bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dialysis‐associated systemic fibrosis (nephrogenic fibrosing dermopathy): Study of inflammatory cells and transforming growth factor β1 expression in affected skin
Authors: Jiménez Sergio A. , Artlett Carol M. , Sandorfi Nora , Derk Chris , Latinis Kevin , Sawaya Heloisa , Haddad Richard , Shanahan Joseph C. 
Published: August 2004

AbstractObjectiveNephrogenic fibrosing dermopathy (NFD) is a newly recognized cutaneous fibrotic disorder occurring in individuals with end‐stage renal disease (ESRD). The aim of the present study was to describe the clinical and histopathologic features of 9 new cases and to characterize the inflammatory cells and expression of transforming growth factor β1 (TGFβ1) in affected skin.MethodsClinical and laboratory assessments, including serology and pulmonary function studies, were performed in 9 patients undergoing long‐term dialysis (8 hemodialysis; 1 peritoneal dialysis) for ESRD of diverse etiologies. Skin, fascia, striated muscles, lungs, and heart were examined by histopathology. Inflammatory cells were characterized by immunophenotyping using specific monoclonal antibodies. TGFβ1 expression was determined by in situ hybridization.ResultsAll patients displayed cutaneous features resembling both systemic sclerosis and diffuse fasciitis, with severe loss of motion and flexion contractures in multiple joints. Six patients displayed woody induration of the muscles of the legs, thighs, and forearms. Five of the 6 patients with lung involvement had a reduced diffusion capacity for carbon monoxide on pulmonary function testing. Marked elevations of the erythrocyte sedimentation rate and/or C‐reactive protein level were found in 6 patients. Antinuclear antibodies were present at low titers in 4 patients. Histopathologic studies indicated that in addition to the dermis, the fibrotic process affected the subcutaneous tissue, fascia, striated muscles, lungs, and myocardium. Large numbers of CD68+/factor XIIIa+ dendritic cells and increased expression of TGFβ1 were found in affected skin and muscle.ConclusionOur findings indicate that the fibrotic process of NFD affects not only the dermis, but also the subcutaneous tissues, fascia, and other organs, including striated muscles, heart, and lungs. We therefore believe this is a systemic fibrosing process, and we suggest that dialysis‐associated systemic fibrosis would be a better term for the condition.
Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis
Authors: Mok Chi Chiu , Ying King Yee , Tang Sydney , Leung Chung Ying , Lee Ka Wing , Ng Woon Leung , Wong Raymond Woon Sing , Lau Chak Sing 
Published: August 2004

AbstractObjectiveTo study the incidence, predictors, and outcome of renal flares after successful cyclophosphamide (CYC) treatment for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE).MethodsBetween 1988 and 2001, patients with biopsy‐proven SLE DPGN who were treated initially with prednisone and CYC were studied. Those who responded to CYC were followed up for the occurrence of renal flares. The cumulative risk, predictors, and outcome of renal flares were evaluated.ResultsWe studied 189 patients (167 women; and 22 men) with SLE DPGN. All were initially treated with prednisone and CYC (49% orally; 51% by intravenous pulse). At the last dose of CYC, 103 patients (55%) and 52 patients (28%) had achieved complete and partial renal responses, respectively. Azathioprine (AZA) was given as maintenance therapy in 117 patients (75%). After a mean followup of 96.5 months, 59 patients (38%) experienced renal flares (42% nephritic; 58% proteinuric). The median time to relapse was 32 months. The cumulative risk of renal flare was 28% at 36 months and 44% at 60 months. Independent predictors of nephritic flares were persistently low C3 levels after CYC treatment and absence of AZA maintenance therapy. At the last clinic visit, 16 patients (10.3%) had developed doubling of the serum creatinine level (cumulative risk of creatinine doubling 7.4% at 5 years after renal biopsy and 14.3% at 10 years). Ten patients (6.5%) developed end‐stage renal disease (ESRD). Renal survival rates at 5 and 10 years were 94.9% and 87.5%, respectively. Increasing histologic chronicity scores, failure to achieve complete response, persistent hypertension after CYC treatment, and nephritic renal flares were unfavorable factors for doubling of the serum creatinine level and for ESRD by univariate analysis. The occurrence of nephritic flares was the only predictor of creatinine doubling by Cox regression analysis.ConclusionIn patients with SLE DPGN, renal flares are common despite initial responses to CYC. Nephritic renal flares are associated with a decline in renal function. Maintenance therapy with AZA reduces, but does not completely prevent, renal flares. More effective maintenance treatment for SLE DPGN after an initial response to CYC should be evaluated.
Identification of two novel female‐specific non–major histocompatibility complex loci regulating collagen‐induced arthritis severity and chronicity, and evidence of epistasis
Authors: Meng Hsiang‐Chi , Griffiths Marie M. , Remmers Elaine F. , Kawahito Yutaka , Li Wentian , Neisa Roberto , Cannon Grant W. , Wilder Ronald L. , Gulko Pércio S. 
Published: August 2004

