Browse

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

ID PMID Title PublicationDate abstract
16720373 Transglutaminase 2 in inflammation. 2006 Sep 1 Many reports have shown that the expression of transglutaminase 2 (TG 2) is increased in inflammatory diseases. Although during the last several decades multiple physiological roles for TG 2 have been demonstrated in various cell types, its role in the inflammatory process is not yet clear. TG 2 is a crosslinking enzyme that is widely used in many biological systems for tissue stabilization purposes and immediate defense against injury or infection. Aberrant activation of TG 2 activity in tissues contributes to a variety of diseases including neurodegenerative diseases, autoimmune diseases, and cancers. In most cases, TG 2 appears to form an inappropriate protein aggregate that may be cytotoxic enough to trigger inflammation and/or apoptosis. In some cases, such as celiac disease and rheumatoid arthritis, TG 2 is also associated with the pathogenic progression, as well as in the generation of autoantibodies. Recently, we discovered that increased TG 2 activity triggers NF-kappaB activation without I-kappaBalpha kinase signaling. TG 2 induces the polymerization of I-kappaBalpha rather than stimulating I-kappaBalpha kinase. This polymerization of I-kappaB results in the direct activation of NF-kappaB in various cell lines. We also found that TG inhibition reverses NF-kappaB activation. Interestingly, this coincides with the reversal of inflammation in conjunctivitis models by treatment with TG 2 inhibitors. Here, I introduce a new role for TG 2 as a signal modulator, which may suggest a new paradigm for the inflammatory process.
16643778 [Construction of Tet-on inducible CXCR1 eukaryotic expression plasmid and identification o 2006 May AIM: To construct tetracycline (Tet)-controlled inducible vector CXCR1-pTREhyg, and then detect the expression character of CXCR1 under the regulation of Dox in NIH3T3 cells. METHODS: A full length cDNA of human CXCR1 was cloned from sample of fibroblast like synovium (FLS) in rheumatoid arthritis (RA) patient by RT-PCR and then sub-cloned into the pTREhyg plasmid after sequence analysis. CXCR1-pTREhyg and pTet-on was co-transfected with Lipofect2000 to NIH3T3 cells, and the expression of IL-8RA was detected by Western blot after given different concentration of Dox. RESULTS: Western blot showed that CXCR1 could be induced by Dox in NIH3T3 cells, and the phosphorylated Erk-1/2 level was significantly increased after IL-8 stimulation. CONCLUSION: Tet inducible recombinant vector of CXCR1-pTREhyg was successfully constructed, and it could be expressed in NIH3T3 cells. The stimulation of IL-8 obviously changed the activity of Erk-1/2 in the transfected NIH3T3 cells. This work has laid foundations for further study on the relationship between CXCR1 and RA disease.
16506237 Absence of the medial sesamoid bone associated with metatarsophalangeal pain. 2006 Oct Pain at the first metatarsophalangeal (MTP) joint can result from inflammation, chondromalacia, flexor hallucis brevis tendinitis, osteochondritis dessecans, fracture of a sesamoid bone, avascular necrosis of sesamoids, inflamed bursae, intractable keratoses, infection, sesamoiditis, gout arthropathy, and rheumatoid arthritis. Congenital absence of a sesamoid bone is extremely rare. We present a 17-year-old male patient with pain at the plantar aspect of the right MTP joint associated with congenital absence of the medial sesamoid. There was tenderness and the range of motion was minimally restricted. He described the pain as necessitating changes in his social life. On radiographs, the medial hallucial sesamoid was absent on the right side. The MTP joint was also evaluated using magnetic resonance imaging (MRI). A metatarsal pad was prescribed and the patient was satisfied with the treatment at the 2 months follow-up period. MRI revealed no pathological tissue at the medial sesamoid site. Hallucial sesamoids absorb pressure, reduce friction, protect the tendons, act like a fulcrum to increase the mechanical force of the tendons, and provide a dynamic function to the great toe by elevating first metatarsal head. Congenital absence of these bones is very rare but we must consider it in a patient with MTP joint pain.
