bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of the dermatomyositis autoantigen Mi‐2 in regenerating muscle
Authors: Mammen Andrew L. , Casciola‐Rosen Livia A. , Hall John C. , Christopher‐Stine Lisa , Corse Andrea M. , Rosen Antony 
Published: November 2009

AbstractObjectiveAutoantibodies against the chromatin remodeler Mi‐2 are found in a distinct subset of patients with dermatomyositis (DM). Previous quantitative immunoblotting experiments demonstrated that Mi‐2 protein levels are up‐regulated in DM muscle. This study was undertaken to define the population of cells expressing high levels of Mi‐2 in DM muscle and to explore the regulation and functional role of Mi‐2 during muscle regeneration.MethodsThe expression of Mi‐2 was analyzed by immunofluorescence microscopy in human muscle biopsy specimens. In an experimental mouse model, cardiotoxin was used to induce muscle injury and repair, and expression of Mi‐2 during muscle regeneration was studied in this model by immunofluorescence and immunoblotting analyses. In addition, a cell culture system of muscle differentiation was utilized to artificially modulate Mi‐2 levels during proliferation and differentiation of myoblasts.ResultsIn human DM muscle tissue, increased Mi‐2 expression was found preferentially in the myofibers within fascicles affected by perifascicular atrophy, particularly in the centralized nuclei of small perifascicular muscle fibers expressing markers of regeneration. In injured mouse muscle tissue, Mi‐2 levels were dramatically and persistently up‐regulated during muscle regeneration in vivo. Premature silencing of Mi‐2 with RNA interference in vitro resulted in accelerated myoblast differentiation.ConclusionExpression of Mi‐2 is markedly up‐regulated during muscle regeneration in a mouse model of muscle injury and repair. It is also up‐regulated in human DM myofibers expressing markers of regeneration. Results of the in vitro studies indicate that this protein may play a role in modulating the kinetics of myoblast differentiation. Our findings thus suggest that high levels of Mi‐2 expression in muscle biopsy tissue from patients with DM reflect the presence of incompletely differentiated muscle cells.
MLN3897 plus methotrexate in patients with rheumatoid arthritis: Safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double‐blind, placebo‐controlled, randomized, proof‐of‐concept study
Authors: Vergunst Clarissa E. , Gerlag Danielle M. , von Moltke Lisa , Karol Michael , Wyant Tim , Chi Xuedong , Matzkin Ellen , Leach Timothy , Tak Paul P. 
Published: November 2009

AbstractObjectiveTo assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX).MethodsIn this phase IIa, proof‐of‐concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for ≥6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1–83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897‐treated group compared with that in the placebo‐treated group.ResultsMLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent‐to‐treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897‐treated patients and placebo‐treated patients (35% versus 33%, respectively;P= 0.72). Results were similar for the per‐protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (≥90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1α internalization assay).ConclusionMLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.
Associations between the American College of Rheumatology pediatric response measures and the continuous measures of disease activity used in adult rheumatoid arthritis: A secondary analysis of clinical trial data from children with Polyarticular‐Course Juvenile Idiopathic Arthritis
Authors: Ringold Sarah , Chon Yun , Singer Nora G. 
Published: November 2009

