bluuebunny/crossref_metadata_2025 huggingface dataset:
Epoxy nanocomposites containing mercaptopropyl polyhedral oligomeric silsesquioxane: Morphology, thermal properties, and toughening mechanism
Authors: Fu Jifang , Shi Liyi , Chen Yi , Yuan Shuai , Wu Jun , Liang Xinlin , Zhong Qingdong
Published: March 2008

A novel polyhedral oligomeric silsesquioxane (POSS) containing a mercaptopropyl group [mercaptopropyl polyhedral oligomeric silsesquioxane (MPOSS)] was synthesized via the hydrolytic condensation of γ‐mercaptopropyl triethoxysilane in an ethanol solution catalyzed by concentrated hydrochloric acid and was used to modify epoxy–amine networks by a cocuring reaction with diglycidyl ether of bisphenol A (DGEBA). The structure, morphology, and thermal and mechanical properties of these MPOSS/DGEBA epoxy nanocomposites were studied and investigated with thermogravimetric analysis/differential thermal analysis (TGA–DTA), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR). From SEM analysis, we observed that the miscibility between epoxy and POSS occurred at a relatively high POSS content, which characterized this mixture as a polymer nanocomposite system. The impact test showed that MPOSS reinforced the epoxy effectively, and the SEM study of the impact fracture surface showed that the fibrous yielding phenomenon observed was an indication of the transition of the brittle stage to a ductile stage and correlated well with the large increases in the impact strength; this was in agreement with the in situ reinforcing and toughening mechanism. The TGA–DTA analysis indicated that the MPOSS/DGEBA epoxy hybrids exhibited lower thermostability at a lower temperature but higher thermostability and higher efficiency in char formation at an elevated temperature. Differential scanning calorimetry showed that the glass transition temperature (Tg) of the MPOSS/epoxy hybrids were lower than that of the neat epoxy. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Electrochemical copolymerization of 3,4‐ethylenedioxythiophene and 5‐methylindole and characterizations of the copolymers
Authors: Nie Guangming , Qu Liangyan , Zhang Yan , Xu Jingkun , Zhang Shusheng
Published: March 2008

Electrocopolymerization of 3,4‐ethylenedioxythiophene (EDOT) and 5‐methylindole (5MeIn) was successfully carried out in acetonitrile containing lithium perchlorate as supporting electrolyte although the oxidation potentials of 5MeIn and EDOT were quite different. The influence of feed ratios and applied potentials on the copolymerization were investigated. The novel low band gap copolymers own both the advantages of P5MeIn and poly(3,4‐ethylenedioxythiophene), i.e., good redox activity, good thermal stability, and high conductivity. The resulting copolymers were characterized by electrochemistry, FT‐IR and ultra violet‐visible spectroscopy, elemental analysis, thermal analysis, conductivity, and scanning electron microscopy, respectively. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Thermal analysis and topographical characterization of films of styrene‐butadiene blends
Authors: Ihalainen Petri , Backfolk Kaj , Sirviö Petri , Peltonen Jouko
Published: March 2008

Scanning probe microscopy (SPM) was used to study the thermal characteristics of latex films consisting of blends of two different styrene‐butadiene copolymers with different glass transition temperatures (Tg). The resonance frequency (ω) and the quality factor (Qp) of an SPM probe oscillating above the sample surface were determined at different probe temperatures (Tp). Thermal transitions associated with a change in heat capacity were observed in the Δω‐Tp curves. The results were compared with differential scanning calorimetry measurements. The very slow heating rate used in the SPM method effectively eliminated the contribution of volumetric changes of the films around Tg. Annealing of the samples in an oven did not influence the thermal transitions observed in the Δω‐Tp curves. The SPM method also enabled a novel approach for determining transition‐induced dimensional changes (vertical contraction, expansion) of the films. Annealing was found to increase the dimensional stability of the blend films. The latex blends were also annealed by the SPM probe and the film progressed from particulate phase morphology to a continuous phase. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Strengthening of poly(butylene adipate‐co‐terephthalate) by melt blending with a liquid crystalline polymer
Authors: Iwakura Yuko , Li Yongjin , Nakayama Kazuo , Shimizu Hiroshi
Published: March 2008

Poly(butylene adipate‐co‐terephthalate) (PBAT) is a soft biodegradable polymer with a low melting temperature. PBAT has been melt‐blended with a liquid crystalline polymer (LCP) aiming at preparing a new biodegradable polymer blend with improved mechanical properties. The phase structure and crystalline morphologies of the PBAT/LCP blends were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), small‐angle X‐ray scattering (SAXS), and transmission electron microscopy (TEM). It was found that the LCP domains are precisely dispersed in the PBAT matrix and that these domains act as the nuclei for PBAT crystallization. The nonisothermal crystallization temperature from the melt was dramatically shifted from 50°C to about 95°C by the addition of 20% LCP. In addition, the tensile modulus of the prepared blends increases gradually with increasing LCP content, indicating the excellent strengthening effects of LCP on the PBAT matrix. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
A type I collagen defect leads to rapidly progressive osteoarthritis in a mouse model
Authors: Blair‐Levy J. M. , Watts C. E. , Fiorientino N. M. , Dimitriadis E. K. , Marini J. C. , Lipsky P. E.
Published: March 2008

Objective

This study was undertaken to test the hypothesis that abnormalities of the subchondral bone can result in osteoarthritis (OA).

