bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air‐pouch model of acute gouty arthritis
Authors: Ryckman Carle , McColl Shaun R. , Vandal Karen , de Médicis Rinaldo , Lussier André , Poubelle Patrice E. , Tessier Philippe A. 
Published: August 2003

AbstractObjectiveTo examine the role of chemokines, S100A8, and S100A9 in neutrophil accumulation induced by the causative agent of gout, monosodium urate monohydrate (MSU) crystals.MethodsMSU crystal–induced neutrophil migration was studied in the murine air‐pouch model. Release of chemokines, S100A8, S100A9, and S100A8/A9 in response to MSU crystals was quantified by enzyme‐linked immunosorbent assays. Recruited cells were counted following acetic blue staining, and the subpopulations were characterized by Wright‐Giemsa staining of cytospins.ResultsMSU crystals induced the accumulation of neutrophils following injection in the air pouch, which correlated with the release of the chemokines CXCL1, CXCL2, CCL2, and CCL3. However, none of these was found to play an important role in neutrophil migration induced by MSU crystals by passive immunization with antibodies directed against each chemokine. S100A8, S100A9, and S100A8/A9 were also found at high levels in the pouch exudates following injection of MSU crystals. In addition, injection of S100A8, S100A9, or S100A8/A9 led to the accumulation of neutrophils in the murine air pouch, demonstrating their proinflammatory activities in vivo. Passive immunization with anti‐S100A8 and anti‐S100A9 led to a total inhibition of the accumulation of neutrophils. Finally, S100A8/A9 was found at high concentrations in the synovial fluid of patients with gout.ConclusionS100A8 and S100A8/A9 are essential to neutrophil migration induced by MSU crystals. These results suggest that they might be involved in the pathogenesis of gout.
Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients
Authors: Luzina Irina G. , Atamas Sergei P. , Wise Robert , Wigley Fredrick M. , Choi Jung , Xiao Hui Qing , White Barbara 
Published: August 2003

AbstractObjectivePulmonary fibrosis is a major cause of death in scleroderma patients. Previous studies have shown an increase in CD8+ T cells in the lungs of scleroderma patients. In the present study, we sought to determine whether activated CD8+ T cells contribute to pulmonary fibrosis in scleroderma patients through the production and activation of profibrotic mediators.MethodsCD8+ cells were isolated from bronchoalveolar lavage fluid obtained from 19 scleroderma patients and 7 healthy subjects. The phenotype of these cells was determined using DNA array technology. Expression of selected genes was confirmed in real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay experiments.ResultsHierarchical clustering of gene expression profiles revealed 2 groups of subjects. Group 1 consisted of 11 patients (8 with and 3 without lung inflammation). Group 2 consisted of 15 subjects (7 healthy controls and 2 patients with and 6 without lung inflammation). Gene expression in group 1 indicated T cell activation, a type 2 phenotype, production of profibrotic factors and matrix metalloproteinases, and reduced activation‐induced cell death. Increased expression of β6 integrin messenger RNA by CD8+ T cells in group 1 suggested the possibility that these T cells might induce cell‐contact–dependent activation of latent transforming growth factor β (TGFβ).ConclusionA subset of scleroderma patients at higher risk of progressive lung disease have activated, long‐lived CD8+ T cells in their lungs that could promote fibrosis directly, through production of profibrotic factors such as interleukin‐4 and oncostatin M, as well as indirectly, through activation of TGFβ.
Effects of oral cyclophosphamide and prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis
Authors: Apras Sule , Ertenli Ihsan , Ozbalkan Zeynep , Kiraz Sedat , Ozturk M. Akif , Haznedaroglu Ibrahim C. , Çobankara Veli , Pay Salih , Calguneri Meral 
Published: August 2003

