bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression of carotid intima‐media thickness and plaque in women with systemic lupus erythematosus
Authors: Thompson Trina , Sutton‐Tyrrell Kim , Wildman Rachel P. , Kao Amy , Fitzgerald Shirley G. , Shook Betsy , Tracy Russell P. , Kuller Lewis H. , Brockwell Sarah , Manzi Susan 
Published: March 2008

AbstractObjectiveWomen with systemic lupus erythematosus (SLE) are at high risk of cardiovascular disease (CVD). The goals of this study were to determine the extent of atherosclerotic progression among women with SLE compared with a group of healthy controls and to determine whether factors attributed to SLE or its treatment were associated with atherosclerotic progression independent of traditional CVD risk factors.MethodsA longitudinal study of women with SLE from the Pittsburgh Lupus Registry was conducted. Women 18 years of age and older (n = 217) underwent carotid ultrasound at baseline and at followup, an average of 4.19 years later. Clinical, serologic, and SLE‐related factors, and disease treatment were evaluated. Outcomes were changes in carotid intima‐media thickness (IMT) and plaque. Progression of CVD in a sample of women without lupus was used for comparison.ResultsThe patients' mean ± SD age at baseline was 45.1 ± 10.3 years, and the mean ± SD IMT progression rate was 0.011 ± 0.03 mm per year. After controlling for traditional CVD risk factors, higher serum creatinine levels were associated with IMT progression (P = 0.0006). Plaque prevalence was 31% at baseline and 40% at followup; plaque progression occurred in 27% of the patients. Higher serum C3 levels and immunosuppressant use at baseline were related to plaque progression (P = 0.04 and P = 0.02, respectively) independent of traditional CVD risk factors. The plaque progression rate was higher than, and the IMT progression rate was similar to, those in the control group.ConclusionSLE patients have accelerated plaque progression compared with controls. SLE‐related risk factors are associated with the progression of IMT and plaque after controlling for traditional CVD risk factors. Carotid B‐mode ultrasound may serve as a surrogate end point in SLE intervention trials and clinically to track SLE management.
Matrix metalloproteinase 9 activity leads to elastin breakdown in an animal model of Kawasaki disease
Authors: Lau Andrew C. , Duong Trang T. , Ito Shinya , Yeung Rae S. M. 
Published: March 2008

AbstractObjectiveKawasaki disease (KD) is a multisystem vasculitis leading to damage in the coronary circulation and aneurysm formation. Because cardiac tissue from affected children is not available, investigation of the mechanisms responsible for coronary artery damage in KD requires use of a disease model. The present study was undertaken to examine, in an experimental model, the role of matrix metalloproteinase 9 (MMP‐9) on coronary artery inflammation and vascular damage.MethodsC57BL/6 mice were injected with Lactobacillus casei cell wall extract to induce coronary arteritis. Hearts were isolated and assayed for MMP‐9 protein expression and enzymatic activity by immunoblotting or confocal microscopy and zymography, respectively. MMP‐9–deficient mice were used to examine the necessity of MMP‐9 for disease development.ResultsLocalized inflammation at the coronary artery led to elastin breakdown and aneurysm formation. This occurred in the absence of smooth muscle cell apoptosis. Following disease induction, there was an increase in the amount and enzymatic activity of MMP‐9, an elastolytic protease. MMP‐9 was up‐regulated by tumor necrosis factor α (TNFα) and produced primarily by vascular smooth muscle cells. In MMP‐9–deficient animals, vascular inflammation continued to develop, but the incidence of elastin breakdown was significantly reduced. Elastin breakdown in the coronary artery was virtually eliminated by ablation of MMP‐9.ConclusionThese findings show that TNFα up‐regulates expression of MMP‐9, an important proteinase responsible for extracellular matrix breakdown, leading to coronary artery damage in this model of KD. These results have important implications regarding treatments for improving coronary outcome in affected children.
Anakinra improves sensory deafness in a Japanese patient with Muckle‐Wells syndrome, possibly by inhibiting the cryopyrin inflammasome
Authors: Yamazaki Takashi , Masumoto Junya , Agematsu Kazunaga , Sawai Nobukuni , Kobayashi Shinji , Shigemura Tomonari , Yasui Kozo , Koike Kenichi 
Published: March 2008

