Browse

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

ID PMID Title PublicationDate abstract
11685652 Synovial cells from a patient with rheumatoid arthritis produce osteoclastogenesis inhibit 2001 To understand the involvement of osteoclastogenesis inhibitory factor (OCIF), also called osteoprotegerin (OPG), in the pathogenesis of bone destruction in rheumatoid arthritis (RA), we investigated the cytokine network involved in the production of OCIF by human fibroblast-like synovial (HFLS) cells from a patient with RA. Inflammatory cytokines, such as interleukin (IL)-1beta, IL-6 plus soluble IL-6 receptor (sIL-6R), IL-17, and tumor necrosis factor (TNF)-alpha, which are elevated in synovial fluid in RA, upregulated the production of OCIF to a level (5-20 ng/ml) sufficient to inhibit osteoclastogenesis in vitro. These inflammatory cytokines (except for IL-6 plus sIL-6R) stimulate OCIF production directly or indirectly through stimulation of prostaglandin E2 (PGE2) synthesis. In contrast to the findings with inflammatory cytokines, basic fibroblast growth factor (bFGF) inhibited the production of OCIF by the cells in a dose-dependent manner. While bFGF enhanced both the inflammatory cytokine-mediated release of PGE2 and the PGE2-mediated OCIF production, it significantly suppressed OCIF production by negating the direct stimulatory effect of the inflammatory cytokines. These findings suggest that bFGF in the synovial fluid of patients with RA may lead to severe joint destruction by suppressing the production of OCIF by HFLS cells.
10229397 Local expression of acute phase serum amyloid A mRNA in rheumatoid arthritis synovial tiss 1999 Apr OBJECTIVE: Serum amyloid A (SAA) protein, a bioactive protein produced during inflammation, is present in synovial fluid (SF) of patients with rheumatoid arthritis (RA). Based on our recent finding that SF SAA concentration exceeded the serum counterpart in some patients with RA, we examined the local steady state concentration of SAA mRNA isoforms in synovia and in synovial cells cultured from patients with RA and osteoarthritis (OA). METHODS: Total cellular RNA from synovial membranes of patients with RA or OA and from cultured synovial cells of patients with RA was analyzed by reverse transcription polymerase chain reaction and Northern blot. RESULTS: Acute phase SAA (A-SAA) mRNA isoforms were detected only in RA synovia, but not in OA synovia; however, the constitutive SAA (C-SAA) mRNA isoform was detected in similar abundance in both OA and RA synovia. There was evidence of C-SAA, but not A-SAA mRNA in cultured synovial cells at quiescence. After stimulation with both 1 mM dexamethasone and 10 ng/ml interleukin 1beta (IL-1beta), the quantity of steady state A-SAA muRNA in cultured synovial cells was markedly increased. CONCLUSION: Both A-SAA and C-SAA mRNA are detectable in RA synovia, while only C-SAA mRNA is detectable in OA and in quiescent cultured synovial cells. The steady state A-SAA mRNA isoform in cultured synovial cells was markedly increased in the presence of dexamethasone plus IL-1beta. The local synthesis of A-SAA may contribute, at least in part, to the concentration of A-SAA protein in SF and may contribute to the altered molecular and cellular physiology in RA joints.
9330926 Alternatively spliced CS-1 fibronectin isoform and its receptor VLA-4 in rheumatoid arthri 1997 Oct OBJECTIVE: Extracellular matrix components and cell adhesion molecules play a role in the pathogenesis of rheumatoid arthritis (RA). Interaction between the integrin very late antigen-4 (VLA-4) and the connecting segment-1 (CS-1) fibronectin (FN) isoform may contribute to lymphocyte interaction in RA synovium. We examined both mRNA and protein expression of CS-1 FN in inflamed synovium, and VLA-4 expression in synovial tissue and on cultured fibroblast-like synoviocytes from patients with RA. METHODS: Snap frozen synovial tissue specimens of 10 patients with RA and 4 patients with osteoarthritis were examined for expression of CS-1 FN mRNA and protein by in situ hybridization and immunohistochemistry. VLA-4 expression of synovial fibroblasts and in synovial tissue was evaluated by flow cytometry and immunohistochemistry. RESULTS: CS-1 FN mRNA was detected in RA lining layer synoviocytes, around terminal vessels, and in endothelial cells. Double labeling revealed that most lining synoviocytes expressing CS-1 FN mRNA were CD68 negative. VLA-4 was found in RA synovial fibroblasts, sublining mononuclear cells, and lymphoid aggregates. CONCLUSION: Our findings suggest that expression of CS-1 FN may partially correlate with cell proliferation in the RA lining layer. VLA-4 was found in RA synovial lining, as well as on cultured synovial fibroblasts. Thus, VLA-4/CS-1 FN interaction may facilitate lymphocyte interaction and synovial proliferation in RA.
