bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurophysiologic evidence for a central sensitization in patients with fibromyalgia
Authors: Desmeules J. A. , Cedraschi C. , Rapiti E. , Baumgartner E. , Finckh A. , Cohen P. , Dayer P. , Vischer T. L. 
Published: May 2003

AbstractObjectiveTo determine whether abnormalities of peripheral and central nociceptive sensory input processing exist outside areas of spontaneous pain in patients with fibromyalgia (FM) as compared with controls, by using quantitative sensory testing (QST) and a neurophysiologic paradigm independent from subjective reports.MethodsA total of 164 outpatients with FM who were attending a self‐management program were invited to participate in the study. Data for 85 patients were available and were compared with those for 40 non‐FM controls matched for age and sex. QST was performed using thermal, mechanical, and electrical stimuli at locations of nonspontaneous pain. Pain assessment was 2‐fold and included use of subjective scales and the spinal nociceptive flexion reflex (NFR), a specific physiologic correlate for the objective evaluation of central nociceptive pathways. Questionnaires regarding quality of life and the impact of FM were available.ResultsParticipants were mainly middle‐aged women, with a mean disease duration of 8 years. Between‐group differences were significant for neurophysiologic, clinical, and quality of life measures. In patients with FM, peripheral QST showed significantly altered cold and heat pain thresholds, and tolerance to cold pain was radically reduced. The median NFR threshold in patients with FM (22.7 mA [range 17.5–31.7]) was significantly decreased compared with that in controls (33 mA [range 28.1–41]). A cutoff value of <27.6 mA for NFR provided sensitivity of 73% and specificity of 80% for detecting central allodynia in the setting of FM.ConclusionOur results strongly, although indirectly, point to a state of central hyperexcitability of the nociceptive system in patients with FM. The NFR can be used to assess central allodynia in FM. It may also help discriminate patients who may benefit from use of centrally acting analgesics.
Cytokine gene polymorphisms: Association with psoriatic arthritis susceptibility and severity
Authors: Balding Joanna , Kane David , Livingstone Wendy , Mynett‐Johnson Lesley , Bresnihan Barry , Smith Owen , FitzGerald Oliver 
Published: May 2003

AbstractObjectiveTo determine whether functional cytokine gene polymorphisms influence disease susceptibility and phenotype in patients with psoriatic arthritis (PsA).MethodsDNA was obtained from 147 PsA patients and 389 controls. Seven functional proinflammatory (interleukin‐1β [IL‐1β] +3953, IL‐6 −174, tumor necrosis factor α [TNFα] −308, TNFβ +252) and antiinflammatory (IL‐10 −1082, IL‐10 −592, IL‐1 receptor antagonist [intron 2, 86 bp, variable‐number tandem repeat]) gene polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism assays.ResultsNo significant difference in genotype frequencies was observed between the control and the PsA patient populations, and no association with Steinbrocker functional class, disease classification (polyarticular or oligoarticular), presence of spinal involvement, or age at PsA onset was observed. The presence of joint erosions was significantly associated with the TNFα −308 and TNFβ +252 polymorphisms (P < 0.0001 and P = 0.0017, respectively). Frequencies of the TNFα −308 and TNFβ +252 genotypes were also significantly different (P = 0.0078 and P = 0.0486, respectively) in a group of progressors (patients with early PsA in whom the number of joint erosions in the hands and feet increased over a median interval of 24 months) compared with a group of nonprogressors. Age at psoriasis onset was significantly associated with the TNFβ +252 and TNFα −308 polymorphisms (P = 0.0003 and P = 0.0081, respectively). The TNFB2B2 and TNFα −308 AA genotypes were associated with the earliest mean ages at psoriasis onset.ConclusionThe TNFα −308 and TNFβ +252 polymorphisms were significantly associated with age at psoriasis onset, presence of joint erosions in PsA, and progression of joint erosions in early PsA. TNF gene polymorphisms may be useful prognostic markers in PsA, and these results support the rationale for using anti‐TNF treatment in patients with severe, progressive PsA.
Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an Fcγ receptor I–directed immunotoxin
Authors: Van Roon Joel A. G. , Van Vuuren Anneke J. , Wijngaarden Siska , Jacobs Kim M. G. , Bijlsma Johannes W. J. , Lafeber Floris P. J. G. , Thepen Theo , Van De Winkel Jan G. J. 
Published: May 2003

