bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two single‐nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus
Authors: D'Alfonso S. , Barizzone N. , Giordano M. , Chiocchetti A. , Magnani C. , Castelli L. , Indelicato M. , Giacopelli F. , Marchini M. , Scorza R. , Danieli M. G. , Cappelli M. , Migliaresi S. , Bigliardo B. , Sabbadini M. G. , Baldissera E. , Galeazzi M. , Sebastiani G. D. , Minisola G. , Ravazzolo R. , Dianzani U. , Momigliano‐Richiardi P. 
Published: February 2005

AbstractObjectiveTo test the association of osteopontin (OPN) polymorphisms with systemic lupus erythematosus (SLE).MethodsThe coding 5′ and 3′ flanking regions of the OPN gene were scanned for polymorphisms by denaturing high‐performance liquid chromatography. A case–control association study was performed in 394 Italian SLE patients and 479 matched controls. OPN serum levels were determined by enzyme‐linked immunosorbent assay in 40 patients and 124 controls, and the mean levels were compared between the different OPN genotypes.ResultsAmong the 13 detected single‐nucleotide polymorphisms (SNPs), alleles −156G (frequency 0.714 versus 0.651; P = 0.006, corrected P [Pcorr] = 0.036) and +1239C (0.377 versus 0.297; P = 0.00094, Pcorr = 0.0056) were significantly increased in the SLE patients compared with the controls. The presence of the associated allele in single or double dose conferred an odds ratio (OR) of 2.35 (95% confidence interval [95% CI] 1.38–4.02) for SNP −156 and an OR of 1.57 (95% CI 1.16–2.13) for SNP +1239. These effects were independent of each other, i.e., not a consequence of linkage disequilibrium between the 2 alleles. The risk associated with a double dose of susceptibility alleles at both SNPs was 3.8‐fold higher (95% CI 2.0–7.4) relative to the complete absence of susceptibility alleles. With regard to individual clinical and immunologic features, a significant association was seen between lymphadenopathy and −156 genotypes (overall P = 0.0011, Pcorr = 0.046). A significantly increased OPN serum level was detected in healthy individuals carrying +1239C (P = 0.002), which is indicative of an association between the SLE susceptibility allele and OPN levels.ConclusionThese data suggest the independent effect of a promoter (−156) and a 3′‐untranslated region (+1239) SNP in SLE susceptibility. We can speculate that these sequence variants (or others in perfect linkage disequilibrium) create a predisposition to high production of OPN, and that this in turn may confer susceptibility to SLE.
Oral treatment with PD‐0200347, an α2δ ligand, reduces the development of experimental osteoarthritis by inhibiting metalloproteinases and inducible nitric oxide synthase gene expression and synthesis in cartilage chondrocytes
Authors: Boileau Christelle , Martel‐Pelletier Johanne , Brunet Julie , Tardif Ginette , Schrier Denis , Flory Craig , El‐Kattan Ayman , Boily Martin , Pelletier Jean‐Pierre 
Published: February 2005