AbstractMuckle‐Wells syndrome (MWS) is a dominantly inherited autoinflammatory syndrome. Patients with MWS have a mutation in CIAS1, the gene encoding cryopyrin, a component of the inflammasome that regulates the processing of interleukin‐1β (IL‐1β). In this report we describe an 8‐year‐old Japanese girl with MWS who had symptoms of periodic fever, urticarial rash, conjunctivitis, arthropathy, and sensory deafness. Laboratory analysis of the patient's serum showed abnormally high concentrations of C‐reactive protein, serum amyloid A, and IL‐1β, and she had a heterozygous mutation in the CIAS1 gene, with C‐to‐T transversion at nucleotide position 778, encoding an arginine‐to‐tryptophan mutation at position 260 (R260W). Mononuclear cells (MNCs) isolated from the patient secreted large amounts of IL‐1β, without stimulation, and were highly sensitive to muramyldipeptide and lipopolysaccharide. After treatment with anakinra, laboratory results normalized, and clinical symptoms, including sensory deafness, disappeared, while MNCs appeared to remain activated. Thus, our case suggests that anakinra possibly affects the cryopyrin inflammasome and markedly improves the clinical and laboratory manifestations of MWS.
ADAM‐12 (meltrin α) is involved in chondrocyte proliferation via cleavage of insulin‐like growth factor binding protein 5 in osteoarthritic cartilage
Authors: Okada Aiko , Mochizuki Satsuki , Yatabe Taku , Kimura Tokuhiro , Shiomi Takayuki , Fujita Yoshinari , Matsumoto Hideo , Sehara‐Fujisawa Atsuko , Iwamoto Yukihide , Okada Yasunori 
Published: March 2008

AbstractObjectiveADAMs are a gene family of multifunctional proteins. We undertook this study to determine which ADAM species is up‐regulated in osteoarthritic (OA) cartilage and to examine its pathobiologic function.MethodsExpression of the 13 different metalloproteinase‐type ADAMs was screened by reverse transcription–polymerase chain reaction (PCR), and expression levels of prototype membrane‐anchored ADAM‐12 (ADAM‐12m) were determined by real‐time PCR. ADAM‐12m expression in articular cartilage was examined by in situ hybridization, immunohistochemistry, and immunoblotting. Chondrocytes were used for functional analyses of ADAM‐12m.ResultsADAM‐12m was selectively expressed in 87% of OA cartilage, and the expression level was significantly higher in OA cartilage than in normal cartilage. In situ hybridization showed that OA chondrocytes were responsible for the expression. ADAM‐12m was immunolocalized on the membranes of OA chondrocytes, and its immunoreactivity correlated directly with the Mankin score and with degrees of chondrocyte cloning and proliferation. Immunoblotting analysis of OA chondrocytes demonstrated an active form of ADAM‐12m. ADAM‐12m expression in OA chondrocytes was selectively enhanced by transforming growth factor β (TGFβ), which also induced chondrocyte proliferation and degradation of insulin‐like growth factor binding protein 5 (IGFBP‐5). TGFβ‐induced chondrocyte proliferation was inhibited by suppression of IGF‐1 signaling. In addition, TGFβ‐induced chondrocyte proliferation, chondrocyte cloning in agarose gel culture, and digestion of IGFBP‐5 were inhibited with ADAM inhibitor, anti–ADAM‐12 antibody, and small interfering RNA for ADAM‐12.ConclusionThese data suggest a novel function of ADAM‐12m in chondrocyte proliferation and cloning in OA cartilage through enhanced bioavailability of IGF‐1 from the IGF‐1–IGFBP‐5 complex by selective IGFBP‐5 digestion.
Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis
Authors: Guo Yongzhi , Li Jinan , Hagström Elin , Ny Tor 
Published: March 2008

