bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential expression of stromal cell–derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications
Authors: Cipriani Paola , Franca Milia Anna , Liakouli Vasiliki , Pacini Alessandra , Manetti Mirko , Marrelli Alessandra , Toscano Annarita , Pingiotti Elisa , Fulminis Antonietta , Guiducci Serena , Perricone Roberto , Kahaleh Bashar , Matucci‐Cerinic Marco , Ibba‐Manneschi Lidia , Giacomelli Roberto 
Published: August 2006

AbstractObjectiveSystemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell–derived factor 1 (SDF‐1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF‐1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc.MethodsWe enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF‐1 and CXCR4 was assessed by immunohistochemistry, reverse transcription–polymerase chain reaction (RT‐PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF‐1 and CXCR4 by confocal laser scanning microscopy, RT‐PCR, and Western blotting.ResultsSDF‐1 and CXCR4 were up‐regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF‐1 in the early stage of disease, with a progressive reduction of SDF‐1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF‐1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function.ConclusionDue to its transient expression, SDF‐1 could be considered a future therapeutic target to induce new vessel formation in SSc.
A proposal for a pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index based on the analysis of 1,015 patients with juvenile‐onset systemic lupus erythematosus
Authors: Gutiérrez‐Suárez Raul , Ruperto Nicolino , Gastaldi Roberto , Pistorio Angela , Felici Enrico , Burgos‐Vargas Rubén , Martini Alberto , Ravelli Angelo 
Published: August 2006

AbstractObjectiveTo devise a modified version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) for use in children and adolescents with systemic lupus erythematosus (SLE), based on the frequency and distribution of damage in patients with juvenile‐onset SLE and the sources of damage that are most suitable for inclusion in a pediatric damage index.MethodsIn this cross‐sectional study, damage was assessed through the SDI. Clinical assessments included evaluation of growth failure and delayed puberty, which were believed to be important sources of damage that are not incorporated in the SDI but should be included in a pediatric version of the instrument.ResultsA total of 1,015 patients with juvenile‐onset SLE in 39 countries were enrolled in the study. Of these, 405 patients (39.9%) had an SDI score of ≥1 (mean ± SD score 0.8 ± 1.4). Renal damage (13%), neuropsychiatric damage (10.7%), and musculoskeletal damage (10.7%) were observed most frequently, followed by ocular damage (8.2%) and skin damage (7.6%). Growth failure and delayed puberty were recorded in 15.3% and 11.3% of patients, respectively. A pediatric version of the SDI was devised, with inclusion of growth failure and delayed puberty as new domains.ConclusionWe propose a modified version of the SDI for use in patients with juvenile‐onset SLE. This new instrument warrants prospective validation in other populations of patients seen in different clinical or research settings.
Measuring function in rheumatoid arthritis: Identifying reversible and irreversible components
Authors: Aletaha Daniel , Smolen Josef , Ward Michael M. 
Published: August 2006

AbstractObjectiveMeasurement of physical function at one point in time cannot distinguish impairment caused by the active disease process from chronic irreversible impairment. We aimed to dissect these two components of functional limitation in rheumatoid arthritis (RA) by using the disability index of the Health Assessment Questionnaire (HAQ) as the measure of function.MethodsWe performed a secondary analysis of data from 6 contemporary clinical trials of RA (2,763 patients). Patients in whom remission was achieved in the trials, based on a simplified disease activity index, were identified. In an individual patient, HAQ scores at trial entry represented both reversible and irreversible impairments, while HAQ scores at the time of RA remission represented the mostly irreversible component, and the difference between these corresponded to the component related to disease activity. We tested the concept that the HAQ has a reversible and an irreversible component by associating the HAQ score during remission with 2 measures associated with the degree of accrued damage: duration of RA and radiographic severity.ResultsAmong patients in whom clinical remission was achieved (n = 295), average HAQ scores despite clinical remission increased progressively with the duration of RA, from 0.19 (<2 years of RA) to 0.36 (2–<5 years) to 0.38 (5–<10 years) to 0.55 (≥10 years) (P < 0.001). The reversibility of HAQ scores decreased with the duration of RA (median 100%, 83.3%, 81.9%, and 66.7%, respectively; P < 0.001). Findings were similar in patients subgrouped by quartile of radiographic scores.ConclusionDifferences in the sources of functional limitations should be considered in the interpretation of functional measures, and in their use for prediction and in cost analyses.
Insulin resistance and impaired beta cell function in rheumatoid arthritis
Authors: Dessein Patrick H. , Joffe Barry I. 
Published: August 2006