AbstractObjectiveTo identify additional sex‐specific and epistatic quantitative trait loci (QTL) regulating collagen‐induced arthritis (CIA) severity overall, as well as within different stages during the disease course, in an intercross between major histocompatibility complex–identical inbred rat strains DA/Bkl (susceptible) and ACI/Hsd (resistant).MethodsArthritic male (DA × ACI)F2 intercross offspring (n = 143) were analyzed separately from the females (n = 184). Phenotypic extremes (maximum arthritis scores [MAS]) were genotyped and used for QTL analysis. All 327 rats were genotyped with the simple sequence‐length polymorphism (SSLP) markers closest to the peak of Cia7 and Cia10, the major loci previously identified in this intercross, and with SSLPs covering chromosomes 12 and 18. Phenotypes studied were disease onset, arthritis severity scores on days 14–39, MAS, mean and cumulative arthritis scores, delayed‐type hypersensitivity, and antibody responses to rat type II collagen.ResultsA new female‐specific arthritis‐severity recessive locus was identified on rat chromosome 12 (Cia25), with a maximum effect observed on day 28 (logarithm of odds [LOD] 4.7). The homozygous DA genotype at Cia25 was associated with a 45% higher median arthritis score in females. Sequencing analyses of the Cia25 candidate gene Ncf1 revealed polymorphisms between DA and ACI. The previously identified locus, Cia10, was found to be male‐specific. A 2‐locus interaction model analysis identified a novel recessive chromosome 18 QTL, Cia26, which was dependent on Cia7, with its maximum effect observed at later stages during the disease course (peak LOD score of 3.6 for arthritis scores on day 39).ConclusionThis study identified 2 novel female‐specific loci, and 1 male‐specific locus. Cia25 regulates MAS and disease severity during the mid‐to‐late stages of the disease course and may be accounted for by Ncf1 polymorphisms. Cia26 is in epistasis with Cia7 and regulates later stages of disease, suggesting an involvement in disease perpetuation and/or chronicity.
Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts
Authors: Nakano Kazuhisa , Okada Yosuke , Saito Kazuyoshi , Tanaka Yoshiya 
Published: August 2004

AbstractObjectiveRheumatoid arthritis (RA) is characterized by progressive joint destruction. The aim of this study was to clarify the relevance of RA synovial fibroblasts (RASFs) and fibroblast growth factor 2 (FGF‐2), which is produced abundantly by RASFs, to the osteoclastogenesis and bone resorption in RA.MethodsSynovial fibroblasts were prepared from the synovial tissues of 10 patients with active RA and 7 patients with osteoarthritis (OA). The expression of RANKL, intercellular adhesion molecule 1 (ICAM‐1), FGF receptor 1 (FGFR‐1), and heparan sulfate proteoglycan (HSPG) on synovial fibroblasts was measured by FACScan. Osteoclast formation in cocultures of RASFs and peripheral blood mononuclear cells (PBMCs) was evaluated by tartrate‐resistant acid phosphatase staining and a pit‐formation assay using dentin slices.ResultsFGF‐2 induced the expression of both RANKL and ICAM‐1 on RASFs more so than on OA synovial fibroblasts (OASFs). FGF‐2–induced up‐regulation of RANKL and ICAM‐1 was inhibited by anti–FGF‐2 antibody. Although FGFR‐1 was equally expressed on RASFs and OASFs, HSPG was highly expressed on RASFs. Up‐regulation of RANKL by FGF‐2 on RASFs was diminished by the removal of heparan sulfate with heparitinase. Osteoclast formation from PBMCs induced by RASFs was inhibited by the addition of either heparitinase, anti–ICAM‐1 antibody, anti–FGF‐2 antibody, or osteoprotegerin. FGF‐2–induced RANKL on RASFs and osteoclast formation were suppressed by an inhibitor of ERK.ConclusionFGF‐2 was transferred to FGFR‐1 through binding to HSPG, which is characteristically expressed on RASFs, resulting in RANKL‐ and ICAM‐1–mediated maturation of osteoclasts via ERK activation. Thus, we propose that FGF‐2 not only augments the proliferation of RASFs, but also is involved in osteoclast maturation, which leads to bone destruction in RA.
Effects of dehydroepiandrosterone on articular cartilage during the development of osteoarthritis
Authors: Jo Hyunchul , Ahn Hyun Jeong , Kim Eun Mi , Kim Hee Joong , Seong Sang Cheol , Lee InBum , Lee Myung Chul 
Published: August 2004

