bluuebunny/crossref_metadata_2025_split huggingface dataset:
A sodium dodecyl sulfate–polyacrylamide gel electrophoresis–liquid chromatography tandem mass spectrometry analysis of bovine cartilage tissue response to mechanical compression injury and the inflammatory cytokines tumor necrosis factor α and interleukin‐1β
Authors: Stevens Anna L. , Wishnok John S. , Chai Diana H. , Grodzinsky Alan J. , Tannenbaum Steven R. 
Published: January 2008

AbstractObjectiveTo compare the response of chondrocytes and cartilage matrix to injurious mechanical compression and treatment with interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNFα), by characterizing proteins lost to the medium from cartilage explant culture.MethodsCartilage explants from young bovine stifle joints were treated with 10 ng/ml of IL‐1β or 100 ng/ml of TNFα or were subjected to uniaxial, radially‐unconfined injurious compression (50% strain; 100%/second strain rate) and were then cultured for 5 days. Pooled media were subjected to gel‐based separation (sodium dodecyl sulfate–polyacrylamide gel electrophoresis) and analysis by liquid chromatography tandem mass spectrometry, and the data were analyzed by Spectrum Mill proteomics software, focusing on protein identification, expression levels, and matrix protein proteolysis.ResultsMore than 250 proteins were detected, including extracellular matrix (ECM) structural proteins, pericellular matrix proteins important in cell–cell interactions, and novel cartilage proteins CD109, platelet‐derived growth factor receptor–like, angiopoietin‐like 7, and adipocyte enhancer binding protein 1. IL‐1β and TNFα caused increased release of chitinase 3–like protein 1 (CHI3L1), CHI3L2, complement factor B, matrix metalloproteinase 3, ECM‐1, haptoglobin, serum amyloid A3, and clusterin. Injurious compression caused the release of intracellular proteins, including Grp58, Grp78, α4‐actinin, pyruvate kinase, and vimentin. Injurious compression also caused increased release and evidence of proteolysis of type VI collagen subunits, cartilage oligomeric matrix protein, and fibronectin.ConclusionOverload compression injury caused a loss of cartilage integrity, including matrix damage and cell membrane disruption, which likely occurred through strain‐induced mechanical disruption of cells and matrix. IL‐1β and TNFα caused the release of proteins associated with an innate immune and stress response by the chondrocytes, which may play a role in host defense against pathogens or may protect cells against stress‐induced damage.
Serum uric acid is an independent predictor of all‐cause mortality in patients at high risk of cardiovascular disease: A preventive cardiology information system (PreCIS) database cohort study
Authors: Ioachimescu Adriana G. , Brennan Danielle M. , Hoar Brian M. , Hazen Stanley L. , Hoogwerf Byron J. 
Published: January 2008

AbstractObjectiveUric acid is a product of the activity of xanthine oxidase, an enzyme linked to oxidative stress, endothelial dysfunction, and heart failure. It is unclear whether adding uric acid levels to the assessment of cardiovascular risk might contribute to the improved ability to stratify cardiovascular risk. The purpose of this study was to evaluate the prognostic value of serum uric acid levels in a large cohort of men and women at high risk of cardiovascular disease.MethodsSerum uric acid levels were determined in all patients seen for primary/secondary cardiovascular disease prevention at the Cleveland Clinic Section of Preventive Cardiology and Rehabilitation between 1998 and 2004, and all data were entered into the Preventive Cardiology Information System (PreCIS) database. Vital status of the patients was determined through the Social Security Death Index. Death from all causes was summarized across quartiles of uric acid values.ResultsA total of 3,098 patients (age range 18–87 years) were identified in the database, among whom 43% had cardiovascular disease. There were 156 deaths (5%) during the 14,262 person‐years of followup. For each 1‐mg/dl increase in the serum uric acid level, there was a 39% increase in the risk of death (by Cox regression analysis). After adjusting for age, sex, smoking status, alcohol consumption, weight, body mass index, waist circumference, blood pressure, history of cardiovascular disease, estimated glomerular filtration rate, levels of cholesterol fractions, and plasma glucose levels, the serum uric acid level continued to predict the risk of death (hazard ratio = 1.26 [95% confidence interval 1.15–1.38], P < 0.001). This association was present regardless of diuretic use. Concordance index (C statistic) analyses showed that uric acid significantly improved the predictive accuracy of a model that included Framingham Heart Study score factors, metabolic syndrome components, and fibrinogen levels.ConclusionSerum uric acid levels are an independent predictor of death in patients at high risk of cardiovascular disease. Further studies are warranted to evaluate its prognostic implications and potential utility in the monitoring of therapy.
Cell‐based resurfacing of large cartilage defects: Long‐term evaluation of grafts from autologous transgene‐activated periosteal cells in a porcine model of osteoarthritis
Authors: Gelse Kolja , Mühle Christiane , Franke Oliver , Park Jung , Jehle Marc , Durst Karsten , Göken Mathias , Hennig Friedrich , Mark Klaus Von Der , Schneider Holm 
Published: January 2008

