bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis
Authors: Steinman Lawrence , Zamvil Scott S. 
Published: June 2006

AbstractIn their Point of View entitled “Experimental Allergic Encephalomyelitis: A Misleading Model of Multiple Sclerosis,” Sriram and Steiner1 wrote, “The most disappointing aspect of EAE [experimental allergic encephalomyelitis] as a potential model for MS is its almost total inability to point toward a meaningful therapy or therapeutic approach for MS.” Actually, EAE has led directly to the development of three therapies approved for use in multiple sclerosis (MS): glatiramer acetate, mitoxantrone, and natalizumab. Several new approaches to MS are in clinical trials based on positive indications in preclinical work relying on EAE. New clues to the pathogenesis of MS and new potential surrogate markers for MS are shown from research involving EAE when it is critically coupled with actual findings in MS. There are pitfalls in overreliance on the EAE model, or on any animal model for any human disease. Nevertheless, over the past 73 years, the EAE model has proved itself remarkably useful for aiding research on MS. Ann Neurol 2006;60:12–21
Thermodynamic and spectroscopic study of the binding of dimethyltin(IV) by citrate at 25 °C
Authors: Cardiano Paola , Giuffrè Ottavia , Pellerito Lorenzo , Pettignano Alberto , Sammartano Silvio , Scopelliti Michelangelo 
Published: June 2006

AbstractThermodynamic (potentiometric and calorimetric) and spectroscopic (1H NMR, 119Sn Mössbauer) studies were performed in aqueous solution in order to characterize the interaction of dimethyltin(IV) cation with citrate ligand. Six species {(CH3)2Sn(cit)−; [(CH3)2Sn]2(cit)22−; (CH3)2Sn(cit)H0; (CH3)2Sn(cit)OH2−; [(CH3)2Sn]2(cit)OH0; [(CH3)2Sn]2(cit)(OH)2−} were found. All the species formed in this system are quite stable and formation percentages are fairly high. For example, at pH = 7.5 and C = Ccit = 10 mmol l−1, Σ% for [(CH3)2Sn]2(cit)(OH)2− and (CH3)2Sn(cit)OH2− species reaches 65%. Overall thermodynamic parameters obtained show that the main contribution to stability is entropic in nature. Thermodynamic parameters were discussed in comparison with a simple tricarboxylate ligand (1,2,3‐propanetricarboxylate). Two empirical relationships were derived from thermodynamic formation parameters. Spectroscopic results fully confirm the speciation model defined potentiometrically and show the mononuclear species to have an eq‐(CH3)2Tbp structure with different arrangements around the metal, while for [(CH3)2Sn]2(cit)(OH)2− there are two different Sn(IV) environments, namely trans‐(CH3)2 octahedral and cis‐(CH3)2 Tbp. Copyright © 2005 John Wiley & Sons, Ltd.
Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized, double‐blind, placebo‐controlled trial
Authors: van der Heijde Désirée , Kivitz Alan , Schiff Michael H. , Sieper Joachim , Dijkmans Ben A. C. , Braun Jürgen , Dougados Maxime , Reveille John D. , Wong Robert L. , Kupper Hartmut , Davis John C. 
Published: June 2006

AbstractObjectiveTo evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS).MethodsThis was a multicenter, randomized (2:1 ratio), double‐blind, placebo‐controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission.ResultsAt week 12, 58.2% of adalimumab‐treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo‐treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab‐treated patients than placebo‐treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab‐treated patients reported more adverse events (75.0% versus 59.8% of placebo‐treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity.ConclusionAdalimumab was well‐tolerated during the 24‐week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.
Overexpression of synoviolin in peripheral blood and synoviocytes from rheumatoid arthritis patients and continued elevation in nonresponders to infliximab treatment
Authors: Toh Myew‐Ling , Marotte Hubert , Blond Jean‐Luc , Jhumka Umar , Eljaafari Assia , Mougin Bruno , Miossec Pierre 
Published: June 2006