Methods

We used a knockin model of human osteogenesis imperfecta, the Brittle IV (Brtl) mouse, in which defective type I collagen is expressed in bone. OA in individual mice was documented by micro–magnetic resonance imaging (micro‐MRI) and micro–computed tomography (micro‐CT). Alterations in the knee joints were confirmed by histopathologic and immunohistochemical analysis. In addition, atomic force microscopy (AFM) was used to assess the ultrastructure of the articular cartilage and subchondral bone matrix.

Results

Brtl mice had decreased integrity of bone but initially normal articular cartilage. However, by the second month of life, Brtl mice developed alterations of the cartilage that were characteristic of OA, as documented by micro‐CT, micro‐MRI, and histologic evaluation. In addition, chondrocyte loss and breakdown of the collagen matrix in the residual cartilage were demonstrated using AFM.

Conclusion

The Brtl mouse model demonstrates that progressive destruction of articular cartilage characteristic of OA may be secondary to altered architecture of the underlying subchondral bone.
In vivo delivery of lentiviral vectors expressing vasoactive intestinal peptide complementary DNA as gene therapy for collagen‐induced arthritis
Authors: Delgado Mario , Toscano Miguel G. , Benabdellah Karim , Cobo Marien , O'Valle Francisco , Gonzalez‐Rey Elena , Martı´n Francisco
Published: March 2008

Objective

Vasoactive intestinal peptide (VIP) has been shown to exert potent immunomodulatory activity, and the use of lentiviral vectors has been found to be an effective means of gene delivery. The present study was therefore undertaken to investigate the feasibility and efficiency of gene therapy using lentiviral vectors expressing VIP (LentiVIP) for the treatment of rheumatoid arthritis (RA).

Methods

We evaluated the therapeutic potential of the gene therapy strategy in the collagen‐induced arthritis (CIA) mouse model, administrating the vectors at different phases of the disease. The inflammatory response was determined by measuring the levels of various inflammatory cytokines and chemokines in the joints and serum. The Th1‐mediated response was evaluated by determining the proliferative response and cytokine profile of T cells stimulated with autoantigen.

Results

A single intraperitoneal injection of LentiVIP was highly effective in treating CIA. Mice with established, severe arthritis showed complete regression of the disease. The therapeutic effect of LentiVIP was associated with widespread biodistribution of the vector and increased VIP levels, especially in joints and lymphoid organs, and was mediated through a striking reduction of the 2 deleterious components of the disease, i.e., the autoimmune response (self‐reactive Th1 cell activity and autoantibody production) and the inflammatory response. LentiVIP treatment also induced the generation and/or activation of CD4+,CD25+,FoxP3+ Treg cells in arthritic mice.

Conclusion

Our findings show that in vivo administration of lentiviral vector expressing VIP produces one of the most potent therapeutic effects described so far in any animal model of RA. We propose that VIP gene transfer should be further investigated as a potential novel, effective treatment of RA and other chronic autoimmune disorders.
Mathematical modeling of the cause of tuberculosis during tumor necrosis factor blockade
Authors: Wallis Robert S.
Published: March 2008

Objective

Tumor necrosis factor (TNF) blockade increases the risk of tuberculosis (TB). The purpose of this study was to use Markov modeling to examine the contributions of reactivation of latent tuberculous infection (LTBI) and the progression of new infection with Mycobacterium tuberculosis to active TB due to TNF blockade. These 2 pathogenic mechanisms cannot otherwise be readily distinguished.

Methods

Monte Carlo simulation was used to represent the range of reported values for the incidence of TB associated with infliximab (TNF monoclonal antibody) and etanercept (soluble TNF receptor) therapy. Iterative methods were then used to identify for each pair of incidence rates the Markov model parameters that most accurately represented the distribution of time to onset of TB as reported to the Food and Drug Administration.

Results

Modeling revealed an apparent median monthly rate of reactivation of LTBI by infliximab treatment of 20.8%, which was 12.1 times that with etanercept treatment (P < 0.001). In contrast, both drugs appeared to pose a high risk of progression of new M tuberculosis infection to active TB. Progression of new infection appeared to cause nearly half of the etanercept‐associated cases; it became the predominant cause of infliximab‐associated cases only after the first year.

Conclusion

Despite sharing a common therapeutic target, infliximab and etanercept differ markedly in the rates at which they reactivate LTBI. Confirmation of these findings will require the application of molecular epidemiologic tools to studies of TB in future biologics registries. Hidden Markov modeling and Monte Carlo simulation are powerful tools for revealing otherwise hidden aspects of the pathogenesis of TB.
Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis
Authors: Colmegna Inés , Diaz‐Borjon Alejandro , Fujii Hiroshi , Schaefer Linda , Goronzy Jörg J. , Weyand Cornelia M.
Published: March 2008

Objective

In rheumatoid arthritis (RA), telomeres of lymphoid and myeloid cells are age‐inappropriately shortened, suggesting excessive turnover of hematopoietic precursor cells (HPCs). The purpose of this study was to examine the functional competence (proliferative capacity, maintenance of telomeric reserve) of CD34+ HPCs in RA.

