bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with depression and suicidal ideation among individuals with arthritis or rheumatism: Findings from a representative community survey
Authors: Fuller‐Thomson Esme , Shaked Yael 
Published: June 2009

AbstractObjectiveTo investigate factors associated with depression and suicidal ideation among individuals with arthritis or rheumatism.MethodsThe nationally representative Canadian Community Health Survey 2000–2001 included 130,880 respondents (response rate 84.7%). Respondents were diagnosed as depressed using a subset of items from the Composite International Diagnostic Interview. There were 23,405 respondents age ≥20 years who reported that they had been diagnosed with arthritis or rheumatism by a health professional. Logistic regression analyses were conducted to investigate depression and suicidal ideation.ResultsOne in 10 Canadians with arthritis had clinically relevant levels of major depression. The age‐ and sex‐adjusted odds ratios (ORs) of major depression (OR 2.24, 95% confidence interval [95% CI] 2.11–2.38) and suicidal ideation (OR 2.01, 95% CI 1.75–2.31) among those with arthritis were approximately twice that of those without arthritis. The adjusted ORs of major depression among those with arthritis were significantly higher among women, the unmarried, younger, and poorer individuals. Individuals in pain, with limitations in activities of daily living, with limitations in instrumental activities of daily living, and with greater numbers of chronic conditions had higher odds of major depression. Less than half of those with major depression had consulted a mental health professional. One in 5 individuals with arthritis and major depression had been suicidal in the past year.ConclusionThe majority of individuals with arthritis and major depression were not receiving adequate treatment for major depression. Clients should be screened for major depression and suicidal ideation, particularly if they fall into the identified vulnerable groups.
Functional analysis of the osteoarthritis susceptibility–associated GDF5 regulatory polymorphism
Authors: Egli Rainer J. , Southam Lorraine , Wilkins James M. , Lorenzen Inken , Pombo‐Suarez Manuel , Gonzalez Antonio , Carr Andrew , Chapman Kay , Loughlin John 
Published: June 2009

AbstractObjectiveSingle‐nucleotide polymorphism (SNP) rs143383 (T to C) in the 5′‐untranslated region (5′‐UTR) of GDF5 has recently been reported to be associated with osteoarthritis (OA) susceptibility, with lower expression of the risk‐associated T allele observed in vitro and in vivo. The in vivo studies were performed on cartilage tissue from OA patients. The present study was undertaken to expand the analysis of the effect of this SNP on GDF5 allelic expression to more joint tissue types, to investigate for cis and trans factors that interact with the SNP, and to examine novel cis‐acting GDF5 regulatory polymorphisms.MethodsTissue samples were collected from OA patients undergoing joint replacement of the hip or knee. Nucleic acid was extracted, and, using rs143383 and an assay that discriminates and quantifies allelic expression, the relative amount of GDF5 expression from the T and C alleles was measured. Additional common variants in the GDF5 transcript sequence were interrogated as potential regulatory elements using allelic expression and luciferase reporter assays, and electrophoretic mobility shift assays were used to search for trans factors binding to rs143383.ResultsWe observed a consistent allelic expression imbalance of GDF5 in all tissues tested, implying that the functional effect mediated by rs143383 on GDF5 expression is joint‐wide. We identified a second polymorphism, located in the 3′‐UTR of GDF5, that influenced allelic expression of the gene independent of rs143383. Finally, we observed differential binding of deformed epidermal autoregulatory factor 1 (DEAF‐1) to the 2 alleles of rs143383.ConclusionThese findings show that the OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. The existence of an additional cis‐acting regulatory polymorphism highlights the complexity of the regulation of expression of this important OA susceptibility locus. DEAF‐1 is a trans‐acting factor that merits further investigation as a potential tool for modulating GDF5 expression.
Severe gouty arthritis and mild neurologic symptoms due to F199C, a newly identified variant of the hypoxanthine guanine phosphoribosyltransferase
Authors: Ea Hang‐Korng , Bardin Thomas , Jinnah H. A. , Aral Bernard , Lioté Frédéric , Ceballos‐Picot Irène 
Published: June 2009