AbstractObjectiveSynoviolin is a novel E3 ubiquitin ligase that has been implicated in the pathogenesis of rheumatoid arthritis (RA). The purpose of this study was to examine the expression and regulation of synoviolin by tumor necrosis factor α (TNFα), both in vivo and in vitro.MethodsA total of 54 RA patients and 23 healthy control subjects were analyzed before, 4 hours after the first infusion, and at week 22 of infliximab treatment. Clinical response was assessed by the American College of Rheumatology criteria for 20% improvement and the Disease Activity Score in 28 joints (DAS28) at 6 months. Synoviolin messenger RNA expression was measured by real‐time reverse transcription–polymerase chain reaction in peripheral blood (PB) and fibroblast‐like synoviocytes (FLS) and with and without TNFα or interleukin‐1β (IL‐1β) stimulation.ResultsSynoviolin expression was increased in whole PB obtained from RA patients as compared with that from healthy controls and was significantly reduced early and late after infliximab treatment in responders, but in not nonresponders. Reduction in synoviolin expression was associated with reduced levels of markers of disease activity, including C‐reactive protein levels. Nonresponders to infliximab therapy had significantly higher synoviolin expression at baseline as compared with responders, and this elevation persisted despite infliximab therapy. PB CD14+ monocytes expressed increased synoviolin levels compared with CD3+ lymphocytes, and TNFα or IL‐1β induced a further increase in expression in CD3+ cells. TNFα or IL‐1β induced sustained synoviolin expression in RA FLS.ConclusionElevated PB levels of synoviolin were identified in circulating PB mononuclear cells and were associated with nonresponse to infliximab treatment. Sustained up‐regulation of synoviolin by IL‐1β and TNFα may contribute to prolonged survival of immune cells and dysregulated FLS proliferation, leading to RA chronicity.
Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein–dependent and –independent pathways by cyclin‐dependent kinase 4/6
Authors: Nonomura Yoshinori , Nagasaka Kenji , Hagiyama Hiroyuki , Sekine Chiyoko , Nanki Toshihiro , Tamamori‐Adachi Mimi , Miyasaka Nobuyuki , Kohsaka Hitoshi 
Published: June 2006

AbstractObjectiveIt is known that the cyclin‐dependent kinase inhibitor (CDKI) gene p21Cip1 suppresses rheumatoid inflammation by down‐modulating type I interleukin‐1 receptor (IL‐1RI) expression and inhibiting JNK activity. The purpose of this study was to determine whether CDK activity directly modulates the production of inflammatory molecules in patients with rheumatoid arthritis (RA).MethodsGenes for the CDKIs p16INK4a and p18INK4c, a constitutively active form of retinoblastoma (RB) gene product, cyclin D1, and CDK‐4, were transferred into RA synovial fibroblasts (RASFs). RASFs were also treated with a synthetic CDK‐4/6 inhibitor (CDK4I). Levels of matrix metalloproteinase 3 (MMP‐3), monocyte chemoattractant protein 1 (MCP‐1), and IL‐1RI expression were determined by Northern blotting, real‐time polymerase chain reaction analysis, and enzyme‐linked immunosorbent assay. CDKIs were immunoprecipitated to reveal their association with JNK.ResultsTransfer of the p16INK4a and p18INK4c genes and CDK4I suppressed the production of MMP‐3 and MCP‐1. Unlike p21Cip1, neither CDKI gene inhibited IL‐1RI or JNK. The expression of MMP‐3 was up‐regulated when CDK‐4 activity was augmented. This regulation functioned at the messenger RNA (mRNA) level in MMP‐3, but not in MCP‐1. Transfer of active RB suppressed the production of MMP‐3 and MCP‐1 without changing their mRNA levels.ConclusionCDK‐4/6 modulated the production of MMP‐3 and MCP‐1. MMP‐3 production was regulated primarily at the mRNA level in an RB‐independent manner, whereas MCP‐1 production was controlled posttranscriptionally by RB. These results show that cell cycle proteins are associated with control of mediators of inflammation through multiple pathways.
Association between serum total cholesterol level and renal outcome in systemic lupus erythematosus
Authors: Tisseverasinghe Annaliese , Lim Sooyeol , Greenwood Celia , Urowitz Murray , Gladman Dafna , Fortin Paul R. 
Published: June 2006

