bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acceleration of the onset of collagen‐induced arthritis by a deficiency of platelet endothelial cell adhesion molecule 1
Authors: Tada Yoshifumi , Koarada Syuichi , Morito Fumitaka , Ushiyama Osamu , Haruta Yoshio , Kanegae Futoshi , Ohta Akihide , Ho Alexandra , Mak Tak W. , Nagasawa Kohei 
Published: November 2003

AbstractObjectivePlatelet endothelial cell adhesion molecule 1 (PECAM‐1; CD31) is a member of the immunoglobulin superfamily that is expressed in platelets, leukocytes, and endothelial cells. PECAM‐1 has been shown to play a role in transendothelial migration of leukocytes and contains immunoreceptor tyrosine‐based inhibitory motifs in its cytoplasmic tail and inhibits cellular responses. We examined the role of PECAM‐1 in the development of collagen‐induced arthritis (CIA).MethodsCIA was induced in PECAM‐1–deficient DBA/1 mice. The incidence of arthritis and the arthritis index were examined. Anti–type II collagen (anti‐CII) antibody levels and interferon‐γ (IFNγ) production by lymph node cells and spleen cells were determined. Lymphocytes from arthritic PECAM‐1–deficient and wild‐type mice were labeled with dye, transferred to arthritic PECAM‐1+/− mice, and cell migration to inflamed joints was examined.ResultsPECAM‐1–deficient mice showed accelerated onset of arthritis and increased severity only during the early phase. Anti‐CII antibody levels were also increased during the early phase. IFNγ production by lymph node cells and spleen cells from PECAM‐1–deficient mice in response to CII was higher than that in wild‐type mice. Lymphocytes from arthritic PECAM‐1–deficient mice showed accelerated migration to inflamed joints, but not lymph nodes or spleen. The development of anti‐CII antibody–induced arthritis was similar in PECAM‐1–deficient and wild‐type mice.ConclusionThese results indicate that PECAM‐1 negatively regulates humoral and cell‐mediated immune responses and lymphocyte migration into joints and, consequently, the development of CIA. In addition, the role of PECAM‐1 in the transendothelial migration of leukocytes appears to be redundant in this model.
Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy
Authors: Van Staa T. P. , Laan R. F. , Barton I. P. , Cohen S. , Reid D. M. , Cooper C. 
Published: November 2003

AbstractObjectiveTo evaluate predictors of vertebral fractures, including a threshold for bone mineral density (BMD), in patients receiving oral glucocorticoids (GCs).MethodsData were obtained from 2 randomized clinical trials (prevention and treatment trials of risedronate) using similar methods, but different inclusion criteria were applied with regard to prior exposure to GCs. Predictors of vertebral fracture in the placebo group were identified using Cox regression with forward selection. The BMD threshold analysis involved a comparison of the 1‐year fracture risk in postmenopausal women receiving placebo in the GC trials with that in postmenopausal women not taking GCs in 3 other trials.ResultsThe study population comprised 306 patients with baseline and 1‐year followup data on vertebral fractures (111 receiving placebo and 195 receiving risedronate). In the placebo group, the statistically significant predictors of incident fracture were the baseline lumbar spine BMD (for each 1‐point decrease in T score, relative risk [RR] 1.85, 95% confidence interval [95% CI] 1.06–3.21) and the daily GC dose (for each 10‐mg dose increase, RR 1.62, 95% CI 1.11–2.36). In the BMD threshold analysis, compared with nonusers of GCs, patients receiving GCs were younger, had a higher BMD at baseline, and had fewer prevalent fractures; nevertheless, the risk of fracture was higher in the GC users compared with nonusers (adjusted RR 5.67, 95% CI 2.57–12.54). The increased risk of fracture was observed in GC users regardless of whether osteoporosis was present.ConclusionThe daily, but not cumulative, GC dose was found to be a strong predictor of vertebral fracture in patients receiving GCs. At similar levels of BMD, postmenopausal women taking GCs, as compared with nonusers of GCs, had considerably higher risks of fracture.
Nitrite‐mediated protection against hypochlorous acid–induced chondrocyte toxicity: A novel cytoprotective role of nitric oxide in the inflamed joint?
Authors: Whiteman Matthew , Rose Peter , Siau Jia Ling , Halliwell Barry 
Published: November 2003

