bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of hypoxia on the expression and activity of cyclooxygenase 2 in fibroblast‐like synoviocytes: Interactions with monocyte‐derived soluble mediators
Authors: Demasi Maryanne , Cleland Leslie G. , Cook‐Johnson Rebecca J. , James Michael J. 
Published: August 2004

AbstractObjectiveRheumatoid synovium is characterized by hyperplasia of fibroblast‐like (type B) synoviocytes (FLS), infiltration with mononuclear leukocytes, and tissue hypoxia. Although the latter is well documented, it has received little attention in dissection of the biochemical events that mediate the inflammatory lesion in rheumatoid arthritis (RA). Therefore, this study was designed to assess the effect of hypoxia on FLS responses to the monokine interleukin‐1β (IL‐1β) and to monocyte conditioned medium.MethodsFLS obtained from serial cultures of synovial fluid aspirates were treated with IL‐1β or monocyte conditioned medium, under normoxia and hypoxia.ResultsIn hypoxia, transcription of cyclooxygenase 2 (COX‐2), expression of COX‐2 protein, and production of COX‐2–derived eicosanoids and matrix metalloproteinase (MMP) activity by FLS were all increased in response to IL‐1β. In contrast to our recent observations concerning monocytes, there was no change in COX‐2 message stability and cytosolic phospholipase A2 activity in the FLS under hypoxia. Treatment of monocyte conditioned medium with an IL‐1β blocking antibody showed that most of the effect of the conditioned medium was attributable to IL‐1β.ConclusionThe findings suggest that hypoxia is an important factor in aggravating the inflammatory lesion in RA, through increased production of COX‐2–derived nociceptive eicosanoids and increased release of tissue‐damaging MMPs.
B cell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose‐escalation trial of rituximab
Authors: Looney R. John , Anolik Jennifer H. , Campbell Debbie , Felgar Raymond E. , Young Faith , Arend Lois J. , Sloand James A. , Rosenblatt Joseph , Sanz Iñaki 
Published: August 2004

AbstractObjectiveSafer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE.MethodsA phase I/II dose‐escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy.ResultsRituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/μl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t‐test). This improvement persisted for 12 months, despite the absence of a significant change in anti–double‐stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level ≥100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion.ConclusionRituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.
Increased levels of C‐reactive protein in serum from blood donors before the onset of rheumatoid arthritis
Authors: Nielen Markus M. J. , Van Schaardenburg Dirkjan , Reesink Henk W. , Twisk Jos W. R. , Van De Stadt Rob J. , Van Der Horst‐Bruinsma Irene E. , De Gast Truus , Habibuw Moud R. , Vandenbroucke Jan P. , Dijkmans Ben A. C. 
Published: August 2004

AbstractObjectiveWe previously reported that approximately half of the patients with rheumatoid arthritis (RA) have specific serologic abnormalities (elevated serum concentrations of IgM rheumatoid factor and/or anti–cyclic citrullinated peptide antibodies) starting several years before the onset of symptoms. In this study, the presence of serologic signs of inflammation in patients with preclinical RA was investigated with serial measurements of C‐reactive protein (CRP).MethodsSeventy‐nine patients (61% female; mean age at onset of symptoms 51 years) who had been blood donors before the onset of RA were identified. Frozen serum samples from each donor were retrieved, together with 1 sample from a control donor matched for age, sex, and date of donation. CRP was measured using a highly sensitive latex‐enhanced assay. The dates of donation were categorized into 15 1‐year periods preceding the onset of RA symptoms. For each period, the median CRP levels in the patient and control groups were compared using the Mann‐Whitney U test. The course of CRP concentrations over time in the patient group was estimated with random coefficient analysis.ResultsA median of 13 samples (range 1–51) per patient were available; the earliest donation was made a median of 7.5 years (range 0.4–14.5 years) before the onset of symptoms. A total of 1,078 patient samples and 1,071 control samples were tested. For all 1‐year periods, the median CRP concentration was increased in the patient group compared with the control group, but this difference was statistically significant only for the periods 0–1 year, 1–2 years, and 4–5 years before the onset of symptoms. The CRP concentration increased significantly over time in patients with preclinical RA; levels were slightly higher in the group of patients who had serologic abnormalities before the onset of symptoms than in those without such serologic abnormalities.ConclusionAfter observing specific serologic abnormalities 5 years before the onset of RA symptoms, we now report increased levels of CRP in blood donors in whom RA later developed; these increases were most common within the 2 years before the onset of symptoms. The preclinical increase in CRP levels was observed both in donors with and in those without serologic abnormalities.
Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: Prevalence, clinical associations, and long‐term outcome
Authors: Tektonidou Maria G. , Sotsiou Flora , Nakopoulou Lidia , Vlachoyiannopoulos Panayiotis G. , Moutsopoulos Haralampos M. 
Published: August 2004

