bluuebunny/crossref_metadata_2025_split huggingface dataset:
A serology‐based approach combined with clinical examination of 125 Ro/SSA‐positive patients to define incidence and prevalence of subacute cutaneous lupus erythematosus
Authors: Popovic Karin , Nyberg Fredrik , Wahren‐Herlenius Marie , Nyberg Filippa 
Published: December 2006

AbstractObjectiveTo estimate the incidence and prevalence of Ro/SSA‐positive subacute cutaneous lupus erythematosus (SCLE) in Stockholm County, Sweden (1.8 million inhabitants) and to investigate the frequency of photosensitivity and other clinical manifestations associated with Ro/SSA autoantibodies.MethodsRo/SSA‐positive patients in Stockholm were identified via registry‐based searches. All patients who tested positive for the presence of Ro/SSA autoantibodies during 1996–2002 (n = 1,323; 85% women) were identified. A questionnaire was sent to all patients still living in Stockholm in 2003 (n = 1,048). Patients who reported having skin symptoms and photosensitivity (n = 125) underwent a clinical examination.ResultsOf the 741 (71%) of 1,048 Ro/SSA‐positive patients who responded to the questionnaire, 400 (54%) reported having photosensitivity, and of these patients, 125 agreed to be clinically examined. A diagnosis of LE was confirmed in 59 of the 125 patients (SCLE in 20, systemic LE [SLE] in 33, and chronic CLE in 6). Eighty‐six patients reported experiencing symptoms consistent with polymorphous light eruption (PLE). Comorbidities such as cardiovascular disease, autoimmune disease, and other skin diseases were common. The incidence of Ro/SSA‐positive SCLE during the study period was estimated to be 0.7 cases per 100,000 persons per year and the prevalence was ∼6.2–14 in 100,000 persons.ConclusionThe incidence of Ro/SSA‐positive SCLE in Stockholm County, Sweden is estimated to be 0.7 per 100,000 persons per year as compared with an incidence of SLE in Sweden of 4.8 per 100,000 persons per year. The prevalence is estimated to be 6.2–14 in 100,000 persons. Self‐reported photosensitivity commonly corresponds to a history of PLE in Ro/SSA‐positive patients, even when the clinical profile of SCLE is absent. Photoprotection should therefore be included in the treatment recommendations for these patients.
Restricted T cell receptor BV gene usage in the lungs and muscles of patients with idiopathic inflammatory myopathies
Authors: Englund Pernilla , Wahlström Jan , Fathi Maryam , Rasmussen Elsbeth , Grunewald Johan , Tornling Göran , Lundberg Ingrid E. 
Published: December 2006

AbstractObjectiveTo investigate T cell receptor (TCR) expression in 3 different compartments that could be involved in patients with myositis: muscle, lung, and peripheral blood.MethodsNine patients with polymyositis (PM), dermatomyositis, or inclusion body myositis underwent bronchoscopy and bronchoalveolar lavage (BAL) as well as muscle biopsy and blood sampling. A panel of 19 monoclonal antibodies specific for TCR Vβ (BV) and Vα (AV) were used to characterize the TCR profile in CD4+ and CD8+ T cell populations in BAL fluid and peripheral blood by flow cytometry. Muscle biopsy tissues were analyzed by immunohistochemistry. Patients were also typed for HLA–DRB1 and DRB3 alleles.ResultsA total of 17 T cell expansions were detected in BAL fluid, 6 in the CD4+ T cell population and 11 in the CD8+ T cell population. Four T cell expansions were detected in peripheral blood. A selective TCR V usage was found in muscle. Two PM patients, both of whom had BAL fluid BV3+ T cell expansions in the CD4 population and in whom BV3 was also a prominent TCR V segment in muscle tissue, shared the HLA–DRB1*03 allele. These 2 patients were the only ones who were positive for anti–Jo‐1 antibody.ConclusionWe found a restricted accumulation of T lymphocytes expressing selected TCR V‐gene segments in the target organ compartments (i.e., lung and muscle). The occurrence of shared TCR gene segment usage in muscle and lungs could suggest common target antigens in these organs.
Fracture risk with intermittent high‐dose oral glucocorticoid therapy
Authors: De Vries Frank , Bracke Madelon , Leufkens Hubert G. M. , Lammers Jan‐Willem J. , Cooper Cyrus , Van Staa Tjeerd P. 
Published: December 2006

