bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of widespread body pain with an increased risk of cancer and reduced cancer survival: A prospective, population‐based study
Authors: McBeth John , Silman Alan J. , Macfarlane Gary J. 
Published: June 2003

AbstractObjectiveTo determine whether reported widespread body pain is related to an increased incidence of cancer and/or reduced survival from cancer, since our previous population surveys have demonstrated a relationship between widespread body pain and a subsequent 2‐fold increase in mortality from cancer over an 8‐year period.MethodsA total of 6,565 subjects in Northwest England participated in 2 health surveys during 1991–1992. The subjects were classified according to their reported pain status (no pain, regional pain, and widespread pain), and were subsequently followed up prospectively until December 31, 1999. During followup, information was collected on incidence of cancer and survival rates among those developing cancer. Associations between the original pain status and development of cancer and cancer survival were expressed as the incidence rate ratio (IRR) and mortality rate ratio (MRR), respectively. All analyses were adjusted for age, sex, and study location, the latter being a proxy measure of socioeconomic status.ResultsAmong the study population, 6,331 had never been diagnosed with cancer at the time of participation in the survey. Of these subjects, 956 (15%) were classified as having widespread pain, 3,061 (48%) as having regional pain, and 2,314 (37%) as having no pain. There were a total of 395 first malignancies recorded during followup. In comparison with subjects reporting no pain, those with regional pain (IRR 1.19, 95% confidence interval [95% CI] 0.94–1.50) and widespread pain (IRR 1.61, 95% CI 1.21–2.13) experienced an excess incidence of cancer during the followup period. The increased incidence among subjects previously reporting widespread pain was related, most strongly, to breast cancer (IRR 3.67, 95% CI 1.39–9.68), but there were also cancers of the prostate (IRR 3.46, 95% CI 1.25–9.59), large bowel (IRR 2.35, 95% CI 0.96–5.77), and lung (IRR 2.04, 95% CI 0.96–4.34). Subjects reporting widespread pain who subsequently developed cancer, in comparison with those previously reporting no pain, had an increased risk of death (MRR 1.82, 95% CI 1.18–2.80). This decreased survival was highest among subjects with cancers of the breast and prostate, although the effects on site‐specific survival were nonsignificant.ConclusionThis study has demonstrated that widespread pain reported in population surveys is associated with a substantial subsequent increased incidence of cancer and reduced cancer survival. At present there are no satisfactory biologic explanations for this observation, although several possible leads have been identified.
Selective inhibition of cyclooxygenase 2–generated prostaglandin E2 synthesis in rheumatoid arthritis synoviocytes by taurine chloramine
Authors: Kontny Ewa , Rudnicka Weronika , Kowalczewski Jacek , Marcinkiewicz Janusz , Maslinski Wlodzimierz 
Published: June 2003

AbstractObjectiveTo investigate the effects of taurine chloramine (Tau‐Cl), a chlorinated derivative of the amino acid taurine, on the expression of cyclooxygenase (COX) isoenzymes and prostaglandin E2 (PGE2) synthesis in rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS).MethodsFLS, isolated from the synovial tissue of RA patients, were treated in vitro with either interleukin‐1β (IL‐1β; 1 ng/ml) alone or together with 200–500 μM Tau‐Cl. The expression of COX isoenzymes was evaluated at both the protein (Western blotting) and the messenger RNA (mRNA) (reverse transcriptase–polymerase chain reaction) levels. The concentration of PGE2 was measured by competitive acetylcholinesterase enzyme immunoassay.ResultsResting FLS expressed mRNA encoding both COX‐1 and COX‐2, but only COX‐1 was present at the protein level. These cells produced negligible amounts of PGE2. Upon stimulation with IL‐1β, elevation of COX‐2, but not COX‐1, mRNA and protein preceded the enhancement of PGE2 synthesis. In the presence of 300–400 μM Tau‐Cl, significant inhibition of IL‐1β–triggered COX‐2 mRNA and protein, and a related decrease in PGE2 production, was observed. In contrast, no significant changes in COX‐1 mRNA and protein levels were noted.ConclusionTau‐Cl inhibits IL‐1β–triggered elevation of COX‐2 and generation of PGE2 by RA FLS. These results expand the spectrum of known antiinflammatory activities of this compound.
Blockade of parathyroid hormone–related protein prevents joint destruction and granuloma formation in streptococcal cell wall–induced arthritis
Authors: Funk J. L. , Chen J. , Downey K. J. , Davee S. M. , Stafford G. 
Published: June 2003