AbstractObjectiveTo measure associations between the American College of Rheumatology (ACR) pediatric criteria for improvement and the continuous measures of disease activity used for rheumatoid arthritis in adult patients with polyarticular‐course juvenile idiopathic arthritis (JIA).MethodsIn this retrospective analysis of 2 etanercept trials, disease activity was calculated at baseline, 3 months, and 6 months using the Disease Activity Score (DAS), the DAS based on 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). The ACR pediatric response and the European League Against Rheumatism (EULAR) response were also determined for the 3‐month and 6‐month evaluations. Data were analyzed in 94 patients with JIA independent of the treatment arm. Correlation coefficients between measures were calculated for each visit. The areas under the receiver operating characteristic curve (AUC of ROC) were calculated to assess the discriminative properties of the scores for the ACR pediatric response measures.ResultsThe mean DAS, DAS28, CDAI score, and SDAI score were 3.7, 4.7, 30.8, and 36.4, respectively, at baseline, corresponding to high levels of disease activity (CDAI/SDAI) or moderate levels of disease activity (DAS/DAS28). At 3 months, the mean scores corresponded to low (DAS/DAS28) or moderate (CDAI/SDAI) disease activity. At 6 months, the mean scores corresponded to low disease activity (DAS/DAS28/CDAI) or moderate disease activity (SDAI). Most children met the criteria for a good or moderate EULAR response at 3 months and 6 months. The correlation between continuous outcome measures and each pediatric core set component was moderate to very good. The AUC of ROC values for each measure were high (range 0.76–0.98).ConclusionGood correlation and discriminative abilities were seen between the DAS, DAS28, CDAI, and SDAI for the ACR pediatric criteria for improvement. These disease activity measures may be useful for research and clinical care in polyarticular‐course JIA.
Insurer and out‐of‐pocket costs of osteoarthritis in the US: Evidence from national survey data
Authors: Kotlarz Harry , Gunnarsson Candace L. , Fang Hai , Rizzo John A. 
Published: November 2009

AbstractObjectiveOsteoarthritis (OA) is a major debilitating disease affecting ∼27 million persons in the US. Yet, the financial costs to patients and insurers remain poorly understood. The purpose of this study was to quantify by multivariate analyses the relationships between OA and annual health care expenditures borne by patients and insurers.MethodsData from the Medical Expenditure Panel Survey (MEPS) for the years 1996–2005 were used. MEPS is a large, nationally representative US database that includes information on health care expenditures, medical conditions, health insurance status, and sociodemographic characteristics. Individual and nationally aggregated cost estimates are provided.ResultsOA was found to contribute substantially to health care expenditures. Among women, OA increased out‐of‐pocket (OOP) expenditures by $1,379 per annum (2007 dollars) and insurer expenditures by $4,833. Among men, OA increased OOP expenditures by $694 per annum and insurer expenditures by $4,036. Given the high prevalence of OA, the aggregate effects on health care expenditures were very large. OA raised aggregate annual medical care expenditures by $185.5 billion. Of that amount, insurer expenditures were $149.4 billion and OOP expenditures were $36.1 billion. Because of the greater prevalence of OA in women and their more intensive use of health care, total expenditures for this group accounted for $118 billion, or almost two‐thirds of the total increase in health care expenditures resulting from OA.ConclusionThe health care cost burden associated with OA is quite large for all groups examined and is disproportionately higher for women. Although insurers bear the brunt of treatment costs for OA, the OOP costs are also substantial.
Glucocorticoids increase α5 integrin expression and adhesion of synovial fibroblasts but inhibit ERK signaling, migration, and cartilage invasion
Authors: Lowin Torsten , Straub Rainer H. , Neumann Elena , Bosserhoff Anja , Vogel Corinna , Moissl Christine , Anders Sven , Müller‐Ladner Ulf , Schedel Jörg 
Published: November 2009

