bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homeostatic effects of the metalloproteinase disintegrin ADAM15 in degenerative cartilage remodeling
Authors: Böhm Beate B. , Aigner Thomas , Roy Barbara , Brodie Thomas A. , Blobel Carl P. , Burkhardt Harald 
Published: April 2005

AbstractObjectiveThe membrane‐anchored metalloproteinase disintegrin ADAM15 is up‐regulated in osteoarthritis and has been implicated in proteolysis and cell–matrix interactions. To address its role in cartilage metabolism, we performed an analysis of joint morphology in aging mice with a targeted inactivation of the ADAM15 gene (ADAM15−/−). In addition, a human chondrocyte cell line overexpressing ADAM15 was used to investigate the role of ADAM15 in an in vitro model of chondrocyte–matrix interactions.MethodsKnee joint sections from 3‐, 6‐, and 12–14‐month‐old ADAM15−/− and wild‐type (WT) 129/SvJ mice were examined for synovial hyperplasia, cartilage degradation, and osteophyte formation. Stable transfection of the human T/C28a4 chondrocyte cell line with full‐length human ADAM15 complementary DNA led to the establishment of ADAM15‐overexpressing chondrocytes that were further analyzed for their capability to adhere to and to survive on cartilage matrix molecules (fibronectin and types II and VI collagen) under conditions of serum starvation. ADAM15 expression was investigated by reverse transcription–polymerase chain reaction and Western blotting.ResultsAging ADAM15−/− mice exhibited accelerated development of osteoarthritic lesions compared with WT mice, and the difference was statistically significant at age 12 months. The osteoarthritic changes preferentially affected male ADAM15−/− mice. ADAM15 overexpression in T/C28a4 cells led to the specific reinforcement of chondrocyte adhesion to cartilage types II and VI collagen, and this was associated with enhanced cell viability under conditions of serum starvation.ConclusionThe accelerated development of murine osteoarthritis in ADAM15 deficiency as well as the proadhesive and cell survival–promoting in vitro effect of ADAM15 overexpression suggest a homeostatic rather than a destructive role of ADAM15 in cartilage remodeling.
Effects of treatment with small interfering RNA on joint inflammation in mice with collagen‐induced arthritis
Authors: Schiffelers Raymond M. , Xu Jun , Storm Gert , Woodle Martin C. , Scaria Puthupparampil V. 
Published: April 2005

AbstractObjectiveRNA interference is a process in which genes can be silenced sequence‐specifically. In mammals, RNA interference can be invoked by introduction of small (19–21‐nucleotide) double‐stranded RNA molecules known as small interfering RNA (siRNA) into cells. Thereby, siRNA offers promise as a novel therapeutic modality. However, siRNA is a relatively large, highly charged molecule and does not readily enter cells. This study was undertaken to investigate the use of electroporation for in vivo transfection of siRNA into joint tissue in arthritic mice to achieve local RNA interference.MethodsProof of principle that siRNA is able to inhibit gene expression in vivo in the mouse joint was studied by local injection and electroporation of siRNA designed to silence reporter genes. In mice with collagen‐induced arthritis (CIA), the disease‐modulating activity of siRNA designed to silence tumor necrosis factor α (TNFα) was investigated.ResultsLuciferase activity could be reduced by >90% with luciferase‐specific siRNA as compared with the activity measured after electroporation without siRNA or with irrelevant siRNA. The effect was observed only locally. In mice with CIA, electroporation of siRNA designed to inhibit TNFα strongly inhibited joint inflammation, whereas electroporation of irrelevant siRNA or injection of siRNA against TNFα without electroporation failed to produce therapeutic effects.ConclusionLocal electroporation of siRNA in joint tissue can inhibit CIA in mice. These results offer promise for the use of siRNA as a new strategy for therapeutic intervention in rheumatoid arthritis and may serve as a tool to study arthritis disease pathways through loss‐of‐function phenotypes.
Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor α receptor fusion protein etanercept
Authors: Baraliakos X. , Davis J. , Tsuji W. , Braun J. 
Published: April 2005