Methods

Frequencies of peripheral blood CD34+,CD45+ HPCs from 63 rheumatoid factor–positive RA patients and 48 controls matched for age, sex, and ethnicity were measured by flow cytometry. Proliferative burst, cell cycle dynamics, and induction of lineage‐restricted receptors were tested in purified CD34+ HPCs after stimulation with early hematopoietins. Telomere sequences were quantified by real‐time polymerase chain reaction. HPC functions were correlated with the duration, activity, and severity of RA as well as its treatment.

Results

In healthy donors, CD34+ HPCs accounted for 0.05% of nucleated cells; their numbers were strictly age dependent and declined at a rate of 1.3% per year. In RA patients, CD34+ HPC frequencies were age‐independently reduced to 0.03%. Upon growth factor stimulation, control HPCs passed through 5 replication cycles over 4 days. In contrast, RA‐derived HPCs completed only 3 generations. Telomeres of RA CD34+ HPCs were age‐inappropriately shortened by 1,600 bp. All HPC defects were independent of disease duration, disease activity, and smoking status, and were present to the same degree in untreated patients.

Conclusion

In RA, circulating bone marrow–derived progenitor cells were diminished, and concentrations stagnated at levels typical of those in old control subjects. HPCs from RA patients displayed growth factor nonresponsiveness and sluggish cell cycle progression; marked telomere shortening indicated proliferative stress‐induced senescence. Defective HPC function independent of disease activity markers suggests bone marrow failure as a potential pathogenic factor in RA.
Biologic drugs for rheumatoid arthritis in the medicare program: A cost‐effectiveness analysis
Authors: Wailoo Allan J. , Bansback Nick , Brennan Alan , Michaud Kaleb , Nixon Richard M. , Wolfe Fred
Published: March 2008

Objective

Since the introduction of the Medicare Prescription Drug Improvement and Modernization Act and its associated demonstration project, coverage of selected biologic drugs has been expanded for Medicare beneficiaries. For rheumatoid arthritis, coverage was extended to etanercept, adalimumab, and anakinra in addition to the previously covered infliximab. We undertook to develop a model to compare the costs and quality‐adjusted life years (QALYs) generated by each of the 4 biologic agents.

Methods

Data were drawn from meta‐analysis of randomized controlled trials and from a large longitudinal outcomes databank. Uncertainty was addressed using probabilistic and one‐way sensitivity analyses. A lifetime horizon and Medicare viewpoint were adopted.

Results

In the base case analysis, anakinra was the least effective and least costly strategy. Etanercept, adalimumab, and infliximab were similar in terms of effectiveness, but infliximab was more costly. If decision makers are willing to pay a maximum of $50,000/QALY, the probability that infliximab is cost‐effective is <1%. Findings were robust to a range of sensitivity analyses. Only if the dose of infliximab remains constant over time is this likely to be a cost‐effective strategy.

Conclusion

Infliximab is unlikely to be cost‐effective in the Medicare population compared with either etanercept or adalimumab. Anakinra is substantially less costly but is also less effective than the 3 tumor necrosis factor α inhibitors.
A B cell apotope of Ro 60 in systemic lupus erythematosus
Authors: Reed Joanne H. , Jackson Michael W. , Gordon Tom P.
Published: March 2008

Objective

Previous studies have attempted to segregate anti–60‐kd Ro/SSA (anti–Ro 60) responses in systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (SS) but have shown limited disease preference. The aim of the present study was to determine whether the presence of autoantibodies against an Ro 60 apotope (an epitope expressed on apoptotic cells) distinguishes anti–Ro 60 responses in SLE and primary SS.

Methods

Multiparameter flow cytometry was used to select early apoptotic cells and measure the simultaneous binding of annexin V, propidium iodide, and anti–Ro 60–positive IgG from SLE patients (n = 21) and patients with primary SS (n = 19). The specificity of the Ro 60 apotope was determined by inhibition experiments with recombinant and native Ro 60.

Results

Autoantibodies against the Ro 60 apotope were prevalent in SLE patients (13 of 21, 62%) and were rarely observed in patients with primary SS (1 of 19, 5%) (P = 0.0002). Further, within SLE patients, autoantibodies to the Ro 60 apotope strongly distinguished patients with anti–Ro 60 alone (12 of 13, 92%) from those with both anti–Ro 60 and anti‐La (1 of 8, 13%) (P = 0.0005). When we considered all patients with anti–Ro 60 alone, the presence of autoantibodies to the Ro 60 apotope had both high sensitivity (92.3%) and high specificity (85.7%) for SLE compared with primary SS (P = 0.0012). The presence of autoantibodies to the Ro 60 apotope may therefore be of diagnostic value in patients with isolated anti–Ro 60 responses.

