bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis
Authors: Stanczyk Joanna , Pedrioli Deena M. Leslie , Brentano Fabia , Sanchez‐Pernaute Olga , Kolling Christoph , Gay Renate E. , Detmar Michael , Gay Steffen , Kyburz Diego 
Published: March 2008

AbstractObjectiveMicroRNAs (miRNA) have recently emerged as a new class of modulators of gene expression. In this study we investigated the expression, regulation, and function of miR‐155 and miR‐146a in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) and RA synovial tissue.MethodsLocked nucleic acid microarray was used to screen for differentially expressed miRNA in RASFs treated with tumor necrosis factor α (TNFα). TaqMan‐based real‐time polymerase chain reaction was applied to measure the levels of miR‐155 and miR‐146a. Enforced overexpression of miR‐155 was used to investigate the function of miR‐155 in RASFs.ResultsMicroarray analysis of miRNA expressed in RASFs treated with TNFα revealed a prominent up‐regulation of miR‐155. Constitutive expression of both miR‐155 and miR‐146a was higher in RASFs than in those from patients with osteoarthritis (OA), and expression of miR‐155 could be further induced by TNFα, interleukin‐1β, lipopolysaccharide, poly(I‐C), and bacterial lipoprotein. The expression of miR‐155 in RA synovial tissue was higher than in OA synovial tissue. Enforced expression of miR‐155 in RASFs was found to repress the levels of matrix metalloproteinase 3 (MMP‐3) and reduce the induction of MMPs 3 and 1 by Toll‐like receptor ligands and cytokines. Moreover, compared with monocytes from RA peripheral blood, RA synovial fluid monocytes displayed higher levels of miR‐155.ConclusionThis study provides the first description of increased expression of miRNA miR‐155 and miR‐146a in RA. Based on these findings, we postulate that the inflammatory milieu may alter miRNA expression profiles in resident cells of the rheumatoid joints. Considering the repressive effect of miR‐155 on the expression of MMPs 3 and 1 in RASFs, we hypothesize that miR‐155 may be involved in modulation of the destructive properties of RASFs.
Beta2‐glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti–β2‐glycoprotein I autoantibodies
Authors: Rahgozar Soheila , Giannakopoulos Bill , Yan Xiaokai , Wei Jiewei , Cheng Qi Jian , Gemmell Rosalie , Krilis Steven A. 
Published: March 2008

AbstractObjectiveBeta2‐glycoprotein I (β2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that β2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of β2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti‐β2GPI antibodies was also examined.MethodsHCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved β2GPI and anti‐β2GPI antibodies was determined in these systems.Resultsβ2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of β2GPI at Lys317–Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti‐β2GPI antibodies potentiated the procoagulant influence of β2GPI in this system.ConclusionThese novel findings suggest that β2GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti‐β2GPI antibodies potentiate the protective effect of β2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS.
Modulation of aggrecan and ADAMTS expression in ovine tendinopathy induced by altered strain
Authors: Smith M. M. , Sakurai G. , Smith S. M. , Young A. A. , Melrose J. , Stewart C. M. , Appleyard R. C. , Peterson J. L. , Gillies R. M. , Dart A. J. , Sonnabend D. H. , Little C. B. 
Published: March 2008