AbstractObjectiveTo identify factors that regulate glucose metabolism in rheumatoid arthritis (RA).MethodsWe evaluated the homeostatic model assessment of insulin resistance (HOMA‐IR) and beta cell function (HOMA‐B) in 94 RA patients. We investigated the relationship between characteristics known to affect glucose metabolism in the general population (age, abdominal obesity [waist circumference], hypertension, antihypertensive therapy) as well as characteristics of RA (disease activity, glucocorticoid therapy) and insulin resistance and beta cell function.ResultsPatients with high‐grade inflammation (high‐sensitivity C‐reactive protein value >1.92 mg/liter) (n = 81) were more insulin resistant than patients with low‐grade inflammation (n = 13), whereas beta cell function was similar in both groups. Insulin resistance and beta cell function were similar in both groups after adjustment for waist circumference. All recorded characteristics except for age were associated with HOMA‐IR or/and HOMA‐B in univariate analyses. In mixed regression models, abdominal obesity and patient's assessment of disease activity (by visual analog scale) were predictors of insulin resistance. The Disease Activity Score assessed using 28‐joint counts for swelling and tenderness, tender joint count, and patient's assessment of disease activity were associated with reduced beta cell function, and the cumulative dose of glucocorticoids was associated with enhanced beta cell function. The cumulative glucocorticoid dose in all study patients was a mean of only 536 mg (95% confidence interval 239–1,173). In patients with high‐grade inflammation, age was further associated with impaired beta cell function, whereas use of angiotensin‐converting enzyme inhibitors or angiotensin II type 1 receptor blockers was associated with enhanced beta cell function.ConclusionThe modifiable factors of abdominal obesity, antihypertensive therapy, disease activity, and use of glucocorticoids appear to affect glucose metabolism in RA.
Tumor necrosis factor α antagonist use and cancer in patients with rheumatoid arthritis
Authors: Setoguchi Soko , Solomon Daniel H. , Weinblatt Michael E. , Katz Jeffrey N. , Avorn Jerry , Glynn Robert J. , Cook E. Francis , Carney Greg , Schneeweiss Sebastian 
Published: August 2006

AbstractObjectiveConcerns persist about a possible association between tumor necrosis factor α (TNFα) antagonist treatment and development of cancers in patients with rheumatoid arthritis (RA). This study was undertaken to estimate the association between treatment with biologic disease‐modifying antirheumatic drugs (DMARDs) and development of cancer in patients with RA.MethodsWe conducted a cohort study pooling administrative databases from 2 US states and 1 Canadian province. A cohort of patients who had received a diagnosis of RA on ≥1 occasion and had been prescribed DMARDs was identified. We categorized patients with a prescription for a biologic DMARD as biologic DMARD users, and those with a prescription for methotrexate (MTX) but no biologic DMARD as MTX users. We used time‐varying propensity scores to adjust for the large number of possible confounders and stratified proportional hazards regression to estimate the effects of biologic DMARDs on cancer. The primary end points were hematologic malignancies (lymphoma, multiple myeloma, and leukemia) and common solid tumors (colorectal, lung, stomach, breast, prostate, uterine, ovarian, urinary tract/bladder, and melanoma).ResultsThe pooled cohort included 1,152 biologic DMARD users and 7,306 MTX users. We identified 11 hematologic malignancies and 46 solid tumors during 2,940 person‐years of biologic DMARD use, and 88 hematologic malignancies and 558 solid tumors during 30,300 person‐years of MTX use. Comparing biologic DMARD users with MTX users, the propensity score–adjusted pooled hazard ratio was 1.37 (95% confidence interval 0.71–2.65) for hematologic malignancies and 0.91 (95% confidence interval 0.65–1.26) for solid tumors.ConclusionOur results indicate that users of biologic agents are unlikely to have a substantial increase in the risk of hematologic malignancies and solid tumors as compared with MTX users. Despite the use of large combined data sets, studying the effect of an infrequent exposure (biologic DMARDs) on rare diseases (hematologic malignancies) remains a challenge.
Association of HLA–C3 and smoking with vasculitis in patients with rheumatoid arthritis
Authors: Turesson Carl , Schaid Daniel J. , Weyand Cornelia M. , Jacobsson Lennart T. , Goronzy Jörg J. , Petersson Ingemar F. , Dechant Sonja A. , Nyähll‐Wåhlin Britt‐Marie , Truedsson Lennart , Sturfelt Gunnar , Matteson Eric L. 
Published: August 2006