AbstractObjectiveTo determine whether monocyte/macrophages from rheumatoid arthritis (RA) patients can be selectively eliminated by a toxin‐conjugated antibody CD64–ricin A (CD64‐RiA) directed toward the high‐affinity receptor for IgG (FcγRI), exploiting the capacity of FcγRI to efficiently endocytose antibody which it has bound.MethodsMononuclear cells from peripheral blood (PB) and synovial fluid (SF) obtained from RA patients were cultured in the presence of CD64‐RiA. Cell death of monocyte/macrophages was measured by phenotypic changes (light‐scatter patterns and CD14 and FcγRI expression) and apoptosis (nuclear DNA fragmentation). We then tested whether CD64‐RiA–induced cell death of macrophages affected their capacity to stimulate antigen‐induced lymphocyte proliferation and to secrete cytokines. Additionally, the capacity of CD64‐RiA to inhibit proinflammatory activity and cartilage degradation by RA synovial tissue explants was evaluated.ResultsInflammatory macrophages from RA SF expressed elevated levels of FcγRI and were selectively eliminated by CD64‐RiA via apoptotic cell death. Monocyte/macrophages from RA PB, which had lower levels of FcγRI expression, were much less affected. Induction of SF macrophage apoptosis was associated with efficient inhibition of antigen‐induced lymphocyte proliferation and a reduction in tumor necrosis factor α (TNFα) release. Consistent with these effects on SF macrophages, CD64‐RiA also inhibited TNFα production, interleukin‐1β production, and cartilage‐degrading activity of RA synovial tissue explants.ConclusionTogether, these data underscore the crucial role of synovial macrophages in RA joint inflammation and indicate that selective elimination of these cells through FcγRI‐directed immunotoxins could be a novel approach to the treatment of RA.
β1 integrin–mediated signaling induces intercellular adhesion molecule 1 and Fas on rheumatoid synovial cells and Fas‐mediated apoptosis
Authors: Nakayamada Shingo , Saito Kazuyoshi , Fujii Koichi , Yasuda Manabu , Tamura Masahito , Tanaka Yoshiya 
Published: May 2003

AbstractObjectiveRheumatoid arthritis (RA) synovial cells interact with inflammatory cells, as well as extracellular matrices, through integrins. However, the relevance of β1 integrin to inflammatory processes in RA remains unclear. We examined the role of β1 integrin–mediated signaling in RA.MethodsExpression of cell‐surface molecules was assessed by FACScan. Engagement of β1 integrins was performed by crosslinking using a specific monoclonal antibody (mAb) and ligand matrices such as fibronectin or collagen. To determine the involvement of tyrosine kinases in β1 integrin–mediated signaling, the cells were pretreated with various inhibitors of intracytoplasmic signaling or were transfected with a wild‐type focal adhesion kinase (FAK) or a dominant negative truncation of the FAK expression plasmid via cationic liposome‐mediated transfection. Apoptosis of synovial cells was detected by double staining with propidium iodide and annexin V.Resultsβ1 integrin was highly expressed on RA synovial cells. Engagement of β1 integrins by crosslinking as well as by ligand matrices markedly up‐regulated expression of intercellular adhesion molecule 1 (ICAM‐1) and Fas. Up‐regulation of ICAM‐1 and Fas induced by β1 integrin was mediated by the tyrosine kinase signaling pathway, especially involving FAK. Fas‐mediated early apoptotic change in the cells was amplified by β1 crosslinking.ConclusionOur results suggest that interaction of β1 integrins with extracellular matrix augments expression of ICAM‐1 and Fas on RA synovial cells, as well as Fas‐mediated apoptosis of synovial cells. This might lead to the spontaneous growth arrest through the Fas/Fas ligand pathway observed in RA synovitis.
Responses to the proinflammatory cytokines interleukin‐1 and tumor necrosis factor α in cells derived from rheumatoid synovium and other joint tissues involve nuclear factor κB–mediated induction of the Ets transcription factor ESE‐1
Authors: Grall Franck , Gu Xuesong , Tan Lujian , Cho Je‐Yoel , Inan Mehmet Sait , Pettit Allison R. , Thamrongsak Usanee , Choy Bob K. , Manning Cathy , Akbarali Yasmin , Zerbini Luiz , Rudders Susan , Goldring Steven R. , Gravallese Ellen M. , Oettgen Peter , Goldring Mary B. , Libermann Towia A. 
Published: May 2003