AbstractObjectiveTo investigate the potential of transgene‐activated periosteal cells for permanently resurfacing large partial‐thickness cartilage defects.MethodsIn miniature pigs, autologous periosteal cells stimulated ex vivo by bone morphogenetic protein 2 gene transfer, using liposomes or a combination of adeno‐associated virus (AAV) and adenovirus (Ad) vectors, were applied on a bioresorbable scaffold to chondral lesions comprising the entire medial half of the patella. The resulting repair tissue was assessed, 6 and 26 weeks after transplantation, by histochemical and immunohistochemical methods. The biomechanical properties of the repair tissue were characterized by nanoindentation measurements. Implants of unstimulated cells and untreated lesions served as controls.ResultsAll grafts showed satisfactory integration into the preexisting cartilage. Six weeks after transplantation, AAV/Ad‐stimulated periosteal cells had adopted a chondrocyte‐like phenotype in all layers; the newly formed matrix was rich in proteoglycans and type II collagen, and its contact stiffness was close to that of healthy hyaline cartilage. Unstimulated periosteal cells and cells activated by liposomal gene transfer formed only fibrocartilaginous repair tissue with minor contact stiffness. However, within 6 months following transplantation, the AAV/Ad‐stimulated cells in the superficial zone tended to dedifferentiate, as indicated by a switch from type II to type I collagen synthesis and reduced contact stiffness. In deeper zones, these cells retained their chondrocytic phenotype, coinciding with positive staining for type II collagen in the matrix.ConclusionLarge partial‐thickness cartilage defects can be resurfaced efficiently with hyaline‐like cartilage formed by transgene‐activated periosteal cells. The long‐term stability of the cartilage seems to depend on physicobiochemical factors that are active only in deeper zones of the cartilaginous tissue.
Heparan sulfate–dependent ERK activation contributes to the overexpression of fibrotic proteins and enhanced contraction by scleroderma fibroblasts
Authors: Chen Yunliang , Leask Andrew , Abraham David J. , Pala Daphne , Shiwen Xu , Khan Korsa , Liu Shangxi , Carter David E. , Wilcox‐Adelman Sarah , Goetinck Paul , Denton Christopher P. , Black Carol M. , Pitsillides Andrew A. , Sarraf Catherine E. , Eastwood Mark 
Published: January 2008