AbstractObjectiveThe endothelial damage of microvascular structures in systemic sclerosis (SSc; scleroderma) is associated with increased levels of endothelial adhesion molecules and endothelium‐associated cytokines, including E‐selectin and thrombomodulin. Although there is still no ideal specific pharmacologic therapy for SSc, cyclophosphamide has resulted in clinical improvement in patients with SSc‐related active alveolitis. This study was designed to assess the expression of E‐selectin and thrombomodulin in patients with early diffuse SSc, and to investigate the effects of oral cyclophosphamide combined with prednisolone therapy on the levels of these endothelium‐associated cytokines and on the patients' clinical outcomes.MethodsThirteen patients with early diffuse SSc were treated with oral cyclophosphamide (2–2.5 mg/kg/day) and methylprednisolone (30 mg/every other day) for 1 year. The outcomes were determined as clinical (skin score) and laboratory parameters (including the erythrocyte sedimentation rate, complete blood cell count, levels of C‐reactive protein, antinuclear antibody, anti–double‐stranded DNA, rate of creatinine clearance, and findings on pulmonary function tests, esophageal manometry, and echocardiography). The concentrations of E‐selectin and thrombomodulin were measured in the pretreatment and posttreatment serum samples from the SSc patients and from 12 healthy adults as controls.ResultsIn the patients with early diffuse SSc, pretreatment and posttreatment mean levels of E‐selectin were 51 ng/ml (range 34.2–135.5) and 33.4 ng/ml (range 23–62.5), respectively (P = 0.01), and those of thrombomodulin were 82 ng/ml (range 35.8–120.5) and 74.6 ng/ml (range 23.3–91.3), respectively (P = 0.016). Clinical and laboratory parameters (the skin score and measures of pulmonary function [forced vital capacity and diffusing capacity for carbon monoxide]) were also improved (P < 0.05 for each) at the end of the followup period.ConclusionCombination therapy with cylophosphamide plus prednisolone is effective in the treatment of early diffuse SSc. Circulating levels of E‐selectin and thrombomodulin not only demonstrate the extent of endothelial injury and/or activation, but also could be a useful marker to monitor the disease activity in SSc.
Molecular mechanisms of interleukin‐4–induced up‐regulation of type I collagen gene expression in murine fibroblasts
Authors: McGaha Tracy L. , Le Maithao , Kodera Takao , Stoica Cristina , Zhu Jinfang , Paul William E. , Bona Constantin A. 
Published: August 2003

AbstractObjectiveThere is evidence that interleukin‐4 (IL‐4) plays a major role in the induction of extracellular matrix protein synthesis in fibrotic disease. We therefore examined the effect of IL‐4 on collagen synthesis in primary fibroblasts isolated from normal and TSK/+ mice, which spontaneously develop a scleroderma‐like syndrome characterized by diffuse cutaneous hyperplasia.MethodsExpression of the IL‐4 receptor was determined by flow cytometry and Western blotting. The IL‐4 signal transduction cascade was analyzed by Western blotting. We assessed the role of signal transducer and activator of transcription 6 (STAT‐6) in IL‐4 induction of α2(I) collagen promoter activity and message levels via luciferase reporter assay and real‐time polymerase chain reaction. The activation status of the transcription factors activator protein 1 (AP‐1) and Sp‐1 upon stimulation with IL‐4 in normal and TSK/+ fibroblasts was examined by electrophoretic mobility shift assay.ResultsFlow cytometry and Western blotting showed that IL‐4 receptor α expression was elevated in TSK/+ fibroblasts compared with normal fibroblasts. After IL‐4 stimulation, janus‐activated kinase 1 (JAK‐1) and JAK‐2 were phosphorylated to a greater degree in TSK/+ fibroblasts than in C57BL/6 fibroblasts. TSK/+ fibroblasts appeared to be hyperresponsive to IL‐4, displaying increased synthesis of α1(I) collagen messenger RNA (mRNA), collagen protein, and activity of a luciferase reporter construct containing the −300 to +54 murine α2(I) collagen promoter. Overexpression of STAT‐6 enhanced this effect, whereas expression of a dominant‐negative STAT‐6 abrogated the ability of IL‐4 to induce α1(I) collagen mRNA in TSK/+ fibroblasts. Moreover, IL‐4 induced increased DNA binding activity of transcription factors that are important for collagen synthesis.ConclusionOur observations indicate that IL‐4 has a profound effect on several factors that have been identified as playing major roles in the regulation of collagen synthesis and suggest that IL‐4 increases the expression of type I collagen through a mechanism involving the activation of transcription factors that bind to and activate collagen promoter.
Synovial fluid exoglycosidases are predictors of rheumatoid arthritis and are effective in cartilage glycosaminoglycan depletion
Authors: Ortutay Zsuzsanna , Polgár Anna , Gömör Béla , Géher Pál , Lakatos Tamás , Glant Tibor T. , Gay Renate E. , Gay Steffen , Pállinger Éva , Farkas Csaba , Farkas Éva , Tóthfalusi László , Kocsis Katalin , Falus András , Buzás Edit I. 
Published: August 2003