AbstractObjectiveTo evaluate the prevalence, clinical associations, and outcome of antiphospholipid syndrome (APS) nephropathy in patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL) and in SLE patients without aPL.MethodsKidney biopsy specimens obtained from 81 patients with aPL (18 of whom had APS) and 70 patients without aPL were retrospectively examined for the presence of APS nephropathy. Clinical and serologic data obtained at the time of kidney biopsy and during a mean followup of 7 years were recorded. In cases for which serial kidney biopsy specimens were available, the evolution of APS nephropathy was examined.ResultsAPS nephropathy existed in 39.5% of patients with aPL, compared with only 4.3% of patients without aPL. APS nephropathy was associated with both lupus anticoagulant and anticardiolipin antibodies. Among aPL‐positive SLE patients, APS nephropathy was found in two‐thirds of those with APS and in one‐third of those without APS. A strong association between APS nephropathy and the presence of arterial thrombosis and livedo reticularis was noted. Patients with APS nephropathy had a higher frequency of hypertension and elevated serum creatinine levels at the time of kidney biopsy but did not have a higher frequency of renal insufficiency, end‐stage renal disease, or death at the end of followup. Serial kidney biopsy specimens were available from 11 patients and showed progression of APS nephropathy lesions. During followup, manifestations of APS (especially arterial thromboses) developed more frequently in the SLE/non‐APS patients with APS nephropathy than in those without APS nephropathy.ConclusionAmong patients with SLE, APS nephropathy occurs almost exclusively in those with aPL, suggesting an important role of aPL in the pathogenesis of APS nephropathy. Patients with APS nephropathy develop hypertension, raised serum creatinine levels, and progression of histologic lesions, all of which are associated with a poor renal outcome. Manifestations of APS also tend to develop in these patients. APS nephropathy should be included in the APS classification criteria, and the use of appropriate anticoagulant therapy should be tested.
Association of PDCD1 with susceptibility to systemic lupus erythematosus
Authors: Ferreiros‐Vidal Isabel , Gomez‐Reino Juan J. , Barros Francisco , Carracedo Angel , Carreira Patricia , Gonzalez‐Escribano Francisca , Liz Myriam , Martin Javier , Ordi Josep , Vicario Jose L. , Gonzalez Antonio 
Published: August 2004

