bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis
Authors: Young Deborah A. , Hegen Martin , Ma Hak Ling Margery , Whitters Matthew J. , Albert Leo M. , Lowe Leslie , Senices Mayra , Wu Paul W. , Sibley Barbara , Leathurby Yelena , Brown Tom P. , Nickerson‐Nutter Cheryl , Keith James C. , Collins Mary 
Published: March 2007

AbstractObjectiveInterleukin‐21 (IL‐21) is a T cell–derived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL‐21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL‐21 contributes to their pathologic processes.MethodsDBA/1 mice were immunized with bovine type II collagen and then treated with murine IL‐21 receptor Fc fusion protein (IL‐21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL‐21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL‐21R.Fc on the production of interferon‐γ (IFNγ) by T cells were examined.ResultsTreatment of DBA/1 mice with IL‐21R.Fc reduced the clinical and histologic signs of collagen‐induced arthritis. Nonspecific IgG1 levels were decreased in response to treatment. The levels of IL‐6 mRNA in the paws and the serum IL‐6 levels were decreased after treatment with IL‐21R.Fc. IFNγ mRNA levels were increased in the paws, and the addition of IL‐21R.Fc to collagen‐activated lymph node cultures enhanced the levels of IFNγ. Collagen‐specific spleen cell responses in IL‐21R.Fc–treated mice were observed as reduced levels of IFNγ and increased levels of IL‐6. Treatment of Lewis rats with IL‐21R.Fc after induction of adjuvant‐induced arthritis resulted in reversal of disease signs and improvements in histologic parameters.ConclusionThese findings demonstrate a pathogenic role for IL‐21 in animal models of RA, and support consideration of IL‐21 as a therapeutic target in human RA.
Role of matrix metalloproteinases, proinflammatory cytokines, and oxidative stress–derived molecules in hepatitis C virus–associated mixed cryoglobulinemia vasculitis neuropathy
Authors: Saadoun David , Bieche Ivan , Authier François‐Jérome , Laurendeau Ingrid , Jambou Florence , Piette Jean Charles , Vidaud Michel , Maisonobe Thierry , Cacoub Patrice 
Published: March 2007

AbstractObjectiveMixed cryoglobulinemia (MC) is a systemic vasculitis, usually associated with hepatitis C virus (HCV) infection. The molecular mechanisms responsible for HCV‐associated MC (HCV‐MC) vasculitis are largely unknown. This study was undertaken to assess the expression profile of selected genes involved in inflammatory vascular damage in patients with HCV‐MC vasculitis, patients with polyarteritis nodosa (PAN), and patients with noninflammatory idiopathic neuropathy.MethodsThe quantitative expression levels of 42 selected genes involved in inflammatory vascular damage were assessed in nerve lesions of patients with HCV‐MC vasculitis, PAN (rheumatic disease controls), and noninflammatory idiopathic neuropathy (noninflammatory neuropathy controls), using real‐time reverse transcriptase–polymerase chain reaction. Genes were considered to be differentially expressed when there was a >2‐fold difference in mean expression levels between groups and the P value was less than 0.05.ResultsExpression levels of 8 genes were significantly increased in HCV‐MC patients versus control patients with noninflammatory idiopathic neuropathy, with the highest increase for metallothionein 1 H (MT1H), a hypoxic and oxidative stress protein. Compared with PAN patients, HCV‐MC patients had higher expression levels of genes encoding oxidative stress–derived molecules (MT1H, endothelial cell nitric oxide synthase 3, Hsp70, and Hsp90) and tissue plasminogen activator and lower expression levels of matrix metalloproteinase 7 (MMP‐7). HCV‐MC neuropathies were classified according to their morphologic pattern and the presence or absence of necrotizing arteritis. MMP‐1, MMP‐7, MMP‐9, and interleukin‐1β were up‐regulated in patients with necrotizing arteritis.ConclusionThis comprehensive molecular study of HCV‐MC vasculitis provides strong evidence that MMPs, proinflammatory cytokines, and oxidative stress–derived molecules have a role in the pathogenesis of HCV‐MC vasculitis neuropathy.
Gabapentin in the treatment of fibromyalgia: A randomized, double‐blind, placebo‐controlled, multicenter trial
Authors: Arnold Lesley M. , Goldenberg Don L. , Stanford Sharon B. , Lalonde Justine K. , Sandhu H. S. , Keck Paul E. , Welge Jeffrey A. , Bishop Fred , Stanford Kevin E. , Hess Evelyn V. , Hudson James I. 
Published: March 2007