AbstractObjectiveTo evaluate histologic, immunohistochemical, and molecular changes in tendon induced by altered strain in a large‐animal model.MethodsA full‐thickness partial‐width laceration of the infraspinatus tendon was created in 5 sheep, while 5 sham‐operated sheep were used as controls. Sheep were killed after 4 weeks, and 4 differentially stressed tendon regions (tensile or near bone attachment from overstressed or stress‐deprived halves) were evaluated for histopathology, proteoglycan (PG) accumulation, and characterization of glycosaminoglycans and aggrecan catabolites. Gene expression of matrix components, enzymes, and inhibitors was analyzed by reverse transcriptase–polymerase chain reaction.ResultsHistopathologic changes were detected in both overstressed and stress‐deprived tensile tendon, but only in stress‐deprived tendon near bone. In overstressed and stress‐deprived tensile tendon, levels of keratan sulfate, chondroitin 4‐sulfate, and chondroitin 6‐sulfate were increased. In overstressed tensile tendon, levels of ADAMTS‐generated aggrecan catabolites were increased. There was increased matrix metalloproteinase 13 (MMP‐13) and decreased fibromodulin and decorin expression in all regions. Increased MMP‐1, MMP‐9, MMP‐14, and ADAMTS‐1 expression, and decreased type II collagen expression were restricted to stress‐deprived tendon. In stress‐deprived bone‐attachment regions, messenger RNA (mRNA) for aggrecan was decreased, and ADAMTS was increased. In overstressed tensile tendon, aggrecan mRNA was increased, and ADAMTS was decreased.ConclusionThe distinct molecular changes in adjacent tissue implicate altered strain rather than humoral factors in controlling abnormal tenocyte metabolism, and highlight the importance of regional sampling. Tendon abnormalities induced by increased strain are accompanied by increased aggrecan, decreased ADAMTS, and low PG expression, which may negatively impact the structural integrity of the tissue and predispose to rupture.
Results of a two‐year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate
Authors: Kremer Joel M. , Genant Harry K. , Moreland Larry W. , Russell Anthony S. , Emery Paul , Abud‐Mendoza Carlos , Szechiński Jacek , Li Tracy , Teng Julie , Becker Jean‐Claude , Westhovens René 
Published: March 2008

AbstractObjectiveTo evaluate the efficacy, radiographic changes, and safety of abatacept and methotrexate therapy through 2 years in a long‐term extension of a previously published 1‐year study.MethodsPatients who received placebo during year 1 were switched to abatacept. Patients taking abatacept continued to take it. Efficacy and safety were assessed through 2 years.ResultsOf 539 patients enrolled in the initial 1‐year study, 488 completed 1 year of the long‐term extension (2% discontinued for lack of efficacy). At 2 years, patients taking abatacept had maintained their responses on the American College of Rheumatology (ACR) improvement criteria and the Disease Activity Score in 28 joints (DAS28; using the C‐reactive protein [CRP] level), as well as their physical function (according to the Health Assessment Questionnaire [HAQ] disability index [DI]) and health‐related quality of life (HRQOL; assessed with the Short Form 36 [SF‐36] health survey), that were observed at the end of the double‐blind period (year 1 versus year 2 values were 81.9% versus 80.3% for ACR 20% improvement, 25.4% versus 30.9% for a DAS28 [CRP] of <2.6, 71.8% versus 66.8% for the HAQ DI, and 9.7 versus 10.6 and 7.3 versus 7.2, respectively, for the mean change in the physical and mental components summary scores of the SF‐36). In the abatacept group, post hoc analysis demonstrated further inhibition of radiographic progression during year 2 (57% reduction in mean change of total score in year 2 versus year 1; P < 0.0001), and minimal radiographic progression was observed (mean change in total score from baseline was 1.1 and 1.6 at year 1 and 2, respectively). Rates of adverse events (AEs) and severe AEs were consistent throughout the cumulative period.ConclusionThe improvements in signs and symptoms, physical function, and HRQOL observed after 1 year of abatacept treatment were maintained through 2 years of treatment. This durability was accompanied by a safety profile consistent with that in the double‐blind portion of the study. Radiographic progression was further inhibited in year 2 compared with year 1, suggesting an increasing effect of abatacept on the inhibition of structural damage in year 2.
Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus
Authors: Arinuma Yoshiyuki , Yanagida Tamiko , Hirohata Shunsei 
Published: March 2008