AbstractObjectiveTo investigate the in vivo effects of dehydroepiandrosterone (DHEA) on knee joints during the development of experimentally induced osteoarthritis (OA).MethodsTwenty‐two mature NZW rabbits underwent bilateral anterior cruciate ligament transection (ACLT) and received 0.3‐ml intraarticular injections of DHEA (at a concentration of 100 μM in phosphate buffered saline) and control solution in the right and left knees, respectively, beginning 4 weeks after ACLT and continuing once weekly for 5 weeks. All animals were killed 9 weeks after surgery, and the knee joints were assessed by gross morphologic, histologic, histomorphometric, and biochemical methods.ResultsGross morphologic inspection following India ink application showed that the right femoral condyles, which received DHEA, demonstrated less severe cartilage damage than did the contralateral condyles. The thickness, area, and roughness of the DHEA‐treated femoral condyles provided evidence of a cartilage‐protecting effect of DHEA following ACLT. These results were supported by gene expression analysis. Messenger RNA expression of a proinflammatory cytokine, interleukin‐1β, and catabolic enzymes, matrix metalloproteinases 1 and 3, was reduced in the cartilage of the DHEA‐treated knee joints, and expression of tissue inhibitor of metalloproteinase 1 was increased.ConclusionResults of the present study demonstrate a cartilage‐protecting effect of DHEA during the development of OA following ACLT in a rabbit model.
Detection of anti–type 3 muscarinic acetylcholine receptor autoantibodies in the sera of Sjögren's syndrome patients by use of a transfected cell line assay
Authors: Gao Juehua , Cha Seunghee , Jonsson Roland , Opalko Jeffrey , Peck Ammon B. 
Published: August 2004

AbstractObjectiveSjögren's syndrome (SS) is an autoimmune disease affecting primarily the salivary and lacrimal glands, leading to dry mouth and dry eyes. Recent studies have suggested that autoantibodies reactive with the type 3 muscarinic acetylcholine receptors (M3Rs) expressed on salivary and lacrimal gland cells may be highly specific for SS. To test this hypothesis, we constructed a cell line expressing the human M3R gene in order to screen for anti‐M3R autoantibodies in sera from SS patients.MethodsComplementary DNA encoding the open‐reading frame (ORF) of the human M3R gene was amplified, ligated into the pcDNA5/FRT/V5‐His‐TOPO TA vector, and then used to transform Escherichia coli bacteria. Plasmid DNA containing the M3R ORF with the correct orientation was transfected into Flp‐In Chinese hamster ovary (CHO) cells using Flp recombinase–mediated site‐specific recombination. An M3R‐transfected CHO cell line, selected and propagated in hygromycin, was used to detect anti‐M3R autoantibodies in SS patient and healthy control sera by flow cytometry.ResultsTesting of sera for the presence of anti‐M3R autoantibodies bound to CHO‐transfected cells revealed the presence of anti‐M3R autoantibodies in SS patients (9 of 11) but not in healthy controls (0 of 11). Although the anti‐M3R autoantibodies detected in patient sera were of multiple isotypes, the most consistently detected were IgG1, IgG3, and IgA.ConclusionUsing a newly constructed cell line expressing human M3R, anti‐M3R autoantibodies were easily detected in sera from SS patients. These autoantibodies were skewed toward the IgG1, IgG3, and IgA isotypes, probably recognizing a tertiary epitope created by extracellular domains of the receptor protein. Anti‐M3R autoantibodies represent a highly promising clinical marker for the identification of SS.
The genetic epidemiology of joint hypermobility: A population study of female twins
Authors: Hakim Alan J. , Cherkas Lynn F. , Grahame Rodney , Spector Tim D. , MacGregor Alexander J. 
Published: August 2004