AbstractObjectiveTo assess the functional roles of plasmin in a murine model of Staphylococcus aureus–induced bacterial arthritis.MethodsBacterial arthritis was induced in plasminogen‐deficient (Plg−/−) and wild‐type (Plg+/+) littermates by local injection of 1 × 106 colony‐forming units of S aureus into the knee joints. Human plasminogen was administered to Plg−/− mice on days 0–7 or days 7–14. Antibiotic treatment was administered to Plg−/− mice on days 7–14. Bacteria counts and histologic, immunohistochemical, and Western blot analyses were performed.ResultsIn Plg+/+ mice, S aureus counts had declined within 2 days, and by day 28 the bacteria had been completely eliminated. However, S aureus was still detectable in all injected joints from Plg−/− mice, and bacteria counts were 27 times higher than the amount injected on day 0. The extent of macrophage and neutrophil recruitment to the infected joints was comparable for Plg+/+ and Plg−/− mice on days 1, 7, and 14. The activation of these inflammatory cells appeared to be impaired in Plg−/− mice, however. Treatment of Plg−/− mice with antibiotic (cloxacillin) resulted in successful killing of the bacteria, but the necrotic tissue remained in the infected joints. When human plasminogen was given intravenously to Plg−/− mice daily for 7 days, bacterial clearance was greatly improved as compared with their untreated counterparts, and the amount of necrotic tissue in the joint cavity was dramatically reduced. The expression of interleukin 6 (IL‐6) and IL‐10 was higher in Plg+/+ mice than in Plg−/− mice during bacterial arthritis.ConclusionOur findings indicate that plasmin plays a pluripotent role in protecting against S aureus–induced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression.
Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon‐α–producing antigen‐presenting cells
Authors: Yan Bing , Ye Shuang , Chen Guangjie , Kuang Miao , Shen Nan , Chen Shunle 
Published: March 2008

AbstractObjectiveTo explore whether there are extrinsic factors that impair the suppressive function of CD4+,CD25+ regulatory T cells in patients with untreated active systemic lupus erythematosus (SLE).MethodsWe studied 15 patients with untreated active SLE, 10 patients with SLE in remission, and 15 healthy control subjects. Percentages of CD4+,CD25+,FoxP3+ Treg cells and levels of forkhead box P3 (FoxP3) protein were analyzed by flow cytometry. Expression of messenger RNA (mRNA) for FoxP3 in purified Treg cell populations was assessed by real‐time polymerase chain reaction analysis. Experiments examining Treg cell function in SLE were designed to distinguish primary from secondary T cell dysfunction. Levels of interferon‐α (IFNα) in supernatants from the function assays were determined with an IFN‐stimulated response element–luciferase reporter assay.ResultsThe percentage of CD4+,CD25+, FoxP3+ cells in peripheral blood was significantly increased in SLE patients as compared with controls (mean ± SEM 9.11 ± 0.73% versus 4.78 ± 0.43%; P < 0.0001). We found no difference in FoxP3 expression at either the mRNA or protein level in any CD4+,CD25+ T cell subset from SLE patients as compared with controls. Antigen‐presenting cells (APCs) from SLE patients were responsible for decreased Treg cell activity and could also render dysfunctional Treg cells from healthy control subjects. CD4+,CD25+ Treg cells from SLE patients exhibited normal suppressive activity when cultured with APCs from healthy controls. A partial Treg cell blockade effect was induced by the high levels of IFNα derived from SLE patient APCs.ConclusionWe suggest that blockade of Treg cell–mediated suppression by IFNα‐producing APCs in SLE patients may contribute to a pathogenic loss of peripheral tolerance in this disease.
Does tumor necrosis factor α inhibition promote or prevent heart failure in patients with rheumatoid arthritis?
Authors: Listing Joachim , Strangfeld Anja , Kekow Jörn , Schneider Matthias , Kapelle Andreas , Wassenberg Siegfried , Zink Angela 
Published: March 2008

