bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperuricemia and risk of stroke: A systematic review and meta‐analysis
Authors: Kim Seo Young , Guevara James P. , Kim Kyoung Mi , Choi Hyon K. , Heitjan Daniel F. , Albert Daniel A. 
Published: June 2009

AbstractObjectiveTo assess the association between hyperuricemia and risk of stroke incidence and mortality because hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but, to date, results from observational studies are conflicting.MethodsA systematic review and meta‐analysis were conducted. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Prospective cohort studies were included only if they contained data on stroke incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the association of stroke incidence and mortality with serum uric acid levels were calculated.ResultsA total of 16 studies including 238,449 adults were eligible and abstracted. Hyperuricemia was associated with a significantly higher risk of both stroke incidence (6 studies; RR 1.41, 95% confidence interval [95% CI] 1.05, 1.76) and mortality (6 studies; RR 1.36, 95% CI 1.03, 1.69) in our meta‐analyses of unadjusted study estimates. Subgroup analyses of studies adjusting for known risk factors such as age, hypertension, diabetes mellitus, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence (4 studies; RR 1.47, 95% CI 1.19, 1.76) and mortality (6 studies; RR 1.26, 95% CI 1.12, 1.39). The pooled estimate of multivariate RRs did not differ significantly by sex.ConclusionHyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future research is needed to determine whether lowering uric acid level has any beneficial effects on stroke.
Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways
Authors: Trouw L. A. , Haisma E. M. , Levarht E. W. N. , van der Woude D. , Ioan‐Facsinay A. , Daha M. R. , Huizinga T. W. J. , Toes R. E. 
Published: June 2009

AbstractObjectiveIt has been suggested that anti–citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti–cyclic citrullinated peptide (anti‐CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.MethodsWe set up novel assays to analyze complement activation by anti‐CCP antibodies, using cyclic citrullinated peptide–coated plates, specific buffers, and normal and complement‐deficient sera as a source of complement.ResultsAnti‐CCP antibodies activated complement in a dose‐dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti‐CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.ConclusionOur findings indicate that anti‐CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement‐mediated damage in RA.
Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β through the NF‐κB and MAPK pathways in rheumatoid arthritis
Authors: Zheng Wenxin , Li Runsheng , Pan Heng , He Dongyi , Xu Rong , Guo Taylor B. , Guo Yajun , Zhang Jingwu Z. 
Published: June 2009

AbstractObjectiveOsteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP‐1) and macrophage inflammatory protein 1β (MIP‐1β), in RA.MethodsEnzyme‐linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation.ResultsThe effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP‐1 and MIP‐1β in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP‐1 or MIP‐1β in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP‐1 or MIP‐1β, and this effect could be blocked by an anti‐OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50–83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF‐κB and MAPK pathways, involving the activation of IKKβ, p38, and JNK.ConclusionThese results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP‐1 and MIP‐1β.
Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women
Authors: Valdes Ana M. , Lories Rik J. , van Meurs Joyce B. , Kerkhof Hanneke , Doherty Sally , Hofman Albert , Hart Deborah J. , Zhang Feng , Luyten Frank P. , Uitterlinden Andre G. , Doherty Michael , Spector Tim D. 
Published: June 2009

AbstractObjectiveThe ANP32A gene encodes a tumor suppressor molecule that plays a regulatory role in apoptosis and interferes with canonical Wnt signaling in vitro. We undertook this study to test whether genetic variation at ANP32A was associated with osteoarthritis (OA) in women.MethodsSingle‐nucleotide polymorphisms (SNPs) in the ANP32A gene were genotyped in 438 control women, 425 women with total knee replacements (TKRs), and 537 women with total hip replacements (THRs) from the Nottingham case–control study as well as in 820 women from the population‐based Chingford Study cohort for whom hip and knee radiographs were available. The most highly associated SNP was further tested in women from the Rotterdam Study (131 with THRs, 633 with knee OA, and 1,567 controls) and the TwinsUK Study cohort (67 with THRs, 43 with TKRs, and 358 controls), for a total of 2,170 patients with OA and 2,849 controls.ResultsThe ANP32A transcript was abundantly expressed in normal and OA articular cartilage. Three SNPs in the ANP32A gene were significantly associated in Nottingham patients with hip OA, but not knee OA. One of these (rs7164503) was associated with hip and knee OA in the Chingford Study cohort and with THR in the TwinsUK Study cohort, but the association was not statistically significant in the Rotterdam Study. When we combined hip data from all 4 cohorts, we found that the minor allele of rs7164503 was associated with a significantly lower risk of hip OA (Mantel‐Haenszel odds ratio 0.67 [95% confidence interval 0.53–0.84], P < 3.8 × 10−4) and that a similar trend was observed for knee OA (Mantel‐Haenszel odds ratio 0.87 [95% confidence interval 0.73–1.01], P < 0.055).ConclusionOur results provide evidence suggesting that ANP32A is involved in the pathogenesis of OA of the hip.
Characterization and peripheral blood biomarker assessment of anti–Jo‐1 antibody–positive interstitial lung disease
Authors: Richards Thomas J. , Eggebeen Aaron , Gibson Kevin , Yousem Samuel , Fuhrman Carl , Gochuico Bernadette R. , Fertig Noreen , Oddis Chester V. , Kaminski Naftali , Rosas Ivan O. , Ascherman Dana P. 
Published: June 2009

