Browse

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

ID PMID Title PublicationDate abstract
24153020 Undenatured type II collagen (UC-II®) for joint support: a randomized, double-blind, plac 2013 Oct 24 BACKGROUND: UC-II contains a patented form of undenatured type II collagen derived from chicken sternum. Previous preclinical and clinical studies support the safety and efficacy of UC-II in modulating joint discomfort in osteoarthritis and rheumatoid arthritis. The purpose of this study was to assess the efficacy and tolerability of UC-II in moderating joint function and joint pain due to strenuous exercise in healthy subjects. METHODS: This randomized, double-blind, placebo-controlled study was conducted in healthy subjects who had no prior history of arthritic disease or joint pain at rest but experienced joint discomfort with physical activity. Fifty-five subjects who reported knee pain after participating in a standardized stepmill performance test were randomized to receive placebo (n = 28) or the UC-II (40 mg daily, n = 27) product for 120 days. Joint function was assessed by changes in degree of knee flexion and knee extension as well as measuring the time to experiencing and recovering from joint pain following strenuous stepmill exertion. RESULTS: After 120 days of supplementation, subjects in the UC-II group exhibited a statistically significant improvement in average knee extension compared to placebo (81.0 ± 1.3º vs 74.0 ± 2.2º; p = 0.011) and to baseline (81.0 ± 1.3º vs 73.2 ± 1.9º; p = 0.002). The UC-II cohort also demonstrated a statistically significant change in average knee extension at day 90 (78.8 ± 1.9º vs 73.2 ± 1.9º; p = 0.045) versus baseline. No significant change in knee extension was observed in the placebo group at any time. It was also noted that the UC-II group exercised longer before experiencing any initial joint discomfort at day 120 (2.8 ± 0.5 min, p = 0.019), compared to baseline (1.4 ± 0.2 min). By contrast, no significant changes were seen in the placebo group. No product related adverse events were observed during the study. At study conclusion, five individuals in the UC-II cohort reported no pain during or after the stepmill protocol (p = 0.031, within visit) as compared to one subject in the placebo group. CONCLUSIONS: Daily supplementation with 40 mg of UC-II was well tolerated and led to improved knee joint extension in healthy subjects. UC-II also demonstrated the potential to lengthen the period of pain free strenuous exertion and alleviate the joint pain that occasionally arises from such activities.
24129055 Evidence of genetic variations associated with rotator cuff disease. 2014 Feb BACKGROUND: Rotator cuff disease (RCD) is a complex process influenced by a multitude of factors, and a number of gene pathways are altered in rotator cuff tears. Polymorphisms in these genes can lead to an extended tendon degeneration process, which explains why subsets of patients are more susceptible to RCD. MATERIALS AND METHODS: Twenty-three single-nucleotide polymorphisms within 6 genes involved in repair and degenerative processes (DEFB1, DENND2C, ESRRB, FGF3, FGF10, and FGFR1) were investigated in 410 patients, 203 with a diagnosis of RCD and 207 presenting with absence of RCD. Exclusion criteria were patients older than 60 years and younger than 45 years with a history of trauma, rheumatoid arthritis, autoimmune syndrome, pregnancy, and use of corticosteroids. Genomic DNA was obtained from saliva samples. Genetic markers were genotyped with TaqMan real-time polymerase chain reaction. The χ(2) test compared genotypes and haplotype differences between groups. Multivariate logistic regression analyzed the significance of many covariates and the incidence of RCD. RESULTS: Statistical analysis revealed female sex (P = .001; odds ratio, 2.07 [1.30-3.30]) and being white (P = .002; odds ratio, 1.88 [1.21-2.90]) to be risk factors for RCD development. A significant association of haplotypes CCTTCCAG in ESRRB (P = .05), CGACG in FGF3 (P = .01), CC in DEFB1 (P = .03), and FGFR1 rs13317 (P = .02) with RCD could be observed. Also, association between FGF10 rs11750845 (P = .03) and rs1011814 (P = .01) was observed after adjustment by ethnic group and sex. CONCLUSIONS: Our work clearly supports the role of DEFB1, ESRRB, FGF3, FGF10, and FGFR1 genes in RCD. Identification of these variants can clarify causal pathways and provide a clue for therapeutic targets.