AbstractObjectiveTo determine the hazard risk of developing or worsening heart failure in rheumatoid arthritis (RA) patients treated with tumor necrosis factor α (TNFα) inhibitors.MethodsRA patients ages 18–75 years who started treatment with infliximab, etanercept, or adalimumab (n = 2,757), or conventional disease‐modifying antirheumatic drugs (controls; n = 1,491) at the time of enrollment in a German biologics register were studied. Cox proportional hazards models were applied to investigate the influence of disease‐related and treatment‐specific risk factors on the incidence or worsening of heart failure.ResultsThe 3‐year incidence rates of heart failure in patients with and patients without cardiovascular disease at the start of treatment were 2.2% and 0.4%, respectively. After adjustment for traditional cardiovascular risk factors, an increased risk of developing heart failure was found in patients who had a higher 28‐joint Disease Activity Score at followup (hazard ratio [HR] 1.47 [95% confidence interval 1.07–2.02], P = 0.019). A residual nonsignificant risk related to treatment with TNFα inhibitors remained (adjusted HR 1.66 [95% confidence interval 0.67–4.1], P = 0.28). This residual risk was balanced by the efficacy of the anti‐TNF treatment. When only baseline characteristics were taken into account, the HR related to TNFα inhibitor treatment decreased to 0.70 (95% confidence interval 0.27–1.84).ConclusionThe findings of this study indicate that TNFα inhibitor treatment that effectively reduces the inflammatory activity of RA is more likely to be beneficial than harmful with regard to the risk of heart failure, especially if there is no concomitant therapy with glucocorticoids or cyclooxygenase 2 inhibitors. Furthermore, the data suggest that TNFα inhibition does not increase the risk of worsening of prevalent heart failure.
Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis–specific autoantibodies to citrullinated proteins complexed with fibrinogen
Authors: Clavel Cyril , Nogueira Leonor , Laurent Laetitia , Iobagiu Cristina , Vincent Christian , Sebbag Mireille , Serre Guy 
Published: March 2008

AbstractObjectiveMacrophage‐derived tumor necrosis factor α (TNFα) is a dominant mediator of synovitis in rheumatoid arthritis (RA). This study was undertaken to assess whether and how immune complexes (ICs) formed by the interaction of disease‐specific autoantibodies to citrullinated proteins (ACPAs) with their main synovial target antigen, citrullinated fibrin, contribute to TNFα production by macrophages.MethodsAn in vitro human model was developed in which monocyte‐derived macrophages were stimulated with ACPA‐containing ICs that were generated by capturing ACPAs from RA sera on immobilized citrullinated fibrinogen. Cellular activation was evaluated by TNFα assay in culture supernatants. Selective blockade of IC interactions with the 3 classes of Fcγ receptors (FcγR) was used to assess the contribution of each receptor to macrophage activation. In addition, 2 citrullinated fibrin–derived peptides bearing major ACPA epitopes were tested for their capacity to inhibit formation of macrophage‐activating ACPA‐containing ICs.ResultsACPA‐containing ICs induced a dose‐dependent TNFα secretion by macrophages from 14 of 20 healthy donors. The macrophage response was systematically higher than that of the paired monocyte precursors. TNFα secretion was not reduced by blockade of FcγRI or FcγRIII, but was strongly repressed when interaction of ICs with FcγRII was prevented. The 2 citrullinated peptides significantly inhibited ACPA reactivity to citrullinated fibrinogen and, when tested together, almost completely abolished formation of macrophage‐activating ICs, thereby diminishing the secreted TNFα levels.ConclusionOur model demonstrates the inflammatory potential of ACPA‐containing ICs via engagement of FcγRIIa at the surface of macrophages, strongly supporting their pathophysiologic involvement. Continuing dissection of these molecular pathways could open the way to new therapeutic approaches in patients with RA.
Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse
Authors: Ward Benjamin D. , Furman Bridgette D. , Huebner Janet L. , Kraus Virginia B. , Guilak Farshid , Olson Steven A. 
Published: March 2008

AbstractObjectivePosttraumatic arthritis is a frequent long‐term complication of intraarticular fractures. A model of a closed intraarticular fracture in C57BL/6 mice that progresses to posttraumatic arthritis has been developed. The MRL/MpJ mouse has shown unique regenerative abilities in response to injury. The objective of this study was to determine if the MRL/MpJ mouse is protected from posttraumatic arthritis after intraarticular fractures.MethodsIntraarticular fractures were created in MRL/MpJ mice and C57BL/6 control mice (n = 16 each). Limbs were analyzed for posttraumatic arthritis 4 and 8 weeks after fracture using microfocal computed tomography bone morphology, subchondral bone thickness evaluation, and histologic evaluation of cartilage degeneration. Serum cytokines and biomarkers were measured after the mice were killed.ResultsIntraarticular fractures were successfully created in all 32 mice. In the experimental fractured limbs, C57BL/6 mice had a decrease in bone density, increased subchondral bone thickness, and increased cartilage degeneration compared with normal contralateral control limbs. In the MRL/MpJ mice, no differences in bone density, subchondral bone thickness, or histologic grading of cartilage degeneration were seen between fractured and contralateral control limbs. Cytokine analysis showed lower systemic levels of the proinflammatory cytokine interleukin‐1α (IL‐1α) and higher levels of the antiinflammatory cytokines IL‐4 and IL‐10 in the MRL/MpJ mice.ConclusionThis study shows that the MRL/MpJ mouse is relatively protected from posttraumatic arthritis after intraarticular fracture. Further investigation into the mechanism involved in this response will hopefully provide new insight into the pathogenesis, prevention, and treatment of posttraumatic arthritis after intraarticular fracture.
Leishmanial lipid suppresses tumor necrosis factor α, interleukin‐1β, and nitric oxide production by adherent synovial fluid mononuclear cells in rheumatoid arthritis patients and induces apoptosis through the mitochondrial‐mediated pathway
Authors: Majumdar Kajal Nayan , Banerjee Aditi , Ratha Jagnyeswar , Mandal Mriganka , Sarkar Rathindra Nath , Saha Krishna Das 
Published: March 2008