AbstractObjectiveTo examine the potential consequences of overproduction of nitric oxide (NO) and nitrite (NO) in the inflamed rheumatoid joint.MethodsHuman articular chondrocytes in culture were exposed to HOCl (hypochlorous acid, a physiologic oxidant formed in increased amounts at sites of chronic inflammation), and assays of cell viability, intracellular ATP and glutathione (GSH), and lactate dehydrogenase (LDH) were performed. HOCl‐induced lipid peroxidation and activation of the MAP kinases ERK‐1/2, JNK‐1/2, and p38 were also measured. The modulatory effects of NO‐derived nitrite (NO) and nitrate (NO) on HOCl‐mediated chondrocyte toxicity were investigated.ResultsExposure of human articular chondrocytes to HOCl resulted in a concentration‐ and time‐dependent loss of viability, decrease in ATP and GSH levels, LDH leakage, and cell death. HOCl induced significant lipid peroxidation as well as activation of the MAP kinases ERK‐1/2 and p38 but not JNK‐1/2. However, the presence of NO but not NO substantially decreased HOCl‐dependent cellular toxicity even when NO was added at low (μM) concentrations. In sharp contrast, NO (1 mM) did not inhibit superoxide‐, hydroxyl radical–, H2O2‐, or peroxynitrite‐mediated cytotoxicity. Furthermore, culture media from cells treated with interleukin‐1β (to generate NO and NO) offered significantly more protection against HOCl‐mediated cytotoxicity than culture media from untreated cells.ConclusionThese data suggest that NO accumulation at chronically inflamed sites where both HOCl and NO are overproduced may be cytoprotective against damage induced by HOCl. Accumulation of NO could represent a novel cytoprotective role of NO in inflamed joints. A mechanism for this is suggested.
Extrasalivary lymphoma development in Sjögren's syndrome: Clonal evolution from parotid gland lymphoproliferation and role of local triggering
Authors: Gasparotto Daniela , De Vita Salvatore , De Re Valli , Marzotto Alessandra , De Marchi Ginevra , Scott Cathryn Ann , Gloghini Annunziata , Ferraccioli Gianfranco , Boiocchi Mauro 
Published: November 2003

AbstractObjectiveTo characterize Sjögren's syndrome (SS)–related B cell lymphoproliferation at the premalignant stage and during the evolution to B cell lymphoma, and to better understand the pathobiologic mechanisms associated with clonal expansion and the possible influence of different microenvironments on neoplastic transformation.MethodsWe analyzed sequential parotid and lung biopsy specimens that were obtained from a single patient with SS at multiple time points over a 7‐year period. Polymerase chain reaction DNA amplification, cloning, and sequencing of the immunoglobulin heavy chain variable region showed clonality, somatic mutations, intraclonal heterogeneity, and genealogic relationships of the B cell clones in the different biopsy specimens.ResultsThe evolution of a nonmalignant B cell clone that was present in the parotid gland and evolved into a B cell lymphoma was documented. During such a process, one subclone was selected that accumulated somatic mutations in a pattern consistent with the preservation of antigen receptor functionality, possibly attributable to continued hypermutation and selection. Intraclonal diversity indicated the presence of local triggers in both the parotid and lung microenvironments.ConclusionMolecular followup of B cell lymphoproliferation in SS, from nonmalignant stage to overt B cell lymphoma, indicated a role for B cell receptor engagement in clonal survival. The outgrowth of one subclone, with malignant transformation in the lung, a target organ different from the initial site of the lymphoproliferative process (the parotid gland), indicates that resident stimuli in different microenvironments may locally sustain ongoing lymphoproliferation and B cell transformation.
Comparison of rheumatoid arthritis clinical trial outcome measures: A simulation study
Authors: Anderson Jennifer J. , Bolognese James A. , Felson David T. 
Published: November 2003