AbstractObjectiveTo determine whether parathyroid hormone–related protein (PTHrP), an interleukin‐1β–inducible, bone‐resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA.MethodsPTHrP expression and the effect of PTHrP 1–34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW)–induced arthritis, an animal model of RA.ResultsAs has been reported in RA, while serum levels of PTHrP did not change during SCW‐induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW‐treated animals. However, PTHrP antibody significantly inhibited SCW‐induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor–positive neutrophils and in SCW‐induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1–34.ConclusionThese findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.
Effect of minodronic acid (ONO‐5920) on bone mineral density and arthritis in adult rats with collagen‐induced arthritis
Authors: Yamane Itsuro , Hagino Hiroshi , Okano Toru , Enokida Makoto , Yamasaki Daisuke , Teshima Ryota 
Published: June 2003

AbstractObjectiveTo study the effect of minodronic acid (ONO‐5920) on bone loss and arthritis in rats with collagen‐induced arthritis (CIA) treated according to 2 different schedules.MethodsFour groups of female Sprague‐Dawley rats (7 months old) were studied: rats without CIA treated with vehicle (controls), CIA rats treated with vehicle (CIA‐V), CIA rats treated therapeutically with minodronic acid (CIA‐T), and CIA rats treated prophylactically with minodronic acid (CIA‐P). Minodronic acid was administered orally at 0.2 mg/kg 3 times a week, beginning 2 weeks after initial sensitization in the CIA‐T rats and beginning the day after initial sensitization in the CIA‐P rats. Bone mineral density (BMD) was measured by peripheral quantitative computed tomography in the proximal metaphysis and diaphysis of the tibia every 2 weeks until week 8, when the rats were killed. The BMD and bone microstructure of the excised femur were evaluated by dual x‐ray absorptiometry and microfocal computed tomography, respectively. Histomorphometry of the proximal tibia was also performed.ResultsIn CIA‐P rats, the incidence of arthritis and the severity of posterior limb swelling were reduced early after sensitization, and the decrease in BMD was prevented throughout the observation period. Bone and joint destruction evaluated by radiography of the foot was reduced in CIA‐P rats. The eroded surface was reduced and the microstructure was maintained in CIA‐P rats compared with CIA‐V rats. The mineral apposition and bone formation rates were not reduced in the CIA‐P rats. In CIA‐T rats, however, the inflammation was not suppressed and the inhibitory effect on bone loss was smaller than that in CIA‐P rats.ConclusionMinodronic acid suppressed the decrease in BMD and the deterioration of the bone microstructure caused by arthritis. Prophylactic administration of minodronic acid had a preventive effect on arthritis at the early stage, although not throughout the observation period.
Increased perivascular synovial membrane expression of myeloid‐related proteins in psoriatic arthritis
Authors: Kane David , Roth Johannes , Frosch Michael , Vogl Thomas , Bresnihan Barry , FitzGerald Oliver 
Published: June 2003