AbstractObjectiveIn rheumatoid arthritis (RA), integrins mediate cell adhesion, migration, and invasion, and their expression is regulated by cytokines and growth factors. The aim of this study was to investigate whether hormones such as cortisol or other steroids can influence integrin expression and function in the synovial cells of patients with RA.MethodsWe performed immunofluorescence and fluorescence‐activated cell sorting analyses to quantify surface integrin levels. Adhesion and migration assays were performed to study the function of synovial fibroblasts (SFs). ERK activation was measured by cellular activation of a signaling enzyme‐linked immunosorbent assay. Invasion of SFs into cartilage was determined in the SCID mouse coimplantation model of RA in vivo.ResultsIn RA, expression of integrin subunits α5, αv, and β1 was higher at the site of invasion compared with the sublining zone. Testosterone and 17β‐estradiol had no influence on integrin levels, but cortisol up‐regulated expression of the α5 subunit in a time‐dependent and dose‐dependent manner. In addition, cortisol increased the adhesion of SFs to fibronectin and inhibited ERK signaling upon integrin activation or upon stimulation with tumor necrosis factor. Small interfering RNA or a neutralizing antibody to α5 integrin increased SF migration, indicating that up‐regulated α5 integrin is responsible for an immobile phenotype. In addition, in the SCID mouse model, SF invasion into cartilage was attenuated by glucocorticoid treatment in vivo.ConclusionGlucocorticoids increase integrin expression and the adhesion of cells to fibronectin, inhibit ERK signaling, and down‐regulate the invasiveness of SFs in vivo. This study demonstrates that an important antiinflammatory aspect of glucocorticoids is regulating the expression and function of α5 integrin.
Serum levels of proinflammatory cytokines interleukin‐1β, interleukin‐6, and tumor necrosis factor α in mixed cryoglobulinemia
Authors: Antonelli Alessandro , Ferri Clodoveo , Ferrari Silvia Martina , Ghiri Emiliano , Goglia Fernando , Pampana Alessandro , Bruschi Fabrizio , Fallahi Poupak 
Published: November 2009

AbstractObjectiveNo single previous study has evaluated serum levels of the proinflammatory cytokines interleukin‐1β (IL‐1β), IL‐6, and tumor necrosis factor α (TNFα) in patients with hepatitis C virus–associated mixed cryoglobulinemia (HCV‐MC). This study was undertaken to evaluate serum levels of these cytokines in patients with HCV‐MC.MethodsSerum IL‐1β, IL‐6, and TNFα were assayed in 43 patients with HCV‐MC, in 43 sex‐ and age‐matched patients with chronic HCV without cryoglobulinemia, and in 43 sex‐ and age‐matched controls.ResultsHCV‐MC patients showed significantly higher mean IL‐1β, IL‐6, and TNFα levels than did the controls (P < 0.01) or the HCV patients (P ≤ 0.04). Serum levels of IL‐6 and TNFα were significantly higher in HCV patients than in controls (P < 0.05).ConclusionOur findings demonstrate elevated serum levels of IL‐1β, IL‐6, and TNFα in patients with HCV‐MC. If the importance of IL‐1β and IL‐6 in the pathogenesis of MC is confirmed, these results will open the way for the evaluation of new therapies for MC.
HLA–DR alleles determine responsiveness to Borrelia burgdorferi antigens in a mouse model of self‐perpetuating arthritis
Authors: Iliopoulou Bettina Panagiota , Guerau‐De‐Arellano Mireia , Huber Brigitte T. 
Published: November 2009

AbstractObjectiveArthritis is a prominent manifestation of Lyme disease, which is caused by infection with Borrelia burgdorferi (Bb). Chronic Lyme arthritis persisting even after antibiotic treatment is linked to HLA–DRB1*0401 (DR4) and related alleles. In contrast, patients whose Lyme arthritis resolves within 3 months postinfection show an increased frequency of HLA–DRB1*1101 (DR11). The aim of this study was to analyze the underlying mechanism by which HLA–DR alleles confer genetic susceptibility or resistance to antibiotic‐refractory Lyme arthritis.MethodsWe generated DR11‐transgenic (DR11‐Tg) mice on a murine MHCII−/− background and compared their immune response to Bb antigens with the response of DR4‐Tg mice after immunization with Bb outer surface protein A (OspA) or infection with live Bb.ResultsT cells from OspA‐immunized and Bb‐infected DR11‐Tg mice had defective production of interferon‐γ as compared with those from DR4‐Tg mice. In contrast, DR11‐Tg mice developed higher titers of anti‐OspA and anti‐Bb antibodies, respectively, than did DR4‐Tg mice. Consistent with this observation, we found that the Bb‐infected DR11‐Tg mice had a decreased spirochetal burden as compared with the DR4‐Tg mice, as measured by quantitative polymerase chain reaction.ConclusionThis study provides direct evidence that in the presence of HLA–DR11, the immune response against Bb antigens is directed toward a protective antibody response. In contrast, an inflammatory Th1 response is induced in the presence of DR4. These observations offer an explanation for the differential genetic susceptibility of DR4+ and DR11+ individuals to the development of chronic Lyme arthritis and, eventually, the progression to antibiotic‐refractory Lyme arthritis.
Prevalence and clinical correlates of pruritus in patients with systemic sclerosis
Authors: Razykov Ilya , Thombs Brett D. , Hudson Marie , Bassel Marielle , Baron Murray ,   The Canadian Scleroderma Research Group
Published: November 2009