AbstractObjectiveUsing a combination of clinical, radiographic, functional, and serum protein biomarker assessments, this study was aimed at defining the prevalence and clinical characteristics of interstitial lung disease (ILD) in a large cohort of patients with anti–Jo‐1 antibodies.MethodsA review of clinical records, pulmonary function test results, and findings on imaging studies determined the existence of ILD in anti–Jo‐1 antibody–positive individuals whose data were accumulated in the University of Pittsburgh Myositis Database from 1982 to 2007. Multiplex enzyme‐linked immunosorbent assays (ELISAs) for serum inflammation markers, cytokines, chemokines, and matrix metalloproteinases in different patient subgroups were performed to assess the serum proteins associated with anti–Jo‐1 antibody–positive ILD.ResultsAmong the 90 anti–Jo‐1 antibody–positive individuals with sufficient clinical, radiographic, and/or pulmonary function data, 77 (86%) met the criteria for ILD. While computed tomography scans revealed a variety of patterns suggestive of underlying usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia, a review of the histopathologic abnormalities in a subset of patients undergoing open lung biopsy or transplantation or whose lung tissue was obtained at autopsy (n = 22) demonstrated a preponderance of UIP and diffuse alveolar damage. Analysis by multiplex ELISA yielded statistically significant associations between anti–Jo‐1 antibody–positive ILD and elevated serum levels of C‐reactive protein (CRP), CXCL9, and CXCL10, which distinguished this disease entity from idiopathic pulmonary fibrosis and anti–signal recognition particle antibody–positive myositis. Recursive partitioning further demonstrated that combinations of these and other serum protein biomarkers can distinguish these disease subgroups at high levels of sensitivity and specificity.ConclusionIn this large cohort of anti–Jo‐1 antibody–positive individuals, the incidence of ILD approached 90%. Multiplex ELISA demonstrated disease‐specific associations between anti–Jo‐1 antibody–positive ILD and serum levels of CRP as well as the interferon‐γ–inducible chemokines CXCL9 and CXCL10, highlighting the potential of this approach to define biologically active molecules contributing to the pathogenesis of myositis‐associated ILD.
Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry
Authors: Tubach F. , Salmon D. , Ravaud P. , Allanore Y. , Goupille P. , Bréban M. , Pallot‐Prades B. , Pouplin S. , Sacchi A. , Chichemanian R. M. , Bretagne S. , Emilie D. , Lemann M. , Lorthololary O. , Mariette X. 
Published: June 2009

AbstractObjectiveTuberculosis (TB) is associated with anti–tumor necrosis factor (anti‐TNF) monoclonal antibody (mAb) therapy, but whether this association is drug‐specific remains a concern. Our objective was to describe cases of TB associated with anti‐TNF mAb therapy, identify risk factors, and estimate the incidence.MethodsWe conducted an incidence study and a case–control analysis to investigate the risk of newly diagnosed TB associated with the use of anti‐TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti‐TNF mAb therapy for any indication; for each case, 2 patients treated with anti‐TNF agents served as control subjects.ResultsWe collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex‐ and age‐adjusted incidence rate of TB was 116.7 per 100,000 patient‐years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7–15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4–25.8] and SIR 29.3 [95% CI 20.3–42.4] versus SIR 1.8 [95% CI 0.7–4.3], respectively). In the case–control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6–69.0] and OR 17.1 [95% CI 3.6–80.6], respectively). Other risk factors were age, the first year of anti‐TNF mAb treatment, and being born in an endemic area.ConclusionThe risk of TB is higher for patients receiving anti‐TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti‐TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.
The small ubiquitin‐like modifier mediates the resistance of prosthesis‐loosening fibroblast‐like synoviocytes against fas‐induced apoptosis
Authors: Meinecke Ingmar , Pap Géza , Mendoza Heidi , Drange Steffen , Ender Stephan , Strietholt Simon , Gay Renate E. , Seyfert Christine , Ink Barbara , Gay Steffen , Pap Thomas , Peters Marvin A. 
Published: June 2009