AbstractObjectiveTo explore the association of antibodies directed against N‐methyl‐D‐aspartate receptor subunit NR2 (anti‐NR2) in cerebrospinal fluid (CSF) with neuropsychiatric manifestations in systemic lupus erythematosus (NPSLE).MethodsPaired serum and CSF specimens were obtained from 56 patients with NPSLE (38 with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 18 with neurologic syndromes or peripheral neuropathy [focal NPSLE]) and from 20 control patients with noninflammatory neurologic diseases. IgG anti‐NR2 antibodies were measured by enzyme‐linked immunosorbent assay using synthetic peptide containing the extracellular ligand‐binding domain of NR2. The binding of affinity‐purified anti‐NR2 to human neuroblastoma cell line SK‐N‐MC was examined by flow cytometry.ResultsPurified anti‐NR2 bound to the surface of SK‐N‐MC cells. Levels of anti‐NR2 antibodies in CSF were significantly elevated in patients with diffuse NPSLE compared with levels in control patients or those with focal NPSLE, whereas there were no significant differences in serum anti‐NR2 levels among the 3 groups. In 31 of the 38 patients with diffuse NPSLE (81.6%) and 8 of the 18 patients with focal NPSLE (44.4%), CSF anti‐NR2 levels were more than 3 SD above the mean level in the control patients (P = 0.0120 by chi‐square test).ConclusionThese results indicate that anti‐NR2 is a constituent of antineuronal antibodies and, more importantly, that anti‐NR2 antibodies in CSF, but not in serum, are associated with diffuse NPSLE.
Familial clustering of non‐nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus
Authors: Hunnangkul Saowalak , Nitsch Dorothea , Rhodes Benjamin , Chadha Sapna , Roberton Cheri A. , Pessôa‐Lopes Pedro , Norsworthy Peter J. , Fernando Michelle M. A. , Charles Peter , Mackworth‐Young Charles , Isenberg David A. , Whittaker John C. , Vyse Timothy J. 
Published: March 2008

AbstractObjectiveTo determine whether key features of systemic lupus erythematosus (SLE), namely, production of non‐nuclear antibodies (anti‐C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti‐C1q and C3 and C4 levels.MethodsThe study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti‐C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set.ResultsWe demonstrated associations between siblings for anti‐C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti‐C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti‐C1q, C3, and C4 (∼45%). Anti‐C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives.ConclusionNon‐nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti‐C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.
High prevalence of temporomandibular joint arthritis at disease onset in children with juvenile idiopathic arthritis, as detected by magnetic resonance imaging but not by ultrasound
Authors: Weiss Pamela F. , Arabshahi Bita , Johnson Ann , Bilaniuk Larissa T. , Zarnow Deborah , Cahill Anne Marie , Feudtner Chris , Cron Randy Q. 
Published: March 2008

AbstractObjectiveTo determine the prevalence of temporomandibular joint (TMJ) disease in a cohort of children with new‐onset juvenile idiopathic arthritis (JIA), and to compare magnetic resonance imaging (MRI) with ultrasound (US) for the detection of acute and chronic changes of TMJ arthritis.MethodsBetween January 2005 and April 2007, children with newly diagnosed JIA were prospectively evaluated for TMJ arthritis. Prior to imaging, jaw pain and disability were assessed with questionnaires and physical examination. The TMJs of all patients were imaged with MRI and US within 8 weeks of diagnosis.ResultsOf the 32 patients enrolled, 78% were female, and the median age was 8.6 years (range 1.5–17.2 years). Acute TMJ arthritis was diagnosed in 75% of the children by MRI and in none by US; chronic arthritis was diagnosed in 69% by MRI and in 28% by US. Findings of both acute and chronic TMJ disease were detected by MRI in 53% of the patients. Of those with acute TMJ arthritis, 71% were asymptomatic, and 63% had normal findings on jaw examination. Fifty‐six percent of patients with acute disease had an improved maximal incisal opening after corticosteroid injection. Among these responders, 56% had been asymptomatic and had normal jaw examination findings.ConclusionTMJ arthritis was present in the majority of patients with new‐onset JIA. Findings on MRI along with responses to treatment among asymptomatic patients with normal jaw examination findings suggest that a history review and physical examination are not sufficient to screen for TMJ disease. Our results also suggest that MRI and US findings are not well correlated, and that MRI is preferable for the detection of TMJ disease in new‐onset JIA.
The influence of age at symptom onset and length of followup on mortality in patients with recent‐onset inflammatory polyarthritis
Authors: Naz Sophia M. , Farragher Tracey M. , Bunn Diane K. , Symmons Deborah P. M. , Bruce Ian N. 
Published: March 2008