AbstractObjectiveTo analyze S‐100 protein expression, in the form of myeloid‐related protein 8 (MRP8), MRP14, and the heterodimer MRP8/MRP14, in psoriatic arthritis (PsA) patients compared with rheumatoid arthritis (RA) and spondylarthropathy (SpA) patients, and to determine the effect of methotrexate (MTX) on the MRP antigen expression in PsA patients.MethodsSerum, synovial fluid (SF), and synovium (taken at arthroscopy) samples were obtained from PsA (before and after MTX treatment), RA, and SpA patients. Concentrations of MRP8/MRP14 in serum and SF were measured by enzyme‐linked immunosorbent assay. Expression of MRP8, MRP14, and MRP8/MRP14 in synovium was determined by immunohistochemistry.ResultsMRP8, MRP14, and MRP8/MRP14 levels were increased in serum, SF, and synovium from PsA, RA, and SpA patients. In all 3 groups, paired samples of serum and SF showed significantly higher MRP8/MRP14 levels in SF (mean ± SD 15,310 ± 16,999 ng/ml [median 11,400]) than in serum (908 ± 679 ng/ml [median 695]) (P = 0.0001). MRP8/MRP14 levels in serum correlated with systemic parameters of disease activity (erythrocyte sedimentation rate [ESR] r = 0.55, P = 0.005; C‐reactive protein [CRP] level r = 0.55, P = 0.005), whereas levels in SF correlated with local parameters of disease activity (white blood cell count r = 0.45, P = 0.01; acute‐phase serum amyloid A level r = 0.32, P = 0.03). MRP expression was significantly higher in the synovial sublining layer (SLL) of PsA patients compared with RA and SpA patients. MRP antigens were predominantly expressed in perivascular areas of the SLL in PsA patients. Following MTX treatment, MRP expression in serum and synovium from PsA patients was significantly reduced. Serum levels of MRP were more sensitive to the effects of MTX than were the ESR, CRP, or clinical joint scores.ConclusionMRP levels in serum and SF correlate with local and systemic inflammation and are equally increased in PsA, RA, and SpA patients. In contrast, MRP8, MRP14, and MRP8/MRP14 expression in the SLL of PsA patients is increased, particularly in perivascular regions, compared with that in RA and SpA patients, suggesting a central role of MRP proteins in transendothelial migration of leukocytes in PsA. Moreover, MRP expression is reduced following MTX treatment. MRP proteins may represent a novel therapeutic target in inflammatory arthritis.
In vivo selective inhibition of mitogen‐activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes
Authors: Pelletier Jean‐Pierre , Fernandes Julio C. , Brunet Julie , Moldovan Florina , Schrier Denis , Flory Craig , Martel‐Pelletier Johanne 
Published: June 2003

AbstractObjectiveThe primary aim of this study was to investigate, using an experimental rabbit model of osteoarthritis (OA), the effect of a selective mitogen‐activated protein kinase kinase 1/2 (MEK‐1/2) inhibitor, PD 198306, on the development of structural changes. Additional aims were to assess the effects of the inhibitor on levels of phosphorylated extracellular signal–regulated kinase 1/2 (phospho–ERK‐1/2) and matrix metalloproteinase 1 (MMP‐1; collagenase 1) in OA chondrocytes.MethodsAfter surgical sectioning of the anterior cruciate ligament of the right knee joint, rabbits with OA were separated into 3 experimental groups: oral treatment with placebo or with PD 198306 at a therapeutic concentration of 10 mg/kg/day or 30 mg/kg/day. Each treatment started immediately after surgery. The animals were killed 8 weeks after surgery. Macroscopic and histologic studies were performed on the cartilage and synovial membrane. The levels of phospho–ERK‐1/2 and MMP‐1 in OA cartilage chondrocytes were evaluated by immunohistochemistry. Normal, untreated rabbits were used as controls.ResultsOA rabbits treated with the highest dosage of MEK‐1/2 inhibitor showed decreases in the surface area (size) of cartilage macroscopic lesions (P < 0.002) and in osteophyte width on the lateral condyles (P = 0.05). Histologically, the severity of synovial inflammation (villous hyperplasia) was also reduced (P < 0.02). In cartilage from placebo‐treated OA rabbits, a significantly higher percentage of chondrocytes in the superficial layer stained positive for phospho–ERK‐1/2 and MMP‐1 compared with normal controls. Rabbits treated with the highest dosage of PD 198306 demonstrated a significant and dose‐dependent reduction in the level of phospho–ERK‐1/2 and a lower level of MMP‐1.ConclusionThis study demonstrates that, in vivo, PD 198306, a selective inhibitor of MEK‐1/2, can partially decrease the development of some of the structural changes in experimental OA. This effect was associated with a reduction in the level of phospho–ERK‐1/2 in OA chondrocytes, which probably explains the action of the drug.
The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: A five‐year followup study
Authors: Kalden J. R. , Schattenkirchner M. , Sörensen H. , Emery P. , Deighton C. , Rozman B. , Breedveld F. 
Published: June 2003