AbstractObjectiveTo study the expression of small ubiquitin‐like modifier 1 (SUMO‐1) in aseptic loosening of prosthesis implants and to investigate its role in regulating the susceptibility of prosthesis‐loosening fibroblast‐like synoviocytes (FLS) to Fas‐induced apoptosis.MethodsSpecimens of aseptically loosened tissue were obtained at revision surgery, and the expression of SUMO‐1 was analyzed by in situ hybridization. SUMO‐1 levels in FLS were determined by quantitative polymerase chain reaction and Western blot analysis. Immunohistochemistry and confocal microscopy were used to study the subcellular localization of SUMO‐1. The functional role of SUMO‐1 in Fas‐induced apoptosis of prosthesis‐loosening FLS was investigated by small interfering RNA–mediated knockdown of SUMO‐1 and by gene transfer of the nuclear SUMO‐specific protease SENP1.ResultsSUMO‐1 was expressed strongly in aseptically loosened tissue and was found prominently at sites adjacent to bone. Prosthesis‐loosening FLS expressed levels of SUMO‐1 similar to the levels expressed by rheumatoid arthritis (RA) FLS, with SUMO‐1 being found mainly in promyelocytic leukemia protein nuclear bodies. Knockdown of SUMO‐1 had no effect on spontaneous apoptosis but significantly increased the susceptibility of prosthesis‐loosening FLS to Fas‐induced apoptosis. Gene transfer of the nuclear SUMO‐specific protease SENP1 reverted the apoptosis‐inhibiting effects of SUMO‐1.ConclusionThese data suggest that SUMO‐1 is involved in the activation of both RA FLS and prosthesis‐loosening FLS by preventing these cells from undergoing apoptosis. Modification of nuclear proteins by SUMO‐1 contributes to the antiapoptotic effects of SUMO‐1 in prosthesis‐loosening FLS, providing evidence for the specific activation of sumoylation during their differentiation. Therefore, SUMO‐1 may be an interesting target for novel strategies to prevent aseptic prosthesis loosening.
Enthesis inflammation in recurrent acute anterior uveitis without spondylarthritis
Authors: Muñoz‐Fernández Santiago , de Miguel Eugenio , Cobo‐Ibáñez Tatiana , Madero Rosario , Ferreira Antonio , Hidalgo M. Ventura , Schlincker Armelle , Martín‐Mola Emilio 
Published: June 2009

AbstractObjectiveTo investigate whether patients with idiopathic recurrent acute anterior uveitis (AAU) have enthesis alterations comparable with those in patients with spondylarthritis (SpA).MethodsA blinded, controlled study of enthesis evident on ultrasound (US) examination was performed in 100 patients and controls classified into 5 groups, as follows: patients with confirmed SpA (group 1), patients with recurrent AAU who were positive for HLA–B27 and did not have SpA (group 2), patients with recurrent AAU who were negative for HLA–B27 and did not have SpA (group 3), patients with forms of uveitis other than those related to SpA (group 4), and healthy controls (group 5). In total, 12 enthesis locations were explored in each patient and control subject by 2 ultrasonographers who were blinded with regard to the diagnosis. A newly developed US method, the Madrid Sonography Enthesitis Index (MASEI), in which the diagnosis of SpA is determined as a cutoff score of 18 points, was used.ResultsA total of 1,200 entheses were explored by US in 100 patients and controls. The MASEI cutoff limit was met or exceeded by 81%, 55.6%, 40%, 10%, and 19% of the subjects in the 5 groups, respectively. The MASEI score was significantly higher in groups 1 and 2 than in groups 4 and 5. The differences between groups 1 and 3 were also found to be significant.ConclusionOur findings indicate that a high percentage of HLA–B27–positive patients with idiopathic recurrent AAU without features of SpA have enthesis lesions comparable with those seen in patients with SpA. These data suggest that patients with recurrent AAU, especially those who are HLA–B27 positive, have an abortive or incomplete form of SpA.
Changes in proximal femoral mineral geometry precede the onset of radiographic hip osteoarthritis: The study of osteoporotic fractures
Authors: Javaid M. K. , Lane N. E. , Mackey D. C. , Lui L.‐Y. , Arden N. K. , Beck T. J. , Hochberg M. C. , Nevitt M. C. 
Published: June 2009