AbstractObjectiveTo determine whether an elevated serum total cholesterol level in a first‐available sample obtained at a systemic lupus erythematosus (SLE) clinic is associated with worse renal outcome in patients with SLE.MethodsSurvival analysis methods were used on prospectively gathered data on 1,060 patients with SLE who were registered in the University of Toronto Lupus Databank. The effect of total cholesterol and 15 additional variables on the outcomes of renal deterioration, end‐stage renal disease (ESRD), and death was assessed using Cox proportional hazards methods.ResultsIn 474 (45%) of the 1,060 patients, the total cholesterol level exceeded 5.2 mmoles/liter. In the entire study group, the median total cholesterol level was 5.1 mmoles/liter (range 1.6–17.1). During a mean followup period of 8.8 years, 93 patients (9%) experienced renal deterioration, 42 patients (4%) had ESRD, and 161 deaths occurred, 48 (30%) of which were associated with renal dysfunction (renal death), and 113 (70%) of which were not associated with renal dysfunction (nonrenal death). Kaplan‐Meier survival estimates for each outcome were statistically significantly different between patients with normal versus those with elevated total cholesterol levels (cutoff 5.2 mmoles/liter), with a worse outcome observed among those with an elevated total cholesterol concentration. In multivariate analyses, total cholesterol level (hazard ratio [HR] 1.17, 95 confidence interval [95% CI] 1.01–1.36), serum creatinine level (HR 1.06, 95% CI 1.04–1.07), proteinuria (HR 2.44, 95% CI 1.25–4.76), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (HR 1.44, 95% CI 1.16–1.80), and corticosteroid dose (HR 1.01, 95% CI 1.00–1.02) were associated with renal deterioration. Significant predictors of ESRD were baseline proteinuria (HR 6.24, 95% CI 1.96–19.88) and serum creatinine level (HR 1.15, 95% CI 1.08–1.22). The total cholesterol level was correlated with death (HR 1.20, 95% CI 1.11–1.29), retaining statistical significance for renal death (HR 1.33, 95% CI 1.20–1.47) but not for nonrenal death (HR 1.12, 95% CI 0.99–1.25).ConclusionThose results indicate that an elevated serum total cholesterol level in a first‐available sample obtained at an SLE clinic is associated with adverse renal outcomes and mortality.
The heritable determinants of cartilage oligomeric matrix protein
Authors: Williams Frances M. K. , Andrew Toby , Saxne Tore , Heinegard Dick , Spector Tim D. , MacGregor Alex J. 
Published: June 2006

AbstractObjectiveCartilage oligomeric matrix protein (COMP) is a cartilage matrix macromolecule. The protein is detectable in serum and has been investigated as a biomarker of osteoarthritis (OA). An association between COMP and OA has been shown, yet the precise factors governing serum levels of COMP remain unclear. The aim of this study was to determine whether genetic factors influence serum levels of COMP.MethodsA classic twin study was conducted using COMP levels in serum obtained from healthy female twin volunteers. COMP levels were determined by an inhibition enzyme‐linked immunosorbent assay method. The heritability of COMP was determined by comparing correlation among 160 monozygotic and 349 dizygotic twin pairs. Data on potential confounding factors, including age, body mass index, and the presence of OA as assessed by hand, hip, and knee radiographs, were included in the analysis.ResultsSerum levels of COMP showed a correlation of 0.72 (95% confidence interval [95% CI] 0.65–0.80) among monozygotic twin pairs and 0.47 (95% CI 0.39–0.55) in dizygotic pairs. This equated to an estimated heritability for COMP of 40% (95% CI 20–60%). Although age and body mass index were found to be significantly associated with COMP in regression analysis, taking the effects of these factors into account did not influence the estimate of heritability.ConclusionThis study showed that heritable factors influence serum levels of the cartilage matrix biomarker COMP. Together with other published data, the results suggest that genetic factors operate at an early stage in the etiologic pathways that influence the development of radiographically discernible OA.
Increased case fatality rates following a first acute cardiovascular event in patients with rheumatoid arthritis
Authors: Van Doornum S. , Brand C. , King B. , Sundararajan V. 
Published: June 2006