AbstractObjectiveTo assess spinal inflammation by magnetic resonance imaging (MRI) before and after treatment with the tumor necrosis factor receptor fusion protein etanercept compared with placebo.MethodsAs part of a recently published randomized, controlled trial, 40 patients with ankylosing spondylitis (AS) underwent MRI of the lower thoracic and lumbar spine at 4 different time points: baseline, 12 weeks, 24 weeks, and 48 weeks. Nineteen patients received subcutaneous etanercept twice weekly (25 mg twice daily) for 1 year, and 21 patients received placebo for 6 months before being switched to etanercept. The mean age of the patients was 39.7 years, 75% were male, 89% were HLA–B27 positive, and the mean disease duration was 13 years. MRI examinations included T1‐weighted sequences before and after application of gadolinium–diethylenetriaminepentaacetic acid (Gd‐DTPA) and T2‐weighted fat‐saturated sequences. MRI sequences were scored with an adjusted AS spinal MRI score, using predefined vertebral units (VUs) as a basis.ResultsAfter 12 weeks, spinal inflammation (as assessed by T2‐weighted MRI with fat saturation) regressed by 54% in the etanercept group (mean score 1.33 per VU at baseline and 0.61 per VU at 12 weeks; P = 0.002) but worsened by 13% in the placebo group (0.94 at baseline and 1.06 at 12 weeks) (P < 0.001 between groups). After switching to etanercept, placebo patients improved similarly. T1‐weighted Gd‐DTPA MRI sequences performed equally well in detecting spinal changes. At baseline, >50% of all active lesions were detected in the thoracic spine. Deterioration of chronic changes was significant only in patients treated with placebo.ConclusionEtanercept treatment of patients with active AS results in regression of spinal inflammation as assessed by spinal MRI. Inclusion of the thoracic spine in MRI examinations of patients with AS may be of particular importance.
Association of sporadic chondrocalcinosis with a −4‐basepair G‐to‐A transition in the 5′‐untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate
Authors: Zhang Yun , Johnson Kristen , Russell R. Graham G. , Wordsworth B. Paul , Carr Andrew J. , Terkeltaub Robert A. , Brown Matthew A. 
Published: April 2005

AbstractObjectiveCertain mutations in ANKH, which encodes a multiple‐pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal‐dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis.MethodsANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH‐8 articular chondrocytes.ResultsSporadic chondrocalcinosis was associated with a G‐to‐A transition in the ANKH 5′‐untranslated region (5′‐UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This −4‐bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C‐to‐T and C‐terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143‐bp T‐to‐C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild‐type ANKH and the −4‐bp ANKH protein variant promoted increased extracellular PPi in CH‐8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen.ConclusionA subset of sporadic chondrocalcinosis appears to be heritable via a −4‐bp G‐to‐A ANKH 5′‐UTR transition that up‐regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.
Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: A detailed subanalysis of data from the anti–tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study
Authors: Smolen J. S. , Han C. , Bala M. , Maini R. N. , Kalden J. R. , van der Heijde D. , Breedveld F. C. , Furst D. E. , Lipsky P. E. ,   ATTRACT Study Group
Published: April 2005

AbstractObjectiveTo assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment.MethodsChanges from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti–Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial.ResultsAt week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28‐joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C‐reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo–treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX–treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001).ConclusionEven in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.
Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: Results of a fifty‐two–week, randomized, controlled study
Authors: van der Heijde Désirée , Baraf Herbert S. B. , Ramos‐Remus Cesar , Calin Andrei , Weaver Arthur L. , Schiff Michael , James Margaret , Markind Jan E. , Reicin Alise S. , Melian Agustin , Dougados Maxime 
Published: April 2005

AbstractObjectiveTo assess the efficacy, safety, and tolerability of etoricoxib, a cyclooxygenase 2 (COX‐2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS).MethodsThis 2‐part, multicenter, double‐blind, parallel‐group, 52‐week study evaluated 2 doses of etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6‐week, active‐comparator– and placebo‐controlled period (part I) was followed by a 46‐week active‐comparator–controlled period (part II). The primary outcome measures (on 100‐mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index.ResultsOf the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg etoricoxib, 120 mg etoricoxib, and naproxen demonstrated significantly (P < 0.001) greater improvement in all primary end points; treatment effects (expressed as the difference in least squares mean change versus placebo) were 21–29 mm for spine pain, 18–25 mm for disease activity, and 11–15 mm for function. Compared with patients receiving naproxen, significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks, in each individual etoricoxib treatment group over 6 weeks, and in the combined etoricoxib group over 1 year (all P < 0.05); results for secondary and exploratory end points were generally consistent with those from the primary analysis. Among all groups, there were no significant differences in the incidence of overall clinical, drug‐related, or serious adverse experiences (AEs) and discontinuations due to AEs. Safety observations during part II were generally consistent with those in part I.ConclusionEtoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that etoricoxib is generally safe, well‐tolerated, and efficacious for the treatment of AS.
Generation of novel covalent RNA–protein complexes in cells by ultraviolet B irradiation: Implications for autoimmunity
Authors: Andrade Felipe , Casciola‐Rosen Livia A. , Rosen Antony 
Published: April 2005