AbstractObjectiveTo compare HLA–C genotypes and smoking habits in patients with vasculitis or other severe extraarticular manifestations of rheumatoid arthritis (ExRA) with those in RA patients without extraarticular disease.MethodsPatients were recruited from a large research database of patients with RA at the Mayo Clinic, from 2 Swedish cohorts of prevalent RA cases, and from a regional Swedish early RA cohort. Patients with severe ExRA (n = 159) and control patients with RA but no history of ExRA (non‐ExRA controls) (n = 178) were matched for duration of RA and for clinical center. Data on smoking at RA onset, rheumatoid factor (RF) status, and antinuclear antibodies (ANAs) were extracted from the medical records. Polymerase chain reaction–based HLA–C genotyping was performed using a sequence‐specific primer kit.ResultsThe distribution of HLA–C alleles was significantly different between patients with RA‐associated vasculitis and non‐ExRA controls (P = 0.014). This was mainly due to a positive association of the HLA–C3 allele with vasculitis (allele frequency 0.411 in vasculitis patients versus 0.199 in non‐ExRA controls; P < 0.001) and a decreased frequency of HLA–C7 (0.122 and 0.243, respectively; P = 0.018). The association between HLA–C3 and vasculitis was not due to linkage disequilibrium with HLA–DRB1. Smoking (P = 0.001), RF positivity (P < 0.0001), and presence of ANAs (P < 0.0001) were all associated with ExRA. HLA–C3 and smoking were both significant predictors of vasculitis in a multivariate model.ConclusionVasculitis in RA is associated with HLA–C3. Smoking is an independent predictor of vasculitis and other types of severe ExRA. Our results suggest that these variables are among the genetic and environmental factors that contribute significantly to the pathomechanisms of systemic RA.
Increased collagen degradation around loosened total hip replacement implants
Authors: Ma Guo‐Feng , Ali Ahmed , Verzijl Nicole , Hanemaaijer Roeland , TeKoppele Johan , T. Konttinen Yrjö , Salo Jari 
Published: August 2006