AbstractObjectiveTo assess the efficacy and safety of gabapentin in patients with fibromyalgia.MethodsA 12‐week, randomized, double‐blind study was designed to compare gabapentin (1,200–2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0–10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of ≥30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent‐to‐treat sample, with treatment‐by‐time interaction as the measure of effect.ResultsGabapentin‐treated patients displayed a significantly greater improvement in the BPI average pain severity score (P= 0.015; estimated difference between groups at week 12 = −0.92 [95% confidence interval −1.75, −0.71]). A significantly greater proportion of gabapentin‐treated patients compared with placebo‐treated patients achieved response at end point (51% versus 31%;P= 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.ConclusionGabapentin (1,200–2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.
Examining the role of CD1d and natural killer T cells in the development of nephritis in a genetically susceptible lupus model
Authors: Yang Jun‐Qi , Wen Xiangshu , Liu Hongzhu , Folayan Gbolahan , Dong Xin , Zhou Min , Van Kaer Luc , Singh Ram Raj 
Published: March 2007

AbstractObjectiveCD1d‐reactive invariant natural killer T (iNKT) cells secrete multiple cytokines upon T cell receptor (TCR) engagement and modulate many immune‐mediated conditions. The purpose of this study was to examine the role of these cells in the development of autoimmune disease in genetically lupus‐prone (NZB × NZW)F1 (BWF1) mice.MethodsThe CD1d1‐null genotype was crossed onto the NZB and NZW backgrounds to establish CD1d1‐knockout (CD1d0) BWF1 mice. CD1d0 mice and their wild‐type littermates were monitored for the development of nephritis and assessed for cytokine responses to CD1d‐restricted glycolipid α‐galactosylceramide (αGalCer), anti‐CD3 antibody, and concanavalin A (Con A). Thymus and spleen cells were stained with CD1d tetramers that had been loaded with αGalCer or its analog PBS‐57 to detect iNKT cells, and the cells were compared between BWF1 mice and class II major histocompatibility complex–matched nonautoimmune strains, including BALB/c, (BALB/c × NZW)F1 (CWF1), and NZW.ResultsCD1d0 BWF1 mice had more severe nephritis than did their wild‐type littermates. Although iNKT cells and iNKT cell responses were absent in CD1d0 BWF1 mice, the CD1d0 mice continued to have significant numbers of interferon‐γ–producing NKT‐like (CD1d‐independent TCRβ+,NK1.1+ and/or DX5+) cells. CD1d deficiency also influenced cytokine responses by conventional T cells: upon in vitro stimulation of splenocytes with Con A or anti‐CD3, type 2 cytokine levels were reduced, whereas type 1 cytokine levels were increased or unchanged in CD1d0 mice as compared with their wild‐type littermates. Additionally, numbers of thymic iNKT cells were lower in young wild‐type BWF1 mice than in nonautoimmune strains.ConclusionGermline deletion of CD1d exacerbates lupus in BWF1 mice. This finding, together with reduced thymic iNKT cells in young BWF1 mice as compared with nonautoimmune strains, implies a regulatory role of CD1d and iNKT cells during the development of lupus.
The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model
Authors: Aksentijevich Ivona , D. Putnam Christopher , Remmers Elaine F. , Mueller James L. , Le Julie , Kolodner Richard D. , Moak Zachary , Chuang Michael , Austin Frances , Goldbach‐Mansky Raphaela , Hoffman Hal M. , Kastner Daniel L. 
Published: March 2007

