bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonsteroidal antiinflammatory drugs and prostaglandin E2 modulate the synthesis of osteoprotegerin and RANKL in the cartilage of patients with severe knee osteoarthritis
Authors: Moreno‐Rubio Juan , Herrero‐Beaumont Gabriel , Tardı´o Lidia , álvarez‐Soria M. ángeles , Largo Raquel 
Published: January 2010

AbstractObjectiveAlthough the osteoprotegerin (OPG)/RANK/RANKL system is the main modulator of bone remodeling, it remains unclear whether it is regulated in cartilage during osteoarthritis (OA). The aim of this study was to examine whether nonsteroidal antiinflammatory drug (NSAID) treatment modulates the synthesis of OPG and RANKL in the cartilage of patients with OA, and to investigate whether prostaglandin E2 (PGE2) modifies this system in human OA chondrocytes in culture.MethodsA 3‐month clinical trial was carried out in 20 patients with severe knee OA, all of whom were scheduled to undergo knee replacement surgery. Ten of these patients were treated with celecoxib, and the other 10 patients, who did not want to be treated, served as the control group. After surgery, cartilage was processed for molecular biology studies. We also used human OA chondrocytes to examine the effects of PGE2 on OPG/RANKL synthesis, examining which surface receptors were affected by PGE2.ResultsIn patients with OA, celecoxib decreased RANKL synthesis in the cartilage, thereby increasing the OPG:RANKL ratio. In human OA chondrocytes in culture, PGE2 elicited a dose‐ and time‐dependent increase in the synthesis of RANKL, the extent of which was greater than that of OPG. Confocal microscopy revealed that PGE2 induced RANKL transport to the cell membrane. Only EP2/EP4 agonists reproduced the effects of PGE2 on OPG and RANKL induction.ConclusionLong‐term NSAID treatment inhibited the resorptive signal synthesized by chondrocytes. In vitro, PGE2 regulated the expression and release of these key mediators of bone metabolism by articular chondrocytes. The role of OPG/RANK/RANKL in OA cartilage metabolism is still unknown, although the synthesis of these proteins would enable the cartilage to control the activity of subchondral bone cells.
A four‐gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis
Authors: Farina G. , Lafyatis D. , Lemaire R. , Lafyatis R. 
Published: January 2010

AbstractObjectiveImproved outcome measures in systemic sclerosis (SSc) are critical to finding active therapeutics for this disease. The modified Rodnan skin thickness score (MRSS) is the current standard for evaluating skin disease in SSc, but it is not commonly used in the clinical setting, in part because it requires specialized training to perform accurately and consistently. The purpose of this study was to investigate whether skin gene expression might serve as a more objective surrogate outcome measure to supplement skin score evaluations.MethodsSkin RNAs from a group of patients with diffuse cutaneous SSc were studied for expression levels of genes known to be regulated by transforming growth factor β (TGFβ) and interferon (IFN). These levels were correlated with the MRSS, using multiple regression analyses to obtain best‐fit models.ResultsSkin expression of the TGFβ‐regulated genes cartilage oligomeric matrix protein (COMP) and thrombospondin 1 (TSP‐1) correlated moderately well with the MRSS, but the addition of other TGFβ‐regulated genes failed to significantly improve best‐fit models. IFN‐regulated genes were also found to correlate with the MRSS, and the addition of interferon‐inducible 44 (IFI44) and sialoadhesin (Siglec‐1) to COMP and TSP‐1 in multiple regression analyses significantly improved best‐fit models, achieving an R2 value of 0.89. These results were validated using an independent group of skin biopsy samples. Longitudinal scores using this 4‐gene biomarker indicated that it detects change over time that corresponds to changes in the MRSS.ConclusionWe describe a 4‐gene predictor of the MRSS and validate its performance. This objective measure of skin disease could provide a strong surrogate outcome measure for patient care and for clinical trials.
Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open‐label phase I dosage‐escalation study
Authors: Illei Gabor G. , Shirota Yuko , Yarboro Cheryl H. , Daruwalla Jimmy , Tackey Edward , Takada Kazuki , Fleisher Thomas , Balow James E. , Lipsky Peter E. 
Published: January 2010