AbstractA deficiency in hypoxanthine guanine phosphoribosyltransferase (HPRT) activity leads to overproduction of uric acid. According to the degree of enzymatic deficiency, a large spectrum of neurologic features can also be observed, ranging from mild or no neurologic involvement to complete Lesch‐Nyhan disease. Herein, we describe a patient with hyperuricemia, juvenile‐onset gouty arthritis, nephrolithiasis, and mild neurologic symptoms, attributed to a newly identified variant of the hprt gene, c.596T>G, resulting in the amino acid change p.F199C. Residual HPRT activity (8%) protected against severe neurologic involvement in this patient. Modeling of the mutated protein was used to predict the mechanisms that led to partial enzymatic activity. Careful neurologic examination is warranted in juvenile and middle‐aged patients with gout, in order to detect mild symptoms that may lead to a diagnosis of HPRT deficiency.
Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis
Authors: Prahalad Sampath , Hansen Sterling , Whiting April , Guthery Stephen L. , Clifford Bronte , McNally Bernadette , Zeft Andrew S. , Bohnsack John F. , Jorde Lynn B. 
Published: June 2009

AbstractObjectiveSubtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors.MethodsCases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single‐nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.ResultsThe strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61–0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05–1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02–1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01–1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy‐Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA.ConclusionWe have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.
Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum–induced arthritis in vivo
Authors: Buttgereit Frank , Zhou Hong , Kalak Robert , Gaber Timo , Spies Cornelia M. , Huscher Dörte , Straub Ranier H. , Modzelewski James , Dunstan Colin R. , Seibel Markus J. 
Published: June 2009

AbstractObjectiveEndogenous glucocorticoids (GCs) modulate numerous biologic systems involved in the initiation and maintenance of arthritis. Bone cells play a critical role in the progression of arthritis, and some of the effects of GCs on inflammation may be mediated via these cells. The aim of this study was to investigate the impact of osteoblast‐targeted disruption of GC signaling on joint inflammation, cartilage damage, and bone metabolism in the K/BxN mouse serum transfer model of autoimmune arthritis.MethodsIntracellular GC signaling was disrupted in osteoblasts through transgenic overexpression of 11β‐hydroxysteroid dehydrogenase type 2 under the control of a type I collagen promoter. Arthritis was induced in 5‐week‐old male transgenic mice and their wild‐type (WT) littermates, and paw swelling was assessed daily until the mice were killed. The mice were examined by histology, histomorphometry, and microfocal computed tomography, and serum was analyzed for cytokines, adrenocorticotropic hormone, and corticosterone.ResultsAcute arthritis developed in both transgenic and WT mice treated with K/BxN mouse serum. However, the arthritis and local inflammatory activity were significantly attenuated in transgenic mice, as judged by clinical and histologic indices of inflammation and cartilage damage. Bone turnover and bone volume remained unchanged in arthritic transgenic mice, while WT mice exhibited stimulated bone resorption, suppressed osteoblast activity, and significantly reduced bone volume, compatible with the known effects of active inflammation on bone. Circulating levels of proinflammatory cytokines tended to be lower in arthritic transgenic mice than in control transgenic mice.ConclusionDisruption of GC signaling in osteoblasts significantly attenuates K/BxN mouse serum–induced autoimmune arthritis in mice. These data suggest that osteoblasts modulate the immune‐mediated inflammatory response via a GC‐dependent pathway.
Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen
Authors: Ponticos Markella , Holmes Alan M. , Shi‐Wen Xu , Leoni Patricia , Khan Korsa , Rajkumar Vineeth S. , Hoyles Rachel K. , Bou‐Gharios George , Black Carol M. , Denton Christopher P. , Abraham David J. , Leask Andrew , Lindahl Gisela E. 
Published: June 2009

AbstractObjectiveConnective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor β (TGFβ) and is a mediator of some profibrotic effects of TGFβ in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin‐induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I α2) in this mouse model and in human pulmonary fibroblasts.MethodsTransgenic mice that were carrying luciferase and β‐galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts.ResultsIn the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti‐CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by ∼25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycin‐treated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK‐1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c‐Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK‐1/2 and JNK signaling.ConclusionOur results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation of Col1a2. Blocking strategies revealed the signaling mechanisms involved. These findings show CTGF to be a rational target for therapy in fibrotic diseases such as SSc.
RNA helicase encoded by melanoma differentiation–associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease
Authors: Sato Shinji , Hoshino Kana , Satoh Takashi , Fujita Tomonobu , Kawakami Yutaka , Fujita Takashi , Kuwana Masataka 
Published: June 2009