AbstractObjectiveTo investigate the contribution of heparan sulfate proteoglycan and Ras/MEK/ERK to the overexpression of profibrotic proteins and the enhanced contractile ability of dermal fibroblasts from patients with systemic sclerosis (SSc; scleroderma).MethodsThe effects of the MEK/ERK inhibitor U0126, the heparan sulfate side chain formation inhibitor β‐xyloside, and soluble heparin on the overexpression of profibrotic genes were compared in fibroblasts from lesional skin of patients with diffuse SSc and fibroblasts from healthy control subjects. Identified protein expressions were compared with the contractile abilities of fibroblasts while they resided within a collagen lattice. Forces generated were measured using a culture force monitor.ResultsInhibiting MEK/ERK with U0126 significantly reduced expression of a cohort of proadhesive and procontractile proteins that normally are overexpressed by scleroderma fibroblasts, including integrin α4 and integrin β1. Antagonizing heparan sulfate side chain formation with β‐xyloside or the addition of soluble heparin prevented ERK activation, in addition to reducing the expression of these proadhesive/contractile proteins. Treatment with either U0126, β‐xyloside, or heparin resulted in a reduction in the overall peak contractile force generated by dermal fibroblasts. Blocking platelet‐derived growth factor receptor with Gleevec (imatinib mesylate) reduced overall contractile ability and the elevated syndecan 4 expression and ERK activation in SSc fibroblasts.ConclusionThe results of this study suggest that heparan sulfate–dependent ERK activation contributes to the enhanced contractile ability demonstrated by dermal fibroblasts from lesional skin of patients with scleroderma. These results are consistent with the notion that the MEK/ERK procontractile pathway is dysregulated in scleroderma dermal fibroblasts. Additionally, the results suggest that antagonizing the MEK/ERK pathway is likely to modulate heparan sulfate proteoglycan activity, which in turn may have a profound effect on the fibrotic response in SSc.
Effective treatment with oral administration of rebamipide in a mouse model of Sjögren's syndrome
Authors: Kohashi Masayuki , Ishimaru Naozumi , Arakaki Rieko , Hayashi Yoshio 
Published: January 2008

AbstractObjectiveTo determine whether oral administration of rebamipide, a mucosal protective agent, is effective in the treatment of Sjögren's syndrome (SS) in the NFS/sld mouse model of the disease.MethodsNFS/sld mice were given daily oral doses of rebamipide (0.3 mg/kg of body weight or 3 mg/kg) or vehicle alone starting from the age of 4 weeks to the age of 8 weeks. The volume of saliva and tears was monitored during and after treatment. After the final dose, histologic features of the tissues, TUNEL+ apoptotic duct cells in affected glands, T cell and cytokine function, and levels of immunoglobulin isotypes and serum autoantibodies were examined.ResultsThe 3‐mg/kg dose of rebamipide prevented the development of autoimmune lesions. The average volume of saliva in rebamipide‐treated mice was significantly higher than that in control mice. We found decreased TUNEL+ apoptotic duct cells in the salivary and lacrimal glands of rebamipide‐treated mice as compared with control mice. Rebamipide treatment suppressed the activation of CD4+ T cells and Th1 cytokines (interleukin‐2, interferon‐γ) associated with impaired NF‐κB activity. Production of serum autoantibodies, IgM, and IgG1 was clearly inhibited.ConclusionOur findings demonstrate the efficacy of oral administration of rebamipide in the treatment of SS. Rebamipide represents a new therapeutic strategy for the treatment of patients with sicca symptoms caused by SS, as well as for patients with other diseases.
Folding of HLA–B27 subtypes is determined by the global effect of polymorphic residues and shows incomplete correspondence to ankylosing spondylitis
Authors: Galocha Begoña , de Castro José A. López 
Published: January 2008