AbstractObjectiveTo investigate the influence of age at symptom onset and length of followup on mortality in patients with recent‐onset inflammatory polyarthritis (IP), and to examine predictors of mortality in relation to disease duration.MethodsFrom 1990 to 1994, patients with recent‐onset IP were registered with the Norfolk Arthritis Register (NOAR) and followed up prospectively. Standardized mortality ratios (SMRs) were calculated for all‐cause and cardiovascular disease (CVD) mortality and for those who were younger than age 55 years at disease onset and for the first 5 and 10 years of followup. Cox proportional hazards models were developed to assess predictors of early and later mortality.ResultsOf 1,098 patients, 224 (20%) had died by the end of 2004. All‐cause and CVD mortality were increased in rheumatoid factor (RF)–positive patients and in this subgroup, CVD mortality was increased at both early and later followup (SMR 5‐year followup 1.93 [95% confidence interval 1.08–3.19]; SMR 10‐year followup 2.00 [95% confidence interval 1.37–2.80]). CVD mortality was highest in seropositive patients <55 years of age at disease onset (SMR 5.58 [95% confidence interval 2.24–11.50]). In multivariate models, age at onset, male sex, RF positivity, Health Assessment Questionnaire score ≥1.5, and nodules were predictors of early and later mortality.ConclusionPatients with IP had higher rates of CVD mortality throughout the followup period studied, and this was highest in seropositive patients who were <55 years of age at symptom onset. This subgroup deserves particular attention in terms of disease and risk factor modification. Nodules were independent predictors of CVD mortality, suggesting that extraarticular/vascular inflammation identifies patients at particularly high CVD risk.
Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts
Authors: Juarranz Yasmina , Gutiérrez‐Cañas Irene , Santiago Begoña , Carrión Mar , Pablos José L. , Gomariz Rosa P. 
Published: March 2008

AbstractObjectiveVasoactive intestinal peptide (VIP) has shown potent antiinflammatory effects in murine arthritis and ex vivo in human rheumatoid arthritis (RA) synovial cells. To investigate the potential endogenous participation of this system in the pathogenesis of RA, we analyzed the expression and regulation of VIP and its functional receptors in human fibroblast‐like synoviocytes (FLS) from patients with osteoarthritis (OA) and patients with RA.MethodsThe expression of VIP was studied by reverse transcription–polymerase chain reaction (RT‐PCR), enzyme immunoassay, and immunofluorescence in cultured FLS, and by immunohistochemical analysis in synovial tissue. The expression and function of the potential VIP receptors in FLS were studied by RT‐PCR, determination of intracellular cAMP production, cell membrane adenylate cyclase (AC) activity, and interleukin‐6, CCL2, and CXCL8 production in response to VIP or specific agonists and antagonists.ResultsVIP expression was detected in human FLS at the messenger RNA and protein levels, and it was significantly decreased in RA FLS compared with OA FLS. VIP receptor type 1 (VPAC1) was the dominant AC‐coupled receptor in OA FLS, in contrast with RA FLS, in which VPAC2 was dominant. Tumor necrosis factor α–treated OA FLS reproduced the VIP and VPAC receptor expression pattern of RA FLS. The antagonistic effects of VIP on FLS proinflammatory factor production were reproduced by VPAC1‐ and VPAC2‐specific agonists in OA FLS and RA FLS, respectively.ConclusionVIP expression is down‐regulated in RA and in tumor necrosis factor α–treated FLS, suggesting that down‐regulation of this endogenous antiinflammatory factor may contribute to the pathogenesis of RA. In RA FLS, VPAC2 mediates the antiinflammatory effects of VIP, suggesting that VPAC2 agonists may be an alternative to VIP as antiinflammatory agents.
Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus
Authors: Biesen Robert , Demir Cemal , Barkhudarova Fidan , Grün Joachim R. , Steinbrich‐Zöllner Marta , Backhaus Marina , Häupl Thomas , Rudwaleit Martin , Riemekasten Gabriela , Radbruch Andreas , Hiepe Falk , Burmester Gerd‐Rüdiger , Grützkau Andreas 
Published: March 2008