AbstractObjectiveIsolated studies have suggested that continuous measures of response may be better than predefined, dichotomous definitions (e.g., the American College of Rheumatology 20% improvement criteria [ACR20]) for discriminating between rheumatoid arthritis (RA) treatments. Our goal was to determine the statistical power of predefined dichotomous outcome measures (termed “a priori”), compared with that of continuous measures derived from trial data in which there was no predefined response threshold (termed “data driven”), and to evaluate the sensitivity to change of these measures in the context of different treatments and early versus later‐stage disease. In order to generalize beyond results from a single trial, we performed simulation studies.MethodsWe obtained summary data from trials comparing disease‐modifying antirheumatic drugs (DMARDs) and from comparative coxib–placebo trials to test the power of 2 a priori outcomes, the ACR20 and improvement of the Disease Activity Score (DDAS), as well as 2 data‐driven outcomes. We studied patients with early RA and those with later‐stage RA (duration of <4 years and 4–9 years, respectively). We performed simulation studies, using the interrelationship of ACR core set measures in the trials to generate multiple trial data sets consistent with the original data.ResultsThe data‐driven outcomes had greater power than did the a priori measures. The DMARD comparison was more powerful in early disease than in later‐stage disease (the sample sizes needed to achieve 80% power for the most powerful test were 64 for early disease versus 100 for later disease), but the coxib‐versus‐placebo comparison was less powerful in early disease than in later disease (the sample sizes needed to achieve 80% power were 200 and 100, respectively). When the effects of treatment on core set items were small and/or inconsistent, power was reduced, particularly for a less broadly based outcome (e.g., DDAS) compared with the ACR20.ConclusionThe simulation studies demonstrate that data‐driven outcome definitions can provide better sensitivity to change than does the ACR20 or DDAS. Using such methods would improve power, but at the expense of trial standardization. The studies also show how patient population and treatment characteristics affect the power of specific outcome measures in RA clinical trials, and provide quantification of those effects.
Risk factors for coronary heart disease in women with systemic lupus erythematosus: The Toronto Risk Factor Study
Authors: Bruce Ian N. , Urowitz Murray B. , Gladman Dafna D. , Ibañez Dominique , Steiner George 
Published: November 2003

AbstractObjectiveBecause women with systemic lupus erythematosus (SLE) are 5–8 times more likely to develop coronary heart disease (CHD) than are women in the general population, we assessed the prevalence of classic risk factors for CHD in women with SLE.MethodsConsecutive female patients with SLE who were without evidence of CHD and were attending a large lupus clinic in Toronto were studied. The control population was recruited from among age‐matched subjects attending a family practice unit for an annual physical examination. The prevalence of classic CHD risk factors and the 10‐year risk of a CHD‐related event were determined using the Framingham risk assessment formula. Lipid subfractions, other metabolic risk factors, lifestyle variables, and demographic characteristics were also compared between the 2 groups.ResultsWe studied 250 SLE patients and 250 controls whose mean ± SD age was 44.8 ± 12 years and 44.3 ± 15 years, respectively. Hypertension and diabetes were significantly more common among the SLE patients. Although the SLE patients had a higher mean number of CHD risk factors per patient, the 10‐year risk of a CHD‐related event, using the Framingham multiple risk factor assessment, was the same in SLE patients and controls (3.2%). Compared with controls, SLE patients had higher levels of very low‐density lipoprotein cholesterol and total triglycerides, and had higher levels of homocysteine despite having higher folate levels. Premature menopause, sedentary lifestyle, and an at‐risk body habitus were also more prevalent in SLE patients.ConclusionWomen with SLE have a range of detectable coronary risk factors that are not fully reflected in the Framingham risk factor formula. These factors are likely to contribute to the loss of protection from CHD that has been observed in SLE.
Articular, monoclonal γ3 heavy‐chain deposition disease: Characterization of a partially deleted heavy‐chain gene and its protein product synthesized in vivo and in vitro
Authors: Thompson Keith M. , Sletten Knut , Brandtzaeg Per , Källberg Eva , Wien Tale Norbye , Husby Gunnar 
Published: November 2003