Conclusion

The preferential targeting of an Ro 60 apotope exposed on early apoptotic cells in a subset of SLE patients implies disease‐specific pathways for the induction of anti–Ro 60 autoimmunity.
CD200‐FC, a novel antiarthritic biologic agent that targets proinflammatory cytokine expression in the joints of mice with collagen‐induced arthritis
Authors: Šimelyte Egle , Criado Gabriel , Essex David , Uger Robert A. , Feldmann Marc , Williams Richard O.
Published: March 2008

Objective

The CD200 receptor (CD200R) is an inhibitory receptor expressed by myeloid cells that is postulated to play an important role in regulation of the immune system. The purpose of this study was to evaluate the efficacy of a soluble ligand of CD200R in established collagen‐induced arthritis (CIA) in mice and to analyze changes in cytokine expression following therapy in order to understand its primary mechanism of action.

Methods

Arthritis was induced in DBA/1 mice, and CD200‐Fc fusion protein, an isotype control monoclonal antibody, or TNFR‐Fc fusion protein was administered over a period of 10 days (total of 4 doses). Cytokine expression in the joint was assessed by flow cytometry, enzyme‐linked immunosorbent assay, and quantitative real‐time polymerase chain reaction.

Results

CD200‐Fc significantly reduced the severity of established arthritis at the clinical and histologic levels. The therapeutic effect of CD200‐Fc at 1 mg/kg was comparable with that of TNFR‐Fc at 4 mg/kg. CD200R was found to be expressed in arthritic synovia and in lymph nodes, yet no changes in T cell cytokine levels (interferon‐γ, interleukin‐5 [IL‐5], IL‐10, IL‐17) were detected after CD200‐Fc therapy. There was no evidence of an expansion of forkhead box P3–positive regulatory T cells or a change in serum anticollagen IgG1 and IgG2a levels. However, administration of CD200‐Fc markedly decreased the expression of messenger RNA for tumor necrosis factor α, IL‐1β, IL‐10, and matrix metalloproteinase 13 in the joint to the same extent as administration of TNFR‐Fc.

Conclusion

CD200‐Fc is an effective therapeutic agent in established CIA that targets proinflammatory cytokine expression in the joint without any obvious systemic immunosuppressive effects. Our findings indicate that CD200‐Fc has considerable potential as a novel therapeutic agent in rheumatoid arthritis in humans.
Fibroblast‐specific perturbation of transforming growth factor β signaling provides insight into potential pathogenic mechanisms of scleroderma‐associated lung fibrosis: Exaggerated response to alveolar epithelial injury in a novel mouse model
Authors: Hoyles Rachel K. , Khan Korsa , Shiwen Xu , Howat Sarah L. , Lindahl Gisela E. , Leoni Patricia , du Bois Roland M. , Wells Athol U. , Black Carol M. , Abraham David J. , Denton Christopher P.
Published: March 2008

Objective

To explore increased susceptibility to fibrosis following experimental injury to alveolar epithelial cells (AECs) in a novel transgenic mouse model of scleroderma with fibroblast‐specific perturbation of transforming growth factor β (TGFβ) signaling (TβRIIΔk‐fib mice).

Methods

Wild‐type (WT) and transgenic mice were injured with intratracheally administered saline or bleomycin, and the lungs were harvested for biochemical, histologic, and electron microscopic analysis.

Results

Electron microscopy revealed AEC abnormalities in the lungs of untreated transgenic mice and bleomycin‐treated WT mice; the lungs of transgenic mice treated with bleomycin showed severe epithelial damage. Compared with lungs from bleomycin‐treated WT mice, lungs from bleomycin‐treated transgenic mice demonstrated increased fibroproliferation, myofibroblast persistence, and impaired hyperplasia and increased apoptosis of type II AECs. The lungs from saline‐treated transgenic mice and those from bleomycin‐treated WT mice had phenotypic similarities, suggesting enhanced susceptibility to minor epithelial injury in the transgenic strain. The level of collagen was increased in the lungs from transgenic mice compared with that in the lungs from WT mice after treatment with either bleomycin or saline. Persistent fibrosis in bleomycin‐treated transgenic mice was independent of ongoing neutrophil inflammation but was associated with impaired alveolar epithelial repair.

Conclusion

These results suggest that in the context of fibroblast‐specific perturbation of TGFβ signaling, even minor epithelial injury induces significant fibrosis. The model supports a central role for TGFβ in determining fibrosis and demonstrates that lung fibroblasts may regulate the response of AECs to injury. Our findings provide insight into likely pathogenic mechanisms in scleroderma‐associated pulmonary fibrosis.
Articular cartilage repair using dedifferentiated articular chondrocytes and bone morphogenetic protein 4 in a rabbit model of articular cartilage defects
Authors: Lin Lin , Zhou Chunyan , Wei Xuelei , Hou Yu , Zhao Liheng , Fu Xin , Zhang Jiying , Yu Changlong
Published: March 2008

Objective

To observe redifferentiation of dedifferentiated chondrocytes after transplantation into the joint, and to evaluate the ability of dedifferentiated chondrocytes transduced with adenovirus containing bone morphogenetic protein 4 (BMP‐4) to redifferentiate in vitro and in vivo in a rabbit model of articular cartilage defects.