24107363 Advanced oxidation protein products induce inflammatory response in fibroblast-like synovi 2013 BACKGROUND: Advanced oxidation protein products (AOPPs), a marker of oxidative stress, are prevalent in many kinds of disorders. Rheumatoid arthritis (RA), mainly resulting from the dysfunction of fibroblast-like synoviocytes (FLSs), is related to oxidative stress. Although the increased levels of AOPPs in RA patients were reported, the effect of AOPPs on FLSs function still remains unclear. Therefore, our study aims to investigate whether AOPPs have an effect on the inflammatory response of FLSs in vitro. METHODS: FLSs obtained from both knees of rats were treated with or without AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. The mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin(IL)-1β, matrix metalloproteinases(MMP)-3, MMP-13 and vascular endothelial growth factor (VEGF) were measured by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. Reactive oxygen species (ROS) generation was detected by fluorescent microscope and fluorescence microplate reader. Immunoprecipitation, Co-Immunoprecipitation and western blot were performed to examine the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor kappa B (NF-κB). RESULTS: Exposure of FLSs to AOPPs upregulated the mRNA and protein expression of TNF-α, IL-1β, MMP-3, MMP-13 and VEGF in a concentration dependent manner. AOPPs treatment triggered ROS production in FLSs, which was significantly abolished by ROS scavenger N-acetyl-L-cysteine (NAC), superoxide dismutase (SOD), NADPH oxidase inhibitors diphenyleneiodonium (DPI) and apocynin. Challenged AOPPs induced phosphorylation of p47(phox), triggered an interaction between p47(phox), p22(phox) and gp91(phox), and significantly upregulated expression of NADPH oxidase subunits p47(phox), p22(phox) and gp91(phox). IκB degradation and nuclear translocation of NF-κB p65 induced by AOPPs were significantly blocked by SOD, NAC, DPI and apocynin. CONCLUSIONS: These data indicate that AOPPs induce inflammatory response in FLSs is medicated through NADPH oxidase-dependent activation of NF-κB.
24055469 Comparison of active constituents, acute toxicity, anti-nociceptive and anti-inflammatory 2013 Nov 25 ETHNOPHARMACOLOGICAL RELEVANCE: Erycibe obtusifolia and Erycibe schmidtii, which belong to the same genus as Erycibe, are widely used in traditional medicine for the treatment of joint pain and rheumatoid arthritis (RA). Porana sinensis has become a widely used substitute for Erycibe obtusifolia and Erycibe schmidtii as they have declined in the wild. In the present work, the content of the main active components, the acute toxicity, the anti-nociceptive and anti-inflammatory activities of Porana sinensis, Erycibe obtusifolia and Erycibe schmidtii were compared, and the mechanisms of anti-nociceptive and anti-inflammatory activities were discussed. MATERIALS AND METHODS: A quantitative HPLC (high performance liquid chromatography) method was first developed to compare the content of the main active components (scopoletin, scopolin and chlorogenic acid). The anti-inflammatory and anti-nociceptive activities of 40% ethanolic extracts of the three plants were compared using the models of xylene-induced ear edema, formalin-induced inflammation, carrageenan-induced air pouch inflammation, acetic acid-induced writhing and formalin-induced nociception. The acute toxicity of the 40% ethanolic extracts of the three plants was studied. RESULTS: The assay suggested a large content of scopoletin, scopolin and chlorogenic acid in the three plants. The 40% ethanolic extracts of the three plants were almost non-toxic at the dose of 5g/kg and all of them showed significant anti-inflammatory effects in the tests of xylene-induced ear edema and formalin-induced inflammation. In the carrageenan-induced air pouch inflammation test, the synthesis of PGE2 was significantly inhibited by all the extracts. They significantly inhibited the number of contortions induced by acetic acid and the second phase of the formalin-induced licking response. Naloxone was not able to reverse the analgesic effect of these extracts. CONCLUSION: The study identifies the similarity of the three plants in their main active components as well as acute toxicity, anti-nociceptive and anti-inflammatory activities. It supports the use of Porana sinensis as a suitable substitute, but further studies are needed to confirm this.