AbstractObjectiveRadiographic hip osteoarthritis (RHOA) is associated with increased hip areal bone mineral density (aBMD). This study was undertaken to examine whether femoral geometry is associated with RHOA independent of aBMD.MethodsParticipants in the Study of Osteoporotic Fractures in whom pelvic radiographs had been obtained at visits 1 and 5 (mean 8.3 years apart) and hip dual x‐ray absorptiometry (DXA) had been performed (2 years after baseline) were included. Prevalent and incident RHOA phenotypes were defined as composite (osteophytes and joint space narrowing [JSN]), atrophic (JSN without osteophytes), or osteophytic (femoral osteophytes without JSN). Analogous definitions of progression were based on minimum joint space and total osteophyte score. Hip DXA scans were assessed using the Hip Structural Analysis program to derive geometric measures, including femoral neck length, width, and centroid position. Relative risks and 95% confidence intervals for prevalent, incident, and progressive RHOA per SD increase in geometric measure were estimated in a hip‐based analysis using multinomial logistic regression with adjustment for age, body mass index, knee height, and total hip aBMD.ResultsIn 5,245 women (mean age 72.6 years), a wider femoral neck with a more medial centroid position was associated with prevalent and incident osteophytic and composite RHOA phenotypes (P < 0.05). Increased neck width and centroid position were associated with osteophyte progression (both P < 0.05). No significant geometric associations with atrophic RHOA were found.ConclusionDifferences in proximal femoral bone geometry and spatial distribution of bone mass occur early in hip OA and predict prevalent, incident, and progressive osteophytic and composite phenotypes, but not the atrophic phenotype. These bone differences may reflect responses to loading occurring early in the natural history of RHOA.
Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis
Authors: Chia Shi‐Lu , Sawaji Yasunobu , Burleigh Annika , McLean Celia , Inglis Julia , Saklatvala Jeremy , Vincent Tonia 
Published: June 2009

AbstractObjectiveWe have previously identified in articular cartilage an abundant pool of the heparin‐binding growth factor, fibroblast growth factor 2 (FGF‐2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF‐2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF‐2 suppresses interleukin‐1–driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF‐2 in murine cartilage.MethodsBasal characteristics of the articular cartilage of Fgf2−/− and Fgf2+/+ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase–polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2−/− and Fgf2+/+ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF‐2 on OA progression was assessed in Fgf2−/− mice.ResultsFgf2−/− mice were morphologically indistinguishable from wild‐type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2−/− mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2−/− mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF‐2. Increased disease in Fgf2−/− mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase.ConclusionThese data identify FGF‐2 as a novel endogenous chondroprotective agent in articular cartilage.
The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome
Authors: Miceli‐Richard Corinne , Gestermann Nicolas , Ittah Marc , Comets Emmanuelle , Loiseau Pascale , Puechal Xavier , Hachulla Eric , Gottenberg Jacques‐Eric , Lebon Pierre , Becquemont Laurent , Mariette Xavier 
Published: June 2009

AbstractObjectiveInterferon regulatory factor 5 is a transcription factor involved in type I interferon (IFN) secretion. This study was undertaken to investigate whether a 5‐bp (CGGGG insertion/deletion) promoter polymorphism is involved in genetic predisposition to primary Sjögren's syndrome (SS) and to assess the functional consequences of this polymorphism.MethodsThe exploratory cohort consisted of 185 patients with primary SS and 157 healthy controls, and the replication cohort consisted of 200 patients with primary SS and 282 healthy controls. Levels of IRF5 messenger RNA (mRNA) were assessed at baseline and after in vitro infection with reovirus in peripheral blood mononuclear cells (PBMCs) from 30 patients with primary SS and from salivary gland epithelial cells that had been cultured for 4 weeks from patients with primary SS or sicca symptoms.ResultsCarriage of the IRF5 4R CGGGG allele was associated with a greatly increased risk of primary SS in both cohorts (odds ratio 2.00 [95% confidence interval 1.5–2.7], P = 6.6 × 10−6). The CGGGG insertion/deletion polymorphism alone was sufficient to explain the association of primary SS with IRF5. The level of IRF5 mRNA in PBMCs depended significantly on genotype (P = 0.002) and was correlated with the levels of mRNA for the IFN‐induced genes MX1 and IFITM1. Cultured salivary gland epithelial cells from patients carrying the 4R CGGGG IRF5 allele showed a high level of IRF5 mRNA (P = 0.04), which was amplified after reovirus infection (P = 0.026).ConclusionOur findings indicate an association of the CGGGG insertion/deletion polymorphism of the IRF5 promoter with primary SS. Patients carrying the 4R CGGGG IRF5 allele had a high level of mRNA for IRF5 in PBMCs and salivary gland epithelial cells, mainly after in vitro viral infection. Patients with high levels of mRNA for IRF5 also had high levels of mRNA for type I IFN–induced genes in PBMCs.