AbstractObjectiveThe A allele of the PD1.3 single‐nucleotide polymorphism (SNP) on the programmed cell death gene PDCD1 was markedly more frequent in patients with systemic lupus erythematosus (SLE) than in unaffected controls in a recent study involving large sets of Swedish, European American, and Mexican families. This study sought to determine the role of PDCD1 in susceptibility to SLE in the Spanish population.MethodsSeven PDCD1 SNPs were studied in 518 SLE patients and 800 healthy control subjects who had been recruited in 5 distant towns spanning continental Spain. Patients and controls were of Spanish ancestry. The diagnosis of SLE was in accordance with the American College of Rheumatology updated classification criteria.ResultsThe A allele of the PD1.3 polymorphism was significantly less frequent in Spanish female patients with SLE than in Spanish female controls (9.0% versus 13.0%, odds ratio 0.67, 95% confidence interval 0.50–0.89). This difference was consistent across the 5 sets of samples grouped by town of recruitment. The other PDCD1 SNPs were not associated with SLE susceptibility. The haplotype structure of PDCD1 in the Spanish controls was different from that reported in other healthy control populations.ConclusionOur results confirm the association of PDCD1 with susceptibility to SLE, but the findings show a lack of involvement of the PD1.3 SNP, which is contrary to the role of the PD1.3 A allele observed previously. These contradictory results probably reflect population differences in the haplotype structure of the PDCD1 locus. More research focusing on new polymorphisms and identifying associations in other populations will be needed to clarify the role of PDCD1 in SLE susceptibility.
The Vλ–Jλ repertoire of patients with systemic lupus erythematosus manifests characteristics of the natural antibody repertoire
Authors: Lee Jisoo , Cho Young Joo , Lipsky Peter E. 
Published: August 2004

AbstractObjectiveTo understand in detail the mechanisms of autoantibody production in patients with systemic lupus erythematosus (SLE), we performed a comprehensive analysis of the normal human immunoglobulin light chain Vλ repertoire and compared it with the Vλ repertoire in SLE patients.MethodsThe SLE Vλ repertoire of B cells obtained from 3 SLE patients was analyzed and compared in detail with the Vλ repertoire of IgM+ B cells obtained from 3 human fetal spleens and IgM+,CD5+ B cells obtained from 2 normal adults. Conventional IgM+,CD5– B cells obtained from normal adults were used as controls. Vλ–Jλ rearrangements were amplified from the genomic DNA of individual B cells by polymerase chain reaction.ResultsThe expressed Vλ repertoire of SLE patients contained several similarities with the expressed repertoire of the fetus and the adult CD5+ B cells. The Vλ genes 3L and 1G were overexpressed in the fetus, the adult CD5+ B cells, and the patients with SLE. The selection for rearrangements with restricted junctional diversity by utilization of homology‐mediated joining, together with diminished N nucleotide addition, was a prominent feature of fetal, adult CD5+, and SLE B cell repertoires. Furthermore, profound expansion of Vλ clones with identical third complementarity‐determining regions was observed in the adult CD5+, fetal, and SLE B cell repertoires. Notably, significant numbers of expanded adult CD5+ B cells, fetal, and SLE Vλ clones utilized homology‐mediated joining at the Vλ–Jλ junctions.ConclusionThese data demonstrate that the SLE Vλ–Jλ repertoire manifests characteristics of normal adult IgM+,CD5+ and fetal B cell populations that are known to be enriched for the production of natural autoantibodies.
Differential gene expression and regulation of the bone morphogenetic protein antagonists follistatin and gremlin in normal and osteoarthritic human chondrocytes and synovial fibroblasts
Authors: Tardif Ginette , Hum David , Pelletier Jean‐Pierre , Boileau Christelle , Ranger Pierre , Martel‐Pelletier Johanne 
Published: August 2004

