bluuebunny/crossref_metadata_2025_split huggingface dataset:
Freshly isolated osteoarthritic chondrocytes are catabolically more active than normal chondrocytes, but less responsive to catabolic stimulation with interleukin‐1β
Authors: Fan Zhiyong , Bau Brigitte , Yang Huiqing , Soeder Stephan , Aigner Thomas 
Published: January 2005

AbstractObjectiveInterleukin‐1β (IL‐1β) is one potentially important cytokine during cartilage destruction. The aim of this study was to investigate whether there are different effects of low and high concentrations of IL‐1β on the expression level of anabolic genes (type II collagen, aggrecan), catabolic genes (matrix metalloproteinase 1 [MMP‐1], MMP‐2, MMP‐3, MMP‐13, and ADAMTS‐4), and cytokines (IL‐1β, IL‐6, and leukemia inhibitory factor [LIF]) by articular chondrocytes (normal and osteoarthritic). Determination of whether there was a difference in reactivity between normal and osteoarthritic chondrocytes was also a goal of this study.MethodsGene expression levels were detected by real‐time polymerase chain reaction from isolated (nonpassaged) chondrocytes (normal [n = 6]; osteoarthritic [n = 7]) after stimulation with 0.01 ng, 0.1 ng, 1 ng, and 10 ng/ml IL‐1β.ResultsIn normal adult articular chondrocytes the expression of both aggrecan and type II collagen genes was significantly down‐regulated, whereas matrix‐degrading proteases (except MMP‐2), as well as the investigated cytokines, were induced by IL‐1β in a dose‐dependent manner. The strongest regulation was found for IL‐6 and LIF. Osteoarthritic chondrocytes showed strongly increased levels of catabolic enzymes and mediators, but were less responsive to further stimulation with IL‐1β.ConclusionOur study confirms that IL‐1β activity is critically dependent on both the applied concentration and the reactivity of the cells stimulated. The responsiveness appears to be significantly reduced in late‐stage osteoarthritic chondrocytes. However, these cells show high basic expression levels of catabolic enzymes and mediators. Thus, it remains open whether our data indicate that osteoarthritic chondrocytes are per se not responsive to IL‐1β or are already so strongly stimulated (e.g., by IL‐1) during the disease process that they are refractory to further stimulation.
Repair of articular cartilage defect by autologous transplantation of basic fibroblast growth factor gene–transduced chondrocytes with adeno‐associated virus vector
Authors: Yokoo Naoki , Saito Tomoyuki , Uesugi Masaaki , Kobayashi Naomi , Xin Ke‐Qin , Okuda Kenji , Mizukami Hiroaki , Ozawa Keiya , Koshino Tomihisa 
Published: January 2005

AbstractObjectiveTo examine the effects of basic fibroblast growth factor (bFGF) gene–transduced chondrocytes on the repair of articular cartilage defects.MethodsLacZ gene or bFGF gene was transduced into primary isolated rabbit chondrocytes with the use of a recombinant adeno‐associated virus (AAV) vector. These gene‐transduced chondrocytes were embedded in collagen gel and transplanted into a full‐thickness defect in the articular cartilage of the patellar groove of a rabbit. The efficiency of gene transduction was assessed according to the percentage of LacZ‐positive cells among the total number of living cells. The concentration of bFGF in the culture supernatant was measured by enzyme‐linked immunosorbent assay to confirm the production by bFGF gene–transduced chondrocytes. At 4, 8, and 12 weeks after transplantation, cartilage repair was evaluated histologically and graded semiquantitatively using a histologic scoring system ranging from 0 (complete regeneration) to 14 (no regeneration) points.ResultsLacZ gene expression by chondrocytes was maintained until 8 weeks in >85% of the in vitro population. LacZ‐positive cells were found at the transplant sites for at least 4 weeks after surgery. The mean concentration of bFGF was significantly increased in bFGF gene–transduced cells compared with control cells (P < 0.01). Semiquantitative histologic scoring indicated that the total score was significantly lower in the bFGF‐transduced group than in the control group throughout the observation period.ConclusionThese results demonstrated that gene transfer to chondrocytes by an ex vivo method was established with the AAV vector, and transplantation of bFGF gene–transduced chondrocytes had a clear beneficial effect on the repair of rabbit articular cartilage defects.
Responses of lymphocytes of patients with rheumatoid arthritis to IgG modified by oxygen radicals or peroxynitrite
Authors: Grinnell Susan , Yoshida Koji , Jasin Hugo E. 
Published: January 2005