AbstractObjectiveTo evaluate the risk of fracture in patients receiving intermittent therapy with high‐dose oral glucocorticoids (GCs).MethodsThe study group comprised 191,752 patients from the UK General Practice Database who were 40 years of age and older and received therapy with GCs. The followup time period was divided into the categories of “current” and “no exposure.” The daily dose and cumulative dose for each time period were determined. Relative risks were estimated using Cox proportional hazards models, adjusted for age, sex, body mass index, smoking, disease history, and drug history. Fractures of the radius/ulna, humerus, rib, femur/hip, pelvis, or vertebrae were included in the evaluation.ResultsPatients who intermittently received high‐dose GCs (daily dose ≥15 mg) and had no or little previous exposure to GCs (cumulative exposure ≤1 gm) had a small increased risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increasing cumulative exposure. Among patients who received a daily dose ≥30 mg and whose cumulative exposure was >5 gm, the relative risk (RR) of osteoporotic fracture was 3.63 (95% confidence interval [95% CI] 2.54–5.20), the RR of fracture of the hip/femur was 3.13 (95% CI 1.49–6.59), and the RR of vertebral fracture was 14.42 (95% CI 8.29–25.08).ConclusionIntermittent use of high‐dose oral GCs (daily dose ≥15 mg and cumulative exposure ≤1 gm) may result in a small increased risk of osteoporotic fracture. Conversely, patients who receive several courses of high‐dose GCs (daily dose ≥15 mg and cumulative exposure >1 gm) have a substantially increased risk of fracture.
HLA–B27 up‐regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis‐like disease
Authors: Turner Matthew J. , DeLay Monica L. , Bai Shuzhen , Klenk Erin , Colbert Robert A. 
Published: December 2006

AbstractObjectiveHLA–B27 is implicated in the pathogenesis of spondylarthritis (SpA), yet the molecular mechanisms are incompletely defined. HLA–B27 misfolding has been associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in macrophages from HLA–B27/human β2‐microglobulin–transgenic (B27‐transgenic) rats. This study was performed to assess the mechanisms that drive activation of the HLA–B27–induced UPR and to determine whether splenocytes respond in a similar manner.MethodsSplenocytes were isolated and bone marrow macrophages were derived from B27‐transgenic and wild‐type rats. Cells were treated for up to 24 hours with cytokines that induce class I major histocompatibility complex expression. HLA–B27 expression and misfolding were assessed by real‐time reverse transcription–polymerase chain reaction, flow cytometry, and immunoblotting. Activation of the UPR was measured by quantifying UPR target gene expression and X‐box binding protein 1 messenger RNA (mRNA) splicing.ResultsHLA–B27 mRNA up‐regulation was accompanied by a dramatic increase in the accumulation of misfolded heavy chains and preceded robust activation of the UPR in macrophages. When macrophages were treated with various cytokines, the magnitude of the UPR correlated strongly with the degree of HLA–B27 up‐regulation. In contrast, B27‐transgenic splenocytes exhibited only low‐level differences in the expression of UPR target genes after exposure to interferon‐γ or concanavalin A, which resulted in minimal HLA–B27 up‐regulation.ConclusionThese results suggest that HLA–B27–associated activation of the UPR in macrophages is attributable to the accumulation of misfolded heavy chains, and that certain cell types may be more susceptible to the effects of HLA–B27 misfolding. Strategies that eliminate HLA–B27 up‐regulation and/or the accumulation of misfolded heavy chains may be useful in evaluating the role of these events in the pathogenesis of SpA.
Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: An in vitro study
Authors: Jansen Nathalie W. D. , Roosendaal Goris , Bijlsma Johannes W. J. , DeGroot Jeroen , Lafeber Floris P. J. G. 
Published: December 2006