AbstractObjectiveTo assess collagen degradation and its relationship to some of the key collagenolytic proteinases in the aggressive synovial membrane–like interface tissue around aseptically loosened hip replacement implants.MethodsThe medical indication for the primary total hip replacement was osteoarthritis in all study patients. Samples from the study patients were compared with control synovial membranes obtained from trauma (hip fracture) patients. Proteoglycans were extracted with 4M guanidinium chloride. Denatured collagen in the remaining matrix was solubilized with α‐chymotrypsin. Nonsoluble matrix and supernatant fractions were acid hydrolyzed before measurement of hydroxyproline. The proportion of soluble (in vivo–degraded) collagen of the total sample collagen content was calculated. Proteinases were stained using the avidin–biotin–peroxidase complex method.ResultsCollagen in the interface membrane from the implants was highly degraded (mean ± SEM 20 ± 3%) compared with that in the control synovial membranes (12 ± 1%; P = 0.007). In controls, the degree of collagen degradation did not correlate with levels of matrix metalloproteinase 1 (MMP‐1), MMP‐13, or cathepsin K, although MMP‐1 approached statistical significance. In interface membranes, the correlations were r = 0.88 (P = 0.002), r = 0.92 (P = 0.001), and r = 0.98 (P < 0.0001) for MMP‐1, MMP‐13, and cathepsin K, respectively.ConclusionIn normal synovial membrane, collagen matrix remodeling may be mainly an intracellular process. In contrast, pathologic tissue destruction in the interface membrane from prosthetic hip joints is associated with a shift toward MMP‐13 and cathepsin K, which become activated and overcome their endogenous inhibitors (tissue inhibitors of metalloproteinases and cystatin C). The highly significant correlation between collagen degradation and cathepsin K indicates an extracellular role of this acidic endoproteinase, consistent with previous observations concerning the acidity of the interface membrane.
Clinical differences between idiopathic and scleroderma‐related pulmonary hypertension
Authors: Fisher Micah R. , Mathai Stephen C. , Champion Hunter C. , Girgis Reda E. , Housten‐Harris Traci , Hummers Laura , Krishnan Jerry A. , Wigley Fredrick , Hassoun Paul M. 
Published: August 2006

AbstractObjectivePulmonary arterial hypertension related to scleroderma (PAH‐Scl) is associated with high morbidity and mortality as well as poorer response to therapy and worse outcomes compared with the idiopathic form of PAH (IPAH). Scleroderma is an autoimmune disease that can affect left and right heart function directly through inflammation and fibrosis and indirectly through systemic and pulmonary hypertension. This study tested the hypothesis that an increased prevalence of left heart disease might explain the higher mortality in patients with PAH‐Scl compared with patients with IPAH.MethodsThe study was designed as a retrospective cohort study comparing the baseline clinical data from 91 consecutive patients (41 with IPAH and 50 with PAH‐Scl). Cox proportional hazards models were used to predict the effect of clinical covariates on patient survival.ResultsPatients with PAH‐Scl had a lower mean pulmonary artery pressure (46.6 mm Hg versus 54.4 mm Hg in patients with IPAH; P = 0.002) despite similar levels of cardiac dysfunction (cardiac index 2.2 and 2.1 liters/minute/m2, respectively; P = 0.19). Echocardiography revealed similar degrees of right ventricular dysfunction in the 2 groups, whereas a predominance of left heart dysfunction was observed in patients with PAH‐Scl. One‐ and three‐year survival estimates were 87.8% and 48.9%, respectively, in patients with PAH‐Scl and 95.1% and 83.6%, respectively, in those with IPAH. Patients with PAH‐Scl were 3.06 times more likely to die than were patients with IPAH, after controlling for the presence of pericardial effusion; there was no significant change in increased risk of death in PAH‐Scl after controlling for left heart disease.ConclusionThe results confirm that there are significant clinical and survival differences between IPAH and PAH‐Scl. The presence of left heart disease, although more common in PAH‐Scl, was not predictive of the higher mortality in these patients.
Up‐regulated transforming growth factor β–inducible gene h3 in rheumatoid arthritis mediates adhesion and migration of synoviocytes through αvβ3 integrin: Regulation by cytokines
Authors: Nam Eon Jeong , Sa Keum Hee , You Dong Wan , Cho Jang Hee , Seo Jae Seok , Han Seung Woo , Park Jae Yong , Kim Sung Il , Kyung Hee Soo , Kim In San , Kang Young Mo 
Published: August 2006