23922794 15-Deoxy-Δ12,14-prostaglandin J2 inhibits macrophage colonization by Salmonella enterica 2013 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-γ. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this prostaglandin.
23719833 The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metaboli 2013 Jun Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.
23658798 Identification and characterization of the direct interaction between methotrexate (MTX) a 2013 BACKGROUND: Methotrexate (MTX) is an agent used in chemotherapy of tumors and autoimmune disease including rheumatoid arthritis (RA). In addition, MTX has some anti-inflammatory activity. Although dihydrofolate reductase (DHFR) is a well-known target for the anti-tumor effect of MTX, the mode of action for the anti-inflammatory activity of MTX is not fully understood. METHODOLOGY/RESULT: Here, we performed a screening of MTX-binding proteins using T7 phage display with a synthetic biotinylated MTX derivative. We then characterized the interactions using surface plasmon resonance (SPR) analysis and electrophoretic mobility shift assay (EMSA). Using a T7 phage display screen, we identified T7 phages that displayed part of high-mobility group box 1 (HMGB1) protein (K86-V175). Binding affinities as well as likely binding sites were characterized using genetically engineered truncated versions of HMGB1 protein (Al G1-K87, Bj: F88-K181), indicating that MTX binds to HMGB1 via two independent sites with a dissociation constants (KD) of 0.50±0.03 µM for Al and 0.24 ± 0.01 µM for Bj. Although MTX did not inhibit the binding of HMGB1 to DNA via these domains, HMGB1/RAGE association was impeded in the presence of MTX. These data suggested that binding of MTX to part of the RAGE-binding region (K149-V175) in HMGB1 might be significant for the anti-inflammatory effect of MTX. Indeed, in murine macrophage-like cells (RAW 264.7), TNF-α release and mitogenic activity elicited by specific RAGE stimulation with a truncated monomeric HMGB1 were inhibited in the presence of MTX. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that HMGB1 is a direct binding protein of MTX. Moreover, binding of MTX to RAGE-binding region in HMGB1 inhibited the HMGB1/RAGE interaction at the molecular and cellular levels. These data might explain the molecular basis underlying the mechanism of action for the anti-inflammatory effect of MTX.
23596642 [(99m)Tc-Gly-Gly-Cys]-Ornithine-ornithine-ornithine-cyclo(Arg-Gly-Asp-d-Phe-Lys). 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled RGD analogs have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-d-Phe-Lys) ((111)In-DOTA-E-c(RGDfK)) for single-photon emission computed tomography (SPECT) imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors. Tsiapa et al. (14) prepared [(99m)Tc -Gly-Gly-Cys]-ornithine-ornithine-ornithine-cyclo(Arg-Gly-Asp-d-Phe-Lys) ([(99m)Tc-GGC]-(Orn)(3)-c(RGDfK)) as a radioligand for use in tumor imaging showing relatively high tumor accumulation and renal elimination with low abdominal accumulation in mice.