AbstractObjectiveWe have previously demonstrated the presence of IgG aggregates modified by oxygen radicals (chlorinated IgG [Cl‐IgG]) and peroxynitrite (nitrated IgG [N‐IgG]) in synovial fluid of patients with rheumatoid arthritis (RA). A possible explanation for the longstanding chronic inflammatory process in RA is the establishment of an immune response to autoantigens. This study was undertaken to examine whether a T cell response to oxidatively modified IgG contributes to the inflammation in RA.MethodsWe studied in vitro lymphocyte proliferation and interleukin 2 (IL‐2) secretion in response to a common antigen (mumps), N‐IgG, Cl‐IgG, and heat‐aggregated IgG (H‐IgG) (control) in 15 normal blood donors and 16 RA patients not receiving immunosuppressive drugs.ResultsThe responses of RA lymphocytes to mumps antigen were significantly lower that those in controls (mean ± SEM 2,577 ± 217 versus 6,367 ± 365 counts per minute/well; P < 0.02). However, whereas in normal donors the cell responses to N‐IgG and Cl‐IgG were not significantly different than responses to H‐IgG (N‐IgG/H‐IgG ratio 1.2 ± 0.2, Cl‐IgG/H‐IgG 1.5 ± 0.2), the RA lymphocyte responses to N‐IgG and Cl‐IgG were significantly higher than the responses to H‐IgG (N‐IgG/H‐IgG 7.4 ± 2.5, Cl‐IgG/H‐IgG 4.8 ± 1.2). When ratios in RA cells were compared with normal cell responses as a group, there was a significant difference for both N‐IgG (P < 0.017) and Cl‐IgG (P < 0.014). When selected normal and RA lymphocyte culture supernatants were assayed for IL‐2 secretion, the increase in IL‐2 never exceeded 2‐fold in normal cell cultures incubated with any of the IgG compared with unstimulated cultures, whereas responses of RA cells, particularly those incubated with N‐IgG, were increased (range 2.6–15.7‐fold) compared with unstimulated controls.ConclusionThese results suggest that in RA there are circulating T cells that are responsive to oxidatively modified IgG, a possible pathogenic mechanism contributing to the chronic inflammatory process within the inflamed joint.
Intake of purine‐rich foods, protein, and dairy products and relationship to serum levels of uric acid: The Third National Health and Nutrition Examination Survey
Authors: Choi Hyon K. , Liu Simin , Curhan Gary 
Published: January 2005

AbstractObjectiveVarious commonly consumed foods have long been suspected of affecting the serum uric acid level, but few data are available to support or refute this impression. Our objective was to evaluate the relationship between dietary factors and serum uric acid levels in a nationally representative sample of men and women in the US.MethodsUsing data from 14,809 participants (6,932 men and 7,877 women) ages 20 years and older in the Third National Health and Nutrition Examination Survey (for the years 1988–1994), we examined the relationship between the intake of purine‐rich foods, protein, and dairy products and serum levels of uric acid. Diet was assessed with a food‐frequency questionnaire. We used multivariate linear regression to adjust for age, sex, total energy intake, body mass index, use of diuretics, β‐blockers, allopurinol, and uricosuric agents, self‐reported hypertension and gout, serum creatinine level, and intake of alcohol.ResultsThe serum uric acid level increased with increasing total meat or seafood intake and decreased with increasing dairy intake. After adjusting for age, the differences in uric acid levels between the extreme quintiles of intake were 0.48 mg/dl for total meat (95% confidence interval [95% CI] 0.34, 0.61; P < 0.001 for trend), 0.16 mg/dl for seafood (95% CI 0.06, 0.27; P = 0.005 for trend), and –0.21 mg/dl for total dairy intake (95% CI –0.37, –0.04; P = 0.02 for trend). After adjusting for other covariates, the differences between the extreme quintiles were attenuated but remained significant (P < 0.05 for all comparisons). The total protein intake was not associated with the serum uric acid level in multivariate analyses (P = 0.74 for trend). Those who consumed milk 1 or more times per day had a lower serum uric acid level than did those who did not drink milk (multivariate difference –0.25 [95% CI –0.40, –0.09]; P < 0.001 for trend). Similarly, those who consumed yogurt at least once every other day had a lower serum uric acid level than did those who did not consume yogurt (multivariate difference –0.26 [95% CI –0.41, –0.12]; P < 0.001 for trend).ConclusionThese findings from a nationally representative sample of adults in the US suggest that higher levels of meat and seafood consumption are associated with higher serum levels of uric acid but that total protein intake is not. Dairy consumption was inversely associated with the serum uric acid level.
Successful treatment of psoriatic onycho‐pachydermo periostitis (POPP) with adalimumab
Authors: Bongartz T. , Härle P. , Friedrich S. , Karrer S. , Vogt T. , Seitz A. , Müller‐Ladner U. 
Published: January 2005