AbstractObjectiveTo examine the in vivo effects of PD‐0200347, an α2δ ligand of voltage‐activated Ca2+ channels and a compound chemically related to pregabalin and gabapentin, on the development of cartilage structural changes in an experimental dog model of osteoarthritis (OA). The effects of PD‐0200347 on the major pathways involved in OA cartilage degradation, including matrix metalloproteinases (MMPs) and the inducible form of nitric oxide synthase (iNOS), were also studied.MethodsOA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were randomly distributed into 3 groups and treated orally with either 1) placebo, 2) 15 mg/kg/day of PD‐0200347, or 3) 90 mg/kg/day of PD‐0200347. Dogs were killed 12 weeks after surgery. The severity of the lesions was scored macroscopically and histologically. Cartilage specimens from the femoral condyles and tibial plateaus were processed for RNA extraction and quantitative reverse transcription–polymerase chain reaction (RT‐PCR) or immunohistochemistry. Specific probes and antibodies were used to study the messenger RNA and protein levels of iNOS, MMP‐1, MMP‐3, and MMP‐13.ResultsNo clinical signs of drug toxicity were noted in the treated animals. Treatment with PD‐0200347 at both dosages tested (15 and 90 mg/kg/day) reduced the development of cartilage lesions. There was a reduction in the score of lesions, with a statistically significant (P = 0.01) difference when the highest dosage of the drug was administered. The reduction in the score was mainly related to a decrease in the surface size of the lesions. Quantitative RT‐PCR showed that PD‐0200347 significantly reduced the expression of MMP‐13, a key mediator in OA. Immunohistochemical analyses showed that treatment with PD‐0200347 significantly reduced the synthesis of all key OA mediators studied.ConclusionThis study demonstrated the efficacy of PD‐0200347 in reducing the progression of cartilage structural changes in a dog model of OA. It also showed that this effect is linked to the inhibition of the major pathophysiologic mediators responsible for cartilage degradation.
Fibroblast‐like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity: Evidence of a link between an increased myofibroblast‐like phenotype and high‐inflammation synovitis
Authors: Kasperkovitz Pia V. , Timmer Trieneke C. G. , Smeets Tom J. , Verbeet Nicolette L. , Tak Paul P. , van baarsen Lisa G. M. , Baltus Belinda , Huizinga Tom W. J. , Pieterman Elsbet , Fero Mike , Firestein Gary S. , van der Pouw Kraan Tineke C. T. M. , Verweij Cornelis L. 
Published: February 2005

AbstractObjectiveGiven the heterogeneity of gene expression patterns and cellular distribution between rheumatoid arthritis (RA) synovial tissues, we sought to determine whether this variability was also reflected at the level of the fibroblast‐like synoviocyte (FLS) cultured from RA synovial tissues.MethodsGene expression profiles in FLS cultured from synovial tissues obtained from 19 RA patients were analyzed using complementary DNA microarrays and hierarchical cluster analysis. To validate the subclassification, we performed prediction analysis and principal components analysis. Genes that differed significantly in their expression between FLS cultures were selected using Statistical Analysis of Microarrays software. Real‐time quantitative polymerase chain reaction was performed to validate the microarray data. Immunocytochemistry was applied to study the expression of the genes of interest in FLS and synovial tissues.ResultsHierarchical clustering identified 2 main groups of FLS characterized by distinctive gene expression profiles. FLS from high‐inflammation synovial tissues revealed increased expression of a transforming growth factor β/activin A–inducible gene profile that is characteristic of myofibroblasts, a cell type considered to be involved in wound healing, whereas increased production of growth factor (insulin‐like growth factor 2/insulin‐like growth factor binding protein 5) appeared to constitute a characteristic feature of FLS derived from low‐inflammation synovial tissues. The molecular feature that defines the myofibroblast‐like phenotype was reflected as an increased proportion of myofibroblast‐like cells in the heterogeneous FLS population. Myofibroblast‐like cells were also found upon immunohistochemical analysis of synovial tissue.ConclusionOur findings support the notion that heterogeneity between synovial tissues is reflected in FLS as a stable trait, and provide evidence of a possible link between the behavior of FLS and the inflammation status of RA synovium.
Rituximab in the treatment of dermatomyositis: An open‐label pilot study
Authors: Levine Todd D. 
Published: February 2005

AbstractObjectiveTo test the hypothesis that B cells play a role in the pathophysiology of dermatomyositis (DM) by examining the effect of B cell depletion in patients with symptomatic DM. Patients were treated with rituximab, a CD20+ B cell–depleting monoclonal antibody.MethodsThis was an open‐label uncontrolled pilot trial in 7 adult patients with DM, 6 of whom had longstanding illness that was responding inadequately to a number of currently available immunosuppressive agents. All patients received 4 intravenous infusions of rituximab given at weekly intervals. Patients were followed up for up to 1 year without further treatment with rituximab. One patient was lost to followup. The principal efficacy outcome was muscle strength, measured by quantitative dynomometry.ResultsAll 6 evaluable patients exhibited major clinical improvement, with muscle strength increasing over baseline by 36–113%. Maximal improvements in muscle strength occurred as early as 12 weeks after the initial infusion of rituximab. CD20+ B cells were effectively depleted in all patients by 12 weeks. Four patients experienced a return of symptoms that coincided with the return of B cells before the 52‐week end point. Two patients maintained their increased muscle strength at 52 weeks, and 1 of these patients maintained this strength even after the return of B cells. Other symptoms of DM, including rash, alopecia, and reduced forced vital capacity, improved markedly in patients with these symptoms. Rituximab was well tolerated, with no treatment‐related severe or serious adverse events during the observation period of this study.ConclusionThis small open‐label study of DM patients treated with rituximab provided sufficiently encouraging results to justify a more formal evaluation of the value of B cell depletion therapy in the treatment of DM.
Inhibition of the development of collagen‐induced arthritis in rhesus monkeys by a small molecular weight antagonist of CCR5
Authors: Vierboom Michel P. M. , Zavodny Paul J. , Chou Chuan‐Chu , Tagat Jayaram R. , Pugliese‐Sivo Catherine , Strizki Julie , Steensma Ruo W. , McCombie Stuart W. , Çelebi‐Paul Liesbeth , Remarque Ed , Jonker Margreet , Narula Satwant K. , Hart Bert't 
Published: February 2005