AbstractObjectiveTo delineate the expression of transforming growth factor β–inducible gene h3 (βIG‐H3) in rheumatoid synovitis and to determine the regulatory role of βIG‐H3 in the adhesion and migration of fibroblast‐like synoviocytes (FLS).MethodsSynovial tissue was obtained from patients with rheumatoid arthritis (RA) during joint replacement surgery, and FLS were isolated using enzymatic treatment. Immunohistochemical staining was performed to show the expression of βIG‐H3 within rheumatoid synovium. Synthesis of βIG‐H3 from FLS was determined by semiquantitative reverse transcription–polymerase chain reaction, Western blot analysis, and enzyme‐linked immunosorbent assay. Cell adhesion and migration assays were performed using the YH18 peptide in the fourth fas‐1 domain of βIG‐H3 and function‐blocking antibodies to integrins.ResultsExpression of βIG‐H3 was up‐regulated in RA synovial tissue compared with synovial tissue from patients with osteoarthritis. FLS isolated from RA synovial tissue constitutively produced βIG‐H3, which was up‐regulated by transforming growth factor β1, interleukin‐1β, and tumor necrosis factor α. Although FLS expressed a variety of integrins, βIG‐H3 mediated adhesion and migration of FLS through interaction with αvβ3 integrin. Cytokines failed to affect the βIG‐H3–mediated adhesion. However, migration of FLS guided by βIG‐H3 was enhanced by interferon‐γ and platelet‐derived growth factor type BB. The YH18 peptide in the fourth fas‐1 domain of βIG‐H3 inhibited adhesion and migration in a dose‐dependent manner.ConclusionThe results suggest that βIG‐H3, which is abundantly expressed in RA synovial tissue, plays a regulatory role in chronic destructive inflammation through the modulation of the adhesion and migration of FLS. This finding indicates the relevance of βIG‐H3 and αvβ3 integrin–interacting motifs as potential therapeutic targets in this disease.
Differential tissue expression and activation of p38 MAPK α, β, γ, and δ isoforms in rheumatoid arthritis
Authors: Korb Adelheid , Tohidast‐Akrad Makiyeh , Cetin Erdal , Axmann Roland , Smolen Josef , Schett Georg 
Published: August 2006

AbstractObjectiveActivation of p38 MAPK is a key signaling step in chronic inflammation. Inhibition of p38 MAPK is considered to be a promising future strategy to control inflammatory diseases, but studies of compounds to inhibit this kinase have so far been limited to investigation of their side effects. We undertook the present study to investigate which specific molecule, among 4 different isoforms of p38 MAPK (α, β, γ, and δ), is predominantly expressed and activated in inflammation. Such knowledge could allow more specific targeting of p38 MAPK in inflammatory disease.MethodsStudies were performed on inflamed tissue from patients with rheumatoid arthritis, as a prototype of inflammatory disease. The expression and activation of the α, β, γ, and δ isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry.ResultsImmunoblot analysis revealed that α and γ were the predominantly expressed p38 MAPK isoforms, whereas the other 2 isoforms were less frequently present. By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels. Colabeling with cell‐specific markers revealed that macrophages expressed the α and γ isoforms, synovial fibroblasts the β and γ isoforms, and granulocytes the δ isoform, whereas T lymphocytes were rarely positive for any p38 MAPK isoform. Double‐labeling with isoform‐specific antibody and pan‐p38 antibody against the phosphorylated form of p38 MAPK showed activation of the α and γ isoforms. Occasional activation of the β isoform was also noted in the synovial lining and the endothelium, whereas the δ isoform, although expressed in pericytes around blood vessels, was not phosphorylated. This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPKα and ‐γ but not p38 MAPKβ or ‐δ.ConclusionThese data show that the α and γ isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms.
Rapamycin reduces disease activity and normalizes T cell activation–induced calcium fluxing in patients with systemic lupus erythematosus
Authors: Fernandez David , Bonilla Eduardo , Mirza Naureen , Niland Brian , Perl Andras 
Published: August 2006

AbstractObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca2+ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca2+ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus‐prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE.MethodsNine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca2+ fluxing were assessed by flow cytometry.ResultsIn patients treated with rapamycin, the BILAG score was reduced by a mean ± SEM of 1.93 ± 0.9 (P = 0.0218), the SLEDAI by 5.3 ± 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 ± 6.7 mg/day (P = 0.0062) compared with pre–rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca2+ levels and T cell activation–induced rapid Ca2+ fluxing were normalized in rapamycin‐treated patients.ConclusionRapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca2+ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.