AbstractObjectiveTo assess the safety of interleukin‐6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).MethodsIn an open‐label phase I dosage‐escalation study, 16 patients with mild‐to‐moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks.ResultsThe infusions were well tolerated. Tocilizumab treatment led to dosage‐related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of ≥4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti–double‐stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody‐producing cells.ConclusionAlthough neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.
Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon‐β/α ratios in rheumatoid arthritis patients: A post hoc analysis of a predominantly Hispanic cohort
Authors: Mavragani Clio P. , La Dan T. , Stohl William , Crow Mary K. 
Published: January 2010

AbstractObjectiveDespite the substantial clinical efficacy of tumor necrosis factor α (TNFα) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy.MethodsRA patients (n = 35), the majority of whom were Hispanic, from a single center were evaluated before and after initiation of TNF antagonist therapy. As controls, 12 RA patients from the same center who were not treated with a TNF antagonist were studied. Plasma type I IFN activity was measured using a reporter cell assay, and disease status was assessed using the Disease Activity Score in 28 joints (DAS28). Levels of interleukin‐1 receptor antagonist (IL‐1Ra) were determined in baseline plasma samples using a commercial enzyme‐linked immunosorbent assay. The clinical response was classified according to the European League Against Rheumatism criteria for improvement in RA.ResultsPlasma type I IFN activity at baseline was significantly associated with clinical response (odds ratio 1.36 [95% confidence interval 1.05–1.76], P = 0.020), with high baseline IFN activity associated with a good response. Changes in DAS28 scores were greater among patients with a baseline plasma IFNβ/α ratio >0.8 (indicating elevated plasma IFNβ levels). Consistent with the capacity of IFNβ to induce IL‐1Ra, elevated baseline IL‐1Ra levels were associated with better therapeutic outcomes (odds ratio 1.82 [95% confidence interval 1.1–3.29], P = 0.027).ConclusionThe plasma type I IFN activity, the IFNβ/α ratio, and the IL‐1Ra level were predictive of the therapeutic response in TNF antagonist–treated RA patients, indicating that these parameters might define clinically meaningful subgroups of RA patients with distinct responses to therapeutic agents.
Clinical features and outcomes in 348 patients with polyarteritis nodosa: A systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French vasculitis study group database
Authors: Pagnoux Christian , Seror Raphaèle , Henegar Corneliu , Mahr Alfred , Cohen Pascal , Le Guern Véronique , Bienvenu Boris , Mouthon Luc , Guillevin Loïc 
Published: January 2010

AbstractObjectivePrevious studies of polyarteritis nodosa (PAN) included patients with microscopic polyangiitis, because these entities were not distinguished prior to the Chapel Hill Consensus Conference (CHCC). This study was undertaken to describe the main characteristics of and long‐term outcomes in patients with well‐characterized PAN diagnoses.MethodsWe conducted a systematic retrospective study of 348 patients who were diagnosed as having PAN between March 1963 and October 2005, were registered in the French Vasculitis Study Group database, and satisfied the American College of Rheumatology and CHCC criteria. Patient characteristics and outcomes were analyzed and compared according to hepatitis B virus (HBV) status.ResultsAt diagnosis, the mean ± SD age was 51.2 ± 17.3 years. The most frequent findings were general symptoms (93.1%), neurologic manifestations (79%), skin involvement (49.7%), abdominal pain (35.6%), and hypertension (34.8%); 66.2% had renal artery microaneurysms; 70.1% had histologically proven PAN. Patients with HBV‐related PAN (n = 123) had more frequent peripheral neuropathy, abdominal pain, cardiomyopathy, orchitis, and hypertension compared with patients with non–HBV‐related PAN (n = 225). During a mean ± SD followup of 68.3 ± 63.5 months, 76 patients (21.8%) relapsed (63 with non–HBV‐related PAN [28%] versus 13 with HBV‐related PAN [10.6%];P< 0.001); 86 patients (24.7%) died (44 with non–HBV‐related PAN [19.6%] versus 42 with HBV‐related PAN [34.1%];P= 0.003). Five‐year relapse‐free survival rates were 59.4% (95% confidence interval [95% CI] 52.6–67.0) versus 67.0% (95% CI 58.5–76.8) for non–HBV‐related PAN and HBV‐related PAN, respectively. Multivariate analysis retained age >65 years, hypertension, and gastrointestinal manifestations requiring surgery or at least consultation with a surgeon as independent predictors of death, whereas patients with cutaneous manifestations or non–HBV‐related PAN had a higher risk of relapse.ConclusionOur findings indicate that the rate of mortality from PAN remains high, especially for the elderly, and relapses do occur, particularly in patients with non–HBV‐related PAN with cutaneous manifestations.
Treatment of polyarteritis nodosa and microscopic polyangiitis without poor‐prognosis factors: A prospective randomized study of one hundred twenty‐four patients
Authors: Ribi Camillo , Cohen Pascal , Pagnoux Christian , Mahr Alfred , Arène Jean‐Pierre , Puéchal Xavier , Carli Philippe , Kyndt Xavier , Le Hello Claire , Letellier Philippe , Cordier Jean‐François , Guillevin Loïc 
Published: January 2010