16351011 [MCTD--mixed connective tissue disease]. 2005 Feb Mixed connective tissue disease is a disease entity characterized by overlapping symptoms of lupus erythematosus (LE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA). Diagnostic criteria include high titers of antibodies against U1RNP as well as the presence of at least 3 of 5 of the following clinical features: edema of hands, synovitis, myositis, Raynaud phenomenon and acroscierosis. In terms of the pathogenesis, genetic as well as infectious (viral) factors appear to play a role. The acceptance of MCTD as a distinct disease entity is controversial. Terms such as "undifferentiated connective tissue disease" or "overlapping syndromes" are not helpful. One-quarter of MCTD patients transform into LE, while one-third progress to SSc. Therapeutic recommendations are glucocorticoids in combination with immunosuppressive agents and endothelin receptor antagonists. Double blind studies are not available. The prognosis is relatively good. Causes of death include pulmonary hypertension, infections and both pulmonary and cardiac failure.
19079899 The impact of long-chain n-3 polyunsaturated fatty acids on human health. 2005 Jun A considerable literature has been published on the health benefits of fish, oil-rich fish and fish oils and their constituent long-chain (LC) n-3 PUFA. Evidence from epidemiological studies highlights the cardioprotective attributes of diets rich in fish, especially oil-rich fish. Data from intervention trials are consistent in suggesting that LC n-3 PUFA lower the risk of CVD, probably by the multiple mechanisms of lowering serum triacylglycerols, improving the LDL:HDL ratio, anti-arrhythmic effects on heart muscle, improved plaque stability, anti-thrombotic effects and reduced endothelial activation. Research indicates LC n-3 PUFA provision has an impact during development, and there is preliminary evidence that docosahexaenoic acid supplementation during pregnancy could optimise brain and retina development in the infant. LC n-3 PUFA are also postulated to ameliorate behavioural and mental health disturbances such as depression, schizophrenia, dementia and attention deficit hyperactivity disorder. However, despite some positive evidence in each of these areas, use of LC n-3 PUFA in these conditions remains at the experimental stage. In the case of immune function, there is little doubt that LC n-3 PUFA have a positive effect. Although intervention trials in rheumatoid arthritis show strong evidence of benefit, evidence for efficacy in other inflammatory conditions, including Crohn's disease, ulcerative colitis, psoriasis, lupus, multiple sclerosis, cystic fibrosis and asthma, is inconsistent or inadequate. More promising evidence in some conditions may come from studies which attempt to modify the fetal environment using LC n-3 PUFA supplementation during pregnancy.
15871661 IL-6 transsignaling: the in vivo consequences. 2005 May Cytokine receptors exist in membrane-bound and soluble forms. They bind their ligands with comparable affinity. Although most soluble receptors are antagonists because they compete with their membrane counterparts for their ligands, some soluble receptors are agonists. In this case, on target cells, the complex of cytokine and soluble cytokine receptor binds to a second receptor subunit and initiates intracellular signal transduction. The soluble receptors of the interleukin-6 (IL-6) family of cytokines--soluble IL-6 receptor (sIL-6R), sIL-11R, and soluble ciliary neurotrophic factor receptor (sCNTFR)--are agonists. In vivo, the IL-6/sIL-6R complex stimulates several types of target cells not stimulated by IL-6 alone, as they do not express the membrane- bound IL-6R. This process has been named transsignaling. We have shown recently that in several chronic inflammatory diseases, such as chronic inflammatory bowl disease, peritonitis, and rheumatoid arthritis, as well as in colon cancer, transsignaling via the sIL-6R complexed to IL-6 is a crucial point in the maintenance of the disease. The mechanism by which the IL-6/sIL-6R complex regulates the inflammatory or neoplastic state is discussed.
15864052 Axial radiography of the distal femur to assess rotational alignment in total knee arthrop 2005 May A method for taking an axial radiograph of the distal femur was developed to see the epicondyles and posterior condyles of the femur. It was hypothesized that these radiographs would be acceptable for evaluating rotational alignment in total knee arthroplasty with comparable reproducibility and good correlation to the results obtained with computed tomography images. Radiographs were obtained of 50 knees in 32 patients having total knee arthroplasty. The radiographs were taken while the patients were with the knee in 90 degrees flexion. The angle between the clinical epicondylar axis and the posterior condylar axis (twist angle) was measured and compared with the results obtained by conventional computed tomography. The interobserver variation in the axial radiography was less than or comparable to the computed tomography method. The mean discrepancy between the two methods (+/- standard deviation) was 0.5 degrees +/- 0.4 degrees (range, 0-1.9 degrees ), and a strong correlation was observed. This plain radiography is acceptable for evaluation of femoral component rotation with comparable reproducibility and correlation to the results with computed tomography. It has several advantages regarding cost, radiation dose, and lack of scatter when used for postoperative assessment.