Methods

Monolayer and pellet culture systems were used to evaluate the redifferentiation of dedifferentiated chondrocytes transduced with BMP‐4. A rabbit model of partial‐thickness articular cartilage defects was used to evaluate cartilage repair macroscopically and histologically, 6 and 12 weeks after transplantation with first‐passage, fifth‐passage, or transduced fifth‐passage chondrocytes. Histologic grading of the repaired tissue was performed. Expression of BMP‐4 and the ability of transplanted cells to recover a chondrocytic phenotype were also assessed.

Results

BMP‐4–expressing dedifferentiated chondrocytes recovered a chondrocytic phenotype in vitro. After transplantation into the joint, some of the dedifferentiated chondrocytes in the defect sites could undergo redifferentiation and formed matrix that displayed positive toluidine blue staining for glycosaminoglycans. Histologic scores of the regenerative tissue revealed significantly better cartilage repair in rabbits transplanted with BMP‐4–expressing cells than in the other treatment groups. Staining with toluidine blue revealed expression of BMP‐4 in the cells and in the matrix surrounding the cells.

Conclusion

Some dedifferentiated chondrocytes can redifferentiate after transplantation into the load‐bearing joint. BMP‐4 can be used to induce redifferentiation of dedifferentiated chondrocytes in vitro and in vivo, which could help enhance articular cartilage repair.
Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: A randomized, double‐blind, placebo‐controlled, dose‐ranging study
Authors: Kay Jonathan , Matteson Eric L. , Dasgupta Bhaskar , Nash Peter , Durez Patrick , Hall Stephen , Hsia Elizabeth C. , Han John , Wagner Carrie , Xu Zhenhua , Visvanathan Sudha , Rahman Mahboob U.
Published: March 2008

Objective

To assess the efficacy, safety, and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX).

Methods

Patients were randomly assigned in a double‐blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48. Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo.

Results

The primary end point was attained. Sixty‐one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37% of patients in the placebo plus MTX group (P = 0.010). In addition, 79% of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response (P < 0.001 versus placebo). Through week 20 (after which patients receiving placebo were switched to active infliximab therapy), serious adverse events were reported in 9% of patients in the combined golimumab groups and in 6% of patients in the placebo group.

Conclusion

Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX.
Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis
Authors: Stanczyk Joanna , Pedrioli Deena M. Leslie , Brentano Fabia , Sanchez‐Pernaute Olga , Kolling Christoph , Gay Renate E. , Detmar Michael , Gay Steffen , Kyburz Diego
Published: March 2008

Objective

MicroRNAs (miRNA) have recently emerged as a new class of modulators of gene expression. In this study we investigated the expression, regulation, and function of miR‐155 and miR‐146a in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) and RA synovial tissue.

Methods

Locked nucleic acid microarray was used to screen for differentially expressed miRNA in RASFs treated with tumor necrosis factor α (TNFα). TaqMan‐based real‐time polymerase chain reaction was applied to measure the levels of miR‐155 and miR‐146a. Enforced overexpression of miR‐155 was used to investigate the function of miR‐155 in RASFs.

Results

Microarray analysis of miRNA expressed in RASFs treated with TNFα revealed a prominent up‐regulation of miR‐155. Constitutive expression of both miR‐155 and miR‐146a was higher in RASFs than in those from patients with osteoarthritis (OA), and expression of miR‐155 could be further induced by TNFα, interleukin‐1β, lipopolysaccharide, poly(I‐C), and bacterial lipoprotein. The expression of miR‐155 in RA synovial tissue was higher than in OA synovial tissue. Enforced expression of miR‐155 in RASFs was found to repress the levels of matrix metalloproteinase 3 (MMP‐3) and reduce the induction of MMPs 3 and 1 by Toll‐like receptor ligands and cytokines. Moreover, compared with monocytes from RA peripheral blood, RA synovial fluid monocytes displayed higher levels of miR‐155.

Conclusion

This study provides the first description of increased expression of miRNA miR‐155 and miR‐146a in RA. Based on these findings, we postulate that the inflammatory milieu may alter miRNA expression profiles in resident cells of the rheumatoid joints. Considering the repressive effect of miR‐155 on the expression of MMPs 3 and 1 in RASFs, we hypothesize that miR‐155 may be involved in modulation of the destructive properties of RASFs.
Beta2‐glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti–β2‐glycoprotein I autoantibodies
Authors: Rahgozar Soheila , Giannakopoulos Bill , Yan Xiaokai , Wei Jiewei , Cheng Qi Jian , Gemmell Rosalie , Krilis Steven A.
Published: March 2008

Objective

Beta2‐glycoprotein I (β2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that β2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of β2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti‐β2GPI antibodies was also examined.

Methods

HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved β2GPI and anti‐β2GPI antibodies was determined in these systems.

Results

β2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of β2GPI at Lys317–Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti‐β2GPI antibodies potentiated the procoagulant influence of β2GPI in this system.