AbstractPsoriatic onycho‐pachydermo periostitis (POPP) is recognized as a rare subset of psoriatic arthritis, characterized by psoriatic onychodystrophy, connective tissue thickening above the distal phalanx, and a periosteal reaction. Therapy for this rare disease is based on treatments used for psoriatic arthritis, but traditional disease‐modifying antirheumatic drugs, such as sulfasalazine and methotrexate, have shown inconsistent and unsatisfactory results. We report herein a successful therapeutic approach for POPP using the fully human anti–tumor necrosis factor (TNF) antibody adalimumab in a 42‐year‐old male patient. After 4 months of anti‐TNF treatment, a remarkable normalization of the clinical appearance was achieved and magnetic resonance imaging showed complete resolution of the initial inflammatory lesions. Therefore, we consider a TNF‐blocking strategy as promising for treatment of POPP.
Evidence that anti–tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: Extended report
Authors: Catrina Anca Irinel , Trollmo Christina , af Klint Erik , Engstrom Marianne , Lampa Jon , Hermansson Ylva , Klareskog Lars , Ulfgren Ann Kristin 
Published: January 2005

AbstractObjectiveTreatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) antagonists is highly effective, but their mechanisms of action are not completely clear. Since anti‐TNF therapy induces a decrease in synovial cellularity, this study focused on the modulation of RA synovial apoptosis following treatment with either soluble TNF receptor (etanercept) or TNF chimeric monoclonal antibody (infliximab).MethodsApoptosis (TUNEL and active caspase 3 staining) and cell surface markers were evaluated by immunohistochemistry in synovial biopsy samples obtained before and after 8 weeks of treatment with etanercept (12 patients) or infliximab (9 patients). We also determined by flow cytometry the in vitro effect of etanercept and infliximab on apoptosis of RA mononuclear cells derived from the synovial fluid (SF) and peripheral blood (PB).ResultsEight weeks of treatment with etanercept and with infliximab significantly increased synovial apoptosis. This change was accompanied by a significant decrease in the synovial monocyte/macrophage population. The decrease in lymphocyte numbers did not reach statistical significance. In vitro, 24 hours of incubation with either etanercept or infliximab induced apoptosis of the SF monocyte/macrophage population. PB monocyte/macrophages were less susceptible to anti‐TNF–mediated apoptosis. No changes in the rate of apoptosis were observed in the lymphocyte population derived from either SF or PB.ConclusionIn RA patients, both etanercept and infliximab are able to induce cell type–specific apoptosis in the monocyte/macrophage population. This suggests a potential pathway that would account for the diminished synovial inflammation and the decreased numbers of synovial macrophages evident after TNF blockade.
Increased CD4+ T cell infiltrates in rheumatoid arthritis–associated interstitial pneumonitis compared with idiopathic interstitial pneumonitis
Authors: Turesson Carl , Matteson Eric L. , Colby Thomas V. , Vuk‐Pavlovic Zvezdana , Vassallo Robert , Weyand Cornelia M. , Tazelaar Henry D. , Limper Andrew H. 
Published: January 2005