AbstractObjectiveThe cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease‐causing mutations on cryopyrin, in order to gain better understanding of the impact of disease‐associated mutations on protein function.MethodsWe tested for CIAS1 mutations in 22 patients with neonatal‐onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle‐Wells syndrome (MWS), 18 with familial cold‐induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation‐negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin‐1β signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease‐causing mutations were mapped.ResultsForty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease‐causing mutations correlated with disease severity only for a subset of known mutations.ConclusionOur modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease‐associated mutations.
Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against fas‐induced apoptosis
Authors: Hayashi Shinya , Miura Yasushi , Nishiyama Takayuki , Mitani Makoto , Tateishi Koji , Sakai Yoshitada , Hashiramoto Akira , Kurosaka Masahiro , Shiozawa Shunichi , Doita Minoru 
Published: March 2007

AbstractObjectiveDecoy receptor 3 (DcR3), a newly identified member of the tumor necrosis factor receptor (TNFR) superfamily, is a soluble receptor that binds to members of the TNF family, including FasL, LIGHT, and TNF‐like molecule 1A. DcR3 is mostly expressed in tumor cells, and it competitively inhibits binding of TNF to TNFRs. The present study was undertaken to investigate DcR3 expression in fibroblast‐like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and to analyze the effects of DcR3 on Fas‐induced apoptosis in RA FLS.MethodsExpression of DcR3 in FLS was measured by reverse transcriptase–polymerase chain reaction (RT‐PCR) and Western blotting. FLS were incubated with DcR3–Fc chimera protein or transfected with DcR3 small interfering RNA (siRNA) using the lipofection method, before induction of apoptosis. Apoptosis induced by Fas in FLS was detected with TUNEL staining and Western blotting of caspase 8 and poly(ADP‐ribose) polymerase. Finally, FLS were incubated with TNFα prior to Fas‐induced apoptosis, expression of DcR3 was analyzed by quantitative RT‐PCR, and apoptosis was measured.ResultsDcR3 was expressed in both RA FLS and OA FLS. DcR3–Fc protein inhibited Fas‐induced apoptosis in FLS. Down‐regulation of DcR3 in FLS by siRNA increased Fas‐induced apoptosis. TNFα increased DcR3 expression and inhibited Fas‐induced apoptosis in RA FLS, but not in OA FLS.ConclusionDcR3 expressed in RA FLS is increased by TNFα and protects the cells against Fas‐induced apoptosis. These findings indicate that DcR3 may be a possible therapeutic target in RA.
A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti–tumor necrosis factor monoclonal antibody in murine collagen‐induced arthritis
Authors: Saito Hiroaki , Kojima Takefumi , Takahashi Mariko , Horne William C. , Baron Roland , Amagasa Teruo , Ohya Keiichi , Aoki Kazuhiro 
Published: March 2007

AbstractObjectiveThe cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor α (TNFα) recognition loop on TNF receptor I, and it prevents interactions of TNFα with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen‐induced arthritis (CIA) in mice with those of anti‐TNFα monoclonal antibody.MethodsCIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti‐TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed.ResultsWP9QY treatment inhibited CIA‐induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti‐TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA‐induced bone destruction at the knee joints to the same extent as did anti‐TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA‐induced systemic bone loss by WP9QY was more apparent than that by anti‐TNF antibody.ConclusionThe TNFα antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.
Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis
Authors: Gunnarsson Iva , Sundelin Birgitta , Jónsdóttir Thorunn , Jacobson Stefan H. , Henriksson Elisabet Welin , van Vollenhoven Ronald F. 
Published: March 2007