AbstractObjectiveTo assess the efficacy of systemic corticosteroids alone as first‐line treatment of polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA) without poor‐prognosis factors as defined by the Five‐Factors Score (FFS), and to compare the efficacy and safety of azathioprine versus pulse cyclophosphamide as adjunctive immunosuppressive therapy for patients experiencing treatment failure or relapse.MethodsThis prospective, multicenter, therapeutic trial included 124 patients with newly diagnosed PAN or MPA (FFS of 0) treated with corticosteroids alone. At the time of treatment failure or disease relapse, patients were randomized to receive 6 months of therapy with oral azathioprine or 6 pulses of cyclophosphamide. Analyses was performed according to an intent‐to‐treat strategy.ResultsThe mean ± SD followup period was 62 ± 33 months. Treatment with corticosteroids alone induced remission in 98 patients; 50 (40%) of these patients had sustained disease remission, 46 (37%) experienced a relapse, and 2 became corticosteroid dependent (daily prednisone dose ≥20 mg). In 26 patients (21%), treatment with corticosteroids alone failed, and 49 patients (40%) required additional immunosuppression. Among the 39 patients randomized, 13 of 19 achieved remission with cyclophosphamide pulses, and 14 of 20 achieved remission with azathioprine. Among all patients, the 1‐year and 5‐year survival rates were 99% and 92%, respectively. Six deaths occurred in the cyclophosphamide‐treated group compared with 2 deaths in the azathioprine‐treated group. Disease‐free survival was significantly lower for patients with MPA than for those with PAN (P = 0.046).ConclusionFor patients with PAN or MPA with an FFS of 0, overall 5‐year survival was good, but first‐line corticosteroid treatment was able to achieve and maintain remission in only about half of the patients, and 40% of the patients required additional immunosuppressive therapy. Azathioprine or pulse cyclophosphamide was fairly effective for treating corticosteroid‐resistant disease or major relapses.
A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic, cutaneous, articular syndrome/neonatal‐onset multisystem inflammatory disease: Novel evidence of the role of low‐level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases
Authors: Aróstegui Juan I. , Lopez Saldaña Ma Dolores , Pascal Mariona , Clemente Daniel , Aymerich Marta , Balaguer Francesc , Goel Ajay , Fournier del Castillo Concepción , Rius Josefa , Plaza Susana , López Robledillo Juan Carlos , Juan Manel , Ibañez Mercedes , Yagüe Jordi 
Published: January 2010

AbstractObjectiveChronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal‐onset multisystem inflammatory disease (NOMID), is a severe, early‐onset autoinflammatory disease characterized by an urticaria‐like rash, arthritis/arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin‐1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease‐causing mutations in only ∼55–60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID.MethodsClinical data, laboratory results, and information on treatment outcomes were gathered through direct interviews. Exhaustive genetic studies, including Sanger method sequencing, subcloning, restriction fragment length polymorphism assay, and pyrosequencing, were performed.ResultsThe patient's CINCA/NOMID was diagnosed based on clinical features (early onset of the disease, urticaria‐like rash, knee arthropathy, and dysmorphic features). The patient has exhibited a successful response to anakinra within the last 28 months. Analysis of NLRP3 identified a novel heterozygous variant (p.D303H) that was detected in ∼30–38% of circulating leukocytes. The absence of this variant in healthy controls and in the patient's parents suggested a de novo true disease‐causing mutation. Additional analyses showed that this novel mutation was present in both leukocyte subpopulations and epithelial cells.ConclusionOur findings identify the novel p.D303H NLRP3 variant in a Spanish patient with CINCA/NOMID as a new disease‐causing mutation, which was detected as a somatic, nongermline mutation in hematopoietic and nonhematopoietic cell lineages. Our data provide new insight into the role of low‐level mosaicism in NLRP3 as the pathophysiologic mechanism underlying cryopyrin‐associated periodic syndrome.
Transcriptional profiling and biochemical analysis of mechanically induced cartilaginous tissues in a rat model
Authors: Salisbury Palomares Kristy T. , Gerstenfeld Louis C. , Wigner Nathan A. , Lenburg Marc E. , Einhorn Thomas A. , Morgan Elise F. 
Published: January 2010

AbstractObjectiveTo characterize patterns of molecular expression that lead to cartilage formation in vivo in a postnatal setting, by profiling messenger RNA expression across the time course of mechanically induced chondrogenesis.MethodsRetired breeder Sprague‐Dawley rats underwent a noncritical‐sized transverse femoral osteotomy. Experimental animals (n = 45) were subjected to bending stimulation (60° cyclic motion in the sagittal plane for 15 minutes/day) of the osteotomy gap beginning on day 10 after the operation. Control animals (n = 32) experienced continuous rigid fixation. Messenger RNA isolated on days 10, 17, 24, and 38 after surgery was analyzed using a microarray containing 608 genes involved in skeletal development, tissue differentiation, fracture healing, and mechanotransduction. The glycosaminoglycan (GAG) content in the stimulated tissues was compared with that in native articular cartilage as a means of assessing the progression of chondrogenic development of the tissues.ResultsThe majority of the 100 genes that were differentially expressed were up‐regulated in response to mechanical stimulation. Many of these genes are associated with articular cartilage development and maintenance, diarthrodial joint development, cell adhesion, extracellular matrix synthesis, signal transduction, and skeletal development. Quantitative real‐time polymerase chain reaction results were consistent with the microarray findings. The GAG content of the stimulated tissues increased over time and was no different from that of articular cartilage on day 38 after surgery.ConclusionOur findings indicate that mechanical stimulation causes up‐regulation of genes that are principally involved in joint cavity morphogenesis and critical to articular cartilage function. Further study of this type of stimulation may identify key signaling events required for postnatal hyaline cartilage formation.
Human single‐chain variable fragment that specifically targets arthritic cartilage
Authors: Hughes Chris , Faurholm Bjarne , Dell'Accio Francesco , Manzo Antonio , Seed Michael , Eltawil Noha , Marrelli Alessandra , Gould David , Subang Christina , Al‐Kashi Adam , De Bari Cosimo , Winyard Paul , Chernajovsky Yuti , Nissim Ahuva 
Published: January 2010