AbstractObjectiveTo investigate the expression of the novel Ets transcription factor ESE‐1 in rheumatoid synovium and in cells derived from joint tissues, and to analyze the role of nuclear factor κB (NF‐κB) as one of the central downstream targets in mediating the induction of ESE‐1 by proinflammatory cytokines.MethodsESE‐1 protein expression was analyzed by immunohistochemistry using antibodies in synovial tissues from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). ESE‐1 messenger RNA (mRNA) levels were analyzed by reverse transcriptase–polymerase chain reaction or Northern blotting in human chondrocytes, synovial fibroblasts, osteoblasts, and macrophages, before and after exposure to interleukin‐1β (IL‐1β), tumor necrosis factor α (TNFα), or lipopolysaccharide (LPS) with or without prior infection with an adenovirus encoding the inhibitor of nuclear factor κB (IκB). The wild‐type ESE‐1 promoter and the ESE‐1 promoter mutated in the NF‐κB site were cloned into a luciferase reporter vector and analyzed in transient transfections. Electrophoretic mobility shift assays (EMSAs) and supershift assays with antibodies against members of the NF‐κB family were conducted using the NF‐κB site from the ESE‐1 promoter as a probe.ResultsImmunohistochemical analysis showed specific expression of ESE‐1 in cells of the synovial lining layer and in some mononuclear and endothelial cells in RA and OA synovial tissues. ESE‐1 mRNA expression could be induced by IL‐1β and TNFα in cells such as synovial fibroblasts, chondrocytes, osteoblasts, and monocytes. Transient transfection experiments and EMSAs showed that induction of ESE‐1 gene expression by IL‐1β requires activation of NF‐κB and binding of p50 and p65 family members to the NF‐κB site in the ESE‐1 promoter. Overexpression of IκB using an adenoviral vector blocked IL‐1β–induced ESE‐1 mRNA expression. Chromatin immunoprecipitation further confirmed that NF‐κB binds to the ESE‐1 promoter in vivo.ConclusionESE‐1 is expressed in synovial tissues in RA and, to a variable extent, in OA, and is specifically induced in synovial fibroblasts, chondrocytes, osteoblasts, and monocyte/macrophages by IL‐1β, TNFα, or LPS. This induction relies on the translocation of the NF‐κB family members p50 and p65 to the nucleus and transactivation of the ESE‐1 promoter via a high‐affinity NF‐κB binding site. ESE‐1 may play a role in mediating some effects of proinflammatory stimuli in cells at sites of inflammation.
Two distinctive HLA haplotypes harbor the B27 alleles negatively or positively associated with ankylosing spondylitis in Sardinia: Implications for disease pathogenesis
Authors: Fiorillo Maria Teresa , Cauli Alberto , Carcassi Carlo , Bitti Pier Paolo , Vacca Alessandra , Passiu Giuseppe , Bettosini Francesca , Mathieu Alessandro , Sorrentino Rosa 
Published: May 2003

AbstractObjectiveTo compare haplotype distribution in HLA–B27–positive patients with ankylosing spondylitis (AS) and healthy control subjects possessing either AS‐associated HLA–B27 alleles or the non–AS‐associated HLA–B*2709 allele.MethodsDNA samples from 47 HLA–B27–positive patients with AS and 76 HLA–B27–positive healthy controls (19 positive and 57 negative for B*2709) living in different areas of Sardinia were collected and typed for HLA class I and class II alleles. The third exon of the B27 gene was analyzed for the presence of Asp116 or His116, which differentiates B*2709 from the other two B27 subtypes (B*2705 and B*2702) that are mostly found in Sardinia. The parents of 6 subjects positive for B*2709 were also typed for HLA class I and class II alleles. Statistical analysis was performed by Fisher's exact test.ResultsIn Sardinia, the B27 alleles conferring susceptibility to AS appear to be more frequently carried by a haplotype (A2;B27;Cw2;DR16) that reaches its highest frequency in patients with AS (A2 80.8%, B27 100%, Cw2 83%, and DR16 74.5%). Conversely, the non–AS‐associated B*2709 allele is more frequently found together with other HLA alleles whose frequencies are inversely correlated with the disease (A32 or A30, Cw1, and DR12). Familial analysis of 6 subjects positive for HLA–B*2709 confirmed the existence of a “Sardinian” haplotype that is not associated with AS (A32;B*2709;Cw1;DR12).ConclusionIn Sardinia, 2 distinct haplotypes harbor the non–AS‐associated HLA–B*2709 allele or the AS‐associated B27 alleles. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA–B27 may play some role in conferring susceptibility to AS.
Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus
Authors: Jacobi Annett M. , Odendahl Marcus , Reiter Karin , Bruns Anne , Burmester Gerd R. , Radbruch Andreas , Valet Günter , Lipsky Peter E. , Dörner Thomas 
Published: May 2003

