 mm, p=0.27), anti-Hsp 65 (0.73+/-0.16 vs. 0.72+/-0.17 mm, p=0.77), IgG anti-beta2-gp1 (0.73+/-0.16 vs. 0.71+/-0.17 mm, p=0.72), and anti-CCP (0.71+/-0.16 vs. 0.76+/-0.20mm, p=0.36). In addition, IMT did not correlate with antibodies titers: IgG aCL (r=-0.09, p=0.47), IgM aCL (r=-0.15, p=0.21), anti-Hsp 60 (r=0.10, p=0.42), anti-Hsp 65 (r=0.05, p=0.69), IgG anti-beta2-gp1 (r=-0.07, p=0.57), IgM anti-beta2-gp1 (r=-0.05, p=0.69), IgA anti-beta2-gp1 (r=0.03, p=0.79), and anti-CCP (r=-0.07, p=0.57). RA patients with plaques had a significantly higher age compared to those without plaques (p=0.001), as well as higher mean IMT (p<0.001), total cholesterol (p=0.001), and LDL (p=0.003). CONCLUSIONS: In RA a clear association between all autoantibodies studied herein and increased IMT or presence of plaques was not observed. The great prevalence of carotid atherosclerosis in RA was related to age, total and LDL cholesterol, as identified in normal population.
16729724 Belimumab Human Genome Sciences/Cambridge Antibody Technology/GlaxoSmithKline. 2006 May Belimumab, the lead in a series of human monoclonal antibodies against the human protein B-lymphocyte stimulator (BLyS), is under development by Human Genome Sciences, Cambridge Antibody Technology and GlaxoSmithKline for the potential treatment of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). By January 2006, belimumab had completed phase II clinical trials in SLE and RA; a phase III clinical SLE trial is scheduled to begin later this year.
17466926 Expression of angiopoietin-1 in osteoblasts and its inhibition by tumor necrosis factor-al 2007 May Angiogenesis is a crucial component of bone remodeling under both normal and pathophysiological conditions. Among the various mediators that regulate the angiogenic process is the angiopoietin (Ang) family of growth factors. Ang-1 stabilizes new blood vessels by recruiting surrounding mesenchymal cells and promoting their differentiation into vascular smooth muscle cells, whereas Ang-2 is a natural antagonist of Ang-1 and can inhibit angiogenesis. The expression of Ang-1 and Ang-2 in human osteoblasts (hOBs) isolated from rheumatoid arthritis (RA) and osteoarthritis (OA) patients and from healthy individuals has been examined. After incubation in the presence or absence of tumor necrosis factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma), the culture supernatants were assayed for Ang using an enzyme-linked immunosorbent assay. In addition, expression of Ang protein and mRNA was examined using immunohistochemical techniques and quantitative real-time polymerase chain reaction, respectively. It was found that hOBs expressed Ang-1 but not Ang-2 protein, and cultured hOBs from RA and OA patients and from healthy individuals all spontaneously secreted significant amounts of Ang-1 in the absence of any stimulation. Although stimulation with TNF-alpha or IFN-gamma had little or no effect on Ang-1 secretion, costimulation with IFN-gamma plus TNF-alpha dose- and time-dependently diminished secretion of Ang-1 from hOBs. This inhibitory effect was mediated in part by nuclear factor-kappa B via upregulated expression of inducible nitric oxide synthase and enhanced synthesis of nitric oxide. Taken together, these findings suggest that OBs are an important cellular source of Ang-1 and may modulate bone remodeling through regulation of angiogenesis.
17929855 Profiling of endogenous peptides in human synovial fluid by NanoLC-MS: method validation a 2007 Nov Synovial fluid potentially contains markers for early diagnosis and disease progression in degenerative joint diseases such as osteoarthritis. Here, a method is described for profiling endogenous peptides in human synovial fluid, using ultrafiltration, solid-phase extraction, nanoscale liquid chromatography, and high-resolution mass spectrometry. Synovial fluid is characterized by its high viscosity, caused by the presence of the lubricant hyaluronic acid. The method proved to be capable of eliminating the high concentrations of hyaluronic acid, which appeared to be necessary to obtain satisfactory analytical performance, that is, within-day relative standard deviations of 5-15%, between-day relative standard deviations of 6-16%, a linear response of R2=0.994, a limit of detection in the femtomole range, and reproducible recoveries of 14-67%. With the developed method, in a synovial fluid sample from an osteoarthritis patient and a healthy control, in total, 501 peptides originating from 40 proteins were identified. Peptide cleavage products from six proteins that have been associated with osteoarthritis in earlier studies (collagen II, proteoglcycan 4, serum amyloid A, tubulin, vimentin, and Matrix Gla) could also be identified with our profiling method. The robustness of the method indicates that it can be applied in systems biology approaches for further studies on degenerative joint disease, eventually leading to a better understanding of the disease and its therapy, as well as the development of novel biomarkers to monitor these processes.