AbstractObjectiveTo determine whether ultraviolet B (UVB) irradiation induces novel modifications in autoantigens targeted during experimental photoinduced epidermal damage.MethodsTo search for novel UVB‐induced autoantigen modifications, lysates made from UVB‐irradiated human keratinocytes or HeLa cells were immunoblotted using human autoantibodies that recognize ribonucleoprotein autoantigens. Novel autoantigen structures identified were further characterized using nucleases and RNA hybridization.ResultsHuman sera that recognize U1–70 kd (U1‐70K) and La by immunoblotting also recognized multiple novel species when they were used to immunoblot lysates of UVB‐irradiated keratinocytes or HeLa cells. These species were not present in control cells and were not observed when apoptosis was induced by Fas ligation or cytotoxic lymphocyte granule contents. Biochemical analysis using multiple assays revealed that these novel UVB‐induced molecular species result from the covalent crosslinking between the U1 RNA and the hYRNA molecules with their associated proteins, including U1‐70K, La, and likely components of the Sm particle.ConclusionThese data demonstrate that UVB irradiation of live cells can directly induce covalent RNA–protein complexes, which are recognized by human autoantibodies. As previously described for other autoantigens, these covalent complexes of RNA and proteins may have important consequences in terms of antigen capture and processing.
Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort
Authors: Alarcón‐Segovia Donato , Alarcón‐Riquelme Marta E. , Cardiel Mario H. , Caeiro Francisco , Massardo Loreto , Villa Antonio R. , Pons‐Estel Bernardo A. ,   on behalf of the Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL)
Published: April 2005

AbstractObjectiveTo determine whether there is familial aggregation of systemic lupus erythematosus (SLE) and/or other autoimmune diseases in SLE patients and to identify clinical differences between patients with and those without familial autoimmunity.MethodsWe interviewed members of the Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL) inception cohort of 1,214 SLE patients to ascertain whether they had relatives with SLE and/or other autoimmune diseases. Identified relatives were studied. Familial aggregation was tested using reported highest and intermediate population prevalence data for SLE, rheumatoid arthritis (RA), or all autoimmune diseases, and studies were performed to identify the genetic model applicable for SLE.ResultsWe identified 116 first‐, second‐, or third‐degree relatives with SLE, 79 with RA, 23 with autoimmune thyroiditis, 3 with scleroderma, 1 with polymyositis, and 16 with other autoimmune diseases, related to 166 of the 1,177 SLE patients in the GLADEL cohort who agreed to participate. Forty‐two SLE patients had 2 or more relatives with an autoimmune disease. We found a λsibling of 5.8 and 29.0 for SLE and of 3.2–5.3 for RA, when comparing with their reported high or intermediate population prevalence, respectively. We also found familial aggregation for autoimmune disease in general (λsibling = 1.5) and determined that for SLE, a polygenic additive genetic model, rather than a multiplicative one, is applicable.ConclusionIn SLE there is familial aggregation of SLE, RA, and autoimmune disease in general. A polygenic additive model applies for SLE. American Indian–white Mestizo SLE patients and those with higher socioeconomic level were more likely to have familial autoimmunity.
Reduction of arthritis severity in protease‐activated receptor–deficient mice
Authors: Yang Yuan H. , Hall Pam , Little Christopher B. , Fosang Amanda J. , Milenkovski Georgia , Santos Leilani , Xue Jin , Tipping Peter , Morand Eric F. 
Published: April 2005