AbstractObjectiveDisease activity in systemic lupus erythematosus (SLE) is usually assessed with complex disease activity scores comprising a variety of different parameters. In order to determine whether SLE disease activity correlates with abnormal B lymphocyte activity, B cell subsets were analyzed, and their relationship to clinical and humoral measures of disease activity was assessed.MethodsThe distribution of B cell subsets was determined by fluorescence‐activated cell sorting analysis and assessed in relation to the autoantibody profile, disease activity measured by the SLE Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measure scores, disease duration, and therapy.ResultsThe number and frequency of CD27high plasma cells were significantly correlated with the SLE disease activity indices and with the titer of anti–double‐stranded DNA (anti‐dsDNA) autoantibodies. Circulating B cell subsets were not influenced by age or sex, but appeared to relate to the duration of disease and the therapeutic regimen, with the number and frequency of CD27high plasma cells increasing and those of CD27− naive B cells decreasing over time. Patients were divided into those with a SLEDAI score of 0–8 (low disease activity) and those with SLEDAI score >8 (high disease activity). Patients with high disease activity had an increased frequency of both CD19+ B cells and CD27high plasma cells. By using a nonparametric data sieving algorithm, we observed that these B cell abnormalities provided predictive values for nonactive and active disease of 78.0% and 78.9%, respectively. The predictive value of the B cell abnormalities (78.9%) was greater than that of the humoral/clinical data pattern (71.4%), including anti‐dsDNA antibody levels, circulating immune complexes, increased erythrocyte sedimentation rate, mucocutaneous involvement, and acute renal involvement.ConclusionFlow cytometric monitoring of B cell subsets in the peripheral blood provides new insights into abnormalities of B cell function in SLE and may also be a diagnostically valuable option for monitoring the activity of this autoimmune disease.
Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes
Authors: Barbero Andrea , Ploegert Sabine , Heberer Michael , Martin Ivan 
Published: May 2003

AbstractObjectiveTo investigate whether adult human articular chondrocytes (AHACs), dedifferentiated by monolayer expansion, can differentiate toward diverse mesenchymal lineages and, if so, whether this ability is regulated by growth factors during monolayer expansion.MethodsAHACs were expanded as multiclonal or clonal populations in medium without (control) or with factors enhancing cell dedifferentiation (transforming growth factor β1, fibroblast growth factor 2, and platelet‐derived growth factor type BB [TFP]). Cells were then cultured under conditions promoting chondrogenic, osteogenic, or adipogenic differentiation, and the acquired phenotypes were assessed histologically, biochemically, and by real‐time reverse transcriptase–polymerase chain reaction.ResultsMulticlonal populations of both control‐ and TFP‐expanded AHACs differentiated toward the chondrogenic, osteogenic, and adipogenic lineages. Compared with control‐expanded AHACs, TFP‐expanded cells displayed enhanced chondrogenic differentiation capacity (2.4‐fold higher glycosaminoglycan/DNA content and 2,500‐fold higher up‐regulation of type II collagen) and osteogenic differentiation capacity (9.4‐fold higher increase in alkaline phosphatase activity and 12.4‐fold higher up‐regulation of bone sialoprotein), but reduced formation of adipocytes (5.2‐fold lower oil red O–positive cells/area). Clonal populations of AHACs could be efficiently expanded in TFP, but not in control medium. Most TFP‐expanded clones were able to redifferentiate only into chondrocytes (7 of 20) or were unable to differentiate (6 of 20). However, some clones (2 of 20) differentiated toward all of the lineages investigated, thus displaying characteristics of mesenchymal progenitor cells.ConclusionDedifferentiated AHACs exhibit differentiation plasticity, which is modulated by growth factors used during monolayer expansion and is highly heterogeneous across different clones. Clonal culture of AHACs in the presence of regulatory molecules could lead to the identification of AHAC subpopulations with enhanced cartilage repair capacity.
Involvement of CD44 in induction of matrix metalloproteinases by a COOH‐terminal heparin‐binding fragment of fibronectin in human articular cartilage in culture
Authors: Yasuda Tadashi , Poole A. Robin , Shimizu Makoto , Nakagawa Takefumi , Julovi Sohel M. , Tamamura Hirokazu , Fujii Nobutaka , Nakamura Takashi 
Published: May 2003