17357801 Massive myelinolytic leukoencephalopathy in a patient medicated with low-dose oral methotr 2007 Oct The authors describe a 68-year-old female who developed a rapidly progressing leukoencephalopathy involving the cerebrum and brain stem. The disease appeared during low-dose oral methotrexate (MTX) therapy for rheumatoid arthritis. An extensive clinical investigation discounted other possible causes of white matter lesions. Autopsy identified an uninterrupted severe demyelinating, partially liquefactive necrosis-like lesion in the white matter accompanied by astrogliosis and occasional swollen axons therein. The lesion was generally symmetrical, and distributed throughout the whole cerebral white matter except for the bilateral temporal lobes and the rostral part of the frontal lobes. The internal capsules and cerebral peduncles were spongy, and the central and lateral parts of the pons, especially the transverse cerebellopontine tracts, were affected similarly. It was of note that the lesion was accompanied by neither vascular diseases nor lymphocyte infiltration. Thus, the pathological findings were similar to those of a severe form of central and extrapontine myelinolysis, and clearly different from ordinary MTX leukoencephalopathy reported in patients receiving intrathecal or intravenous MTX therapy, known as "disseminated necrotizing leukoencephalopathy". Another possibility is that synergistic effects of several white-matter-damaging disorders may have contributed to the hitherto unknown lesion. To our knowledge, this is the first autopsy record that describes an oral MTX-associated neurological disorder.
19013427 Adiponectin stimulates IL-8 production by rheumatoid synovial fibroblasts. 2009 Jan 9 The adipokines are linked not only to metabolic regulation, but also to immune responses. Adiponectin, but not leptin or resistin induced interleukin-8 production from rheumatoid synovial fibroblasts (RSF). The culture supernatant of RSF treated with adiponectin induced chemotaxis, although adiponectin itself had no such effect. Addition of antibody against adiponectin, and inhibition of adiponectin receptor gene decreased adiponectin-induced IL-8 production. Nuclear translocation of nuclear factor-kappa B was increased by adiponectin. The induction of interleukin-8 was inhibited by mitogen-activated protein kinase inhibitors. These findings suggest that adiponectin contributes to the pathogenesis of rheumatoid arthritis.
18037120 Scleritis and peripheral ulcerative keratitis. 2007 Nov Scleritis and peripheral ulcerative keratitis (PUK) can present as isolated conditions or as part of a systemic inflammatory or infectious disorder. Both are serious ocular conditions that can result in vision loss and require early diagnosis and treatment. Nearly two thirds of patients with non-infectious scleritis require systemic glucocorticoid therapy and one fourth need a glucocorticoid-sparing agent as well. Essentially all patients with non-infectious PUK require systemic glucocorticoids. A detailed clinical history, thorough physical examination, and thoughtful laboratory evaluations are important in the exclusion of underlying disorders and extraocular involvement.
17015746 Serum amyloid A binding to formyl peptide receptor-like 1 induces synovial hyperplasia and 2006 Oct 15 Serum amyloid A (SAA) is a major acute-phase reactant, and has been demonstrated to mediate proinflammatory cellular responses. Although SAA has been used as an indicator for a variety of inflammatory diseases, the role of SAA in synovial hyperplasia and proliferation of endothelial cells, a pathological hallmark of rheumatoid arthritis (RA), has yet to be elucidated. In this study, we have demonstrated that SAA promotes the proliferation of human fibroblast-like synoviocytes (FLS). In addition, SAA protects RA FLS against the apoptotic death induced by serum starvation, anti-Fas IgM, and sodium nitroprusside. The activity of SAA appears to be mediated by the formyl peptide receptor-like 1 (FPRL1) receptor, as it was mimicked by the WKYMVm peptide, a specific ligand for FPRL1, but completely abrogated by down-regulating the FPRL1 transcripts with short interfering RNA. The effect of SAA on FLS hyperplasia was shown to be caused by an increase in the levels of intracellular calcium, as well as the activation of ERK and Akt, which resulted in an elevation in the expression of cyclin D1 and Bcl-2. Moreover, SAA stimulated the proliferation, migration, and tube formation of endothelial cells in vitro, and enhanced the sprouting activity of endothelial cells ex vivo and neovascularization in vivo. These observations indicate that the binding of SAA to FPRL1 may contribute to the destruction of bone and cartilage via the promotion of synoviocyte hyperplasia and angiogenesis, thus providing a potential target for the control of RA.