AbstractObjectiveTo estimate the genetic influence on joint hypermobility in an unselected population using a classic twin study design.MethodsA self‐report questionnaire on joint hypermobility as well as data on age, height, weight, estrogen replacement therapy, and menopause status were obtained from 483 monozygotic (MZ) and 472 dizygotic (DZ) unselected female twin pairs ages 21–81 years who were registered with the St Thomas' Adult Twin Registry in the UK.ResultsThe overall prevalence of hypermobility was 19.5% in MZ twins and 22.1% in DZ twins. The prevalence of hypermobile joints declined with age, falling from 34% in subjects ages 20–30 years to 18.4% in those ages 60 years or older. Significantly greater concordance for joint hypermobility was observed in the MZ twins when compared with the DZ twins (60% versus 36%), consistent with a genetic influence. In variance components analysis, the age‐ and body mass index–adjusted heritability of joint hypermobility was estimated to be 70% (95% confidence interval 57–89%).ConclusionGenetic factors have a substantial contribution to joint hypermobility in the adult female population.
Cartilage atrophy in the knees of patients after seven weeks of partial load bearing
Authors: Hinterwimmer S. , Krammer M. , Krötz M. , Glaser C. , Baumgart R. , Reiser M. , Eckstein F. 
Published: August 2004

AbstractObjectiveIt is currently unknown whether human cartilage properties change during short periods of partial load bearing. We used a post–ankle fracture model to explore whether changes in cartilage morphology occur in the knee under conditions of partial load bearing.MethodsThe knees of 20 patients with Weber type B and type C fractures were examined using magnetic resonance imaging. The first scan was obtained shortly (mean ± SD 3.2 ± 3.0 days) after the injury, and a second scan was obtained 7 weeks later (mean ± SD 50.7 ± 5.5 days). The morphology (mean and maximum thickness, volume, and surface area) of the patellar, tibial, and femoral cartilage was determined from coronal and axial magnetic resonance images (fat‐suppressed gradient‐echo).ResultsBetween week 0 and week 7, the cross‐sectional area of the quadriceps muscle was reduced by 11% (P< 0.001). Changes in the mean (±SD) cartilage thickness ranged from −2.9 ± 3.2% in the patella to −6.6 ± 4.9% in the medial tibia. No significant change in cartilage morphology of the contralateral knee was observed.ConclusionResults of this study demonstrate that in a post–ankle fracture model of partial load bearing, cartilage morphology in all knee compartments is subject to significant change. Changes in the femorotibial joint exceeded those in the patella, whereas no change was observed in the contralateral knee. These findings raise the question of whether cartilage is mechanically less competent and particularly vulnerable after states of partial or complete immobilization.
In vivo imaging of protease activity in arthritis: A novel approach for monitoring treatment response
Authors: Wunder Andreas , Tung Ching‐Hsuan , Müller‐Ladner Ulf , Weissleder Ralph , Mahmood Umar 
Published: August 2004

AbstractObjectiveSensitive noninvasive strategies for monitoring treatment response in rheumatoid arthritis (RA) would be valuable for facilitating appropriate therapy and dosing, evaluating clinical outcome, and developing more effective drugs. Because different proteases are highly up‐regulated in RA and contribute significantly to joint destruction, in the present study we investigated whether such enzymes are suitable in vivo imaging biomarkers for early evaluation of treatment response in a murine model of RA.MethodsUsing a protease‐activated near‐infrared fluorescence (NIRF) imaging “smart” probe, we examined the presence and distribution of fluorescence in arthritic joints of mice with collagen‐induced arthritis by both noninvasive fluorescence imaging and histology. Proteases that target the Lys–Lys cleavage site, including cathepsin B, activate probe fluorescence. Treatment monitoring data were obtained following methotrexate (MTX) therapy.ResultsTwenty‐four hours after intravenous injection of the protease sensor, affected toes and paws of arthritic mice showed significantly higher fluorescence intensity than did toes and paws of healthy mice. Fluorescence from the protease probe and cathepsin B antibody histologic staining were localized in the vast majority of cells in the inflamed synovium. In arthritic animals treated with MTX (35 mg of MTX/kg 48 hours prior to probe injection), a significantly lower fluorescent signal (inflamed paws 50%, inflamed toes 70%) was observed as compared with untreated arthritic animals.ConclusionProtease‐activated NIRF probes are sensitive means of imaging the presence of target enzymes in arthritic joints and can be used for early monitoring of treatment response to antirheumatic drugs such as MTX.
Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody‐mediated arthritis
Authors: Jacobs Jonathan P. , Pettit Allison R. , Shinohara Mari L. , Jansson Marianne , Cantor Harvey , Gravallese Ellen M. , Mathis Diane , Benoist Christophe 
Published: August 2004