AbstractObjectiveTo investigate the maturation and folding of HLA–B27 subtypes and the relationship of these features to ankylosing spondylitis (AS).MethodsStable transfectants expressing B27 subtypes and site‐directed mutants were used. Maturation/export rates were measured by acquisition of endoglycosidase H resistance. Folding efficiency was estimated from the ratio of unfolded heavy chain to folded heavy chain, which was immunoprecipitated with specific antibodies, in pulse‐chase experiments. Association with calnexin was analyzed in coprecipitation experiments. Cytosolic dislocation was estimated by immunoprecipitation of deglycosylated heavy chain after proteasome inhibition. The level of heavy chain expression on unstimulated or interferon‐γ (IFNγ)–stimulated cells was quantified by Western blotting.ResultsThere was no correlation between the export rate and the association of HLA–B27 subtypes with AS. Three of the 4 AS‐associated B27 subtypes showed inefficient folding, but B*2707 folded with the same high efficiency as the non–disease‐associated subtypes. Some individual mutations that mimicked subtype polymorphism profoundly influenced folding, but in a context‐dependent way. The differences in export and folding rates among B27 variants were unrelated to levels of heavy chain expression in the corresponding transfectants, as indicated by the lack of correlation between the two parameters and by heavy chain up‐regulation with IFNγ. Misfolded heavy chain was inefficiently cleared from the endoplasmic reticulum, based on the marginal increase in levels of deglycosylated heavy chain, which resulted from loss of the glycan moiety after cytosolic dislocation, following proteasome inhibition.ConclusionHLA–B27 subtype folding is determined by the overall heavy‐chain structure, since the effect of a given polymorphism depends on its structural context. Heavy chain misfolding does not explain the association of B*2707 with AS.
Stress activation of cellular markers of inflammation in rheumatoid arthritis: Protective effects of tumor necrosis factor α antagonists
Authors: Motivala Sarosh J. , Khanna Dinesh , FitzGerald John , Irwin Michael R. 
Published: January 2008

AbstractObjectivePsychological stress is thought to aggravate disease activity in rheumatoid arthritis (RA), although the physiologic mechanisms are unclear. Tumor necrosis factor α (TNFα) is an inflammatory cytokine involved in the exacerbation of RA, and TNFα antagonists have emerged as efficacious treatments. The purpose of this study was to determine whether RA patients show increased monocyte production of TNFα following acute psychological stress and whether such responses are abrogated in RA patients taking TNFα antagonists.MethodsA standardized stress task was administered to 3 groups of subjects: RA patients taking TNFα antagonists, RA patients not taking such medications, and healthy controls. Lipopolysaccharide‐stimulated monocyte production of inflammatory cytokines was repeatedly measured using intracellular staining and flow cytometry. Subjective stress, cardiovascular responses, adrenocorticotropic hormone (ACTH) levels, and cortisol levels were also measured.ResultsThe stress task induced increases in subjective stress, cardiovascular activity, and levels of ACTH and cortisol, with similar responses in the 3 groups. In addition, the stress task induced a significant increase (P < 0.001) in monocyte production of TNFα among RA patients who were not taking TNFα antagonists. However, monocyte production of TNFα did not change following psychological stress in RA patients taking TNFα antagonists or in healthy controls.ConclusionBrief psychological stress can trigger increased stimulated monocyte production of TNFα in RA patients. The use of TNFα antagonists protects against stress activation of cellular markers of inflammation in RA patients.
Mutations of the hemophagocytic lymphohistiocytosis–associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis
Authors: Hazen Melissa M. , Woodward Amy L. , Hofmann Inga , Degar Barbara A. , Grom Alexei , Filipovich Alexandra H. , Binstadt Bryce A. 
Published: January 2008

AbstractThe clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13‐4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH‐associated genes in patients with systemic JIA have not been reported. We report the case of an 8‐year‐old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.
Infliximab treatment shifts the balance between stimulatory and inhibitory Fcγ receptor type II isoforms on neutrophils in patients with rheumatoid arthritis
Authors: Belostocki Kristina , Pricop Luminita , Redecha Patricia B. , Aydin Ani , Leff Linda , Harrison Melanie J. , Salmon Jane E. 
Published: January 2008

AbstractObjectiveHuman neutrophils express both activating and inhibitory Fcγ receptors (FcγR), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor α (TNFα) up‐regulates the expression of stimulatory FcγRIIa on neutrophils in vitro, and amplifies immune complex–induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFα blockade in patients with rheumatoid arthritis (RA) alters the balance of activating FcγR and inhibitory FcγR and thereby decreases inflammation.MethodsWe used fluorescence‐activated cell sorting and Western blotting to examine FcγR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to ≥3 subsequent infusions.ResultsIn 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating FcγR, FcγRIIa, after treatment with infliximab, an effect that persisted over ≥3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory FcγR, FcγRIIb, was undetectable in neutrophils from 23 of 24 patients with RA, FcγRIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory FcγRIIb was always associated with decreased levels of FcγRIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down‐regulation of FcγRIIa.ConclusionOur findings indicate that TNFα inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory FcγR and thereby raising the threshold for immune complex–mediated activation of neutrophils.
Genetic variation including nonsynonymous polymorphisms of a major aggrecanase, ADAMTS‐5, in susceptibility to osteoarthritis
Authors: Rodriguez‐Lopez Julio , Mustafa Zehra , Pombo‐Suarez Manuel , Malizos Konstantinos N. , Rego Ignacio , Blanco Francisco J. , Tsezou Aspasia , Loughlin John , Gomez‐Reino Juan J. , Gonzalez Antonio 
Published: January 2008