AbstractObjectiveRituximab is a monoclonal antibody directed against the CD20 marker of B cells. Because of its ability to deplete B lymphocytes, it has been suggested that the drug could be of benefit in B cell–dependent diseases, including systemic lupus erythematosus (SLE). The purpose of this study was to investigate the histopathologic and clinical effects of combination treatment with rituximab and cyclophosphamide (CYC) in patients with CYC‐resistant proliferative lupus nephritis.MethodsSeven female patients with proliferative lupus nephritis were treated with rituximab in combination with CYC. Renal biopsies were performed before treatment and during followup. SLE activity was evaluated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group index. In 6 of the 7 patients, immunostaining of lymphocyte subpopulations in the renal tissue was performed before treatment and during followup.ResultsAt 6 months of followup, significant clinical improvement was noted, with a reduction in SLEDAI scores (from a mean of 15 to 3), anti–double‐stranded DNA antibody levels (from a mean of 174 IU/ml to 56 IU/ml), and anti‐C1q antibody levels (from a mean of 35 units/ml to 22 units/ml). On repeat renal biopsy, improvement in the histopathologic class of nephritis occurred in a majority of patients, and a decrease in the renal activity index was noted (from 6 to 3). A reduction in the number of CD3, CD4, and CD20 cells in the renal interstitium was noted in 50% of the patients on repeat biopsy.ConclusionAt 6 months of followup, all patients had responded both clinically and histopathologically to combination therapy. For patients with proliferative lupus nephritis who fail to respond to conventional immunosuppressive therapy including CYC, combined treatment with rituximab and CYC may constitute a new treatment option.
Clinical and immunogenetic features of patients with autoantibodies to asparaginyl–transfer RNA synthetase
Authors: Hirakata Michito , Suwa Akira , Takada Tetsuya , Sato Shinji , Nagai Sonoko , Genth Ekkehard , Song Yeong W. , Mimori Tsuneyo , Targoff Ira N. 
Published: March 2007

AbstractObjectiveWe have previously described anti‐KS autoantibodies and provided evidence that they are directed against asparaginyl–transfer RNA (tRNA) synthetase (AsnRS). The aim of the present study was to identify patients with anti‐AsnRS autoantibodies and elucidate the clinical significance of this sixth antisynthetase antibody. In particular, we studied whether it was associated with the syndrome of myositis (polymyositis or dermatomyositis [DM]), interstitial lung disease (ILD), arthritis, and other features that had been previously associated with the 5 other anti–aminoacyl–tRNA synthetase autoantibodies.MethodsMore than 2,500 sera from patients with connective tissue disease (including myositis and ILD) and controls were examined for anti‐AsnRS autoantibodies by immunoprecipitation (IP). Positive and control sera were tested for the ability to inhibit AsnRS by preincubation of the enzyme source with the serum. The HLA class II (DRB1, DQA1, DQB1, DPB1) alleles were identified from restriction fragment length polymorphism of polymerase chain reaction–amplified genomic DNA.ResultsAnti‐AsnRS antibodies were identified in the sera of 8 patients (5 Japanese, 1 American, 1 German, and 1 Korean) by IP of the same distinctive set of tRNA and protein that differed from those precipitated by the other 5 antisynthetases, and these antibodies showed specific inhibition of AsnRS activity. Two of these patients had DM, but 7 of 8 (88%) had ILD. Four patients (50%) had arthritis, and 1 had Raynaud's phenomenon. This antisynthetase was very rare among myositis patients (present in 0% of Japanese myositis patients), but it was found in 3% of Japanese ILD patients. Thus, most patients with anti‐AsnRS had chronic ILD with or without features of connective tissue disease. Interestingly, all 4 Japanese patients tested had DR2 (DRB1*1501/1502), compared with 33% of healthy controls.ConclusionThese results indicate that anti‐AsnRS autoantibodies, like anti–alanyl–tRNA synthetase autoantibodies, have a stronger association with ILD than with myositis and may be associated with the DR2 phenotype.
Knee alignment does not predict incident osteoarthritis: The Framingham osteoarthritis study
Authors: Hunter David J. , Niu Jingbo , Felson David T. , Harvey William F. , Gross K. Douglas , McCree Paula , Aliabadi Piran , Sack Burton , Zhang Yuqing 
Published: March 2007