AbstractObjectiveTo analyze enzymes involved in joint damage by simultaneous investigation of glycosidases and matrix metalloproteinases (MMPs) in patients with various joint diseases.MethodsActivities of glycosidases (β‐D‐glucuronidase, β‐D‐N‐acetyl‐glucosaminidase, β‐D‐N‐acetyl‐galactosaminidase, β‐D‐galactosidase, and α‐D‐mannosidase) were tested at an acidic pH as well as at the original pH of the synovial fluid (SF) samples in parallel with activities of MMP‐1 and MMP‐9.ResultsPatients with rheumatoid arthritis (RA) were characterized by significantly elevated activities of β‐D‐glucuronidase and β‐D‐N‐acetyl‐glucosaminidase in SF compared with patients with osteoarthritis, seronegative spondylarthritis, or acute sports injury. To select the best predictor for distinguishing among patient groups, a stepwise logistic regression analysis was performed; the strongest association was found to be between RA and β‐D‐glucuronidase/β‐D‐N‐acetyl‐glucosaminidase activities (measured at the pH of the SF). Further, a significant correlation was observed between the activity of SF β‐D‐N‐acetyl‐glucosaminidase and the level of rheumatoid factor. In vitro digestion of human hyaline cartilage samples revealed that the dominant glycosidases, alone or in combination with MMPs, proved to be effective in depleting glycosaminoglycans (GAGs) from cartilage.ConclusionThese results suggest that exoglycosidases, which are present in the SF of RA patients, may contribute to the depletion of GAGs from cartilage and thereby facilitate the invasion of synovial cells and their attachment to cartilage in RA.
A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis
Authors: Olofsson Peter , Lu Shemin , Holmberg Jens , Song Tusheng , Wernhoff Patrik , Pettersson Ulf , Holmdahl Rikard 
Published: August 2003

AbstractObjectiveTo compare the genetic regulation of collagen‐induced arthritis (CIA) with that of pristane‐induced arthritis (PIA) in rats.MethodsA genome‐wide linkage analysis of an (E3 × DA)DA backcross of rats with CIA (n = 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA.ResultsWe found a striking, although not complete, similarity of the arthritis‐controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute‐phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity.ConclusionThe underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage‐specific antigen (type II collagen) to induce CIA but not PIA.
Familial Mediterranean fever among patients from Karabakh and the diagnostic value of MEFV gene analysis in all classically affected populations
Authors: Cazeneuve Cécile , Hovannesyan Zaruhi , Geneviève David , Hayrapetyan Hasmik , Papin Stéphanie , Girodon‐Boulandet Emmanuelle , Boissier Brigitte , Feingold Josué , Atayan Karine , Sarkisian Tamara , Amselem Serge 
Published: August 2003

AbstractObjectiveFamilial Mediterranean fever (FMF) is an autosomal‐recessive disorder that is common in Armenian, Turkish, Arab, and Sephardic Jewish populations. Its clinical diagnosis is one of exclusion, with the patients displaying nonspecific symptoms related to serosal inflammation. MEFV gene analysis has provided the first objective diagnostic criterion for FMF. However, in the absence of an identified mutation (NI/NI genotype), both the sensitivity of the molecular analyses and the involvement of the MEFV gene in FMF are called into question. The present study was designed to further evaluate the diagnostic value of MEFV analysis in another population of Mediterranean extraction.MethodsThe MEFV gene was screened for mutations in 50 patients living in Karabakh (near Armenia) who fulfilled the established criteria for FMF. In addition, we analyzed published series of patients from the above‐mentioned at‐risk populations.ResultsThe mutation spectrum in Karabakhian patients, which consisted of only 6 mutations (with 26% of NI alleles), differed from that reported in Armenian patients. Strikingly, among patients from Karabakh and among all classically affected populations, the distribution of genotypes differed dramatically from Hardy‐Weinberg equilibrium (P = 0.0016 and P < 0.00001, respectively). These results, combined with other population genetics–based data, revealed the existence of an FMF‐like condition that, depending on the patients' ancestry, was shown to affect 85–99% of those with the NI/NI genotype.ConclusionThese data illuminate the meaning of negative results of MEFV analyses and show that in all populations evaluated, most patients with the NI/NI genotype had disease that mimicked FMF and was unrelated to the MEFV gene. Our findings also demonstrate the high sensitivity of a search for very few mutations in order to perform a molecular diagnosis of MEFV‐related FMF.
In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response
Authors: Gottenberg Jacques‐Eric , Busson Marc , Loiseau Pascale , Cohen‐Solal Julien , Lepage Virginia , Charron Dominique , Sibilia Jean , Mariette Xavier 
Published: August 2003