AbstractObjectiveTo investigate the efficacy and safety of leflunomide beyond 2 years in a multinational, open‐label extension of 2 phase III double‐blind studies.MethodsPatients with rheumatoid arthritis (RA) who received leflunomide (100 mg/day for 3 days, 10 mg/day or 20 mg/day thereafter) in the 2 phase III studies and who completed 2 years of treatment were offered inclusion in the open‐label extension phase and were maintained on the same dosage of leflunomide. The American College of Rheumatology revised criteria for 20% improvement (ACR20), ACR50, and ACR70 response rates, the Stanford Health Assessment Questionnaire (HAQ) scores, and C‐reactive protein (CRP) levels were assessed. Safety measures included monitoring of adverse events and laboratory values.ResultsA total of 214 patients (mean age 57 years) were treated with leflunomide for >2 years; 74.8% of the patients were female. The mean disease duration was 4.1 years (range 0.1–26.6 years), and in 44% of patients, RA was first diagnosed within 2 years of entry into the phase III studies. The mean duration of leflunomide treatment was 4.6 years (range 2.8–5.8 years), and 32% of patients had received no previous treatment with disease‐modifying antirheumatic drugs. ACR20, ACR50, and ACR70 response rates and HAQ scores at 1 year were maintained through year 4 or until the end point. No new types of adverse events were observed, and liver function was normal at baseline and at the end point in the majority of patients.ConclusionThe improvements in both functional ability and physician‐based efficacy measures seen with leflunomide after 1 year were maintained for up to 5 years (maximum treatment duration 5.8 years), demonstrating that the early efficacy of leflunomide in patients with RA is sustained long‐term, and that the long‐term safety profile of leflunomide is no different from that observed in phase III trials.
Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis
Authors: Brandt J. , Khariouzov A. , Listing J. , Haibel H. , Sörensen H. , Grassnickel L. , Rudwaleit M. , Sieper J. , Braun J. 
Published: June 2003

AbstractObjectiveThere is increasing evidence that tumor necrosis factor α (TNFα) is centrally involved in the pathogenesis of ankylosing spondylitis (AS) and other spondylarthritides. This study was designed to investigate the efficacy of anti‐TNFα therapy with etanercept, a 75‐kd receptor fusion protein, in active AS.MethodsThis multicenter trial had 2 phases: an initial placebo‐controlled period of 6 weeks' duration and an observational phase lasting 24 weeks. Thirty patients with active AS were included. They were randomized into 2 groups, which received either etanercept (25 mg twice weekly) (n = 14) or placebo (n = 16) for 6 weeks. Then both groups were treated with etanercept. Nonsteroidal antiinflammatory drug (NSAID) treatment could be continued, but disease‐modifying antirheumatic drugs (DMARDs) and steroids had to be withdrawn prior to the study. All patients received etanercept for a total of 12 weeks and were followed up for at least 24 weeks. The Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index, Bath AS Metrology Index, pain level on a numeric rating scale, quality of life by the Short Form 36, and C‐reactive protein (CRP) level were assessed. The primary outcome parameter was a ≥50% improvement in the BASDAI.ResultsTreatment with etanercept resulted in at least a 50% regression of disease activity in 57% of these patients at week 6, versus 6% of the placebo‐treated patients (P = 0.004). After the placebo‐treated patients switched to etanercept, 56% improved. The mean ± SD BASDAI improved from 6.5 ± 1.2 at baseline to 3.5 ± 1.9 at week 6 in the etanercept group, with no improvement in the placebo group (P = 0.003 between groups). Similarly, pain, function, mobility, and quality of life improved with etanercept but not with placebo at week 6 (P < 0.05). Mean CRP levels decreased significantly with etanercept but not with placebo (P = 0.001). There was ongoing improvement in all parameters in both groups until week 12 and week 18, respectively (i.e., throughout the period of etanercept treatment). Disease relapses occurred a mean ± SD of 6.2 ± 3.0 weeks after cessation of etanercept. No severe adverse events, including major infections, were observed during the trial.ConclusionThis study shows that on a short‐term basis (3 months), treatment with etanercept is clearly efficacious in patients with active AS who are receiving NSAID therapy but not DMARDs or steroids. After cessation of therapy, almost all patients experienced a relapse within a few weeks. Thus, it seems probable that etanercept must be administered continuously in most AS patients to achieve permanent inhibition of the inflammatory process.
Differential control of CD22 ligand expression on B and T lymphocytes, and enhanced expression in murine systemic lupus
Authors: Lajaunias Frédéric , Ida Akinori , Kikuchi Shuichi , Fossati‐Jimack Liliane , Martinez‐Soria Eduardo , Moll Thomas , Law Che‐Leung , Izui Shozo 
Published: June 2003