AbstractObjectiveA patient presented with heavy‐chain deposition disease (HCDD), exhibiting severe erosive polyarthropathy caused by synovial deposits of abnormal monoclonal, heavily deleted free γ3 heavy chains lacking the VH and CH1 domains. The absence of VH was surprising, since it is considered important for pathogenic tissue deposition. This study was undertaken to analyze the genetic structure of the heavy chain, the protein product synthesized in vitro, and that deposited in the synovium in comparison with the serum and urinary proteins.MethodsHybridomas were made by fusion of blood and bone marrow mononuclear cells with mouse myeloma cells. Cloned B cell hybridomas secreting γ3 were selected and analyzed by polymerase chain reaction. Purified hybridoma Ig was sequenced by Edman degradation. Antiserum raised to a peptide corresponding to residues 2–15 of the truncated VH was used in Western blots of synovial tissue.ResultsThe hybridomas secreted free γ3 chains consisting of a VH4 gene truncated 21 nucleotides into the first complementarity‐determining region and then reading straight into the hinge region. The amino acid sequence confirmed the presence of residues 1–32 of the VH4 gene. Immunoblotting of synovial tissue showed the presence of Ig with truncated VH.ConclusionThe γ3 heavy chain had a deletion of VH from codon 33 and of the entire CH1. In vivo, the 32 VH amino acids were proteolytically degraded. In the joint, however, the 32 residues of VH remained intact, consistent with a pathogenic role of VH for tissue deposition. To our knowledge, this is the first reported case of γHCDD causing an erosive, polyarticular arthropathy as the dominating clinical feature.
Generation and characterization of LymphoStat‐B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator
Authors: Baker Kevin P. , Edwards Bryan M. , Main Sarah H. , Choi Gil H. , Wager Ruth E. , Halpern Wendy G. , Lappin Patrick B. , Riccobene Todd , Abramian Donara , Sekut Les , Sturm Bonnie , Poortman Carol , Minter Ralph R. , Dobson Claire L. , Williams Elizabeth , Carmen Sara , Smith Rodger , Roschke Viktor , Hilbert David M. , Vaughan Tristan J. , Albert Vivian R. 
Published: November 2003

AbstractObjectiveTo identify and characterize a fully human antibody directed against B lymphocyte stimulator (BLyS), a tumor necrosis factor–related cytokine that plays a critical role in the regulation of B cell maturation and development. Elevated levels of BLyS have been implicated in the pathogenesis of autoimmune diseases.MethodsA human phage display library was screened for antibodies against human BLyS. A human monoclonal antibody, LymphoStat‐B, specific for human BLyS was obtained from the library screening and subsequent affinity optimization mutagenesis. The antibody was tested for inhibition of human BLyS in vitro and in an in vivo murine model. Additionally, the consequences of BLyS inhibition were tested in vivo by administration of LymphoStat‐B to cynomolgus monkeys.ResultsLymphoStat‐B bound with high affinity to human BLyS and inhibited the binding of BLyS to its 3 receptors, TACI, BCMA, and BLyS receptor 3/BAFF‐R. LymphoStat‐B potently inhibited BLyS‐induced proliferation of B cells in vitro, and administration of LymphoStat‐B to mice prevented human BLyS‐induced increases in splenic B cell numbers and IgA titers. In cynomolgus monkeys, administration of LymphoStat‐B resulted in decreased B cell representation in both spleen and mesenteric lymph nodes.ConclusionA fully human monoclonal antibody has been isolated that binds to BLyS with high affinity and neutralizes human BLyS bioactivity in vitro and in vivo. Administration of this antibody to cynomolgus monkeys resulted in B cell depletion in spleen and lymph node. This antibody may prove therapeutically useful in the treatment of autoimmune diseases in humans.
The −174G allele of the interleukin‐6 gene confers susceptibility to systemic arthritis in children: A multicenter study using simplex and multiplex juvenile idiopathic arthritis families
Authors: Ogilvie Emma M. , Fife Mark S. , Thompson Susan D. , Twine Natalie , Tsoras Monica , Moroldo Marta , Fisher Sheila A. , Lewis Cathryn M. , Prieur Anne‐Marie , Glass David N. , Woo Patricia 
Published: November 2003