AbstractObjectiveJoint bleeding, or hemarthrosis, leads in time to severe joint damage. This study was carried out to test the in vitro thresholds of exposure time and concentration that lead to irreversible joint damage, to add to the discussion on the usefulness of aspiration of the joint after a hemorrhage.MethodsExplants of healthy human articular cartilage tissue were cultured in the presence or absence of 50% (volume/volume) blood for 1, 2, 3, or 4 days or in the presence of 0%, 5%, 10%, 20%, 30%, or 50% (v/v) blood for 4 days, followed by a 12‐day period of recovery after withdrawal of blood. The effect of blood exposure on cartilage was determined by measuring the rate of proteoglycan synthesis as well as the release and content of cartilage matrix proteoglycans and the activity of matrix metalloproteinases.ResultsExposure of cartilage to 50% (v/v) blood led to adverse changes that were largely independent of the exposure time. The adverse effects persisted after an initial exposure of up to or exceeding 2 days. Exposure of cartilage to increasing concentrations of blood for 4 days led to concentration‐dependent adverse changes. These effects persisted when the concentration equaled or exceeded 10% (v/v) blood. Moreover, after 2 days of exposure to a blood load of 10% (v/v), the adverse effects on cartilage were not reversible.ConclusionA 2‐day exposure of cartilage in vitro to 10% (v/v) blood leads to prolonged impairment of joint cartilage. This suggests that aspiration of blood from the joint within 2 days after hemarthrosis should be considered to prevent blood‐induced joint damage in the long term.
Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: An international inception cohort study
Authors: Hanly J. G. , Urowitz M. B. , Sanchez‐Guerrero J. , Bae S. C. , Gordon C. , Wallace D. J. , Isenberg D. , Alarcón G. S. , Clarke A. , Bernatsky S. , Merrill J. T. , Petri M. , Dooley M. A. , Gladman D. , Fortin P. R. , Steinsson K. , Bruce I. , Manzi S. , Khamashta M. , Zoma A. , Aranow C. , Ginzler E. , Van Vollenhoven R. , Font J. , Sturfelt G. , Nived O. , Ramsey‐Goldman R. , Kalunian K. , Douglas J. , Thompson K. , Farewell V. ,   Systemic Lupus International Collaborating Clinics
Published: December 2006

AbstractObjectiveTo describe the prevalence, characteristics, attribution, and clinical significance of neuropsychiatric (NP) events in an international inception cohort of systemic lupus erythematosus (SLE) patients.MethodsThe study was conducted by the Systemic Lupus International Collaborating Clinics (SLICC). Patients were enrolled within 15 months of fulfilling the American College of Rheumatology (ACR) SLE classification criteria. All NP events within a predefined enrollment window were identified using the ACR case definitions of 19 NP syndromes. Decision rules were derived to determine the proportion of NP disease attributable to SLE. Clinical significance was determined using the Short Form 36 (SF‐36) Health Survey and the SLICC/ACR Damage Index (SDI).ResultsA total of 572 patients (88% female) were recruited, with a mean ± SD age of 35 ± 14 years. The mean ± SD disease duration was 5.2 ± 4.2 months. Within the enrollment window, 158 of 572 patients (28%) had at least 1 NP event. In total, there were 242 NP events that encompassed 15 of 19 NP syndromes. The proportion of NP events attributed to SLE varied from 19% to 38% using alternate attribution models and occurred in 6.1–11.7% of patients. Those with NP events, regardless of attribution, had lower scores on the SF‐36 and higher SDI scores compared with patients with no NP events.ConclusionTwenty‐eight percent of SLE patients experienced at least 1 NP event around the time of diagnosis of SLE, of which only a minority were attributed to SLE. Regardless of attribution, the occurrence of NP events was associated with reduced quality of life and increased organ damage.
Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human β2‐glycoprotein I: Mutation studies including residues R39 to R43
Authors: Ioannou Yiannis , Pericleous Charis , Giles Ian , Latchman David S. , Isenberg David A. , Rahman Anisur 
Published: December 2006