AbstractObjectiveTo study lymphocyte markers in rheumatoid arthritis (RA)–associated interstitial pneumonitis (IP) compared with idiopathic IP.MethodsParaffin‐embedded lung biopsy specimens from patients with RA (n = 15) and from those without RA (n = 16), all of whom had a diagnosis of either nonspecific IP or usual IP, were studied. Tissue sections from each patient were reviewed by a pathologist, who was blinded to the clinical data. Age and pulmonary function test results were similar in RA and non‐RA patients. After high‐temperature antigen unmasking, sections were incubated with mouse monoclonal antibodies directed against CD3, CD4, CD8, CD16, and CD20. All slides were coded, and digital images (100× magnification) of the entire tissue area were obtained. Staining was quantified using computer‐assisted image analysis.ResultsStaining for CD4 was more prominent in patients with RA than in the non‐RA comparison group (median 9.3 cells/mm2, interquartile range [IQR] 5.5–27.3 versus 0.6 cells/mm2, IQR 0.2–1.9;P= 0.002). CD4+ cell counts were increased in RA patients with nonspecific IP as well as in RA patients with usual IP, with no major difference between these groups. Results were similar for quantification of CD3 (P= 0.012). There was a less striking trend toward more CD8+ cells in RA patients (P= 0.27 versus those with non‐RA lung disease).ConclusionIP lesions in patients with RA are characterized by an increased number of CD4+ cells, as compared with that in patients with idiopathic IP. This finding suggests that CD4+ T cells are critical for the development of pulmonary manifestations in RA, and may have implications for the treatment of RA‐associated lung disease.
Association of a functional single‐nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus
Authors: Orozco Gisela , Sánchez Elena , González‐Gay Miguel A. , López‐Nevot Miguel A. , Torres Belén , Cáliz Rafael , Ortego‐Centeno Norberto , Jiménez‐Alonso Juan , Pascual‐Salcedo Dora , Balsa Alejandro , de Pablo Rosario , Nuñez‐Roldan Antonio , González‐Escribano Ma Francisca , Martín Javier 
Published: January 2005

AbstractObjectiveTo assess the possible association between the PTPN22 gene 1858C→T polymorphism and the predisposition and clinical expression of 2 systemic autoimmune diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).MethodsOur study population consisted of 826 RA patients, 338 SLE patients, and 1,036 healthy subjects. All subjects were of Spanish Caucasian origin. Genotyping of the PTPN22 gene 1858C→T polymorphism was performed by real‐time polymerase chain reaction technology, using the TaqMan 5′‐allele discrimination assay.ResultsThe overall distribution of genotypes in the RA patients was significantly different from that in the controls (P = 0.005, by chi‐square test with 2 × 3 contingency tables). We observed a statistically significant difference in the distribution of the PTPN22 1858T allele between healthy subjects (7.4%), and RA patients (10.4%) (P = 0.001, odds ratio [OR] 1.45 [95% confidence interval (95% CI) 1.15–1.83]). In addition, PTPN22 1858 C/T and T/T genotypes were present at a significantly higher frequency in SLE patients than in controls (P = 0.02, OR 1.55 [95% CI 1.05–2.29]). Differences were also observed when allele frequencies were compared, with the PTPN22 1858T allele being present at a higher frequency among SLE patients (P = 0.03, OR 1.45 [95% CI 1.01–2.09]).ConclusionThese results suggest that the PTPN22 1858T allele may confer differential susceptibility to RA and SLE in the Spanish population.
Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor–negative juvenile idiopathic arthritis in Finnish patients: Haplotype analysis in Finnish families
Authors: Runstadler Jonathan A. , Säilä Hanna , Savolainen Anneli , Leirisalo‐Repo Marjatta , Aho Kimmo , Tuomilehto‐Wolf Eva , Tuomilehto Jaakko , Seldin Michael F. 
Published: January 2005

AbstractObjectiveThe SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)–negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2.MethodsA total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single‐nucleotide polymorphisms: an intragenic insertion/deletion, a promoter microsatellite (NRAMP1), and a 3′ microsatellite (D2S1471).ResultsAnalysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6‐marker, 4‐marker, and 2‐marker haplotypes. Most impressively, 1 of the 6‐marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6–6.2) in all JIA patients, 3.5 (95% CI 1.9–6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5–6.7) in those with polyarticular RF‐negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well‐characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9–9.2] versus P = 0.5, OR 1.6 [95% CI 0.4–6.0]).ConclusionTaken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.
Antibodies against cyclic citrullinated peptide are associated with HLA–DR4 in simplex and multiplex polyarticular‐onset juvenile rheumatoid arthritis
Authors: Ferucci Elizabeth D. , Majka Darcy S. , Parrish Lezlie A. , Moroldo Marta B. , Ryan Mary , Passo Murray , Thompson Susan D. , Deane Kevin D. , Rewers Marian , Arend William P. , Glass David N. , Norris Jill M. , Holers V. Michael 
Published: January 2005