AbstractObjectiveTo reevaluate, in a large series of patients with Sjögren's syndrome (SS) recruited from 2 French centers, the question of whether HLA is associated with SS itself or with a pattern of secretion of autoantibodies.MethodsOne hundred forty‐nine white patients fulfilling the American‐European Consensus Group criteria for SS were divided into 3 subgroups, according to their anti‐Ro/SSA and anti‐La/SSB status, as follows: group 1 (n = 53), no antibody; group 2 (n = 46), anti‐SSA only; group 3 (n = 50), both anti‐SSA and anti‐SSB. Patients were compared with 222 unrelated healthy subjects representative of the white population in France.ResultsComparisons between the 149 SS patients and 222 controls confirmed the association of SS with DRB1*03 (the frequency was 25% in patients versus 10% in controls) and DQB1*02 (32% versus 22%). The association between HLA and SS was restricted to patients with anti‐SSA and/or anti‐SSB; no association with HLA was observed in patients in group 1 (no antibody). The frequency of HLA–DRB1*15 was highest in group 2 (24%), compared with 11% in group 1 and 11% in controls, whereas the frequency of HLA–DRB1*03 was highest in group 3 (44%), compared with 12% in group 1, 19% in group 2, and 10% in controls. Group 2 and group 3 had more clinical and biologic markers of activity than did group 1 but were not clinically different. HLA alleles were not associated with clinical features of the disease, and were associated with only some biologic features: rheumatoid factor positivity, increased serum IgG, and thrombocytopenia were associated with HLA–DRB1*03, and neutropenia was associated with DQB1*01.ConclusionHLA class II markers confer genetic susceptibility to Sjögren's syndrome. The association between HLA and SS is restricted to patients with anti‐SSA and/or anti‐SSB antibodies; HLA is not associated with SS in patients without these autoantibodies. The absence of a difference in disease severity between groups 2 and 3, as well as the restricted association of HLA–DRB1*03 in group 3, strongly suggest that HLA alleles predispose to autoantibody secretion, without being associated with clinical outcome. HLA class II phenotype might support epitope spreading: HLA–DR15 favors anti‐SSA synthesis, whereas HLA–DR3 is associated with both anti‐SSA and anti‐SSB production.
Long‐term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: An open, observational, extension study of a three‐month, randomized, placebo‐controlled trial
Authors: Braun J. , Brandt J. , Listing J. , Zink A. , Alten R. , Burmester G. , Golder W. , Gromnica‐Ihle E. , Kellner H. , Schneider M. , Sörensen H. , Zeidler H. , Reddig J. , Sieper J. 
Published: August 2003