AbstractObjectivePathogenic antiphospholipid antibodies (aPL) bind the self antigen N‐terminal domain (domain I) of β2‐glycoprotein I (β2GPI), with residues G40–R43 being important. However, peptides homologous to other regions of domain I have also been shown to bind aPL. Furthermore, there are no published reports of the effects of altering R39, which has greater surface exposure than the G40–R43 residues.MethodsWe used a novel, efficient method of production and purification of human domain I by Escherichia coli to create multiple mutants of domain I. These domain I mutants were then screened for binding to a range of polyclonal IgG purified from patients with antiphospholipid syndrome, using both solid‐phase and fluid‐phase assays.ResultsE coli–expressed purified domain I selectively bound IgG derived from patients with antiphospholipid syndrome. In region R39–R43, the R39S mutation had the greatest effect in terms of reducing binding to a panel of aPL in the fluid phase (mean ± SD inhibition 14 ± 18.5% versus 44.1 ± 31.7% for G40E and 62.9 ± 25.7% for wild‐type domain I). Conversely, altering both D8 and D9 to S8 and G9, respectively, had the effect of enhancing binding to aPL in the fluid phase. Adding the remainder of the domain I–II interlinker resulted in enhanced binding over wild‐type in the solid phase but not the fluid phase.ConclusionThe binding of aPL to β2GPI domain I is complex and likely to involve discontinuous epitopes that include R39 in addition to G40–R43, the domain I–II interlinker, and possibly D8 and D9. Domain I variants with enhanced binding to aPL compared with wild‐type domain I may aid in the development of novel therapies.
Association of a TNAP haplotype with ankylosing spondylitis
Authors: Tsui Hing Wo , Inman Robert D. , Reveille John D. , Tsui Florence W. L. 
Published: December 2006

AbstractObjectiveTo use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS).MethodsWe genotyped 201 multiplex AS families with 1 exonic and 5 intronic single‐nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissue‐nonspecific alkaline phosphatase, and performed family‐based association analyses.ResultsIn our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) was significantly associated with AS (P = 0.032 by additive model). Haplotype‐Based Association Testing (HBAT) analyses of AS families in which both men and women were affected showed that the same TNAP haplotype was significantly associated with AS (P = 0.002 by additive model). Using setafftrait code 1 0 0 in the HBAT program, testing specifically for affected men in AS families containing affected individuals of both sexes, this TNAP haplotype was also significantly associated with AS (P = 0.001 by additive model). The HBAT –p option (haplotype permutation test) was used to compute the “exact” P value via a Monte Carlo method for each haplotype (haplotype permutation test) and for the minimum observed P value among the haplotypes (whole marker permutation using the minimal P test), and both P values were statistically significant (2‐sided P value for haplotype rs3767155 [G]/rs3738099 [G]/rs1780329 [T] = 0.00059, the smallest observed P value among all the individual haplotype scores = 0.003). Interestingly, this haplotype was not associated with AS in affected women from the same families.ConclusionOur results indicate that the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with AS in multiplex families containing affected individuals of both sexes.
Effect of glutathione S‐TRANSFERASE polymorphisms and proximity to hazardous waste sites on time to systemic lupus erythematosus diagnosis: Results from the roxbury lupus project
Authors: Karlson Elizabeth W. , Watts Julie , Signorovitch James , Bonetti Marco , Wright Elizabeth , Cooper Glinda S. , McAlindon Timothy E. , Costenbader Karen H. , Massarotti Elena M. , Fitzgerald Lisa M. , Jajoo Ramina , Husni M. Elaine , Fossel Anne H. , Pankey Helen , Ding Wei‐Zi , Knorr Robert , Condon Suzanne , Fraser Patricia A. 
Published: December 2006