AbstractObjectiveTo investigate the mechanism of induction of matrix metalloproteinases (MMPs) by a 40‐kd COOH‐terminal heparin‐binding fibronectin fragment (HBFN‐f) containing III12–14 and IIICS domains in human articular cartilage in culture.MethodsHuman articular cartilage was removed from macroscopically normal femoral heads and cultured with HBFN‐f. MMP secretion into conditioned media was analyzed by immunoblotting (MMPs 1 and 13) and by gelatin zymography (MMPs 2 and 9). Type II collagen cleavage by collagenase was monitored in culture by immunoassay. Involvement of specific peptide‐binding domains in HBFN‐f and the involvement of CD44 were assessed with synthetic peptides and an anti‐CD44 antibody. Immunofluorescence histochemistry was performed using fluorescein isothiocyanate–conjugated anti‐CD44 antibody.ResultsHBFN‐f stimulated production of MMPs 1, 2, 9, and 13 in association with type II collagen cleavage by collagenase in human articular cartilage. Peptide V (WQPPRARI) of HBFN‐f, which can bind cell surface heparan sulfate proteoglycan (HSPG), blocked MMP induction by HBFN‐f, while the scrambled peptide V (RPQIPWAR) had no effect. Peptide CS‐1 of 25 amino acids in IIICS of HBFN‐f caused no significant effect. Treatment of cartilage with anti‐CD44 antibody or HSPG resulted in significant inhibition of HBFN‐f–stimulated MMP production. Preincubation with peptide V blocked binding of the anti‐CD44 antibody to chondrocytes in cartilage.ConclusionInteraction of the peptide V sequence in HBFN‐f with glycosaminoglycans, such as those in CD44, plays an important role in HBFN‐f–stimulated MMP production in articular cartilage. Because CD44 is up‐regulated in osteoarthritic and rheumatoid arthritic cartilage, the role of the interaction between CD44 and HBFN‐f in these pathologies should be of relevance and should be studied further.
Genetic basis of tissue specificity of vasculitis in MRL/lpr mice
Authors: Yamada Akihiro , Miyazaki Tatsuhiko , Lu Ling‐Min , Ono Masao , Ito Mitsuko R. , Terada Miho , Mori Shiro , Hata Kazuya , Nozaki Yoshimi , Nakatsuru Shuichi , Nakamura Yusuke , Onji Morikazu , Nose Masato 
Published: May 2003

AbstractObjectiveTo clarify the mode of inheritance of the tissue distribution of vasculitis in MRL/Mp‐lpr/lpr (MRL/lpr) lupus‐prone mice and to identify the susceptibility loci.MethodsVasculitis in individual MRL/lpr, C3H/HeJ‐lpr/lpr (C3H/lpr), (MRL/lpr × C3H/lpr)F1, and (MRL/lpr × C3H/lpr)F2 intercross mice was analyzed by histopathologic grading of main branches of the aorta and of medium‐sized arteries in the lower limbs. Genomic DNA samples from F2 intercross mice were examined by simple sequence‐length polymorphism analysis, and the polymorphic microsatellite markers highly associated with vasculitis in each tissue were determined as vasculitis susceptibility loci.ResultsA susceptibility locus with significant linkage to vasculitis of main branches of the aorta was mapped on chromosome 4 at D4Mit213 (map position 13.3cM) selectively in males, while vasculitis of medium‐sized arteries in the lower limbs was mapped to different chromosomes: at D8Mit31 on chromosome 8 (map position 33.0) selectively in females and at D5Mit36 on chromosome 5 (map position 65.0). All of these were different from the previously defined loci governing susceptibility to vasculitis involving the kidneys.ConclusionSystemic vasculitis in MRL/lpr mice is genetically controlled with cumulative effects of multiple gene loci, each of which has tissue specificity.