AbstractObjectiveCollagen‐induced arthritis (CIA) in the rhesus monkey is a nonhuman primate model of rheumatoid arthritis (RA). The close phylogenetic relationship between humans and the rhesus monkey makes this model useful for the preclinical safety and efficacy testing of new therapies that are inactive in animals more distinctly related to humans. In this study, we tested the therapeutic potential of a novel, small molecular weight antagonist of CCR5, SCH‐X, in this model.MethodsCIA was induced in 10 rhesus monkeys. The animals were allocated to receive SCH‐X or saline as the control (n = 5 in each group). Treatment was initiated on the day of CIA induction and continued for 45 days. Monkeys were monitored before and 63 days after CIA induction for macroscopic signs of clinical arthritis, such as soft‐tissue swelling and body weight. Furthermore, markers of inflammation and joint degradation were monitored to follow the disease course.ResultsOnly 2 of 5 animals in the SCH‐X–treated group displayed prominent soft‐tissue swelling, compared with all 5 saline‐treated monkeys. In addition to the suppression of joint inflammation, treatment with SCH‐X resulted in a reduction in joint destruction, as demonstrated by lower rates of urinary excretion of collagen crosslinks, with confirmation by histology. Whereas in all saline‐treated monkeys, marked erosion of joint cartilage was observed, this was absent in 4 of the 5 SCH‐X–treated monkeys.ConclusionThe systemic effects of treatment with SCH‐X were a suppressed acute‐phase reaction (reduction in C‐reactive protein level) in the 3 treated monkeys with CIA that remained asymptomatic, and an altered antibody response toward type II collagen. The results suggest that the CCR5 antagonist SCH‐X might have a strong clinical potential for treatment during periods of active inflammation, as seen in RA.
The intracellular 52‐kd Ro/SSA autoantigen in keratinocytes is up‐regulated by tumor necrosis factor α via tumor necrosis factor receptor I
Authors: Gerl Velia , Hostmann Björn , Johnen Christa , Waka Aderajew , Gerl Markus , Schumann Frank , Klein Rolf , Radbruch Andreas , Hiepe Falk 
Published: February 2005

AbstractObjectivePrevious studies have shown that the nuclear Ro/SSA autoantigens involved in photosensitive cutaneous lupus manifestations are regulated by ultraviolet B (UVB) irradiation. UVB exposure triggers the release of tumor necrosis factor α (TNFα) from keratinocytes in the epidermis and from mast cells in the dermis. The present study aimed to characterize the effect of TNFα on messenger RNA (mRNA) and protein expression of the intracellular 52‐kd Ro/SSA autoantigen in primary human keratinocytes and to elucidate the TNFα receptor (TNFR) signaling pathways mediating this effect.MethodsExpression of 52‐kd Ro/SSA mRNA in primary human keratinocytes was investigated by quantitative real‐time polymerase chain reaction (LightCycler system) using GAPDH as the housekeeping gene. Expression of 52‐kd Ro/SSA protein was studied by flow cytometry after staining intracellular protein with IgG purified from an anti–52‐kd Ro/SSA–positive serum. TNFR function was assessed by culturing cells in the presence and absence of neutralizing antibodies directed against the TNFR subunits TNFRI and TNFRII.ResultsTNFα‐induced up‐regulation of 52‐kd Ro/SSA mRNA expression peaked at 4 hours, followed by up‐regulation of intracellular 52‐kd Ro/SSA protein expression at 24 hours, independently of apoptosis. Between different donors, a high variability of both constitutive expression levels and TNFα‐induced changes in 52‐kd Ro/SSA mRNA and protein expression was observed. The up‐regulatory effect of TNFα on 52‐kd Ro/SSA mRNA and protein expression was inhibited by anti‐TNFRI antibodies but enhanced by anti‐TNFRII antibodies.ConclusionThe finding that TNFα up‐regulates 52‐kd Ro/SSA expression in keratinocytes via TNFRI suggests that it may play a role in the pathogenesis of anti‐Ro/SSA–associated cutaneous lupus erythematosus.
Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population‐based cohort study
Authors: Maradit‐Kremers Hilal , Crowson Cynthia S. , Nicola Paulo J. , Ballman Karla V. , Roger Véronique L. , Jacobsen Steve J. , Gabriel Sherine E. 
Published: February 2005