17172663 Development of transfection and high-producer screening protocols for the CHOK1SV cell sys 2006 Oct To date, the FDA has approved 18 monoclonal antibody (MAb) therapeutic drugs with targets ranging from asthma and rheumatoid arthritis to leukemia. Many of these approved products are produced in Chinese hamster ovary cells (CHO) making CHO a significant and relevant host system. We studied the applicability of CHOK1SV cells as a potential host cell line for MAb production in terms of timelines, achievable titers, transfectant stability, and reproducibility. CHOK1SV, developed by Lonza Biologics, is a suspension, protein-free-adapted CHOK1-derivative utilizing the glutamine synthetase (GS) gene expression system. CHOK1SV expresses the GS enzyme endogenously; thus, positive transfectants were obtained under the dual selection of methionine sulfoximine (MSX) and glutamine-free media. We examined outgrowth efficiencies, specific productivities, and achievable batch titers of three different IgG MAbs transfected into CHOK1SV. Reducing the MSX concentration in the initial selection medium resulted in a decreased incubation time required for transfectant colonies to appear. Specific productivities of "high-producers" ranged between 11 and 49 pg/c/d with batch titers ranging from 105 to 519 mg/L. Transfectant stability and the effects of MSX also were investigated, which indicated that the addition of MSX was necessary to maintain stable MAb production. Cell growth was stable regardless of MSX concentration.
16995741 A preliminary in silico lead series of 2-phthalimidinoglutaric acid analogues designed as 2006 Sep Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.
16969593 The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis. 2006 Sep Oral glucocorticoids (GCs) are frequently used in the treatment of inflammatory conditions, such as rheumatoid arthritis or asthma. They have adverse skeletal effects, primarily through reductions in bone formation and osteocyte apoptosis. Several findings indicate that changes in the quality of bone may significantly contribute to the increased risk of fracture and that loss of BMD only partially explains the increased risk of fracture in oral GC users. Epidemiological studies have found that the increases in the risk of fracture in oral GC users are dose dependent and occur within three months of starting GC therapy. Daily doses of >2.5 mg prednisone equivalent have been associated with increases in the risk of fractures and randomised studies reported adverse skeletal effects with daily doses as low as 5 mg. After discontinuation of GC treatment, the risk of fracture may reduce towards baseline levels unless patients previously used high cumulative doses of oral GCs. Users of inhaled GCs have also an increased risk of fracture, especially at higher doses. But it is likely that this excess risk is related to the severity of the underlying respiratory disease, rather than to the inhaled GC therapy. It has been recommended that patients who start on oral GC therapy should receive calcium and vitamin D supplementation. Patients with a higher risk of fracture should also receive a bisphosphonate.
16887960 CCR5 in T cell-mediated liver diseases: what's going on? 2006 Aug 15 The chemokine receptor CCR5 came into worldwide prominence a decade ago when it was identified as one of the major coreceptors for HIV infectivity. However, subsequent studies suggested an important modulatory role for CCR5 in the inflammatory response. Specifically, CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Moreover, T cell-mediated immune responses are proposed to be critical in the pathogenesis of autoimmune and viral liver diseases, and recent clinical and experimental studies have also implicated CCR5 in the pathogenesis of autoimmune and viral liver diseases. Therefore, in this brief review, we highlight the evidence that supports an important role of CCR5 in the pathophysiology of T cell-mediated liver diseases with specific emphasis on autoimmune and viral liver diseases.
16868019 A non-major histocompatibility locus determines tissue specificity in the pathogenic proce 2007 Feb BACKGROUND: The incidence and characteristics of spontaneous ankylosis in the ankle of specific F(1) mice descended from two Fas-deficient strains were reported. Here the coincidence of synovial proliferation and ankylosis in the descendent F(2) mice is reported. AIM: To clarify whether the two distinct manifestations are genetically different. METHODS: An arthropathic group of mice (MCF(2)) were bred by intercrossing MRL/Mp.Fas(lpr)-sap(-)/sap(-) and C3H/He.Fas(lpr) mice. All mice were killed by bleeding under anaesthesia when they were 6 months old. Pathological grades for synovial proliferation were determined by microscopical examination. To obtain a linkage locus, the whole genome of male MCF(2) mice was scanned by using 73 microsatellite markers. RESULTS: Synovial proliferation was equally observed in male and female MCF(2) mice. No correlation was observed between the grades of synovial proliferation and the ankylosis occurring in the MCF(2) mice. A suggestive susceptibility locus was shown in the middle of chromosome 11. This locus was an MRL allele with a recessive inheritance mode. CONCLUSION: The pathogenic mechanisms of synovial proliferation and ankylosis are genetically different. The present locus is overlapped with some loci associated with rheumatoid arthritis and with others associated with experimental arthritides.