AbstractObjectiveThe high prevalence of systemic lupus erythematosus (SLE) among African American women may be due to environmental exposures, genetic factors, or a combination of factors. Our goal was to assess association of residential proximity to hazardous waste sites and genetic variation in 3 glutathione Stransferase (GST) genes (GSTM1, GSTT1, and GSTP1) with age at diagnosis of SLE.MethodsResidential histories were obtained by interviewing 93 SLE patients from 3 predominantly African American neighborhoods in Boston. Residential addresses and locations of 416 hazardous waste sites in the study area were geocoded using ArcView software. Time‐varying Cox models were used to study the effect of residential proximity to hazardous sites, GST genotype, and interaction between genotype and exposure in determining age at diagnosis.ResultsThe prevalence of SLE among African American women in these neighborhoods was 3.56 SLE cases per 1,000. Homozygosity for GSTM1‐null and GSTP1 Ile105Val in combination was associated with earlier SLE diagnosis (P= 0.03), but there was no association with proximity to 416 hazardous sites. Available data on specific site contaminants suggested that, at a subset of 67 sites, there was higher potential risk for exposure to volatile organic compounds (P< 0.05 with Bonferroni correction). GST genotypes had a significant interaction with proximity (P= 0.03) in analyses limited to these sites.ConclusionThere was no independent association between residential proximity to hazardous waste sites and the risk of earlier SLE diagnosis in this urban population. However, analysis of a limited number of sites indicated that the risk of earlier SLE associated with proximity to hazardous sites might be modulated by GST polymorphisms.
Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus
Authors: Flores‐Borja Fabian , Kabouridis Panagiotis S. , Jury Elizabeth C. , Isenberg David A. , Mageed Rizgar A. 
Published: December 2006

AbstractObjectiveB lymphocytes from patients with systemic lupus erythematosus (SLE) exhibit defective intracellular signaling, hyperactivity, and autoantibody production. Recent evidence indicates a reduced expression of Lyn kinase, a negative regulator of B cell signaling, and reduced translocation of Lyn into membrane signaling domains in SLE. The present study was undertaken to investigate the causes of this altered regulation of Lyn by assessing the expression levels of regulatory molecules and their translocation into the signaling domains of SLE B lymphocytes.MethodsBlood was obtained from 48 patients with SLE and 28 healthy controls for the assessment of B lymphocytes. Levels and intracellular distribution of Lyn, CD45, COOH‐terminal Src kinase (Csk), and c‐Cbl were studied by Western blotting, confocal microscopy, and flow cytometry. The kinetics of signaling molecule translocation to the B cell receptor (BCR)–antigen synapse were investigated by confocal microscopy.ResultsA profound alteration in the expression and translocation of regulatory signaling molecules in membrane domains of B cells from patients with SLE was observed. B lymphocytes from SLE patients, but not those from healthy controls, expressed a low molecular weight isoform of CD45 in lipid raft signaling microdomains. Kinetic studies revealed that translocation of Lyn, CD45, Csk, and c‐Cbl led to increased recruitment and retention of Lyn and CD45 in the BCR–antigen synapse in SLE B cells.ConclusionThe results provide evidence of altered expression and translocation/interaction of kinases and phosphatases in membrane signaling microdomains of B cells from patients with SLE. Altered translocation of CD45 correlated with reduced expression of Lyn, indicating that Lyn is a key molecule in the regulation of BCR‐mediated signaling.
Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis
Authors: Distler Jörg H. W. , Jüngel Astrid , Huber Lars C. , Schulze‐Horsel Ursula , Zwerina Jochen , Gay Renate E. , Michel Beat A. , Hauser Thomas , Schett Georg , Gay Steffen , Distler Oliver 
Published: December 2006

AbstractObjectiveImatinib mesylate is a clinically well‐tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor β (TGFβ) and platelet‐derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).MethodsThe expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real‐time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin‐induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.ResultsImatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose‐dependent manner. The induction of ECM proteins after stimulation with TGFβ and PDGF was also strongly and dose‐dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects.ConclusionThese data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.