AbstractObjectiveType I interferon (IFN) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and is therefore considered a potential therapeutic target. This study was undertaken to establish a feasible biomarker for IFN effects with respect to disease activity and effectiveness of IFN‐suppressive therapy in SLE patients.MethodsTranscriptomes of purified monocytes from 9 SLE patients and 7 healthy controls were analyzed by Affymetrix GeneChip technology. Levels of sialic acid–binding Ig‐like lectin 1 (Siglec‐1) (sialoadhesin, CD169) in inflammatory and resident monocytes were determined at the protein level in 38 healthy controls and 52 SLE patients, using multicolor flow cytometry.ResultsTranscriptomes of peripheral monocytes from SLE patients revealed a dominant type I IFN signature. Siglec‐1 was identified as one of the most prominent type I IFN–regulated candidate genes. At the protein level, the frequency of Siglec‐1–expressing monocyte subsets was correlated with disease activity (as measured by the SLE Disease Activity Index) and was inversely correlated with levels of complement factors. Most interestingly, levels of anti–double‐stranded DNA (anti‐dsDNA) antibodies were highly correlated with the percentage of resident monocytes, but not inflammatory monocytes, expressing Siglec‐1. High‐dose glucocorticoid treatment resulted in a dramatic reduction of Siglec‐1 expression in cells from patients with active SLE.ConclusionOur findings indicate that Siglec‐1 expression in resident blood monocytes is a potential biomarker for monitoring disease activity, displaying type I IFN responses, and estimating levels of anti‐dsDNA antibodies. Moreover, our results suggest that resident and inflammatory monocytes contribute differently to the process of autoantibody formation in SLE.
Pulmonary capillary endothelial metabolic dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension
Authors: Langleben David , Orfanos Stylianos E. , Giovinazzo Michele , Hirsch Andrew , Baron Murray , Senécal Jean‐Luc , Armaganidis Apostolos , Catravas John D. 
Published: March 2008

AbstractObjectivePulmonary endothelial dysfunction is intertwined with the development and progression of pulmonary arterial hypertension (PAH). Pulmonary endothelium is an active metabolic tissue in healthy human subjects. This study was undertaken to determine the effects of PAH on pulmonary endothelial angiotensin‐converting enzyme (ACE) activity and to identify differences between common PAH types, i.e., PAH related to connective tissue disease (PAH‐CTD) versus idiopathic PAH (IPAH).MethodsNineteen patients with PAH‐CTD, 25 patients with IPAH, and 23 control subjects were evaluated. The single‐pass transpulmonary percent metabolism (%M) and hydrolysis (both reflecting enzyme activity per capillary) of an ACE synthetic substrate were determined. In addition, the calculated functional capillary surface area (FCSA), normalized to body surface area (BSA), was determined.ResultsThe %M values in patients with PAH‐CTD (mean ± SEM 53.6 ± 3.6%) were significantly reduced compared with those in control subjects (P < 0.01) and those in patients with IPAH (P < 0.03), but were similar between the IPAH and control groups (mean ± SEM 66.2 ± 3.6% and 74.7 ± 2.7%, respectively). Substrate hydrolysis was also significantly reduced in patients with PAH‐CTD. The FCSA/BSA was significantly reduced in patients with PAH‐CTD (mean ± SEM 1,068 ± 118 ml/minute/m2) and in patients with IPAH (1,443 ± 186 ml/minute/m2) compared with that in controls (2,948 ± 245 ml/minute/m2; P < 0.01 for both). At a given cardiac index, the FCSA/BSA tended to be lower in the PAH‐CTD group than in the IPAH group. Moreover, unlike in IPAH, a linear relationship between the FCSA/BSA and the diffusing capacity for carbon monoxide (DLCO) was observed in PAH‐CTD (r = 0.54, P < 0.03).ConclusionThe metabolically functional pulmonary capillary bed appears to be reduced to an equal extent in PAH‐CTD and IPAH. However, %M and hydrolysis appear to be reduced in PAH‐CTD but not in IPAH, reflecting relatively diminished ACE activity on the pulmonary capillary endothelial cells of patients with PAH‐CTD, and showing that pulmonary endothelial metabolic function differs between PAH types. This study also provides the first functional evidence that a reduced DLCO value in patients with PAH‐CTD is related to the degree of FCSA loss.