AbstractObjectiveLevels of interleukin‐6 (IL‐6) have been shown to correlate with the fever and disease activity of systemic juvenile idiopathic arthritis (JIA). In a previous case–control study, a significant association between the IL‐6 −174 nucleotide variant and systemic JIA was noted, and HeLa cell transfection assays show functional differences in levels of transcription of the IL‐6 −174 alleles. The present study was undertaken to confirm the previous findings and to assess possible association with variations of the AnTn tract in the promoter.MethodsWe studied a cohort of JIA families from 3 countries, using transmission disequilibrium testing. Genotyping of the −174 nucleotide variant was done by restriction fragment length polymorphism, heteroduplex analysis, or allelic discrimination. The AnTn tract at −392 to −373 was typed using DNA sequencing. Statistical analysis was performed using the programs Transmit and EHplus.ResultsThere was a significant excess transmission of the −174G allele in the systemic JIA families (P = 0.041). The excess transmission was only to systemic JIA patients with age at onset >5 years (P = 0.007). No significant association with the other subtypes was found. No AnTn alleles or −174/AnTn haplotypes were significantly associated with systemic JIA.ConclusionThis study confirms that the IL‐6 –174 nucleotide variant is significantly associated with systemic JIA. The significant excess transmission to patients with age at onset >5 years but not to those with age at onset ≤5 years suggests that there may be genetic heterogeneity between the 2 groups.
Evidence for a key role of leptin in osteoarthritis
Authors: Dumond Hélène , Presle Nathalie , Terlain Bernard , Mainard Didier , Loeuille Damien , Netter Patrick , Pottie Pascale 
Published: November 2003

AbstractObjectiveTo evaluate the contribution of leptin (an adipose tissue–derived hormone) to the pathophysiology of osteoarthritis (OA), by determining the level of leptin in both synovial fluid (SF) and cartilage specimens obtained from human joints. We also investigated the effect of leptin on cartilage, using intraarticular injections of leptin in rats.MethodsLeptin levels in SF samples obtained from OA patients undergoing either knee replacement surgery or knee arthroscopy were measured by enzyme‐linked immunosorbent assay. In addition, histologic sections of articular cartilage and osteophytes obtained during surgery for total knee replacement were graded using the Mankin score, and were immunostained using antibodies to leptin, transforming growth factor β (TGFβ), and insulin‐like growth factor 1 (IGF‐1). For experimental studies, various doses of leptin (10, 30, 100, and 300 μg) were injected into the knee joints of rats. Tibial plateaus were collected and processed for proteoglycan synthesis by radiolabeled sulfate incorporation, and for expression of leptin, its receptor (Ob‐Rb), and growth factors by reverse transcriptase–polymerase chain reaction and immunohistochemical analysis.ResultsLeptin was observed in SF obtained from human OA–affected joints, and leptin concentrations correlated with the body mass index. Marked expression of the protein was observed in OA cartilage and in osteophytes, while in normal cartilage, few chondrocytes produced leptin. Furthermore, the pattern and level of leptin expression were related to the grade of cartilage destruction and paralleled those of growth factors (IGF‐1 and TGFβ1). Animal studies showed that leptin strongly stimulated anabolic functions of chondrocytes and induced the synthesis of IGF‐1 and TGFβ1 in cartilage at both the messenger RNA and the protein levels.ConclusionThese findings suggest a new peripheral function of leptin as a key regulator of chondrocyte metabolism, and indicate that leptin may play an important role in the pathophysiology of OA.
Cyclic tensile stretch loaded on bovine chondrocytes causes depolymerization of hyaluronan: Involvement of reactive oxygen species
Authors: Yamazaki K. , Fukuda K. , Matsukawa M. , Hara F. , Matsushita T. , Yamamoto N. , Yoshida K. , Munakata H. , Hamanishi C. 
Published: November 2003

AbstractObjectiveWe have previously demonstrated that reactive oxygen species (ROS) are involved in cartilage degradation. Decreased size of hyaluronan (HA), the major macromolecule in synovial fluid, to which it imparts viscosity, is reported in patients with arthritis. The purpose of this study was to determine the alteration in the molecular weight range of HA as a result of mechanical deformation loaded on the chondrocytes, as well as the involvement of ROS in this action.MethodsROS were generated via the oxidation of hypoxanthine by xanthine oxidase. Cyclic tensile stretch was loaded using a vacuum‐operated instrument. Levels of HA were measured using a sandwich enzyme‐binding assay. Superoxide dismutase (SOD) activity and ROS were measured using water‐soluble tetrazolium and a chemiluminescent probe, respectively.ResultsROS depolymerized HA molecules. Cyclic tensile stretch depolymerized HA and induced ROS. SOD inhibited not only ROS induction but also HA depolymerization caused by the mechanical stress.ConclusionROS play an important role in mechanical stress–induced HA depolymerization.