10880734 Synthetic peptides that inhibit binding of the collagen type II 261-273 epitope to rheumat 2000 Jul Copolymer 1 [Cop 1, poly (Y, E, A, K)] is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS), a disease that is linked to HLA-DR2 (DRB1*1501). Another copolymer [poly (Y, A, K)] was also identified that binds to rheumatoid arthritis (RA)-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules and inhibits the response of HLA-DR1- and -DR4-restricted T cell clones to an immunodominant epitope of collagen type II (CII) 261-273 (a candidate autoantigen in RA). In the present study various peptides have been synthesized based on binding "motifs" of Cop 1 for HLA-DR1 and -DR4 molecules. Those peptides with K at P-1 or K at P8 were particularly effective as inhibitors of binding of CII 261-273, of Cop 1 and of the influenza virus hemagglutinin peptide 306-318 to these class II proteins. Moreover, several of them were also potent inhibitors of the CII 261-273-reactive T cell clones. These findings suggest that small peptides or their more stable derivatives may be able to substitute for copolymers in the treatment of RA, and by implication of MS.
9263142 Elevated levels of inflammatory cytokines in bone marrow of patients with rheumatoid arthr 1997 Aug OBJECTIVE: Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) play an important role in decreased erythropoiesis in patients with anemia of chronic disease (ACD) and rheumatoid arthritis (RA). Modulation of quantities of bone marrow erythroid progenitors during chronic inflammation may be one of the pathogenetic mechanisms leading to ACD. We studied bone marrow from patients with ACD with RA by investigating, first, local production of inflammatory cytokines in the bone marrow, and second, the relative fraction of late erythroid progenitors (erythropoietin and transferrin receptor positive cells; EpoR+ TrfR+) in bone marrow. In addition, the effects of TNF-alpha on EpoR+ TrfR+ cells were studied in vitro. METHODS: Levels of IL-6 and TNF-alpha were measured by EL ELISA in supernatant of bone marrow and peripheral blood cultures from 14 patients with RA and ACD and 14 patients with RA without anemia. The numbers of EpoR+ TrfR+ cells in bone marrow samples of both groups were assessed by 2 color fluorescence flow cytometry. RESULTS: Levels of IL-6 and TNF-alpha were significantly higher in the supernatant of bone marrow cultures of patients with ACD compared to controls. No significant differences in the fraction of EpoR+ TrfR+ cells in samples was observed between the 2 groups of patients. Incubation of the samples with TNF-alpha did not result in modulation of the number of EpoR+ TrfR+ cells. CONCLUSION: Local production of proinflammatory cytokines in the bone marrow may be associated with the development of ACD in RA.
9855320 The pharmacokinetics and pharmacodynamics of fludarabine in rheumatoid arthritis. 1998 Nov STUDY OBJECTIVE: To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA). DESIGN: Open-label, staggered trial conducted in conjunction with a phase I-II clinical trial. SETTING: Government research hospital. PATIENTS: Twenty-six patients with refractory RA. INTERVENTION: Fludarabine 20 or 30 mg/m2/day was administered as a 0.5-hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo). MEASUREMENTS AND MAIN RESULTS: Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two-compartment model. There were no differences in pharmacokinetics between the low- and high-dose groups. The mean+/-SD total clearance, volume of distribution at steady state, and beta-half-life were 13.68+/-5.1 L/hour, 170.08+/-86.5 L, and 10.9+/-3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters. CONCLUSION: Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate-length distribution phase (approximately 40 min), terminal half-life of 10.9 hours, and significant amount of tissue distribution.