AbstractObjectiveProtease‐activated receptor 1 (PAR‐1) is the cell surface receptor for thrombin. It is unclear whether thrombin contributes to inflammation other than by effects on coagulation. We investigated the proinflammatory participation of PAR‐1 in antigen‐induced arthritis (AIA).MethodsArthritis was induced by intraarticular injection of methylated bovine serum albumin (mBSA) in preimmunized PAR‐1–deficient (PAR‐1−/−) and wild‐type (WT) mice. The disease was assessed after 7 days by histologic examination of knee joints after decalcification and Safranin O/toluidine blue staining. Serum levels of anti‐mBSA IgG, interferon‐γ, and interleukin‐4 (IL‐4) were determined by enzyme‐linked immunosorbent assay. T cell proliferation response was determined by measuring the incorporation of 3H‐thymidine. Cytokine messenger RNA (mRNA) expression was detected in synovial tissues and peritoneal cells by real‐time polymerase chain reaction.ResultsArthritis severity was significantly reduced in PAR‐1−/− mice compared with WT mice (P = 0.017). Analysis of individual aspects of joint histology revealed significant reductions in synovial exudates (P < 0.001), cartilage degradation (P < 0.01), and bone damage (P = 0.05) in PAR‐1−/− mice. Synovial IL‐1, IL‐6, and matrix metalloproteinase 13 (MMP‐13) mRNA was significantly reduced in PAR‐1−/− mice. The titers of antigen‐specific serum anti‐mBSA total IgG, IgG1, and IgG2a were significantly reduced, and serum IL‐4 was significantly increased in arthritic PAR‐1−/− mice. In contrast, no difference was observed in antigen‐induced T cell proliferation between PAR‐1−/− and WT mice. In vitro, thrombin‐induced (but not lipopolysaccharide‐induced) IL‐1, IL‐6, and MMP‐13 mRNA expression was significantly impaired in PAR‐1−/− mice compared with WT controls.ConclusionThese data demonstrate the requirement of PAR‐1 for the expression of AIA, the development of an antigen‐specific Ig response, thrombin‐induced macrophage cytokine and MMP expression, and the inhibitory effect of PAR‐1 on serum IL‐4. We conclude that PAR‐1 plays a significant role in this model of arthritis.
Minimizing complications from nonsteroidal antiinflammatory drugs: Cost‐effectiveness of competing strategies in varying risk groups
Authors: Spiegel Brennan M. R. , Chiou Chiun‐Fang , Ofman Joshua J. 
Published: April 2005

AbstractObjectiveTo appraise the cost‐effectiveness of competing therapeutic strategies in patient cohorts eligible for aspirin prophylaxis with varying degrees of gastrointestinal (GI) and cardiovascular risk.MethodsCost‐effectiveness and cost‐utility analyses were performed to evaluate 3 competing strategies for the management of chronic arthritis: 1) a generic nonselective nonsteroidal antiinflammatory drug (NSAIDNS) alone; 2) NSAIDNSplus a proton pump inhibitor (PPI); and 3) a cyclooxygenase 2‐selective inhibitor (coxib) alone. Cost estimates were from a third‐party payer perspective. The outcomes were incremental cost per ulcer complication avoided and incremental cost per quality‐adjusted life year (QALY) gained. Sensitivity analysis was performed to evaluate the impact of varying patient GI risks and aspirin use.ResultsIn average‐risk patients, the NSAIDNS+ PPI strategy costs an incremental $45,350 per additional ulcer complication avoided and $309,666 per QALY gained compared with the NSAIDNSstrategy. The coxib strategy was less effective and more expensive than the NSAIDNS+ PPI strategy. Sensitivity analysis revealed that the NSAIDNS+ PPI strategy became the dominant approach in patients at high risk for an NSAID adverse event (i.e., patients taking aspirin with ≥1 risk factor for a GI complication).ConclusionGeneric nonselective NSAIDs are most cost‐effective in patients at low risk for an adverse event. However, the addition of a PPI to a nonselective NSAID may be the preferred strategy in patients taking aspirin or otherwise at high risk for a GI or cardiovascular adverse event.
Determinants of sleep quality in women with systemic lupus erythematosus
Authors: Costa Deborah Da , Bernatsky Sasha , Dritsa Maria , Clarke Ann E. , Dasgupta Kaberi , Keshani Anahita , Pineau Christian 
Published: April 2005

AbstractObjectiveTo characterize sleep complaints in women with systemic lupus erythematosus (SLE) and to identify correlates of sleep quality.MethodsSleep quality in 100 women with SLE was assessed using the Pittsburgh Sleep Quality Index (PSQI). Participants completed standardized questionnaires assessing depressed mood, leisure time physical activity, functional disability, and pain severity. A clinical examination determined disease activity, cumulative damage, and whether patients fulfilled the American College of Rheumatology criteria for fibromyalgia. A series of hierarchical multiple regressions were computed.ResultsThe mean ± SD global PSQI score was 6.98 ± 4.03, with moderate to severe sleep impairment reported by 56% of the sample. The first model testing the importance of demographic factors was not statistically significant. In the disease‐related model, the use of prednisone and functional disability both contributed to poor sleep quality (P < 0.001). The addition of level of exercise participation to the demographic set significantly added to the model (P = 0.001). Depression significantly added to the demographic set, explaining 29% of the variance (P < 0.0001). When these variables, along with disease related variables, were simultaneously regressed on the PSQI Global Score, only depressed mood appeared as a significant independent determinant of global sleep quality (P < 0.001). However, the point estimates for the Beta coefficients were consistent with effects for lack of exercise and prednisone use.ConclusionA significant proportion of women with SLE suffer from poor sleep quality. The findings suggest that depressed mood, prednisone use, and lack of exercise contribute to decreased overall sleep quality.