AbstractObjectiveTo examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age‐ and sex‐matched non‐RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors.MethodsWe assembled a population‐based incidence cohort of 603 Rochester, Minnesota residents ages ≥18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age‐ and sex‐matched non‐RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors.ResultsDuring the 2‐year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16–8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29–26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34–0.99) compared with non‐RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13–4.03) and sudden deaths (HR 1.94, 95% CI 1.06–3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16–0.80) compared with non‐RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates.ConclusionPatients with RA have a significantly higher risk of CHD when compared with non‐RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria–based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.
The risk of congestive heart failure in rheumatoid arthritis: A population‐based study over 46 years
Authors: Nicola Paulo J. , Maradit‐Kremers Hilal , Roger Véronique L. , Jacobsen Steven J. , Crowson Cynthia S. , Ballman Karla V. , Gabriel Sherine E. 
Published: February 2005

AbstractObjectiveIt is hypothesized that the systemic inflammation associated with rheumatoid arthritis (RA) promotes an increased risk of cardiovascular (CV) morbidity and mortality. We examined the risk and determinants of congestive heart failure (CHF) in patients with RA.MethodsWe assembled a population‐based, retrospective incidence cohort from among all individuals living in Rochester, Minnesota, in whom RA (defined according to the American College of Rheumatology 1987 criteria) was first diagnosed between 1955 and 1995, and an age‐ and sex‐matched non‐RA cohort. After excluding patients in whom CHF occurred before the RA index date, all subjects were followed up until either death, incident CHF (defined according to the Framingham Heart Study criteria), migration from the county, or until January 1, 2001. Detailed information from the complete medical records (including all inpatient and outpatient care provided by all local providers) regarding RA, ischemic heart disease, and traditional CV risk factors was collected. Cox models were used to estimate the effect of RA on the development of CHF, adjusting for CV risk factors and/or ischemic heart disease.ResultsThe study population included 575 patients with RA and 583 subjects without RA. The CHF incidence rates were 1.99 and 1.16 cases per 100 person‐years in patients with RA and in non‐RA subjects, respectively (rate ratio 1.7, 95% confidence interval [95% CI] 1.3–2.1). After 30 years of followup, the cumulative incidence of CHF was 34.0% in patients with RA and 25.2% in non‐RA subjects (P< 0.001). RA conferred a significant excess risk of CHF (hazard ratio [HR] 1.87, 95% CI 1.47–2.39) after adjusting for demographics, ischemic heart disease, and CV risk factors. The risk was higher among patients with RA who were rheumatoid factor (RF) positive (HR 2.59, 95% CI 1.95–3.43) than among those who were RF negative (HR 1.28, 95% CI 0.93–1.78).ConclusionCompared with persons without RA, patients with RA have twice the risk of developing CHF. This excess risk is not explained by traditional CV risk factors and/or clinical ischemic heart disease.
Antisense inhibition of osteogenic protein 1 disturbs human articular cartilage integrity
Authors: Söder Stephan , Hakimiyan Arnavaz , Rueger David C. , Kuettner Klaus E. , Aigner Thomas , Chubinskaya Susan 
Published: February 2005