12167886 Treatment of an edentulous patient with a dry mouth. 2000 Aug 15 Dental health professionals are being asked to care for a growing number and range of medically compromised patients living with chronic health problems. Although tooth loss overall has declined in the United States, millions of persons, particularly those of more advanced age, still require treatment for the edentulous condition. Particular challenges are faced when this oral state is combined with a complex medical history. The primary learning objective for this case is to increase your general knowledge of and skills in the dental management of the complete denture patient with a dry mouth.
9038498 Pathological anatomy and dynamic effect of the displaced plantar plate and the importance 1997 Jan Normal and deformed forefeet have been investigated by cadaver anatomical dissections and experiments, by radiographs, CT and MRI scanning, and by clinical studies. Evidence is presented to show that the skeleton of the foot rests on and is controlled by a multi-segmental ligamentous and fascial tie-bar system. Transversely across the plantar aspect of the forefoot, the plantar plates and the deep transverse metatarsal ligaments form a strong ligamentous structure which prevents undue splaying of the forefoot. Longitudinally, the five digital processes of the deeper layer of the plantar fascia are inserted into the plantar plates and control the longitudinal arch of the foot. It is suggested that many forefoot deformities result from the failure of parts of the tie-bar system and the dynamic effect of displacement of the plantar plates. Understanding this allows a more logical approach to their treatment.
10554105 A pharmacokinetic model for tenidap in normal volunteers and rheumatoid arthritis patients 1999 Oct PURPOSE: To develop a pharmacokinetic model for tenidap and to identify important relationships between the pharmacokinetic parameters and available covariates. METHODS: Plasma concentration data from several phase I and phase II studies were used to develop a pharmacokinetic model for tenidap, a novel anti-rheumatic drug. An appropriate pharmacokinetic model was selected on the basis of individual nonlinear regression analyses and an EM algorithm was used to perform a nonlinear mixed-effects analysis. Scatter plots of posterior individual pharmacokinetic parameters were used to identify possible covariate effects. RESULTS: Predicted responses were in good agreement with the observed data. A bi-exponential model with zero order absorption was subsequently used to develop the mixed-effects model. Covariate relationships selected on the basis of differences in the objective function, although statistically significant, were not particularly strong. CONCLUSIONS: The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.
11053080 Targeting interleukin 18 with interleukin 18 binding protein. 2000 Nov A novel, constitutively expressed and secreted interleukin 18 (IL18) binding protein (IL18BP) neutralises IL18. IL18BP shares many characteristics with soluble cytokine receptors of the IL1 family in that the protein exhibits specificity for IL18, belongs to the immunoglobulin-like class of receptors and has limited amino acid sequences with those of the IL1 receptor type II. However, unlike soluble cytokine receptors, IL18BP does not have a transmembrane domain and hence is not anchored to the cell membrane. IL18BP is a secreted protein and not cleaved from the cell surface. IL18BP is naturally occurring and was isolated from the urine of healthy subjects. Because IL18 is an important inducer of interferon gamma (IFNgamma), IL18BP suppresses the production of IFNgamma resulting in reduced T-helper type 1 immune responses. There are four human and two mouse isoforms-resulting from mRNA splicing and found in various cDNA libraries. Each of these IL18BP isoforms have been expressed, purified and assessed for binding and neutralisation of IL18 biological activities. Two human IL18BP isoforms exhibited the greatest affinity for IL18 with a rapid on-rate, a slow off-rate and a dissociation constant (kDa) of 399 pM. The two other isoforms with an incomplete immunoglobulin domain were unable to neutralise IL18. The two human isoforms that possess a complete immunoglobulin domain, neutralise >95% IL18 at a molar excess of two. Molecular modelling identified a large mixed electrostatic and hydrophobic binding site in the immunoglobulin domain of IL18BP, which could account for its high affinity binding to the ligand. These high affinity forms may be ideally suited for blocking IL18 in human disease. It is likely that preferential secretion of high affinity functional and non-functional isoforms of IL18BP affect the immune response and the outcome of disease.