AbstractObjectiveAnti–cyclic citrullinated peptide (anti‐CCP) antibodies have been detected in patients with juvenile rheumatoid arthritis (JRA), particularly in those with polyarticular, rheumatoid factor (RF)‐positive JRA. Our objectives were to determine whether anti‐CCP antibodies are associated with HLA–DR4 in children with polyarticular JRA, whether anti‐CCP antibodies are associated with clinical features of disease, and whether affected sibling pairs (ASPs) with JRA are concordant for this antibody.MethodsStored serum samples obtained from 230 HLA‐typed patients with JRA (77 with polyarticular‐onset disease and 153 with pauciarticular‐ or systemic‐onset disease), 100 JRA ASPs, and 688 healthy children were tested for anti‐CCP antibodies and RF.ResultsThirteen percent of the patients with polyarticular‐onset JRA and 2% of the other JRA patients exhibited anti‐CCP antibodies, compared with only 0.6% of the controls. Fifty‐seven percent of RF‐positive patients with polyarticular‐onset JRA had anti‐CCP antibodies. HLA–DR4–positive patients with polyarticular‐onset JRA were more likely to have anti‐CCP antibodies than were those without HLA–DR4 alleles (odds ratio [OR] 5.20, 95% confidence interval [95% CI] 1.30–20.9). Anti‐CCP antibodies were associated with polyarticular onset (OR 7.46, 95% CI 1.99–28.0), a polyarticular disease course (OR 9.78, 95% CI 1.25–76.7), and erosive disease (OR 14.3, 95% CI 3.01–67.9). Concordance rates for anti‐CCP antibodies among ASPs were statistically significant.ConclusionThese data demonstrate increased anti‐CCP antibody formation in HLA–DR4–positive patients with polyarticular‐onset JRA. The overall prevalence of anti‐CCP antibodies in JRA is low, but a substantial proportion of RF‐positive patients with polyarticular‐onset JRA have these antibodies. Anti‐CCP antibodies in JRA are associated with polyarticular onset, a polyarticular course, and erosive disease.
Presentation and analysis of data on radiographic outcome in clinical trials: Experience from the TEMPO study
Authors: Heijde Désirée van der , Landewé Robert , Klareskog Lars , Rodríguez‐Valverde Vicente , Settas Lucas , Pedersen Ronald , Fatenejad Saeed 
Published: January 2005

AbstractObjectiveTo evaluate different methods of presentation and analysis of radiographic data in a rheumatoid arthritis (RA) randomized controlled trial.MethodsA double‐blind randomized controlled trial including 682 patients with active RA who were treated with methotrexate, etanercept, or a combination of the 2 drugs was used for this study. Probability plots of the change from baseline to year 1 were produced to visualize progression, and were compared with usual descriptive statistics. The primary analysis of the trial (based on annualized actual mean change from baseline in total Sharp score at 1 year, using linear imputation) was challenged using various ways of handling missing information with alternative imputation methods, and by various statistical analyses including analysis of covariance (ANCOVA) and mixed model analysis on both raw and log‐transformed data.ResultsProbability plots provided detailed insight into the differentiated treatment effects between the 3 arms of this study. As adjuncts to formal hypothesis testing, these plots were more useful for presenting data than were summary descriptive statistics or use of preset cutoff points to define lack of progression. Additional analyses presented here support the results obtained with the per‐protocol analysis that showed an advantage of the combination treatment compared with the monotherapy arms and for etanercept versus methotrexate alone. Various ways of handling missing information confirmed the robustness of the results. In addition, both ANCOVA and mixed model analyses on raw and on log‐transformed data produced similar results.ConclusionWe suggest a panel of alternative analysis methods and alternative ways of handling missing information to verify that the radiographic results reported in an randomized controlled trial are not influenced by technical factors, such as interpolation, handling of missing data, and choice of statistical tests.