18478202 Cutting errors in total knee replacement: assessment by computer assisted surgery. 2008 Jul The observed errors in the position of the implanted prosthesis can be due to a number of potential causes. One of these is the potential error during execution of the bone cuts. However, there is only minimal information on this in the current literature. The amount of cutting errors in 40 consecutive total knee replacements was reported. All the operations were done by the same surgeon. The amount of cutting error was measured by the use of computer navigation system. It was hypothesized that there was no difference in the amount of error between bone cut through the cutting slot (slotted cutting) and bone cut done on the surface of the cutting guide (open cutting). It was found that the average absolute cutting error was 1 masculine in the coronal plane and 1.4 masculine in the sagittal plane. Significantly more outlier (more than 3 masculine) was observed in the errors in the sagittal plane (P = 0.014, chi square test). Open cutting resulted in less error in the sagittal plane of the tibial cut when compared with slotted cutting (P = 0.031, Mann-Whitney U Test). This was attributed by the use of a thicker saw blade with higher stiffness in the open cutting method.
17159170 Should we reconsider all-polyethylene tibial implants in total knee replacement? 2006 Dec The role of modular tibial implants in total knee replacement is not fully defined. We performed a prospective randomised controlled clinical trial using radiostereophotogrammetric analysis to compare the performance of an all-polyethylene tibia with a metal-backed cruciate-retaining condylar design, PFC-Sigma total knee replacement for up to 24 months. There were 51 patients who were randomised into two treatment groups. There were 10 subsequent withdrawals, leaving 21 all-polyethylene and 20 metal-backed tibial implants. No patient was lost to follow-up. There were no significant demographic differences between the groups. At two years one metal-backed implant showed migration > 1 mm, but no polyethylene implant reached this level. There was a significant increase in the SF-12 and Oxford knee scores after operation in both groups. In an uncomplicated primary total knee replacement the all-polyethylene PFC-Sigma tibial prosthesis showed no statistical difference in migration from that of the metal-backed counterpart. There was no difference in the clinical results as assessed by the SF-12, the Oxford knee score, alignment or range of movement at 24 months, although these assessment measures were not statistically powered in this study.
17322962 Administration of infliximab in general practitioners' offices is safe. 2007 Nov Infliximab is used in the treatment of various diseases, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PA), Crohn's disease (CD) and ankylosing spondylitis (AS). In most countries, infliximab is given in hospitals or infusion centers, which are experienced in the management of infusion reactions. Because of this side effect, general practitioners (GPs) might refuse to administer infliximab in their offices. The aim of this study was to investigate the safety of infliximab administration in GPs' offices. Health system in the provincial state of Upper Austria (Austria) provides reimbursement of biological treatment only in outpatient care. Infliximab is due to cost effectiveness usually administered by GPs after a specific training and initialisation of treatment by specialists in the hospital. We sent out a form to 42 cooperating GPs, containing 20 questions concerning the administration of infliximab. Thirty-four forms were returned and evaluated. Altogether, 69 patients (2 patients per doctor mean) were treated with infliximab (1-42 months; 21 months mean). The overall observation period was 697 patients-months. During this period, 487 infusions (14.5 infusions per doctor mean) were administered. From five doctors, seven adverse events (AE) in six patients were reported. In all seven cases, infusion was discontinued; two had allergic reactions and five had nausea or cardiac symptoms, not definitely of allergic origin. Severe adverse events (SAE), defined as shock, emergency treatment or hospitalisation during or after infliximab administration were reported by two doctors. In contrast, SAE during the infusion of other drugs (e.g. analgetics, vitamins) were previously seen by 16 doctors, showing the overall possibility of infusion reactions with commonly prescribed drugs. Almost all (31/34) confirmed the overall safety of infliximab administration in GP's patient care. The administration of infliximab by specially trained general practitioners with background guidance through rheumatologist or gastroenterologist centers seems to be a safe and acceptable way to provide long-term treatment with infliximab to patients in need of biological treatment.
18675956 Anergic cells generated by blocking CD28 and CD40 costimulatory pathways in vitro ameliora 2008 Collagen type II induced arthritis is an experimental model for studying the pathological mechanisms of therapeutic agents for human rheumatoid arthritis. In this study, we have investigated the effects of anergic cells on the development and disease progression of CIA. Anergic cells inhibited the proliferative response to collagen II primed lymphocytes, whereas the supernatant from anergic cell culture had no suppressive effect. Administration of anergic cells reduced the clinical score of CIA and ameliorated the development of CIA. The messenger RNA levels of IL-2 and IFN-gamma were significantly decreased, whereas mRNA levels of IL-4, IL-10 and TGF-beta showed no significant differences. A decrease in the collagen-specific Th1 associated IgG(2a) response was observed, whereas IgG(1) was unaffected. This effective treatment is associated with a reduction in IFN-gamma production and through cell-cell contact. Our results suggest that anergic cells may be beneficial for the treatment of rheumatoid arthritis.