AbstractObjectiveTo compare gene expression in normal and osteoarthritic (OA) human chondrocytes using microarray technology. Of the novel genes identified, we selected follistatin, a bone morphogenetic protein (BMP) antagonist, and investigated its expression/regulation as well as that of 3 other antagonists, gremlin, chordin, and noggin, in normal and OA chondrocytes and synovial fibroblasts.MethodsBasal and induced gene expression were determined using real‐time polymerase chain reaction. Gene regulation was monitored following treatment with inflammatory, antiinflammatory, growth, and developmental factors. Follistatin protein production was measured using a specific enzyme‐linked immunosorbent assay, and localization of follistatin and gremlin in cartilage was determined by immunohistochemical analysis.ResultsAll BMP antagonists except noggin were expressed in chondrocytes and synovial fibroblasts. Follistatin and gremlin were significantly up‐regulated in OA chondrocytes but not in OA synovial fibroblasts. Chordin was weakly expressed in normal and OA cells. Production of follistatin protein paralleled the gene expression pattern. Follistatin and gremlin were expressed preferentially by the chondrocytes at the superficial layers of cartilage. Tumor necrosis factor α and interferon‐γ significantly stimulated follistatin expression but down‐regulated expression of gremlin. Interleukin‐1β (IL‐1β) had no effect on follistatin but reduced gremlin expression. Conversely, BMP‐2 and BMP‐4 significantly stimulated expression of gremlin but down‐regulated that of follistatin. IL‐13, dexamethasone, transforming growth factor β1, basic fibroblast growth factor, platelet‐derived growth factor type BB, and endothelial cell growth factor down‐regulated the expression of both antagonists.ConclusionThis study is the first to show the possible involvement of follistatin and gremlin in OA pathophysiology. The increased activin/BMP‐binding activities of these antagonists could affect tissue remodeling. The data suggest that follistatin and gremlin might appear at different stages during the OA process, making them interesting targets for the treatment of this disease.
Association study of candidate genes for the prevalence and progression of knee osteoarthritis
Authors: Valdes Ana M. , Hart Deborah J. , Jones Karen A. , Surdulescu Gabriela , Swarbrick Peter , Doyle David V. , Schafer Alan J. , Spector Tim D. 
Published: August 2004

AbstractObjectiveOsteoarthritis (OA), characterized by late‐onset degeneration of articular cartilage, is recognized to have a genetic component. We examined the role of 26 single‐nucleotide polymorphisms (SNPs) from 24 candidate genes in OA susceptibility and progression.MethodsWe compared human complementary DNA libraries from OA‐affected and normal cartilage and synovium and selected 22 genes in addition to the estrogen receptor α and vitamin D receptor genes. Based on the availability of polymorphisms, we proceeded to test whether genetic variation at those genes affected susceptibility to or progression of radiographic knee OA over a 10‐year period in 749 women (mean age 64 years) from the longitudinal Chingford Study.ResultsAfter adjusting for age and body mass index, we observed significant associations at ADAM12, BMP2, CD36, COX2, and NCOR2 with 3 OA susceptibility traits (presence/absence of joint space narrowing [JSN], presence/absence of osteophytes, and Kellgren/Lawrence [K/L] score). For the OA progression traits (change over 10 years in the K/L score, osteophyte grade, and JSN grade), we found significant associations with ADAM12, CILP, OPG, and TNA. Overall, we observed 15 associations with nominal significance (P < 0.05) and, by permutation analysis, found that such a number would be observed by chance only 3.8% of the time. Although these tests require replication, the stronger genetic associations observed are unlikely to be attributable simply to multiple comparisons.ConclusionOur results suggest that OA severity and progression have a multigenic and feature‐specific nature. These findings should encourage the development of genetic diagnostics for OA progression based on multiple SNPs and help unravel some of the complex disease mechanisms in OA.
Regional variation and differential response to therapy for knee synovitis adjacent to the cartilage–pannus junction and suprapatellar pouch in inflammatory arthritis: Implications for pathogenesis and treatment
Authors: Rhodes Laura A. , Tan Ai Lyn , Tanner Steven F. , Radjenovic Aleksandra , Hensor Elizabeth M. A. , Reece Richard , O'Connor Philip , Emery Paul , McGonagle Dennis 
Published: August 2004