23358110 Effect of the GPI anchor of human Thy-1 on antibody recognition and function. 2013 Mar Thymocyte differentiation antigen-1 (Thy-1) is a glycosylphosphatidylinositol (GPI)-linked cell surface glycoprotein expressed on numerous cell types, which regulates signals affecting cell adhesion, migration, differentiation, and survival. In addition, Thy-1 has been detected in the serum, cerebral spinal fluid, wound fluid from venous ulcers, synovial fluid from joints in rheumatoid arthritis, and, more recently, urine. We previously detected Thy-1 in the conditioned media of cytokine-stimulated lung fibroblasts, suggesting that Thy-1 shedding may be a response to cellular stress. Soluble and membrane-bound forms of Thy-1 from in vivo sources have been shown to be identical in size when deglycosylated, suggesting that soluble Thy-1 is separated from the diacyl glycerol portion of its GPI anchor by hydrolysis within the GPI moiety. For Thy-1- and other GPI-anchored proteins, delipidation induces a stable change in conformation that manifests itself in a change in antibody affinity for soluble forms. Using epitope-tagged recombinant soluble Thy-1, we report that widely available monoclonal antibodies to human Thy-1 are unable to detect soluble Thy-1 by immunoblotting. We re-evaluated the Thy-1 that we previously reported in the conditioned media of normal human lung fibroblasts and found it to be entirely insoluble. These findings suggest that most Thy-1 reported in body fluids retains its GPI anchor and may be associated with membrane fragments or vesicles. This phenomenon should be considered in the generation of antibodies and controls for Thy-1 bioassays. Furthermore, the changes in Thy-1 conformation with delipidation, beyond affecting antibody affinity, likely affect the ligand affinity and biological function of soluble vs released membrane-associated forms.
23160276 Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associate 2013 Jan BACKGROUND AND AIM: Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS. METHODS: Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses. RESULTS: rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously. CONCLUSIONS: This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3-12q14.1 region with MS.
22736247 Negative effect of immunosuppressive therapy in the performance of the QuantiFERON gold in 2013 Aug To compare the tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube test (QFG) for the detection of latent tuberculosis infection among patients with immune-mediated inflammatory diseases before antitumor necrosis factor-α therapy. A prospective study including 153 consecutive patients with rheumatoid arthritis (n = 53), psoriasis (n = 45), inflammatory bowel disease (n = 25), and spondyloarthropathy (n = 22) were included. QFG and TST were performed simultaneously. TST was positive in 43/153 (28.1 %) patients. QFG (cutoff ≥ 0.35 IU/ml) was positive in 15/153 (9.8 %) patients, and indeterminate in one (0.7 %). QFG (cutoff ≥ 0.10 IU/ml) was positive in 25/153 (16.3 %). 59.5 % of the patients were on immunosuppressive therapy at the time of testing. There was a significant difference in the rate of positive QFG between patients with and without immunosuppressive therapy after adjustment for age and gender (cutoff ≥ 0.35 IU/ml, 4.6 vs. 17.4 %; adjusted odds ratio [AOR], 0.2; 95 % confidence interval [CI], 0.06-0.8; p = 0.03 and cutoff ≥ 0.10 IU/ml, 11.2 vs. 24.2 %; AOR, 0.3; 95 % CI, 0.1-0.93; p = 0.04). Agreement between TST and QFG was 'fair' (κ = 0.354 and κ = 0.365, for cutoffs ≥ 0.35 and ≥0.10 IU/ml, respectively). Among patients without immunosuppressive therapy, the concordance between TST and QFG was 'moderate-substantial' (κ = 0.593 and κ = 0.690, for cutoffs ≥ 0.35 IU/ml and ≥0.10 IU/ml, respectively). By contrast, among patients on immunosuppressive therapy the concordance was 'poor' (κ = 0.085; κ = 0.041, respectively). Immunosuppressive therapy affects negatively QFG performance. In patients with immune-mediated inflammatory diseases, QFG may have a limited role for screening of latent tuberculosis infection.