AbstractObjectiveThere are no studies of pruritus prevalence or clinical correlates in systemic sclerosis (SSc). The objectives of this study were to document the proportion of SSc patients with pruritus on most days, to determine when in the course of the disease pruritus is most prevalent, and to identify clinical correlates.MethodsWe performed a cross‐sectional, multicenter study of 400 SSc patients from the Canadian Scleroderma Research Group Registry ≥1 year after Registry enrollment. Patients indicated whether they experienced pruritus during the past month on most days and underwent clinical histories and medical examinations. Multiple logistic regression was used to assess the association between sociodemographic and clinical variables and pruritus.ResultsA total of 179 patients (45%) reported pruritus on most days, including 69% (11 of 16) among patients 1.0–1.9 years from onset of non‐Raynaud's symptoms, 41% (38 of 93) for 2.0–4.9 years, 47% (44 of 94) for 5.0–9.9 years, 43% (60 of 140) for 10.0–19.9 years, and 46% (26 of 57) for ≥20 years. In post hoc analysis, patients 1.0–1.9 years from disease onset were significantly more likely to report pruritus (P= 0.049). Patients with pruritus had significantly more skin involvement (P= 0.029), more gastrointestinal (GI) symptoms (P< 0.001), worse breathing problems (P= 0.001), worse Raynaud's symptoms (P= 0.002), and more severe finger ulcers (P= 0.009). Only the number of GI symptoms predicted pruritus in multiple logistic regression analysis (odds ratio 1.25, 95% confidence interval 1.13–1.37;P< 0.001).ConclusionPruritus is common in SSc and is independently associated with GI symptoms. Focused research on sources of pruritus and its management in SSc is needed.
DNA hypomethylation in rheumatoid arthritis synovial fibroblasts
Authors: Karouzakis Emmanuel , Gay Renate E. , Michel Beat A. , Gay Steffen , Neidhart Michel 
Published: November 2009

AbstractObjectiveRheumatoid arthritis synovial fibroblasts (RASFs) are phenotypically activated and aggressive. We undertook this study to investigate whether the intrinsic activation of RASFs is due to global genomic hypomethylation, an epigenetic modification.MethodsGlobal genomic hypomethylation was assessed by immunohistochemistry, flow cytometry, and L1 promoter bisulfite sequencing. The levels of Dnmt1 were determined in synovial tissue and cultured SFs by Western blotting before and after treatment with cytokines and growth factors. Normal SFs were treated for 3 months with a nontoxic dose of the DNA hypomethylation drug 5‐azacytidine (5‐azaC), and changes in gene expression were revealed using complementary DNA arrays. The phenotypic changes were confirmed by flow cytometry.ResultsIn situ and in vitro, RASF DNA had fewer 5‐methylcytosine and methylated CG sites upstream of an L1 open‐reading frame than did DNA of osteoarthritis SFs, and proliferating RASFs were deficient in Dnmt1. Using 5‐azaC, we reproduced the activated phenotype of RASFs in normal SFs. One hundred eighty‐six genes were up‐regulated >2‐fold by hypomethylation, with enhanced protein expression. These included growth factors and receptors, extracellular matrix proteins, adhesion molecules, and matrix‐degrading enzymes. The hypomethylating milieu induced irreversible phenotypic changes in normal SFs, which resembled those of the activated phenotype of RASFs.ConclusionDNA hypomethylation contributes to the chronicity of RA and could be responsible for the limitation of current therapies.
Specifically modified osteopontin in rheumatoid arthritis fibroblast‐like synoviocytes supports interaction with B cells and enhances production of interleukin‐6
Authors: Take Yasuhiro , Nakata Ken , Hashimoto Jun , Tsuboi Hideki , Nishimoto Norihiro , Ochi Takahiro , Yoshikawa Hideki 
Published: November 2009