Conclusion

These novel findings suggest that β2GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti‐β2GPI antibodies potentiate the protective effect of β2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS.
Modulation of aggrecan and ADAMTS expression in ovine tendinopathy induced by altered strain
Authors: Smith M. M. , Sakurai G. , Smith S. M. , Young A. A. , Melrose J. , Stewart C. M. , Appleyard R. C. , Peterson J. L. , Gillies R. M. , Dart A. J. , Sonnabend D. H. , Little C. B.
Published: March 2008

Objective

To evaluate histologic, immunohistochemical, and molecular changes in tendon induced by altered strain in a large‐animal model.

Methods

A full‐thickness partial‐width laceration of the infraspinatus tendon was created in 5 sheep, while 5 sham‐operated sheep were used as controls. Sheep were killed after 4 weeks, and 4 differentially stressed tendon regions (tensile or near bone attachment from overstressed or stress‐deprived halves) were evaluated for histopathology, proteoglycan (PG) accumulation, and characterization of glycosaminoglycans and aggrecan catabolites. Gene expression of matrix components, enzymes, and inhibitors was analyzed by reverse transcriptase–polymerase chain reaction.

Results

Histopathologic changes were detected in both overstressed and stress‐deprived tensile tendon, but only in stress‐deprived tendon near bone. In overstressed and stress‐deprived tensile tendon, levels of keratan sulfate, chondroitin 4‐sulfate, and chondroitin 6‐sulfate were increased. In overstressed tensile tendon, levels of ADAMTS‐generated aggrecan catabolites were increased. There was increased matrix metalloproteinase 13 (MMP‐13) and decreased fibromodulin and decorin expression in all regions. Increased MMP‐1, MMP‐9, MMP‐14, and ADAMTS‐1 expression, and decreased type II collagen expression were restricted to stress‐deprived tendon. In stress‐deprived bone‐attachment regions, messenger RNA (mRNA) for aggrecan was decreased, and ADAMTS was increased. In overstressed tensile tendon, aggrecan mRNA was increased, and ADAMTS was decreased.

Conclusion

The distinct molecular changes in adjacent tissue implicate altered strain rather than humoral factors in controlling abnormal tenocyte metabolism, and highlight the importance of regional sampling. Tendon abnormalities induced by increased strain are accompanied by increased aggrecan, decreased ADAMTS, and low PG expression, which may negatively impact the structural integrity of the tissue and predispose to rupture.
Results of a two‐year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate
Authors: Kremer Joel M. , Genant Harry K. , Moreland Larry W. , Russell Anthony S. , Emery Paul , Abud‐Mendoza Carlos , Szechiński Jacek , Li Tracy , Teng Julie , Becker Jean‐Claude , Westhovens René
Published: March 2008

Objective

To evaluate the efficacy, radiographic changes, and safety of abatacept and methotrexate therapy through 2 years in a long‐term extension of a previously published 1‐year study.

Methods

Patients who received placebo during year 1 were switched to abatacept. Patients taking abatacept continued to take it. Efficacy and safety were assessed through 2 years.

Results

Of 539 patients enrolled in the initial 1‐year study, 488 completed 1 year of the long‐term extension (2% discontinued for lack of efficacy). At 2 years, patients taking abatacept had maintained their responses on the American College of Rheumatology (ACR) improvement criteria and the Disease Activity Score in 28 joints (DAS28; using the C‐reactive protein [CRP] level), as well as their physical function (according to the Health Assessment Questionnaire [HAQ] disability index [DI]) and health‐related quality of life (HRQOL; assessed with the Short Form 36 [SF‐36] health survey), that were observed at the end of the double‐blind period (year 1 versus year 2 values were 81.9% versus 80.3% for ACR 20% improvement, 25.4% versus 30.9% for a DAS28 [CRP] of <2.6, 71.8% versus 66.8% for the HAQ DI, and 9.7 versus 10.6 and 7.3 versus 7.2, respectively, for the mean change in the physical and mental components summary scores of the SF‐36). In the abatacept group, post hoc analysis demonstrated further inhibition of radiographic progression during year 2 (57% reduction in mean change of total score in year 2 versus year 1; P < 0.0001), and minimal radiographic progression was observed (mean change in total score from baseline was 1.1 and 1.6 at year 1 and 2, respectively). Rates of adverse events (AEs) and severe AEs were consistent throughout the cumulative period.

Conclusion

The improvements in signs and symptoms, physical function, and HRQOL observed after 1 year of abatacept treatment were maintained through 2 years of treatment. This durability was accompanied by a safety profile consistent with that in the double‐blind portion of the study. Radiographic progression was further inhibited in year 2 compared with year 1, suggesting an increasing effect of abatacept on the inhibition of structural damage in year 2.
Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus
Authors: Arinuma Yoshiyuki , Yanagida Tamiko , Hirohata Shunsei
Published: March 2008

Objective

To explore the association of antibodies directed against N‐methyl‐D‐aspartate receptor subunit NR2 (anti‐NR2) in cerebrospinal fluid (CSF) with neuropsychiatric manifestations in systemic lupus erythematosus (NPSLE).