11417303 A case of BOOP developed during bucillamine treatment for rheumatoid. 2001 Mar We describe a patient with rheumatoid arthritis(RA) who developed bronchiolitis obliterans organizing pneumonia(BOOP) during the treatment of bucillamine. A 51 year-old man was admitted to the hospital for an abnormal shadow on his chest radiograph. He had been diagnosed as having RA 3 years previously and had been receiving 200 mg of bucillamine for 21 months. Two months prior to admission, he presented with a cough and his chest X-ray showed opacities in both lower lungs. He was treated with antibiotics for 2 months after the development of cough and lesions on the chest X-ray, but the symptoms and lung lesions became more aggravated. On admission, an HRCT revealed airspace consolidations in the subpleural space of both basal lungs and a CT-guided fine needle aspiration biopsy showed Masson's body filling air space, interstitial infiltration of acute and chronic inflammatory cells and type II cell hyperplasia, consistent with BOOP. Bucillamine was stopped and 50 mg of prednisolone was administered. His symptoms and infiltrations on the chest X-ray resolved. We suggest that bucillamine should be considered as a drug possibly associated with BOOP.
9737793 Immunohistochemical localization of metallothionein in synovial tissue of patients with ch 1998 Aug Metallothioneins (MTs) are low-molecular-weight cytosolic proteins, which are thought to participate in metal homeostasis and protection against metal toxicity and oxidative stress. MT synthesis can be induced by a variety of inflammatory mediators and antirheumatic drugs, and high levels of MT have been implicated in resistance of cells to some antirheumatic drugs. We studied the expression and localization of MT in synovial tissue samples from patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or osteoarthritis (OA) by quantitative immunohistochemistry. Immunostaining for MT was detected in a large number of intimal lining cells in most of the investigated synovial tissue samples (75%). In a smaller proportion of samples (42%), some of the fibroblast-like cells of the subsynovial layer were also MT positive. Immunostaining and double-staining experiments with antibodies against monocyte-, macrophage- and leucocyte-associated antigens suggested that most of the MT-positive cells were intimal fibroblast-like cells and subsynovial fibroblasts. However, there were no statistically significant differences in the intensity of staining for MT between the rheumatic diseases and OA at the single-cell level. Thus, MT is expressed in synovial tissue and may participate in homeostatic and protective functions. The interindividual variability in the expression of MT in synovial tissue may be related to the therapeutic efficacy of the gold compounds and chemotherapeutic antirheumatic drugs sequestered by MT.
10769436 Corticosteroid osteoporosis. 2000 Corticosteroids are widely used in the treatment of patients with chronic inflammatory diseases. Since the most rapid bone loss occurs in the first 12-24 months after commencing high dose corticosteroids, it is important to consider two different therapeutic situations, (a) prevention in patients starting corticosteroids and (b) treatment of patients on chronic corticosteroids who will already have some significant degree of corticosteroid related bone loss. An adequate calcium intake is recommended and any contributing factors to osteoporosis should be treated. A bone density will give information about the future risk of osteoporotic fracture and the need for active pharmacological treatment. Patients commencing high dose long-term corticosteroid therapy should be treated prophylactically with a bisphosphonate and/or active vitamin D metabolites (alphacalcidol or calcitriol) and the treatment may need to be continued for 1-2 years. Patients on chronic corticosteroids may improve their bone density by treatment with bisphosphonates and vitamin D metabolites (including the calciferols). In postmenopausal women, concomitant use of estrogen replacement therapy is also appropriate. It is important in a patient on long-term therapy to review the need for continuing treatment or the possibility of dosage reduction.
9470924 Pyoderma gangrenosum: a report of 44 cases with follow-up. 1997 Dec Results of a study of 44 patients with pyoderma gangrenosum (PG) are presented. Each patient was diagnosed using standardized diagnostic criteria and followed up systematically. Thirty patients were women and 14 men. Their mean age was 50 years (range 11-80). Twenty patients had idiopathic and 14 parainflammatory occurrences (e.g. ulcerative colitis, Crohn's disease), whereas in 10 patients an associated haemoproliferative disease or neoplasia was noted. Whereas idiopathic and parainflammatory PG was found predominantly in women, the association with haemoproliferative diseases occurred more often in men. The lower legs and feet represented the typical predilection sites. Fifty-two per cent of patients had one lesion, 37% had up to five, and 11% had more than five lesions. Histologically, lymphocytic and/or leucocytoclastic vasculitis was present in 73% of the biopsy specimens obtained from the borders of the lesions. Long-term follow-up (n = 42, median follow-up 26.5 months) revealed that eight patients had died, in six cases due to the PG and/or the underlying diseases. Of the remaining 34 patients, 44% are in complete remission without further treatment, whereas continuing therapy is needed in 56%. No difference between idiopathic and parainflammatory PG was demonstrable in the follow-up and in no patient with idiopathic PG was a possibly related disease diagnosed in the follow-up. These data suggest that PG should be considered to be an independent disease and not a purely cutaneous complication in most patients.