AbstractObjectiveOsteopontin (OPN) is expressed by fibroblast‐like synoviocytes (FLS) in rheumatoid arthritis (RA), but its pathologic role is still obscure. The present study was undertaken to analyze the role of OPN in RA by focusing on its effects on cell–cell interactions between FLS and B lymphocytes.MethodsFLS obtained from 10 patients with RA and 10 non‐RA subjects and a B lymphocyte cell line were studied. The characteristics of OPN expression by FLS were analyzed by Western blotting, immunoprecipitation, and immunofluorescence studies. In cocultures of FLS and B lymphocytes, the effects of OPN on adhesion of B lymphocytes to FLS and the consequent production of interleukin‐6 (IL‐6) were analyzed in experiments involving overexpression and knockdown of OPN and inhibitory studies with an OPN‐blocking antibody. In vivo, the expression of OPN in RA synovium was examined by immunohistochemistry.ResultsA specifically modified 75‐kd form of OPN was predominantly expressed in RA FLS, and this was associated with expression of >200‐kd thrombin‐cleaved OPN that was crosslinked with fibronectin and localized on the surface of the FLS. In FLS–B lymphocyte cocultures, 75‐kd OPN–positive FLS produced a significantly higher amount of IL‐6 than did 75‐kd OPN–negative FLS. When the FLS were separated from B lymphocytes or cultured alone, the production of IL‐6 was low and was not significantly different between these 2 culture conditions. Moreover, OPN overexpression enhanced production of IL‐6 in 75‐kd OPN–positive FLS–B lymphocyte cocultures. Addition of the OPN‐blocking antibody inhibited the adhesion of B lymphocytes to FLS. Immunohistochemical analyses revealed that localization of IL‐6–positive cells coincided with the sites at which OPN and B lymphocytes were colocalized.ConclusionSpecifically modified 75‐kd OPN was expressed by RA FLS. This form of OPN affected FLS–B lymphocyte interactions by supporting the adhesion of B lymphocytes to FLS and enhancing the production of IL‐6.
Interferon‐α mediates suppression of C‐reactive protein: Explanation for muted C‐reactive protein response in lupus flares?
Authors: Enocsson Helena , Sjöwall Christopher , Skogh Thomas , Eloranta Maija‐Leena , Rönnblom Lars , Wetterö Jonas 
Published: November 2009

AbstractObjectiveC‐reactive protein (CRP) is synthesized by hepatocytes in response to interleukin‐6 (IL‐6) during inflammation. Despite raised IL‐6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon‐α (IFNα), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP.MethodsThe interference of all 12 IFNα subtypes with CRP promoter activity induced by IL‐6 and IL‐1β was studied in a CRP promoter– and luciferase reporter–transfected human hepatoma cell line, Hep‐G2. CRP secretion by primary human hepatocytes was analyzed by enzyme‐linked immunosorbent assay.ResultsCRP promoter activity was inhibited by all single IFNα subtypes, as well as by 2 different mixtures of biologically relevant IFNα subtypes. The most prominent effect was seen using a leukocyte‐produced mixture of IFNα (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFNα was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep‐G2 proliferation/viability were not affected by IFNα.ConclusionThe current study demonstrates that IFNα is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up‐regulated IFNα and a muted CRP response during SLE disease flares. Given the fundamental role of both IFNα and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.