AbstractObjectiveLeishmanial lipid is a strong immunosuppressor of host cells. Inhibition of the inflammatory responses of synovial cells through induction of apoptosis is one of the main targets of therapeutic intervention in rheumatoid arthritis (RA). This study was undertaken to examine the antiinflammatory and apoptosis‐inducing effects of leishmanial lipid on adherent synovial fluid mononuclear cells (SFMCs) in patients with RA.MethodsLipid was extracted from a Leishmania donovani promastigote (MHO/IN/1978/UR6) by the Bligh and Dyer method. Nitric oxide (NO) was measured using the Griess reaction, and enzyme‐linked immunosorbent assays for cytokines, NF‐κB, and cytochrome c were performed. Levels of cytokines, inducible nitric oxide synthase, caspases, Bcl‐2, Bax, t‐Bid, and cytochrome c in the cell lysate and of NF‐κB p65 in the nucleus were determined by Western blotting. Microscopic analysis, nuclear staining, DNA fragmentation assay, fluorescence‐activated cell sorting, colorimetric assay for caspases, and fluorescent probe for measurement of mitochondrial membrane potential were used to study the leishmanial lipid–induced apoptotic pathway in SFMCs.ResultsLeishmanial lipid inhibited the release of tumor necrosis factor α, interleukin‐1β, and NO in the culture, decreased their cytosolic protein levels, and decreased NF‐κB p65 levels in SFMCs, in a dose‐dependent manner. It had the reverse effect on interleukin‐10 levels. Leishmanial lipid–induced apoptosis involved the activation of caspase 3, caspase 9, and Bax, the release of cytochrome c, the alteration of mitochondrial membrane potential, and the down‐regulation of Bcl‐2.ConclusionThese results suggest that leishmanial lipid has strong antiinflammatory and apoptosis‐inducing effects on SFMCs from patients with RA, and that apoptosis occurs via the mitochondrial pathway.
Neuroimaging findings in children with rare or novel de novo chromosomal anomalies
Authors: Epstein Leon G. , Jalali Ali , Chary Ajit N. , Khan Sophia , Ross Joshua , Coppinger Justine , Carlson Katrin , Charrow Joel , Burton Barbara , Zimmerman Donald , Curran John , Kim Francine , Nguyen Pam , Burrowes Delilah , Angle Brad , Stack Cynthia , Shaffer Lisa , Kessler John A. , Bassuk Alexander G. 
Published: February 2008

AbstractBACKGROUND:De novo constitutional chromosomal anomalies provide important insights into the genetic loci responsible for congenital neurological disorders. However, most phenotypic descriptions of patients with rare chromosomal abnormalities are published as individual case reports or small group studies, making genotype‐phenotype correlations unclear. Moreover, many clinical genetic reports do not include neuroimaging.METHODS:We conducted a retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006. The case series was selected from a database containing all chromosomal testing results, clinical data, and neuroimaging. Clinical examination results were assigned by board certified geneticists and/or neurologists and neuroimages were reviewed by both a neurologist or neuroradiologist and a blinded neurologist.RESULTS:Of the 28,108 children in the series, we identified 34 children with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions.CONCLUSIONS:This study demonstrates the utility of large clinical databases in assessing genotype‐phenotype correlations and mapping loci for congenital neurological disorders. We describe a case‐series strategy to analyze existing databases to reveal new genotype‐phenotype correlations. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.