AbstractObjectiveTreatment of ankylosing spondylitis (AS) with infliximab, an anti–tumor necrosis factor α monoclonal antibody, was shown to be efficacious in patients with active disease during a 3‐month treatment period. The purpose of this study was to evaluate the efficacy and safety of infliximab treatment of AS for a 1‐year period.MethodsThis study was an open, observational, extension study of a 3‐month, randomized, placebo‐controlled trial. All patients who had tolerated infliximab (infliximab/infliximab group) or placebo (placebo/infliximab 12‐week crossover group) therapy for 3 months entered the open extension trial (n = 65). Infliximab was administered at a dosage of 5 mg/kg every 6 weeks after the induction phase (weeks 0, 2, and 6). The primary end point was a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).ResultsAt week 54, a total of 54 of the 69 patients (78%) continued to take infliximab. The intent‐to‐treat primary efficacy analysis at week 54 showed that 47% of patients in the infliximab/infliximab group (95% confidence interval 31–63) and 51% of the patients in the placebo/infliximab group (95% confidence interval 36–67) achieved 50% improvement in BASDAI scores. In the analysis of those who completed the study, the mean BASDAI scores improved between weeks 0 and 54 in both treatment groups: from 6.6 to 2.4 in the infliximab/infliximab group and from 6.3 to 2.6 in the placebo/infliximab group. The dosage of nonsteroidal antiinflammatory drugs was reduced in ∼70% of the patients. There were significant improvements in measures of functioning, metrologic parameters, and quality of life. Between weeks 12 and 54, a total of 4 patients had serious adverse events that were possibly related to infliximab and resulted in their discontinuing the study.ConclusionInfliximab therapy in AS patients resulted in a rapid and significant improvement in BASDAI scores (>50% improvement) and a durable response for 1 year. The safety profile of infliximab in AS was comparable to that observed in the postmarketing experience for the approved indications.
Identification of major loci controlling clinical manifestations of ankylosing spondylitis
Authors: Brown Matthew A. , Brophy Sinead , Bradbury Linda , Hamersma Jasmin , Timms Andrew , Laval Steven , Cardon Lon , Calin Andrei , Wordsworth B. Paul 
Published: August 2003

AbstractObjectiveTo identify genomic regions linked with determinants of age at symptom onset, disease activity, and functional impairment in ankylosing spondylitis (AS).MethodsA whole genome linkage scan was performed in 188 affected sibling pair families with 454 affected individuals. Traits assessed were age at symptom onset, disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Parametric and nonparametric quantitative linkage analysis was performed using parameters defined in a previous segregation study.ResultsHeritabilities of the traits studied in this data set were as follows: BASDAI 0.49 (P = 0.0001, 95% confidence interval [95% CI] 0.23–0.75), BASFI 0.76 (P = 10−7, 95% CI 0.49–1.0), and age at symptom onset 0.33 (P = 0.005, 95% CI 0.04–0.62). No linkage was observed between the major histocompatibility complex (MHC) and any of the traits studied (logarithm of odds [LOD] score <1.0). “Significant” linkage (LOD score 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed “suggestive” linkage to chromosome 11p (LOD score 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (LOD score 2.9).ConclusionIn contrast to the genetic determinants of susceptibility to AS, clinical manifestations of the disease measured by the BASDAI, BASFI, and age at symptom onset are largely determined by a small number of genes not encoded within the MHC.
Defects in the regulation of B cell apoptosis are required for the production of citrullinated peptide autoantibodies in mice
Authors: López‐Hoyos Marcos , Marquina Regina , Tamayo Esther , González‐Rojas Jovanna , Izui Shozo , Merino Ramón , Merino Jesús 
Published: August 2003

AbstractObjectiveProtein deimination, a process to modify arginine residues to citrulline by the addition of a neutral oxygen group, is associated with apoptosis. The presence of autoantibodies recognizing citrullinated peptides is highly specific to rheumatoid arthritis (RA) and is therefore a useful marker for the early diagnosis of RA. In this study, we explored whether anti–cyclic citrullinated peptide (anti‐CCP) autoantibodies are produced in several experimental models of autoimmune diseases in mice.MethodsThe levels of anti‐CCP autoantibodies were analyzed by enzyme‐linked immunosorbent assay in several lupus‐prone strains of mice, in animals with type II collagen (CII)–induced arthritis, and after induction of neonatal tolerance to alloantigens.ResultsWe observed the production of these autoantibodies in 2 different lupus‐prone mice, MRL‐lpr/lpr and (NZW × B6)F1‐hbcl‐2 transgenic mice, characterized by the presence of abnormalities in the regulation of B cell apoptosis. Other genetic defects, determining autoimmune susceptibility, present in MRL and NZW mice were additionally required for anti‐CCP autoantibody production. The induction of autoantibodies in normal BALB/c mice injected at birth with semiallogeneic spleen cells from (BALB/c × B6)F1‐hbcl‐2 transgenic mice suggested that these additional autoimmune defects may be related, at least in part, to the establishment of abnormal interactions between T cells and B cells. In addition, anti‐CCP autoantibodies were not produced in the course of CII‐induced arthritis, an experimental model of RA in mice.ConclusionOur study provides evidence for the association between defects in the regulatory cell death machinery of B lymphocytes and the production of certain autoantibody specificities.