AbstractObjectiveTo delineate the role of endogenous osteogenic protein 1 (OP‐1) in human articular cartilage homeostasis via the inhibition of OP‐1 gene expression by antisense oligonucleotides.MethodsHuman adult normal articular cartilage was obtained from the knee and ankle joints of 34 organ donors. Chondrocytes were cultured as tissue explants or isolated cells in alginate or high‐density monolayers for 48 hours in the presence of OP‐1 antisense or sense oligonucleotides. The effect of OP‐1 antisense inhibition was evaluated by reverse transcription–polymerase chain reaction, 35S incorporation, dimethylmethylene blue assay, histology with Safranin O staining, and immunohistochemistry with anti–proOP‐1, anti–mature OP‐1, and anti‐aggrecan antibodies.ResultsAntisense treatment inhibited OP‐1 gene expression by a mean ± SD of 34 ± 12% (P < 0.01) in chondrocytes cultured in monolayers and by 77 ± 27% (P < 0.03) in alginate beads. The inhibition of autocrine OP‐1 caused a striking decrease in aggrecan gene expression, in total proteoglycan content accumulated in cartilage matrix, and in the ability of chondrocytes to newly synthesize proteoglycans. OP‐1 antisense reduced aggrecan messenger RNA expression by 42 ± 17% (P < 0.05) and proteoglycan synthesis by 48 ± 23% (P < 0.01). Histology and immunohistochemistry revealed a dramatic decrease in Safranin O staining and reduced anti‐aggrecan staining (primarily in the superficial and middle cartilage layers) with OP‐1 antisense treatment.ConclusionOur results suggest that OP‐1 is an important endogenous cartilage factor that regulates matrix integrity and possibly needs to be induced or up‐regulated to maintain normal cartilage homeostasis. These findings confirm our hypothesis that a lack of autocrine OP‐1 may lead to an elevated susceptibility of chondrocytes to the catabolic processes, thus contributing/promoting cartilage degeneration.
Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down‐regulation of the T cell costimulatory molecule CD40 ligand: An open‐label trial
Authors: Sfikakis P. P. , Boletis J. N. , Lionaki S. , Vigklis V. , Fragiadaki K. G. , Iniotaki A. , Moutsopoulos H. M. 
Published: February 2005

AbstractObjectiveAutoreactive B cells play a key role in tissue injury in systemic autoimmune disease, and therefore a treatment resulting in B cell depletion could have benefit. This open‐label study was undertaken to evaluate the efficacy of the anti‐CD20 monoclonal antibody rituximab in the treatment of lupus nephritis.MethodsLupus patients with active proliferative nephritis (4 with focal disease and 6 with diffuse disease) received rituximab (4 weekly infusions of 375 mg/m2) combined with oral prednisolone. Clinical, laboratory, and immunologic responses, including peripheral lymphocyte subsets measured by flow cytometry, were prospectively assessed at monthly intervals for 12 months. Complete remission of nephritis was defined as normal serum creatinine and albumin levels, inactive urine sediment, and 24‐hour urinary protein <500 mg. Partial remission was defined as >50% improvement in all renal parameters that were abnormal at baseline.ResultsB cell depletion lasted from 1 month to 7 months and was well tolerated. Partial remission was achieved in 8 of 10 patients within a median of 2 months (range 1–4 months); in 5 of them, complete remission was subsequently established (at a median of 3 months from baseline), and it was sustained at 12 months in 4. As early as 1 month from baseline, the expression of the costimulatory molecule CD40 ligand on CD4+ T cells was decreased by 4‐fold, and it was almost blocked when partial remission was clinically evident. The expression of T cell activation markers CD69 and HLA–DR was significantly decreased at time points when partial remission was observed, and was further decreased during complete remission. In contrast, in patients who did not exhibit a response or when relapse was detected in patients in whom an initial remission had been achieved, such decreases were not prominent. Serum concentrations of double‐stranded DNA autoantibodies were decreased in all patients, regardless of clinical outcome.ConclusionFollowing B cell depletion, clinical remission of lupus nephritis is associated with a decrease in T helper cell activation, suggesting an additional role for B cells, independent of autoantibody production, in promoting disease. A controlled trial to confirm these promising clinical results is warranted.