17559674 Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synov 2007 c-Jun N-terminal kinase (JNK) contributes to metalloproteinase (MMP) gene expression and joint destruction in inflammatory arthritis. It is phosphorylated by at least two upstream kinases, the mitogen-activated protein kinase kinases (MEK) MKK4 and MKK7, which are, in turn, phosphorylated by MEK kinases (MEKKs). However, the MEKKs that are most relevant to JNK activation in synoviocytes have not been determined. These studies were designed to assess the hierarchy of upstream MEKKs, MEKK1, MEKK2, MEKK3, and transforming growth factor-beta activated kinase (TAK)1, in rheumatoid arthritis (RA). Using either small interfering RNA (siRNA) knockdown or knockout fibroblast-like synoviocytes (FLSs), MEKK1, MEKK2, or MEKK3 deficiency (either alone or in combination) had no effect on IL-1beta-stimulated phospho-JNK (P-JNK) induction or MMP expression. However, TAK1 deficiency significantly decreased P-JNK, P-MKK4 and P-MKK7 induction compared with scrambled control. TAK1 knockdown did not affect p38 activation. Kinase assays showed that TAK1 siRNA significantly suppressed JNK kinase function. In addition, MKK4 and MKK7 kinase activity were significantly decreased in TAK1 deficient FLSs. Electrophoretic mobility shift assays demonstrated a significant decrease in IL-1beta induced AP-1 activation due to TAK1 knockdown. Quantitative PCR showed that TAK1 deficiency significantly decreased IL-1beta-induced MMP3 gene expression and IL-6 protein expression. These results show that TAK1 is a critical pathway for IL-1beta-induced activation of JNK and JNK-regulated gene expression in FLSs. In contrast to other cell lineages, MEKK1, MEKK2, and MEKK3 did not contribute to JNK phosphorylation in FLSs. The data identify TAK1 as a pivotal upstream kinase and potential therapeutic target to modulate synoviocyte activation in RA.
18632788 Contralateral hyperalgesia and allodynia following intradermal capsaicin injection in man. 2008 Sep OBJECTIVES: Contralateral responses to unilateral stimuli have been well described in animal models. These range from central sensitization to peripheral inflammatory responses. Our aim was to test for contralateral responses following unilateral intradermal capsaicin injection in man. METHODS: Three groups were investigated. A healthy volunteer group (1) was injected with capsaicin into the volar aspect of one forearm. A group of patients with RA (2) was also injected with capsaicin. A control group of healthy volunteers (3) was not injected with capsaicin. All groups were tested for hyperalgesia and allodynia every 10 min for 1 h following the injection using quantitative sensory testing. RESULTS: A total of 9/14 healthy volunteers (Group 1) and 10/14 patients with RA (Group 2) demonstrated contralateral sensitization that subsided within 1 h following intradermal capsaicin injection. A total of 2/23 control subjects (Group 3) demonstrated positive responses with the monofilaments. The frequency of the contralateral responses in the experimental groups compared with the control group is significant (P < 0.05). The peak hyperalgesia was relatively delayed contralaterally compared with the ipsilateral side (35 min vs 15 min). The area of sensitization, where present, was reduced compared with the ipsilateral side (5-50%). CONCLUSIONS: This is the first demonstration of a contralateral response following a unilateral stimulus in man. Bilateral neural pathways mediating contralateral responses may have a role in the pathophysiology of chronically painful or inflammatory diseases and a confounding influence on using the contralateral limb as a control experimentally. We did not find that a systemic inflammatory disease sensitized for this phenomenon.
17106667 [High-field and ultrahigh-field magnetic resonance imaging: new possibilities for imaging 2006 Dec Whole-body MR tomography at 3 T is moving steadily from research into routine clinical practice. The most important advantage of high-field MRI is the higher signal to noise ratio, which allows acquisitions in the musculo-skeletal system with higher resolution within the same scan time. The imaging of small joints, the visualization of labral anatomy and pathology in the shoulder and hip joints, as well as cartilage imaging will benefit from higher resolution protocols. In addition to improved morphological imaging of articular cartilage, the higher sensitivity of 3 T allows the clinical use of advanced MR techniques of cartilage such as T1 and T2 mapping, diffusion and sodium imaging. The improved spectral resolution with the higher field may improve metabolic imaging of tumors of the skeleton and soft tissues.