10193996 The unmet anti-inflammatory needs in orthopedics. 1999 Mar Approximately half of Americans 70 years of age or older suffer from arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most effective nonsurgical therapies for arthritis, but usage often causes harmful side effects, especially in the gastrointestinal tract. Such effects require supplemental therapy that adds an economic burden and may even cause death. The benefits derived from NSAIDs are believed to be due to suppression of cyclooxygenase-2 (COX-2), while the harmful side effects are believed to be due to suppression of cyclooxygenase-1 (COX-1). COX-2-specific inhibitors that do not inhibit COX-1 may meet arthritis sufferers' needs for therapies that are safe, convenient, and as effective as conventional NSAIDs.
10070275 Down regulation by iron of prostaglandin E2 production by human synovial fibroblasts. 1998 Dec OBJECTIVE: To examine the effect of iron on the prostaglandin (PG) E2 production by human synovial fibroblasts in vitro. METHODS: Human synovial fibroblasts were isolated from synovial tissue of rheumatoid arthritis (RA) and osteoarthritis (OA) patients and cultured in medium. Synovial fibroblasts were stimulated by human recombinant interleukin (IL) 1 beta (0.1-10 ng/ml) with or without ferric citrate (Fe-citrate, 0.01-1 mM). The amount of PGE2 in the culture medium was measured by an enzyme linked immunosorbent assay. RESULTS: The production of PGE2 by the synovial fibroblasts was increased by stimulation with IL1 beta at all concentrations tested. Fe-citrate but not sodium citrate (Na-citrate) down regulated the production of PGE2 by the synovial fibroblasts, both with and without stimulation by IL1 beta. Fe-citrate inhibited the spontaneous PGE2 production by the cells in a dose dependent manner, and a maximum inhibition by Fe-citrate was observed at the concentration of 0.1 mM with IL1 beta stimulation. The down regulation by iron was reversed by the co-addition of desferrioxamine (100 micrograms/ml), an iron chelator. CONCLUSION: Iron down regulates the PGE2 production by synovial fibroblasts in vitro.
9562601 Antiproliferative naphthopyrans: biological activity, mechanistic studies and therapeutic 1998 Jun This article will firstly briefly review the newer generation of immunosuppressant drugs, focusing mainly on tacrolimus (FK-506), sirolimus (rapamycin), mycophenolate mofetil (RS-61443) and leflunomide (HWA 486) and then describe work carried out at the Lilly Research Centre on analogues of leflunomide and subsequent diversion into a structurally distinct series of compounds, the naphthopyrans. A clear structure activity relationship exists within this series and selected data from a Concanavalin A stimulated T-cell proliferation assay are presented to illustrate this. Although the compounds proved to possess little in vivo activity in our rheumatoid arthritis program, examination of the compounds in in vitro and in vivo models within the diabetic complications group showed the compounds behaved as would be anticipated for inhibitors of protein kinase C, although this direct mode of action was clearly not correct. Mechanistic investigations revealed that the favoured compound 290181 blocks phorbol 12,13-dibutyrate-induced binding of transcription factor proteins to the PEA3/TRE sequence of the promoter region of the urokinase plasminogen activator gene. The compounds also showed antiproliferative effects on vascular smooth muscle cells, an in vitro activity that translated into in vivo efficacy in a rat model of restenosis. Mechanistic studies here demonstrated that 290181 blocks proliferation in the G2/M phase of the cell cycle by binding directly to a novel site on tubulin. Finally the compounds were shown to inhibit the release of neutral proteases from interleukin-1 stimulated articular chondrocytes, this activity having implications in the degenerative aspects of osteoarthritis.