AbstractObjectiveTo demonstrate that posttranslational modification of type II collagen (CII) by reactive oxygen species (ROS), which are known to be present in inflamed arthritic joints, can give rise to epitopes specific to damaged cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA) and to establish a proof of concept that antibodies specific to ROS‐modified CII can be used to target therapeutics specifically to inflamed arthritic joints.MethodsWe used a semisynthetic phage display human antibody library to raise single‐chain variable fragments (scFv) specific to ROS‐modified CII. The specificity of anti–ROS‐modified CII scFv to damaged arthritic cartilage was assessed in vitro by immunostaining articular cartilage from RA and OA patients and from normal controls. The in vivo targeting potential was tested using mice with antigen‐induced arthritis, in which localization of anti–ROS‐modified CII scFv in the joints was determined. The therapeutic effect of anti–ROS‐modified CII scFv fused to soluble murine tumor necrosis factor receptor II–Fc fusion protein (mTNFRII‐Fc) was also investigated.ResultsThe anti–ROS‐modified CII scFv bound to damaged arthritic cartilage from patients with RA and OA but not to normal preserved cartilage. When systemically administered to arthritic mice, the anti–ROS‐modified CII accumulated selectively at the inflamed joints. Importantly, when fused to mTNFRII‐Fc, it significantly reduced inflammation in arthritic mice, as compared with the effects of mTNFRII‐Fc alone or of mTNFRII‐Fc fused to an irrelevant scFv.ConclusionOur findings indicate that biologic therapeutics can be targeted specifically to arthritic joints and suggest a new approach for the development of novel treatments of arthritis.
Deletion of either CD55 or CD97 ameliorates arthritis in mouse models
Authors: Hoek Robert M. , de Launay Daphne , Kop Else N. , Yilmaz‐Elis A. Seda , Lin Feng , Reedquist Kris A. , Verbeek J. Sjef , Medof M. Edward , Tak Paul P. , Hamann Jörg 
Published: January 2010

AbstractObjectiveCD55 (decay‐accelerating factor) is best known for its role in the negative regulation of the complement system. Indeed, lack of this molecule leads to disease aggravation in many autoimmune disease models. However, CD55 is abundantly present on fibroblast‐like synoviocytes and is also a ligand of the adhesion‐class heptahelical receptor CD97, which is expressed by infiltrating macrophages. Treatment with antibodies to CD97 ameliorates the collagen‐induced model of rheumatoid arthritis (RA) in DBA/1 mice, but the net contribution of CD55 is unknown. This study was undertaken to investigate the role of CD55 in experimental RA.MethodsArthritis was induced in wild‐type, CD55−/−, and CD97−/− mice using collagen‐induced and K/BxN serum–transfer models. Incidence of arthritis was monitored over time, and disease activity was assessed by clinical and immunohistochemical evaluation.ResultsIn contrast to observations in many inflammatory disease models, lack of CD55 resulted in decreased arthritis in experimental models of RA. Consistent with the previously reported effects of anti‐CD97 antibody treatment, CD97−/− mice had reduced arthritis activity compared with wild‐type controls.ConclusionOur findings indicate that the lack of CD55 or CD97 in 2 different models of arthritis increases resistance to the disease. These findings provide insight into a role for CD55 interaction with CD97 in the pathogenesis of RA and suggest that therapeutic strategies that disrupt CD55/CD97 may be clinically beneficial.
Maps on the basis of the Arts & Humanities Citation Index: The journals Leonardo and Art Journal versus “digital humanities” as a topic
Authors: Leydesdorff Loet , Salah Alkim Almila Akdag 
Published: January 2010

AbstractThe possibilities of using the Arts & Humanities Citation Index (A&HCI) for journal mapping have not been sufficiently recognized because of the absence of a Journal Citations Report (JCR) for this database. A quasi‐JCR for the A&HCI (2008) was constructed from the data contained in the Web of Science and is used for the evaluation of two journals as examples: Leonardo and Art Journal. The maps on the basis of the aggregated journal–journal citations within this domain can be compared with maps including references to journals in the Science Citation Index and Social Science Citation Index. Art journals are cited by (social) science journals more than by other art journals, but these journals draw upon one another in terms of their own references. This cultural impact in terms of being cited is not found when documents with a topic such as “digital humanities” are analyzed. This community of practice functions more as an intellectual organizer than a journal.
Voltammetry in Room Temperature Ionic Liquids: Comparisons and Contrasts with Conventional Electrochemical Solvents.
Authors: Barrosse‐Antle L. E. , Bond A. M. , Compton R. G. , O'Mahony A. M. , Rogers E. I. , Silvester D. S. 
Published: January 2010

AbstractThe recent literature is surveyed to explore the nature of voltammetry in room temperature ionic liquids. The extent of similarities with conventional electrochemical solvents is reported and some surprising differences are noted.