AbstractObjectiveAmong patients with rheumatoid arthritis (RA), cardiovascular mortality is increased compared with the rate among unaffected peers. In this study, 30‐day mortality rates following a first acute cardiovascular event (myocardial infarction or stroke) were compared between RA patients and the general population.MethodsAll cases of a first acute cardiovascular event between July 1, 2001 and November 30, 2003 in Victoria, Australia were identified from hospital discharge data. Individuals were classified as having RA when an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) or an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification code for RA was recorded at the index admission or during the previous 5 years. Thirty‐day mortality rates were determined from linkage to the state death registry.ResultsA total of 29,924 patients experienced a first cardiovascular event during the study period, 359 (1.2%) of whom had RA. Thirty‐day cardiovascular mortality was 17.6% in RA patients versus 10.8% in non‐RA patients. In fully adjusted models, the odds ratio (OR) for cardiovascular death in RA patients following a first acute cardiovascular event was 1.6 (95% confidence interval [95% CI] 1.2–2.2). Analysis of index event subgroups revealed that this increased case fatality rate in patients with RA was accounted for almost entirely by excess deaths following myocardial infarction. The adjusted ORs for cardiovascular death in RA after myocardial infarction and stroke were 1.9 (95% CI 1.3–2.7) and 1.2 (95% CI 0.7–2.0), respectively.ConclusionRA patients have a substantially increased risk of 30‐day case fatality following myocardial infarction, but not stroke, compared with non‐RA patients. This higher case fatality rate is likely to contribute to the observed overall excess of cardiovascular deaths in RA populations.
Inflammatory cytokine regulation of transgene expression in human fibroblast‐like synoviocytes infected with adeno‐associated virus
Authors: Traister Russell S. , Fabre Sylvie , Wang Zhong , Xiao Xiao , Hirsch Raphael 
Published: June 2006

AbstractObjectiveAn ideal gene transfer vector for chronic inflammatory diseases such as rheumatoid arthritis (RA) would provide local transgene expression only when the disease is active. To determine whether adeno‐associated virus (AAV) possesses this ability, the effects of inflammatory cytokines on transgene expression were evaluated in human RA fibroblast‐like synoviocytes (FLS).MethodsHuman FLS were infected with AAV in the presence or absence of inflammatory cytokines or synovial fluid obtained from patients with RA. Transgene expression was monitored by either enzyme‐linked immunosorbent assay or flow cytometry. Transgene messenger RNA (mRNA) was measured by real‐time quantitative reverse transcription–polymerase chain reaction.ResultsInflammatory cytokines increased transgene expression in FLS by up to 60‐fold. Synovial fluid from patients with RA, but not from patients without arthritis, was also able to increase expression in synoviocytes. Protein expression correlated with transgene mRNA levels. The enhanced expression required the continued presence of cytokines because, upon removal, transgene expression returned to baseline levels. Expression could be repeatedly reinduced by reexposure to cytokines. The effect was not promoter specific and was demonstrated to be phosphatidylinositol 3‐kinase–dependent.ConclusionThese results suggest that expression of a therapeutic transgene can be controlled by the presence of inflammation following AAV gene transfer, making it an attractive vector for chronic inflammatory diseases such as RA.
Effects of interleukin‐1 on calcium signaling and the increase of filamentous actin in isolated and in situ articular chondrocytes
Authors: Pritchard Scott , Guilak Farshid 
Published: June 2006

AbstractObjectiveTo determine whether interleukin‐1 (IL‐1) initiates transient changes in the intracellular concentration of [Ca2+]i and the organization of filamentous actin (F‐actin) in articular chondrocytes.MethodsArticular chondrocytes within cartilage explants and enzymatically isolated chondrocytes were loaded with Ca2+‐sensitive fluorescence indicators, and [Ca2+]i was measured using confocal fluorescence ratio imaging during exposure to 10 ng/ml IL‐1α. Inhibitors of Ca2+ mobilization (Ca2+‐free medium, thapsigargin [inhibitor of Ca‐ATPases], U73122 [inhibitor of phospholipase C], and pertussis toxin [inhibitor of G proteins]) were used to determine the mechanisms of increased [Ca2+]i. Cellular F‐actin was quantified using fluorescently labeled phalloidin. Toxin B was used to determine the role of the Rho family of small GTPases in F‐actin reorganization.ResultsIn isolated cells on glass and in in situ chondrocytes within explants, exposure to IL‐1 induced a transient peak in [Ca2+]i that was generally followed by a series of decaying oscillations. Thapsigargin, U73122, and pertussis toxin inhibited the percentage of cells responding to IL‐1. IL‐1 increased F‐actin content in chondrocytes in a manner that was inhibited by toxin B.ConclusionBoth isolated and in situ chondrocytes respond to IL‐1 with transient increases in [Ca2+]i via intracellular Ca2+ release mediated by the phospholipase C and inositol trisphosphate pathways. The influx of Ca2+ from the extracellular space and the activation of G protein–coupled receptors also appear to contribute to these mechanisms. These findings suggest that Ca2+ mobilization may be one of the first signaling events in the response of chondrocytes to IL‐1.
Abnormal differentiation of memory T cells in systemic lupus erythematosus
Authors: Fritsch Ruth D. , Shen Xinglei , Illei Gabor G. , Yarboro Cheryl H. , Prussin Calman , Hathcock Karen S. , Hodes Richard J. , Lipsky Peter E. 
Published: June 2006