24785897 Methicillin-resistant Staphylococcus aureus-related septic pulmonary embolism and sacroili 2014 We herein report the case of a 21-year-old woman with refractory adult-onset Still's disease who developed central venous catheter-related methicillin-resistant Staphylococcus aureus sepsis during aggressive immunosuppressive therapy. She subsequently experienced septic pulmonary embolism (SPE) and sacroiliitis during treatment with intravenous vancomycin and was successfully treated with long-term oral linezolid therapy. This case suggests that the occurrence of methicillin-resistant Staphylococcus aureus infection in immunosuppressive patients can trigger severe clinical manifestations such as SPE and septic sacroiliitis and that linezolid is suitable for treating such conditions.
23841690 An immunodominant La/SSB autoantibody proteome derives from public clonotypes. 2013 Nov The La/SSB autoantigen is a major target of long-term humoral autoimmunity in primary Sjögren's Syndrome (SS) and systemic lupus erythematosus. A majority of patients with linked anti-Ro60/Ro52/La responses target an NH2-terminal epitope designated LaA that is expressed on Ro/La ribonucleoprotein complexes and the surface membrane of apoptotic cells. In this study, we used high-resolution Orbitrap mass spectrometry to determine the clonality, isotype and V-region sequences of LaA-specific autoantibodies in seven patients with primary SS. Anti-LaA immunoglobulin (Ig)Gs purified from polyclonal sera by epitope-specific affinity chromatography were analysed by combined database and de-novo mass spectrometric sequencing. Autoantibody responses comprised two heavily mutated IgG1 kappa-restricted monoclonal species that were shared (public) across unrelated patients; one clonotype was specified by an IGHV3-30 heavy chain paired with IGKV3-15 light chain and the second by an IGHV3-43/IGKV3-20 pairing. Shared amino acid replacement mutations were also seen within heavy and light chain complementarity-determining regions, consistent with a common breach of B cell tolerance followed by antigen-driven clonal selection. The discovery of public clonotypic autoantibodies directed against an immunodominant epitope on La, taken together with recent findings for the linked Ro52 and Ro60 autoantigens, supports a model of systemic autoimmunity in which humoral responses against protein-RNA complexes are mediated by public sets of autoreactive B cell clonotypes.
23333492 Effects of total glucosides of paeony for delaying onset of Sjogren's syndrome: an animal 2013 Oct OBJECTIVE: To investigate the effectiveness of total glucosides of paeony (TGP) on Sjogren's syndrome (SS) using non-obese diabetic (NOD) mice model. STUDY DESIGN: Twenty-seven 8-week-old female NOD mice were assigned into TGP group, hydroxychloroquine (HCQ) group and normal saline (NS) group, receiving corresponding drugs respectively and sacrificed at 24-week-old. Saliva flow rate (SFR), ration of regulatory T cells, level of anti-SSA/SSB, histological changes in submandibular glands (SMG) and microarray analysis were assessed. The data were analyzed using SPSS. RESULTS: Compared to NS group, in TGP group, SFR, SMG index and the ration of regulatory T cells were significantly higher, while anti-SSA/SSB and lymphocytic foci were significantly lower. HCQ group demonstrated similar results except SMG index. Altered gene expression was found in 10.71% of TGP and 13.09% of HCQ of the profile. CONCLUSION: TGP demonstrated a similar effectiveness as HCQ in delaying the onset of SS-like disease in NOD mice.