AbstractObjectiveTo identify the autoantigen recognized by the autoantibody that is associated with clinically amyopathic dermatomyositis (C‐ADM) and rapidly progressive interstitial lung disease (ILD).MethodsAn anti–CADM‐140 antibody–positive prototype serum sample was used to screen a HeLa cell–derived complementary DNA (cDNA) library. Selected cDNA clones were further evaluated by immunoprecipitation of their in vitro–transcribed and in vitro–translated products using anti–CADM‐140 antibody–positive and anti‐CADM‐140 antibody–negative sera. The lysates of COS‐7 cells transfected with the putative antigen were similarly tested. An enzyme‐linked immunosorbent assay (ELISA) to detect the anti–CADM‐140 antibody was established using a recombinant CADM‐140 antigen, and its specificity and sensitivity for C‐ADM and rapidly progressive ILD were assessed in 294 patients with various connective tissue diseases.ResultsBy cDNA library screening and immunoprecipitation of in vitro–transcribed and in vitro–translated products, we obtained a cDNA clone encoding melanoma differentiation–associated gene 5 (MDA‐5). The anti–CADM‐140 antibodies in patients' sera specifically reacted with MDA‐5 protein expressed in cells transfected with full‐length MDA‐5 cDNA, confirming the identity of MDA‐5 as the CADM‐140 autoantigen. The ELISA, using recombinant MDA‐5 protein as the antigen, showed an analytical sensitivity of 85% and analytical specificity of 100%, in comparison with the “gold standard” immunoprecipitation assay, and was useful for identifying patients with C‐ADM and/or rapidly progressive ILD.ConclusionGiven that RNA helicase encoded by MDA‐5 is a critical molecule involved in the innate immune defense against viruses, viral infection may play an important role in the pathogenesis of C‐ADM and rapidly progressive ILD. Moreover, our ELISA using recombinant MDA‐5 protein makes detection of the anti–CADM‐140 antibody routinely available.
Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis
Authors: Rho Young Hee , Solus Joseph , Sokka Tuulikki , Oeser Annette , Chung Cecilia P. , Gebretsadik Tebeb , Shintani Ayumi , Pincus Theodore , Stein C. Michael 
Published: June 2009

AbstractObjectiveObesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA.MethodsWe compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C‐reactive protein [CRP], interleukin‐6 [IL‐6], and tumor necrosis factor α [TNFα]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFα, IL‐6, and CRP).ResultsConcentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32–4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (ρ = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17–0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42–1.73], P = 0.67).ConclusionConcentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.
Systemic activation of the immune system induces aberrant BAFF and APRIL expression in B cells in patients with systemic lupus erythematosus
Authors: Chu Van Trung , Enghard Philipp , Schürer Stefanie , Steinhauser Gudrun , Rudolph Birgit , Riemekasten Gabriela , Berek Claudia 
Published: June 2009

AbstractObjectiveElevated levels of BAFF and APRIL are characteristic of patients with systemic lupus erythematosus (SLE). The reasons for enhanced cytokine production are not well understood. This study was undertaken to identify the cells responsible for the overproduction of these cytokines.MethodsBAFF expression was analyzed on peripheral blood mononuclear cells by multiparameter flow cytometry and in tissue samples by immunofluorescence staining. The levels of BAFF and APRIL mRNA were quantified in sorted B cells. In vitro cultures were used to analyze whether B cell survival and differentiation was supported by autocrine BAFF and/or APRIL.ResultsAberrant activation of B cells in patients with SLE was associated with a significant up‐regulation of BAFF expression in naive, memory, and plasma cells. Furthermore, strong expression of BAFF and APRIL was found in plasma cells from the lymph node, bone marrow, and kidney. The levels of BAFF and APRIL mRNA in CD19+ B cells correlated both with the titer of anti‐double stranded DNA antibodies and with the SLE Disease Activity Index. In vitro experiments demonstrated that B cells released functional BAFF/APRIL upon activation.ConclusionOur data show that B cells contribute to the enhanced levels of circulating BAFF and APRIL. The aberrant up‐regulation of these cytokines may initiate a vicious circle in which enhanced levels of BAFF and APRIL act in an autocrine manner to reinforce the systemic activation of the humoral immune system.
Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis
Authors: Cantaert Tineke , Brouard Sophie , Thurlings Rogier M. , Pallier Annaick , Salinas Gabriela Franco , Braud Christophe , Klarenbeek Paul L. , de Vries Niek , Zhang Yiping , Soulillou Jean‐Paul , Tak Paul P. , Baeten Dominique 
Published: June 2009

AbstractObjectiveThe association of HLA–DRB1 alleles with anti–citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA‐seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA+ versus ACPA– RA patients.MethodsSynovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA+ RA patients, 7 ACPA– RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis.ResultsACPA+ and ACPA– RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA+ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA– synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis.ConclusionThe T cell repertoire is specifically restricted in RA patients with ACPA+ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPA‐seropositive RA.