16831655 Fracture and nonunion of the olecranon in total elbow arthroplasty. 2006 Jul BACKGROUND: While fracture and nonunion of the olecranon have been reported in patients undergoing total elbow arthroplasty, little information exists about the management and outcome of these cases. METHODS: Twenty-four patients (twenty-five elbows) were studied; fifteen (sixteen elbows) with rheumatoid arthritis and nine with post-traumatic elbow disorders. Twenty-three of the twenty-five elbows presented with an olecranon fracture or nonunion prior to the reported arthroplasty. During arthroplasty the olecranon fragment was initially treated by tension band in sixteen elbows, excision in four, suture fixation in two and three with stable fibrous union were left alone. RESULTS: At an average follow-up of 66 months (range, 18 to 242), there were twelve excellent, nine good, three fair and one poor results. The mean pre-operative Mayo Elbow Performance Score improved from 42 (range, 20 to 62) points pre-operatively to 86 (range, 50 to 100) points post-operatively (p < 0.001). Of the eighteen patients undergoing an attempt at union, nine (50%) obtained osseous union, eight (45%) developed a stable fibrous union and one patient underwent subsequent excision of the fragment due a superficial infection (5%). Fifteen of twenty-one could extend the hand above the head against gravity. CONCLUSION: A functional arc of motion and satisfactory clinical outcome can be achieved with osseous or a stable fibrous nonunion.
16829988 [HAQ-DI Italian version in systemic sclerosis]. 2006 Apr OBJECTIVE: To investigate the Italian version of HAQ-DI (Health Assessment Questionnaire Disability Index) in systemic sclerosis (SSc). METHODS: 121 SSc patients, satisfying ACR criteria for the classification of this disease and consecutively admitted to a tertiary Unit, were invited to participate to the study. The Italian version of HAQ-DI, as validated in rheumatoid arthritis, was administered to each of them. The relationships between this parameter and the following disease aspects: disease subset, wide extent of skin sclerosis, joint contractures, myopathy, active digital ulcers, were investigated. RESULTS: HAQ-DI resulted to be 0.772+/-0.074 (mean+/-SE) Statistically significant differences in HAQ-DI scores were detected between patients with and respectively without wide extent of skin sclerosis (ie modified Rodnan skin score >14) (1.158+/-0.176 vs 0.652+/-0.076; P<0.001), joints contractures (0.839+/-0.076 vs 0.159+/-0.147; P<0.001), myopathy (1.875+/-0.184 vs 0.656+/-0.071; P<0.001), digital ulcers (1.047+/-0.135 vs 0.680+/-0.109; P=0.006). CONCLUSIONS: Our data support the validity of the Italian version of HAQ-DI in SSc.
16476049 Dealing with the family: CD147 interactions with cyclophilins. 2006 Mar CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Recently, interaction of CD147 with proteins of the cyclophilin family has been demonstrated and activity of CD147 as a signalling receptor to extracellular cyclophilins A and B has been shown. Given that extracellular cyclophilins are potent chemotactic agents for various immune cells, further studies of the role of cyclophilin-CD147 interaction in inflammation followed. They demonstrated that agents targeting CD147 or cyclophilin had a significant anti-inflammatory effect in animal models of acute or chronic lung diseases and rheumatoid arthritis. Here, we review the current knowledge about interactions between CD147 and cyclophilins.
16471231 [The pathogenesis of inflammatory dermatoses, especially psoriasis]. 2006 Jan 28 The skin contains a variety of cell types and mediators, which together constitute the skin's immune system and play a key role in protecting the human body against dangers from outside. Dysregulation of the skin's immune system, however, frequently occurs and can result in undesirable inflammatory processes in the skin. A typical example of an undesirable inflammation in the skin is the chronic inflammatory skin disease psoriasis. In the pathogenesis of psoriasis, both genetic and environmental factors play a key role. In psoriasis, the complex interactions between T-lymphocytes, antigen-presenting cells, keratinocytes and pro-inflammatory cytokines and chemokines are disturbed. The two most widely accepted hypotheses are: (a) psoriasis is a T-cell mediated autoimmune disease, and (b) psoriasis is the result of a too finely adjusted system for regulating inflammation in the skin. The result of both mechanisms is a chronic inflammatory reaction fuelled by pro-inflammatory type-I cytokines that lead to the psoriasis-skin phenotype. With the development ofbiologicals, it has become feasible to target specific molecules in the immune process, for example type-I cytokines and the molecules present on pathogenic T-cells. This approach has already proved successful in the treatment of rheumatoid arthritis and Crohn's disease, creating novel therapeutic options for psoriasis and other inflammatory dermatoses.