25354755 Prevalence of distal renal tubular acidosis in primary Sjögren's syndrome. 2015 May OBJECTIVES: Our objectives were to analyse the prevalence of distal renal tubular acidosis (dRTA) in primary SS (pSS) and to compare a novel urinary acidification test with furosemide and fludrocortisone (FF) with the gold standard ammonium chloride (NH4Cl) to detect dRTA. METHODS: Urinary acidification was assessed in 57 pSS patients using NH4Cl and FF. A urinary acidification defect was defined as an inability to reach a urinary pH of <5.3 after NH4Cl. RESULTS: The prevalence of complete dRTA (urinary acidification defect with acidosis) was 5% (3/57). All three patients had positive SSA/Ro and SSB/La autoantibodies and impaired kidney function. The prevalence of incomplete dRTA (urinary acidification defect without acidosis) was 25% (14/57). Compared with patients without dRTA, patients with incomplete dRTA had significantly lower venous pH and serum bicarbonate and higher urinary pH. SSB/La antibodies were more prevalent in the dRTA groups (P < 0.05). Compared with NH4Cl, the positive and negative predictive values of FF were 46% and 82%, respectively. Vomiting occurred more often during the urinary acidification test with NH4Cl than with FF (9 vs 0, P < 0.05). CONCLUSION: Incomplete dRTA is common in pSS and causes mild acidaemia and higher urinary pH, which may contribute to bone demineralization and kidney stone formation. FF cannot replace NH4Cl in testing urinary acidification in pSS, but may be considered as a screening tool, given its reasonable negative predictive value and better tolerability.
25190637 Characterization of circulating endothelial microparticles and endothelial progenitor cell 2015 Mar OBJECTIVE: Chronic autoimmune diseases are associated with increased risk of cardiovascular death. Endothelial dysfunction represents the first stage of subclinical atherosclerosis and multiple factors contribute to endothelial injury. Among these, an altered balance between endothelial microparticle (EMP) release and endothelial progenitor cell (EPC) generation promotes endothelial dysfunction. The role of EMPs and EPCs in promoting endothelial damage in primary SS (pSS) has never been investigated. Our aim was to evaluate the role of EMPs and EPCs as markers of endothelial damage in pSS and their correlation with disease clinical and immunological features. METHODS: Circulating EMPs (CD31(+)/CD42(-)), true EPCs (CD34(+)/KDR(+)/CD133(+)) and mature EPCs (CD34(+)/KDR(+)/CD133(-)) were quantified by FACS analysis in 34 pSS patients and 18 age- and sex-matched controls. Correlation between EMP and EPC levels and parameters of disease activity and damage, clinical features and markers of immunological dysfunction was performed. RESULTS: Patients displayed higher EMP numbers with respect to healthy controls [HCs; mean 450 n/μl (S.D. 155) vs 231 (110), P < 0.0001]. EPC and mature EPC levels were higher in patients compared with HCs [mean 226 n/ml (S.D. 181) vs 69 (53), P < 0.001 and 166 (161) vs 36 (32), P < 0.0001, respectively). EMP levels directly correlated with disease duration from symptoms and diagnosis (ρ = 0.5, P < 0.01). Early EPCs inversely correlated with disease duration from symptoms (ρ = -0.5, P < 0.01) and diagnosis (ρ = -0.4, P < 0.05). CONCLUSION: This is the first demonstration of chronic endothelial fragmentation characterizing pSS. The reparative potentiality of the endothelial layer appears to be preserved in the earliest stages of disease. During the course of the disease, progressive exhaustion of the precursor endothelial pool may be hypothesized, leading to defective vascular layer restoration and endothelial dysfunction.
25036233 Usefulness of tacrolimus for refractory adult-onset still's disease: Report of six cases. 2016 Nov Six patients with refractory adult-onset Still's disease (AOSD) were treated with tacrolimus (TAC). Patient 1 was pregnant, for whom high-dose corticosteroid (CS) monotherapy did not achieve clinical remission, whereas TAC concomitant with CS was successful, and her baby had no apparent abnormalities. Patient 2 had hemophagocytic syndrome (HPS), for whom high-dose CS monotherapy did not achieve clinical remission, whereas TAC improved HPS, and a complete clinical remission was achieved with concomitant administration of TAC and methotrexate (MTX) with CS. Cases 3-5 could not have reduced CS doses due to repeated recurrences and other disease-modifying antirheumatic drugs, including MTX, Cyclosporine A, and tumor necrosis factor alpha inhibitors, did not control disease activity. TAC administration allowed for reduced CS doses. Case 6 experienced adverse effects, and TAC was discontinued due to elevated serum creatinine and potassium levels. TAC was useful for five of six patients, which suggests it as an option for refractory AOSD.