AbstractObjectiveGiven the recent characterization of ADAMTS‐5 as the main aggrecanase of cartilage destruction in mouse models, we explored whether genetic variation and, in particular, putative damaging polymorphisms in the ADAMTS‐5 gene modify susceptibility to osteoarthritis (OA).MethodsTwo likely deleterious nonsynonymous single‐nucleotide polymorphisms (SNPs) were identified in ADAMTS‐5 by bioinformatics analysis, rs2830585 in exon 5 affecting a thrombospondin 1 motif, and rs226794 in exon 7. Exploration of their role was carried out in 3 steps, discovery, extension, and replication, on samples obtained from 4 European Caucasian collections, comprising a total of 2,715 patients with knee, hip, or hand OA and 1,185 OA‐free controls. In addition, 6 tagSNPs were studied to fully evaluate genetic variation in the ADAMTS‐5 locus.ResultsInitial analyses of 2 sample collections (n = 277 and n = 159) showed a trend toward decreased frequency of the putative deleterious allele of rs226794 among patients with severe knee OA (P = 0.047 versus controls). However, results in patients with knee OA from 2 additional sample collections (n = 360 and n = 265) did not confirm this trend. No association was found with hip OA or hand OA. None of the other SNPs or haplotypes constructed with these SNPs showed a significant association with OA susceptibility.ConclusionUse of several collections of OA samples allowed us to obtain sound evidence against the participation of genetic variation in ADAMTS‐5 in OA susceptibility. These results indicate the need to further explore the function of this aggrecanase in human OA to determine whether it is as critical as has been observed in mouse models.
Difference in disease features between childhood‐onset and adult‐onset systemic lupus erythematosus
Authors: Brunner Hermine I. , Gladman Dafna D. , Ibañez Dominique , Urowitz Murray D. , Silverman Earl D. 
Published: January 2008

AbstractObjectiveTo investigate potential differences between childhood‐onset and adult‐onset systemic lupus erythematosus (SLE).MethodsAn inception cohort with childhood‐onset SLE (n = 67) was compared with an inception cohort with adult‐onset SLE (n = 131), each of whom was diagnosed between 1990 and 1998 and followed up until February 1999. Prospective information included data on medications, laboratory markers, and disease activity and damage as measured by the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), respectively.ResultsEighty‐five percent of patients with childhood‐onset SLE and 88% of patients with adult‐onset SLE were female; the mean duration of followup was 3.2 and 3.5 years, respectively. On average, the children had more‐active disease than did the adults at the time of diagnosis and during followup. There was a higher incidence of renal disease in those with childhood‐onset SLE (78% versus 52% in adults; P = 0.0005), and the adjusted mean SLEDAI renal score was higher in the children than in the adults (2.37 versus 0.82; P < 0.0001). Treatment with steroids (97% versus 72%; P < 0.0001) and immunosuppressive drugs (66% versus 37%; P = 0.0001) was used significantly more often in children with SLE. Four adult patients with SLE, but none of the children, died during the followup. At the end of the followup, the mean SDI scores in those with childhood‐onset SLE were higher than those with adult‐onset SLE (1.70 versus 0.76; P = 0.008).ConclusionChildren with childhood‐onset SLE have more active disease at presentation and over time than do adults with SLE, especially active renal disease. Compared with adults with SLE, children receive more intensive drug therapy and accrue more damage, often related to steroid toxicity.