AbstractObjectiveTo use magnetic resonance imaging (MRI) to investigate the importance of knee joint synovitis at the cartilage–pannus junction (CPJ) in rheumatoid arthritis (RA) as compared with synovitis at a distant site in the suprapatellar pouch (SPP) and as compared with CPJ synovitis in the spondylarthropathies (SpA), and to assess the relative response of knee joint synovitis to therapy at the CPJ and SPP sites.MethodsDynamic contrast‐enhanced MRI (DEMRI) of actively involved knee joints in 24 patients (13 with RA and 11 with SpA) was undertaken. The area of synovitis was calculated at the CPJ and SPP regions of interest in patients with RA and in patients with SpA. Differences in CPJ and SPP synovitis were determined using calculated DEMRI parameters which included the initial rate of contrast enhancement (IRE) and the maximal enhancement (ME). Changes in the synovial area at the CPJ and SPP were also measured in 10 patients with early RA, following treatment with disease‐modifying antirheumatic drugs (DMARDs) (either methotrexate or leflunomide).ResultsIn patients with RA or SpA, the area of synovitis was significantly larger immediately adjacent to the CPJ compared with a distant site at the SPP (in RA, mean synovitis area 162 mm2 at the CPJ versus 114 mm2 at the SPP [P = 0.010]; in SpA, mean synovitis area 214 mm2 at the CPJ versus 143 mm2 at the SPP [P = 0.002]), but the differences in the areas of synovitis at these sites were not significant between the RA and SpA patients. The IRE and ME values were also higher at the CPJ compared with the SPP, both in the RA patients (IRE P = 0.054, ME P = 0.018) and in the SpA patients (IRE P = 0.002, ME P = 0.001). A larger reduction in the area of synovitis was seen at the SPP compared with the CPJ following DMARD therapy in the RA patients (mean reduction 35% at the SPP [P = 0.023] and 12% at the CPJ [P not significant]).ConclusionThe non–disease‐specific variations in synovitis and the differential responses to therapy in RA patients have implications for improving our understanding of CPJ synovitis. The results suggest that the pathophysiologic events at the CPJ reflect common anatomic, immune system, or biomechanical factors that play a role in modulating the severity of arthritis, and these events are not specific to RA since the same process was observed in other arthritides.
A genome scan for joint‐specific hand osteoarthritis susceptibility: The Framingham Study
Authors: Hunter D. J. , Demissie S. , Cupples L. A. , Aliabadi P. , Felson D. T. 
Published: August 2004

AbstractObjectiveStudies investigating hand osteoarthritis (OA) as a single entity have not shown strong linkage of the disease with any chromosomal sites. We undertook this study to test our hypothesis that phenotypes of hand OA may show stronger linkage than has been shown for overall hand OA.MethodsWe performed a factor analysis on measures of hand OA to determine patterns of disease. Using the joint regions identified by this analysis, we performed a genome‐wide linkage analysis for OA susceptibility loci using 426 original cohort members and 790 offspring cohort members in 267 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence score, osteophytes, and joint space narrowing. Prior to linkage analysis, standardized residuals were computed from regression analysis of each phenotype on age. This was performed separately for each sex and cohort. The variance component model (GeneHunter) was then applied to the normalized scores of the residuals of both sexes and cohorts.ResultsThere was evidence suggestive of linkage (logarithm of odds [LOD] score >1.5) at 16 sites. Four of these sites had LOD scores >3.0. Two of these sites (identified in the full sample) included a linkage region for OA of the distal interphalangeal (DIP) joint on chromosome 7 (155 cM; LOD score 3.06) and a linkage region for OA of the first carpometacarpal (CMC) joint on chromosome 15 (81 cM; LOD score 6.25). The other 2 sites (identified in women) included a linkage region for OA of the DIP joint on chromosome 1 (202 cM; LOD score 3.03) and a linkage region for OA of the first CMC joint on chromosome 20 (4 cM; LOD score 3.74).ConclusionThese data suggest that several chromosomes contain hand OA susceptibility genes and that a joint‐specific approach may be more rewarding than a global approach to the genetics of hand OA. Further investigation of these regions is warranted using finer maps and other populations.