AbstractObjectiveTo examine the relationship of knee malalignment to the occurrence of knee osteoarthritis (OA) among subjects without radiographic OA at baseline to determine whether malalignment is a risk factor for incident disease or simply a marker of increasing disease severity.MethodsWe selected 110 incident tibiofemoral (TF) OA case knees (76 subjects) and 356 random control knees (178 subjects) from among participants in the Framingham Osteoarthritis Study. Case knees did not have OA at baseline (1992–1994 examination) but had developed OA (Kellgren/Lawrence grade ≥2) at followup (2002–2005 examination) (mean of 8.75 years between examinations). Control knees did not have OA at baseline. Standardized digital radiographs of the fully extended knee with weight‐bearing were read using a standard protocol and eFilm viewing software. We measured the anatomic axis, the condylar angle, the tibial plateau angle, and the condylar tibial plateau angle. The interobserver intraclass correlation coefficient (ICC) ranged from 0.93 to 0.96 and the intraobserver ICC from 0.94 to 0.97. In a knee‐specific analysis, we examined the relationship of each alignment measurement to the risk of TF OA using generalized estimating equations, adjusting for age, sex, and body mass index (BMI). We used the same approach to assess the association between each alignment measurement and the risk of medial TF OA.ResultsSubjects in the case population were older and had a higher BMI than the controls. The alignment values were normally distributed and were not different between the cases and the controls. After adjustment for age, sex and BMI, there was no significant increase in incident OA in the highest quartile compared with the lowest quartile category for any of the alignment measures (P for trend for anatomic axis and condylar tibial plateau angle was 0.83 and 0.80, respectively). Similar results were also observed for medial compartment OA.ConclusionWe found that baseline knee alignment is not associated with either incident radiographic TF OA or medial TF OA. These results suggest that malalignment is not a risk factor for OA, but rather is a marker of disease severity and/or its progression.
Reproductive and menopausal factors and risk of systemic lupus erythematosus in women
Authors: Costenbader Karen H. , Feskanich Diane , Stampfer Meir J. , Karlson Elizabeth W. 
Published: March 2007

AbstractObjectiveSystemic lupus erythematosus (SLE) occurs predominantly in women, and hormones may play a role in its etiology. This study was carried out to examine associations between female reproductive and menopausal factors and the development of SLE.MethodsA cohort of 238,308 women was prospectively examined. Subjects were older women (ages 30–55 years at start) and younger women (ages 25–42 years at start) from the Nurses' Health Study (NHS) and NHSII cohorts. Incident SLE diagnosed between 1976 and 2003 was confirmed by medical record review. The relative risk (RR) of SLE was estimated separately in each cohort using Cox proportional hazards models, and then pooled using meta‐analysis random effects models.ResultsTwo hundred sixty‐two incident cases of SLE were confirmed among the women. In multivariable models adjusted for reproductive and other risk factors, age ≤10 years at menarche (pooled RR 2.1, 95% confidence interval [95% CI] 1.4–3.2), oral contraceptive use (pooled RR 1.5, 95% CI 1.1–2.1), and use of postmenopausal hormones (RR 1.9, 95% CI 1.2–3.1) significantly increased the risk of SLE. An elevation of SLE risk was observed among postmenopausal women primarily after surgical menopause (RR 2.3, 95% CI 1.2–4.5), and also among women with earlier age at natural menopause (P for trend < 0.05). Menstrual irregularity was associated with an increased risk of SLE among women in the younger (NHSII) cohort. Age at first birth, parity, and total duration of breastfeeding were not associated with SLE.ConclusionEarly age at menarche, oral contraceptive use, early age at menopause, surgical menopause, and postmenopausal use of hormones were each associated with an increased risk of SLE. These associations may point to the mechanisms underlying the pathogenesis of SLE.