24126553 Polyendocrine syndrome type 3C in a family from Pakistan. 2013 Sep In type 3 polyendocrine syndrome (PAS3), autoimmune thyroiditis occurs with other organ-specific autoimmune disease, but not with autoimmune adrenalitis. In this report we described a family from Pakistan in which mother and three daughters were affected by a PAS3. We studied a family from Pakistan: Father MMu age 44, mother KN aged 44, three daughters MM age 20, MH age 16 and MA age 14 and a son MU age 18. These subjects were tested for thyroids function, metabolic function, adrenal function, autoimmune disease. In this family the four females were shown hypothyroidism with presence of anti thyroid autoantibodies (AA) and high TSH serum concentration in association with the presence of anti transglutaminase AA. Moreover KN, MM and MH were positive for anti nuclear AA (granular pattern) and for antibodies against Saccaromyces cerevisiae. MM was positive for AA against nuclear extractable antigens (SSA and SSB) too. No diabetes or pernicious anemia were observed. Adrenal and Pituitary function were normal. PAS 3C is an uncommon disease. In this family from Pakistan we observed a PAS3C in the four female members: mother and three daughters while father and son were unaffected.
23944604 Association of genes in the NF-κB pathway with antibody-positive primary Sjögren's syndr 2013 Nov Primary Sjögren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-κB in primary SS. NF-κB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-κB and of IKBKE (IKKε), which is an NF-κB activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n = 684) and the UK (n = 421) and 4460 controls (Scandinavia, n = 1662, UK, n = 2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n = 868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P = 3.4 × 10(-5) , OR = 1.33, 95%CI: 1.16-1.52 for rs3792783 and P = 1.3 × 10(-3) , OR = 1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P = 5.7 × 10(-3) , OR = 1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.
23678756 [Analysis on arthroscopic debridement and visco supplement for the treatment of degenerati 2013 Feb OBJECTIVE: To evaluate effects of arthroscopic debridement and visco supplement for the treatment of degenerative osteoarthropathy of ankle. METHODS: From October 2008 to May 2012, 30 patients with degenerative osteoarthropathy of ankle were treated with arthroscopy after ineffective treatment with conservative methods. Two patients lost follow-up. Among the patients, 19 patients were male and 9 patients were female, ranging in age from 28 to 56 years old, with a mean of (40.0+ 5.9)years old. Patients who had inflammatory or postinfectious arthritis,rheumatoid,gout,tuberculosis were excluded. Other exclusion criteria included previous arthroscopic treatment for ankle osteoarthropathy, intraarticular corticosteroid injection within the previous 6 months, a major neurologic deficit, serious medical illness and pregnancy. Articular cartilage iijuries were classified according to Outerbridge by the same doctor. Follow procedures were involved in the surgery: synovectomy,debridement or excision of fragments of articular cartilage or chondral flaps and osteophytes that prevented full extension. Microfracture of chondral defects was not performed. Ogilvie-Harris criteria was used to evaluate therapeutic effects. RESULTS: According to Ogilvie-Harris criteria, 10 patients got an excellent results, 14 good, 3 poor and 1 bad. The mean VAS score of pain decreased from preoperative 7.5+/-1.3 to postoperative 2.4+/-2.3. The score of dorsiflexion range (ROM-D) had no obvious change after operation [preoperative(27.0+/-7.3)degree and postoperative(29.0+/-5.6)degree]. The mean Tegner score increased from preoperative 2.7+/-1.3 to postoperative 5.6+/-2.2. CONCLUSION: Synovectomy, debridement or excision of chondral flaps and osteophytes under arthroscopy, as well as scheduled intraarticular sodium hyaluronate injection should be recommened to treat ankle degenerative osteoarthropathy.