Methods

Paired serum and CSF specimens were obtained from 56 patients with NPSLE (38 with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 18 with neurologic syndromes or peripheral neuropathy [focal NPSLE]) and from 20 control patients with noninflammatory neurologic diseases. IgG anti‐NR2 antibodies were measured by enzyme‐linked immunosorbent assay using synthetic peptide containing the extracellular ligand‐binding domain of NR2. The binding of affinity‐purified anti‐NR2 to human neuroblastoma cell line SK‐N‐MC was examined by flow cytometry.

Results

Purified anti‐NR2 bound to the surface of SK‐N‐MC cells. Levels of anti‐NR2 antibodies in CSF were significantly elevated in patients with diffuse NPSLE compared with levels in control patients or those with focal NPSLE, whereas there were no significant differences in serum anti‐NR2 levels among the 3 groups. In 31 of the 38 patients with diffuse NPSLE (81.6%) and 8 of the 18 patients with focal NPSLE (44.4%), CSF anti‐NR2 levels were more than 3 SD above the mean level in the control patients (P = 0.0120 by chi‐square test).

Conclusion

These results indicate that anti‐NR2 is a constituent of antineuronal antibodies and, more importantly, that anti‐NR2 antibodies in CSF, but not in serum, are associated with diffuse NPSLE.
Familial clustering of non‐nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus
Authors: Hunnangkul Saowalak , Nitsch Dorothea , Rhodes Benjamin , Chadha Sapna , Roberton Cheri A. , Pessôa‐Lopes Pedro , Norsworthy Peter J. , Fernando Michelle M. A. , Charles Peter , Mackworth‐Young Charles , Isenberg David A. , Whittaker John C. , Vyse Timothy J.
Published: March 2008

Objective

To determine whether key features of systemic lupus erythematosus (SLE), namely, production of non‐nuclear antibodies (anti‐C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti‐C1q and C3 and C4 levels.

Methods

The study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti‐C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set.

Results

We demonstrated associations between siblings for anti‐C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti‐C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti‐C1q, C3, and C4 (∼45%). Anti‐C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives.

Conclusion

Non‐nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti‐C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.
High prevalence of temporomandibular joint arthritis at disease onset in children with juvenile idiopathic arthritis, as detected by magnetic resonance imaging but not by ultrasound
Authors: Weiss Pamela F. , Arabshahi Bita , Johnson Ann , Bilaniuk Larissa T. , Zarnow Deborah , Cahill Anne Marie , Feudtner Chris , Cron Randy Q.
Published: March 2008

Objective

To determine the prevalence of temporomandibular joint (TMJ) disease in a cohort of children with new‐onset juvenile idiopathic arthritis (JIA), and to compare magnetic resonance imaging (MRI) with ultrasound (US) for the detection of acute and chronic changes of TMJ arthritis.

Methods

Between January 2005 and April 2007, children with newly diagnosed JIA were prospectively evaluated for TMJ arthritis. Prior to imaging, jaw pain and disability were assessed with questionnaires and physical examination. The TMJs of all patients were imaged with MRI and US within 8 weeks of diagnosis.

Results

Of the 32 patients enrolled, 78% were female, and the median age was 8.6 years (range 1.5–17.2 years). Acute TMJ arthritis was diagnosed in 75% of the children by MRI and in none by US; chronic arthritis was diagnosed in 69% by MRI and in 28% by US. Findings of both acute and chronic TMJ disease were detected by MRI in 53% of the patients. Of those with acute TMJ arthritis, 71% were asymptomatic, and 63% had normal findings on jaw examination. Fifty‐six percent of patients with acute disease had an improved maximal incisal opening after corticosteroid injection. Among these responders, 56% had been asymptomatic and had normal jaw examination findings.

Conclusion

TMJ arthritis was present in the majority of patients with new‐onset JIA. Findings on MRI along with responses to treatment among asymptomatic patients with normal jaw examination findings suggest that a history review and physical examination are not sufficient to screen for TMJ disease. Our results also suggest that MRI and US findings are not well correlated, and that MRI is preferable for the detection of TMJ disease in new‐onset JIA.
The influence of age at symptom onset and length of followup on mortality in patients with recent‐onset inflammatory polyarthritis
Authors: Naz Sophia M. , Farragher Tracey M. , Bunn Diane K. , Symmons Deborah P. M. , Bruce Ian N.
Published: March 2008

Objective

To investigate the influence of age at symptom onset and length of followup on mortality in patients with recent‐onset inflammatory polyarthritis (IP), and to examine predictors of mortality in relation to disease duration.

Methods

From 1990 to 1994, patients with recent‐onset IP were registered with the Norfolk Arthritis Register (NOAR) and followed up prospectively. Standardized mortality ratios (SMRs) were calculated for all‐cause and cardiovascular disease (CVD) mortality and for those who were younger than age 55 years at disease onset and for the first 5 and 10 years of followup. Cox proportional hazards models were developed to assess predictors of early and later mortality.