16393560 [CD4 + CD25 + regulatory T cells and their importance to human illnesses]. 2006 Jan 3 Regulatory T cells ensure a balanced immune response that is competent both to fight pathogens, at the same time, to recognize self-antigens and commensals as harmless. Regulatory mechanisms are essential in preventing autoimmune disorders but may also facilitate the progression of malignant diseases and the establishment of latent infections via suppression of the host immune response. Regulatory T cells arise in the thymus, and regulatory T cell function can be induced in the periphery, so-called infectious tolerance. An absolute or relative defect in regulatory T cell function may contribute to the development of autoimmune disorders such as rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis and chronic inflammatory bowel disease. Regulatory T cell therapy is a tempting strategy for reestablishing the immune balance and thus preventing or reversing these disorders. Reestablishment of the immune balance may be accomplished by adoptive transfer of ex vivo-propagated regulatory T cells or by induction of regulatory functions locally in the organs, although such strategies are in their infancy in human research.
16387690 Transcription factor NF-kappaB: a sensor for smoke and stress signals. 2005 Nov Nuclear factor-kappa B (NF-kappaB) is a transcription factor that resides in the cytoplasm of every cell and translocates to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines, free radicals, carcinogens, tumor promoters, and endotoxins. On activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes (e.g., COX-2, 5-LOX, and iNOS), cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. The constitutive activation of NF-kappaB has been linked with a wide variety of human diseases, including asthma, atherosclerosis, AIDS, rheumatoid arthritis, diabetes, osteoporosis, Alzheimer's disease, and cancer. Several agents are known to suppress NF-kappaB activation, including Th2 cytokines (IL-4, IL-13, and IL-10), interferons, endocrine hormones (LH, HCG, MSH, and GH), phytochemicals, corticosteroids, and immunosuppressive agents. Because of the strong link of NF-kappaB with different stress signals, it has been called a "smoke-sensor" of the body.
16275367 Secretory phospholipases A2 in inflammatory and allergic diseases: not just enzymes. 2005 Nov Secretory phospholipases A(2) (sPLA(2)s) are molecules released in plasma and biologic fluids of patients with systemic inflammatory, autoimmune, and allergic diseases. Several sPLA(2) isoforms are expressed and released by such human inflammatory cells as neutrophils, eosinophils, basophils, T cells, monocytes, macrophages, and mast cells. Certain sPLA(2)s release arachidonic acid, thereby providing the substrate for the biosynthesis of proinflammatory eicosanoids. However, there are other mechanisms by which sPLA(2)s might participate in the synthesis of lipid mediators. Interestingly, sPLA(2)s activate inflammatory cells through mechanisms unrelated to their enzymatic activity. Several sPLA(2)s induce degranulation of mast cells and eosinophils and activate exocytosis in macrophages. Furthermore, sPLA(2)s promote cytokine and chemokine production from macrophages, neutrophils, eosinophils, monocytes, and endothelial cells. Some of these effects are mediated by the binding of sPLA(2)s to specific receptors expressed on effector cells. Thus sPLA(2)s might play important roles in the initiation and amplification of the inflammatory reaction. Selective inhibitors of sPLA(2)s and specific antagonists of sPLA(2) receptors might prove useful in the treatment of allergic and autoimmune diseases, such as bronchial asthma and rheumatoid arthritis.
16101190 Clinical experience with bevacizumab in colorectal cancer. 2005 Sep Angiogenesis, the process of generating new capillary blood vessels, is a fundamental requirement for normal physiological processes including embryogenesis, reproductive function and wound healing. Angiogenesis is also implicated in various pathological conditions including age-related retinal macular degeneration, diabetic retinopathy, rheumatoid arthritis, psoriasis and cancer growth and metastasis. Vascular endothelial growth factor (VEGF) is one of the best characterized of the pro-angiogenic growth factors, and multiple strategies have been developed to inhibit this pathway. Bevacizumab, a monoclonal antibody developed against VEGF, has shown initial preclinical and clinical activity. This review discusses the critical role of VEGF and summarizes the available data on the use of bevacizumab in colorectal cancer.