AbstractObjectiveOsteopontin (OPN) is a secreted glycoprotein involved in a range of physiologic processes, including inflammation, immunity mediated by Th1 cells, and bone remodeling. It is expressed in the joints of rheumatoid arthritis patients and has been the subject of conflicting reports concerning its role in arthritis induced by antibodies against type II collagen. This study assessed the role of OPN in the K/BxN serum‐transfer model of autoantibody‐induced arthritis.MethodsExpression of OPN gene transcripts was assessed by microarray analysis of ankle RNA taken at 6 time points after transfer of K/BxN serum. OPN‐sufficient or OPN‐deficient littermates backcrossed for 10 generations onto the C57BL/6 genetic background were given K/BxN serum. Arthritis severity was measured by ankle thickening and a clinical index. Hind limb sections were stained with hematoxylin and eosin or toluidine blue and scored for inflammation, cartilage damage, and bone erosion.ResultsOPN messenger RNA transcripts progressively increased in ankle joints during the course of K/BxN serum‐transferred arthritis. OPN‐deficient mice receiving K/BxN serum developed arthritis with kinetics and clinical severity comparable with those of OPN‐sufficient littermates. Histologic assessment of arthritic joints from OPN‐deficient mice revealed synovial hyperplasia, pannus formation, mononuclear cell infiltration, bone erosion, cartilage damage at sites adjacent to and distal from pannus invasion, and tartrate‐resistant acid phosphatase–positive multinucleated cells at sites of bone erosion. Histopathologic scoring demonstrated comparable levels of inflammation, cartilage damage, and bone erosion in OPN‐sufficient and OPN‐deficient mice.ConclusionOPN does not have a required role in inflammation, bone erosion, and cartilage damage in the K/BxN serum‐transfer model.
An analysis of CTLA‐4 and proinflammatory cytokine genes in Wegener's granulomatosis
Authors: Zhou Yihua , Huang DeRen , Paris Pamela L. , Sauter Craig S. , Prock Kristin A. , Hoffman Gary S. 
Published: August 2004

AbstractObjectiveThe precipitating event(s) that triggers Wegener's granulomatosis (WG) is unknown. Cytokines, costimulatory molecules, and counterregulatory molecules control the quality and intensity of immune responses. Thus, they are relevant candidates for genetic studies of immune dysregulation in WG, the pathogenesis of which may be facilitated by multiple acquired and/or inherited factors. This study was undertaken to investigate possible genetic associations of various proinflammatory cytokines and CTLA‐4, a receptor for T cell inhibition, with WG.MethodsUsing polymerase chain reaction–based DNA genotyping, we investigated the polymorphisms located in the genes encoding a variety of proinflammatory cytokines and CTLA‐4 in 117 American patients with WG and 123 ethnically matched healthy controls.ResultsCompared with controls, patients with WG had a significantly lower frequency of homozygosity for the shortest allele (designated allele 86) of the Ctla4 microsatellite polymorphism (AT)n located in the 3′‐untranslated region (3′‐UTR) of exon 3 (47.0% versus 69.9%; P = 0.0005). Significant differences between patients and controls in the allelic and genotypic frequencies of polymorphisms in the other cytokine and cytokine receptor genes studied (tumor necrosis factor α [TNFα], TNF receptor I [TNFRI], TNFRII, interleukin‐1β [IL‐1β], IL‐6) were not found.ConclusionThe Ctla4 (AT)n 86 allele has been previously demonstrated to be crucial for maintenance of normal levels of CTLA‐4 expression and balance between T cell activation and inhibition. Our results in American patients confirm findings from a Scandinavian cohort in which a positive association between WG and longer alleles of (AT)n in the Ctla4 3′‐UTR was demonstrated. Diminished frequencies of the most effective allele for CTLA‐4 expression may represent a WG‐related susceptibility mutation that accounts, in part, for increased T cell activation and clonal expansion in WG. Blockade of T cell costimulation using CTLA‐4Ig might be a useful therapeutic intervention, providing an alternative or complementary approach to conventional treatment with immunosuppressive agents.