Results

Of 1,098 patients, 224 (20%) had died by the end of 2004. All‐cause and CVD mortality were increased in rheumatoid factor (RF)–positive patients and in this subgroup, CVD mortality was increased at both early and later followup (SMR 5‐year followup 1.93 [95% confidence interval 1.08–3.19]; SMR 10‐year followup 2.00 [95% confidence interval 1.37–2.80]). CVD mortality was highest in seropositive patients <55 years of age at disease onset (SMR 5.58 [95% confidence interval 2.24–11.50]). In multivariate models, age at onset, male sex, RF positivity, Health Assessment Questionnaire score ≥1.5, and nodules were predictors of early and later mortality.

Conclusion

Patients with IP had higher rates of CVD mortality throughout the followup period studied, and this was highest in seropositive patients who were <55 years of age at symptom onset. This subgroup deserves particular attention in terms of disease and risk factor modification. Nodules were independent predictors of CVD mortality, suggesting that extraarticular/vascular inflammation identifies patients at particularly high CVD risk.
Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts
Authors: Juarranz Yasmina , Gutiérrez‐Cañas Irene , Santiago Begoña , Carrión Mar , Pablos José L. , Gomariz Rosa P.
Published: March 2008

Objective

Vasoactive intestinal peptide (VIP) has shown potent antiinflammatory effects in murine arthritis and ex vivo in human rheumatoid arthritis (RA) synovial cells. To investigate the potential endogenous participation of this system in the pathogenesis of RA, we analyzed the expression and regulation of VIP and its functional receptors in human fibroblast‐like synoviocytes (FLS) from patients with osteoarthritis (OA) and patients with RA.

Methods

The expression of VIP was studied by reverse transcription–polymerase chain reaction (RT‐PCR), enzyme immunoassay, and immunofluorescence in cultured FLS, and by immunohistochemical analysis in synovial tissue. The expression and function of the potential VIP receptors in FLS were studied by RT‐PCR, determination of intracellular cAMP production, cell membrane adenylate cyclase (AC) activity, and interleukin‐6, CCL2, and CXCL8 production in response to VIP or specific agonists and antagonists.

Results

VIP expression was detected in human FLS at the messenger RNA and protein levels, and it was significantly decreased in RA FLS compared with OA FLS. VIP receptor type 1 (VPAC1) was the dominant AC‐coupled receptor in OA FLS, in contrast with RA FLS, in which VPAC2 was dominant. Tumor necrosis factor α–treated OA FLS reproduced the VIP and VPAC receptor expression pattern of RA FLS. The antagonistic effects of VIP on FLS proinflammatory factor production were reproduced by VPAC1‐ and VPAC2‐specific agonists in OA FLS and RA FLS, respectively.

Conclusion

VIP expression is down‐regulated in RA and in tumor necrosis factor α–treated FLS, suggesting that down‐regulation of this endogenous antiinflammatory factor may contribute to the pathogenesis of RA. In RA FLS, VPAC2 mediates the antiinflammatory effects of VIP, suggesting that VPAC2 agonists may be an alternative to VIP as antiinflammatory agents.
Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus
Authors: Biesen Robert , Demir Cemal , Barkhudarova Fidan , Grün Joachim R. , Steinbrich‐Zöllner Marta , Backhaus Marina , Häupl Thomas , Rudwaleit Martin , Riemekasten Gabriela , Radbruch Andreas , Hiepe Falk , Burmester Gerd‐Rüdiger , Grützkau Andreas
Published: March 2008

Objective

Type I interferon (IFN) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and is therefore considered a potential therapeutic target. This study was undertaken to establish a feasible biomarker for IFN effects with respect to disease activity and effectiveness of IFN‐suppressive therapy in SLE patients.

Methods

Transcriptomes of purified monocytes from 9 SLE patients and 7 healthy controls were analyzed by Affymetrix GeneChip technology. Levels of sialic acid–binding Ig‐like lectin 1 (Siglec‐1) (sialoadhesin, CD169) in inflammatory and resident monocytes were determined at the protein level in 38 healthy controls and 52 SLE patients, using multicolor flow cytometry.

Results

Transcriptomes of peripheral monocytes from SLE patients revealed a dominant type I IFN signature. Siglec‐1 was identified as one of the most prominent type I IFN–regulated candidate genes. At the protein level, the frequency of Siglec‐1–expressing monocyte subsets was correlated with disease activity (as measured by the SLE Disease Activity Index) and was inversely correlated with levels of complement factors. Most interestingly, levels of anti–double‐stranded DNA (anti‐dsDNA) antibodies were highly correlated with the percentage of resident monocytes, but not inflammatory monocytes, expressing Siglec‐1. High‐dose glucocorticoid treatment resulted in a dramatic reduction of Siglec‐1 expression in cells from patients with active SLE.

Conclusion

Our findings indicate that Siglec‐1 expression in resident blood monocytes is a potential biomarker for monitoring disease activity, displaying type I IFN responses, and estimating levels of anti‐dsDNA antibodies. Moreover, our results suggest that resident and inflammatory monocytes contribute differently to the process of autoantibody formation in SLE.