AbstractObjectiveThe chemokine receptor CCR7 and the tumor necrosis factor receptor family member CD27 define 3 distinct, progressively more differentiated maturational stages of CD4 memory subpopulations in healthy individuals: the CCR7+,CD27+, the CCR7−, CD27+, and the CCR7−,CD27− populations. The goal of this study was to examine maturational disturbances in CD4 T cell differentiation in systemic lupus erythematosus (SLE), using these phenotypic markers.MethodsPhenotypic analysis by flow cytometry, in vitro stimulation experiments, telomere length measurement, and determination of inducible telomerase were carried out.ResultsIn SLE patients, significant increases of CCR7−,CD27− and CCR7−,CD27+ and a reduction of CCR7+,CD27+ CD4 memory T cells were found. In vitro stimulation of SLE T cells showed a stepwise differentiation from naive to CCR7+,CD27+ to CCR7−,CD27+ to CCR7−,CD27−; telomere length and inducible telomerase decreased in these subsets in the same progressive sequence. The in vitro proliferative response of these populations progressively declined as their susceptibility to apoptosis increased. Interestingly, a significant reduction in inducible telomerase was noted in SLE naive and CCR7+,CD27+ CD4+ memory T cells. Additionally, SLE CCR7−,CD27+ and CCR7−, CD27− CD4 memory T cells proliferated poorly in response to in vitro stimulation and underwent significantly more apoptosis than their normal counterparts. Finally, expression of CXCR4 was significantly reduced in all SLE subsets compared with normal.ConclusionTogether these data indicate an increased degree of in vivo T cell stimulation in SLE, resulting in the accumulation of terminally differentiated memory T cells with a decreased proliferative capacity and an increased tendency to undergo apoptosis upon stimulation.
Anti‐LA/SSB antiidiotypic antibodies in maternal serum: A marker of low risk for neonatal lupus in an offspring
Authors: Stea Eleni A. , Routsias John G. , Clancy Robert M. , Buyon Jill P. , Moutsopoulos Haralampos M. , Tzioufas Athanasios G. 
Published: June 2006

AbstractObjectiveThe anti‐La/SSB response to major B cell epitopes of La/SSB can be blocked by an active idiotypic/antiidiotypic network, which can be identified using synthetic complementary epitopes deduced from the sequence of the major B cell epitopes of the molecule. This study evaluated the role of this network in pregnant women with anti‐Ro/SSA and/or anti‐La/SSB antibodies in the development of neonatal lupus syndrome (NLS).MethodsSixty‐three serum samples collected from anti‐Ro/anti‐La–positive women during pregnancy or within 6 months after delivery were obtained from the Research Registry for Neonatal Lupus and the PR Interval Dexamethasone Evaluation study. These samples, as well as 30 sera from healthy individuals, were tested in a blinded manner by enzyme‐linked immunosorbent assay against synthetic peptides corresponding to major B cell epitopes and complementary epitopes of La/SSB.ResultsSera from mothers giving birth to a healthy child and having no history of a child with NLS exhibited higher antiidiotypic antibody activity compared with mothers carrying a child with NLS (P < 0.0001) or mothers giving birth to a healthy child but who previously gave birth to a child with NLS (P = 0.0151). Sera from mothers of healthy children, which exhibited no apparent epitope activity against amino acids 349–364, revealed a significantly greater frequency of hidden anti–349–364aa epitope responses, blocked by antiidiotypic antibodies, as compared with sera from women pregnant with an affected child (P = 0.0094).ConclusionThe presence of antiidiotypic antibodies to autoantibodies against La/SSB may protect the fetus by blocking pathogenic maternal autoantibodies. Testing for these antiidiotypic responses may be useful in predicting a decreased risk of NLS.