AbstractObjectiveCD22, a B cell–restricted transmembrane glycoprotein, regulates B cell antigen receptor signaling upon interaction with α2,6‐linked sialic acid–bearing glycans, which act as ligands and are expressed on B and T cells. In this study, we investigated how the expression of CD22 ligand (CD22L) is modulated following lymphocyte activation or during the course of systemic lupus erythematosus (SLE).MethodsThe expression levels of CD22L on B and T cells in nonautoimmune mice were assessed by flow cytometric analysis using a soluble recombinant form of CD22, following stimulation with antigen or mitogen in vitro. In addition, the expression levels of CD22L on circulating lymphocytes were correlated with the progression of SLE in lupus‐prone mice.ResultsWe observed a constitutive expression of CD22L on mature B cells, but not T cells, in nonautoimmune mice. However, CD22L levels were up‐regulated selectively on T cells (but not B cells) stimulated with antigens in vitro, while their expression levels on B cells was up‐modulated following polyclonal activation with lipopolysaccharide. Furthermore, expression of CD22L was increased on circulating B cells (and to a lesser extent on T cells) in parallel with progression of SLE in several different lupus‐prone mice and in a cohort of (C57BL/6 × [NZB × C57BL/6.Yaa]F1) backcross mice.ConclusionThe expression of CD22L is differentially regulated in B and T cells, and high expression of CD22L on circulating B cells is a marker for development of severe SLE, suggesting a role for CD22–CD22L interactions in SLE as well as in the regulation of humoral immunity.
Effects of antiinflammatory drugs on arthritic cartilage: A high‐frequency quantitative ultrasound study in rats
Authors: Jaffré Britta , Watrin Astrid , Loeuille Damien , Gillet Pierre , Netter Patrick , Laugier Pascal , Saïed Amena 
Published: June 2003

AbstractObjectiveTo evaluate the ability of 55‐MHz quantitative ultrasound (US) to detect the in vivo effects of experimental arthritis, as well as those of two antiinflammatory drugs, naproxen (NPX) and dexamethasone (DEX), on cartilage and subchondral bone.MethodsArthritis was induced in both knees of 108 rats by intraarticular injection of zymosan (ZYM). Two groups of arthritic rats (n = 36 per group) were treated daily with either NPX (10 mg/kg/day) or DEX (0.1 mg/kg/day). Using a 3‐dimensional US microscope, patellae were explored in vitro on days 5, 14, and 21 after injections. US assessment included the analysis of quantitative indices of local modifications involving cartilage and bone: integrated reflection coefficient (IRC) from the cartilage surface and apparent integrated backscatter from the cartilage internal structure (cartilage matrix) (AIBcartilage) and the cartilage–bone interface (AIBbone).ResultsZYM induced articular surface fibrillation that resulted in a decrease in IRC at all times (P < 0.02) and in an increase in AIBbone on days 5 and 14 (P < 0.005). Fibrillation was not changed by NPX administration, while it disappeared following DEX treatment. Cartilage–bone interface alterations were prevented by DEX and partially compensated for by NPX. Cartilage matrix echogenicity decreased with time in all groups due to maturation (P < 0.05), except in DEX‐treated rats.ConclusionQuantitative 55 MHz US allowed detection of early cartilage and bone lesions due to experimental arthritis, and also allowed detection of the effects of antiinflammatory drugs. NPX seemed to have an effect on subchondral bone lesions, but not on cartilage. DEX appeared to repair articular surface and bone, but prevented animal growth and cartilage maturation.