9500514 The effects of pregnancy on autoimmune diseases. 1998 Mar Internal gestation of a genetically foreign conceptus challenges the maternal host to circumvent immunological processes that recognize and eliminate nonself molecules. Accordingly, human viviparity involves a wide range of immunological modifications. This review examines the relationship between pregnancy and several autoimmune diseases prevalent in women. Pregnancy is associated with improvement in the clinical signs and symptoms of rheumatoid arthritis in more than 70% of patients. Maternal-fetal disparity in alleles of HLA-DRbeta1, DQalpha, and DQbeta has been reported to be associated with pregnancies characterized by remission or improvement. These observations suggest that presentation of fetal DQalpha peptides might correct autoimmunity in patients with RA either by induction of maternal-regulatory T cells, or by affecting the maternal T cell receptor repertoire. In contrast, the course of systemic lupus erythematosus is more variable. Whether flare rates increase during or after pregnancy is unsettled, since individual patient series vary in the characteristics of patients accepted for study and in definitions of flare. Despite a high overall flare rate in some series approaching 60%, recorded flares were usually not severe. Only limited data are available regarding the incidence or outcome for either the mother with scleroderma or her fetus. The extent of diffuse skin disease and systemic involvement, particularly pulmonary, cardiac and renal, may be more important than the duration of the disease; limited disease carries a better prognosis for the mother and fetus. Highly specific autoantibody profiles in the mother (independent of whether she has a clinical disease) are associated with fetal demise and neonatal lupus syndromes, the most serious manifestation of which is isolated congenital heart block. The former is associated with antiphospholipid antibodies and the latter with antibodies directed against SSA/Ro and SSB/La polypeptides.
11352772 Urocortin in the synovial tissue of patients with rheumatoid arthritis. 2001 Jun Urocortin is a newly identified member of the corticotropin-releasing factor (CRF) neuropeptide family, and is known to be involved in the modulation of the inflammatory process. We examined the expression of urocortin, CRF and their receptors (CRF receptor; CRF-R) in the synovial tissue of patients with rheumatoid arthritis (RA) in order to study the possible biological roles of urocortin. Synovial tissues/fluids were obtained from 38 patients with RA, nine patients with osteoarthritis and four with trauma. We studied the concentration of urocortin in the synovial fluid using RIA, and the expression of urocortin in synovial tissue using immunohistochemistry, mRNA in situ hybridization and reverse transcriptase-PCR (RT-PCR). In addition, we examined the immunolocalization of CRF and the expression of CRF-R1, -R2-alpha and -R2-beta mRNAs utilizing RT-PCR in these synovial tissues. Urocortin concentrations in synovial fluid were higher in RA patients (79.8+/-154 pg/ml) than in control patients (12.3+/-4.8 pg/ml; P< or =0.05). Urocortin immunoreactivity and mRNA signals were both detected in synovial cells, lymphocytes, fibroblasts and macrophages. The number of urocortin-positive cells in the synovium was significantly higher in RA (73.1+/-32.1 cells per high-power field) than in control (18.4+/-10.4 cells per high-power field) patients. In addition, both urocortin immunoreactivity and mRNA signals in the synovium reached maximum levels in the active stage of RA inflammation. Moreover, the number of immunoreactive urocortin-positive cells was significantly correlated with the urocortin concentration in synovial fluid (r=0.705; P<0.001) and with histologically defined local inflammatory activity (r=0.641; P<0.001). The distribution and number of immunoreactive CRF-positive cells in synovial tissue were similar to those of urocortin-positive cells (r=0.701; P<0.001). Urocortin, CRF-R1 and CRF-R2-alpha mRNAs detected by RT-PCR were expressed in in the synovium of 10/10, 10/10 and 2/10 RA patients respectively, but CRF-R2-beta was not expressed. Urocortin was actively synthesized in the synovium of RA patients. The present study suggests that urocortin may play an important role as an autocrine and/or paracrine regulator of synovial inflammation in RA.
10685763 Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxici 2000 Feb Trazodone (Desyrel) is a second-generation, nontricyclic antidepressant that has been in use in North America since the early 1980s. It has the advantage of being more sedating and having less anticholinergic side effects than other secondary amines in the piperazine class, namely, desipramine and nortriptyline. Five previous cases of trazodone hepatotoxicity have been reported in the literature, one describing chronic damage and the others, more acute cellular and cholestatic injury. We describe a case of acute reversible liver injury with the use of trazodone. This case is unique in that injury occurred after protracted (18 months) drug use and while the patient was on corticosteroids. Moreover, the diagnosis was confirmed by an inadvertent challenge with trazodone. This case reports not only a well documented instance of trazodone-induced liver injury, but also serves as a basis for a brief discussion of mechanisms, clinical monitoring, and therapy in drug-induced hepatotoxicity.