bluuebunny/crossref_metadata_2025_split huggingface dataset:
A functional haplotype of thePADI4gene associated with increased rheumatoid arthritis susceptibility in Koreans
Authors: Kang Changsoo Paul , Lee Hye‐Soon , Ju Hyoungseok , Cho Hyunmi , Kang Changwon , Bae Sang‐Cheol 
Published: December 2005

AbstractObjectiveAnticitrullinating autoantibodies are specific markers for rheumatoid arthritis (RA). A functional haplotype of 4 exonic single‐nucleotide polymorphisms (SNPs) in a citrullinating enzyme, peptidylarginine deiminase 4 (PADI4), was shown to be associated with susceptibility to RA in a Japanese population and was shown to increase the stability ofPADI4messenger RNA. However, the association was not confirmed in 4 subsequent studies involving Caucasian RA patients living in the UK, a French Caucasian population, and a Spanish population. The aim of the current study was to investigate the association of SNPs in thePADI4gene with RA in a Korean population.MethodsFour exonic SNPs of thePADI4gene (padi4_89, padi4_90, padi4_92, and padi4_104) were genotyped in 545 unrelated patients with RA and 392 controls, using the MassArray SNP genotyping system. Allelic, genotypic, and haplotypic associations of the SNPs with RA susceptibility were examined using the chi‐square test and multivariate logistic regression analyses.ResultsIncreased RA susceptibility was significantly associated with the minor alleles of padi4_89 (P= 2.3 × 10−5), padi4_90 (P= 2.3 × 10−5), padi4_92 (P= 2.1 × 10−5), and padi4_104 (P= 1.1 × 10−3) and the haplotype carrying the 4 minor alleles (P= 1.0 × 10−4). Genotypes carrying the minor alleles and HLA–DRB1 shared epitope (SE) alleles (P= 9.4 × 10−21) were also associated with increased RA susceptibility. The genotypic associations were sustained among individuals who did not carry any SE alleles, except in the case of padi4_104. Individuals carrying the risk SNPs and/or SE alleles were more susceptible to RA than were individuals carrying neither risk SNPs nor SE alleles.ConclusionThePADI4SNPs and haplotypes are associated with RA susceptibility in Koreans. Thus, the association ofPADI4with RA may depend on genetic heterogeneity between Asians and Europeans.
More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, and reduction of heart rate by treatment with diclofenac compared with celecoxib and rofecoxib
Authors: Hinz Burkhard , Dormann Harald , Brune Kay 
Published: December 2005

AbstractObjectiveRecent findings suggest that permanent blockade of cyclooxygenase 2 (COX‐2) is one factor contributing to the cardiovascular side effects of selective COX‐2 inhibitors (coxibs) and nonsteroidal antiinflammatory drugs (NSAIDs). The present study compared the extent and time course of COX‐2 inhibition and the effects on cardiovascular parameters (changes in blood pressure and heart rate) between various antirheumatic doses of diclofenac, celecoxib, and rofecoxib in healthy elderly volunteers.MethodsA randomized, parallel‐group study was conducted in volunteers receiving 75 mg diclofenac twice daily, 200 mg celecoxib twice daily, or 25 mg rofecoxib once daily for 8 days. Blood samples were obtained predose and at specified time points postdose, on days 1 and 8, for assay of drug plasma concentrations and COX‐2 inhibition. Lipopolysaccharide‐induced prostaglandin E2synthesis was measured ex vivo as an index of COX‐2 activity in human whole blood.ResultsCOX‐2 inhibition was significantly less pronounced after treatment with celecoxib and rofecoxib than with diclofenac. Maximal inhibitions after a single dose and at steady state, respectively, were as follows: 99% and 99% with diclofenac, 70% and 81% with celecoxib, and 56% and 72% with rofecoxib. At steady state, only diclofenac caused virtually complete COX‐2 inhibition over the whole dose interval, and this corresponded to the highest increase in systolic blood pressure and greatest reduction in heart rate.ConclusionDiclofenac elicited the most pronounced COX‐2 inhibition, blood pressure elevation, and suppression of heart rate. It is assumed that the extent and time course of intravascular COX‐2 inhibition may determine the differential profile of cardiovascular side effects associated with NSAIDs and coxibs, but this has to be proven in future studies.
Variations of neuronal nitric oxide synthase in systemic sclerosis skin
Authors: Ibba‐Manneschi Lidia , Niissalo Sirkku , Milia Anna Franca , Allanore Yannick , Rosso Angela Del , Pacini Alessandra , Manetti Mirko , Toscano Annarita , Cipriani Paola , Liakouli Vasiliki , Giacomelli Roberto , Kahan André , Konttinen Yrjö T. , Matucci‐Cerinic Marco 
Published: December 2005

AbstractObjectiveIn systemic sclerosis (SSc), derangement of the peripheral nervous system is linked to vascular tone dysfunction. Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS, NOS‐I) might play a dynamic role in the control of vascular tone. This study was performed to verify, by immunohistochemical and biochemical analyses, the presence and expression of nNOS and protein gene product 9.5 (PGP 9.5) in SSc skin, in different subsets and various phases of the disease.MethodsBiopsy samples of clinically involved skin from 32 SSc patients (12 with limited cutaneous SSc [lcSSc] and 20 with the diffuse form [dcSSc]) and skin samples from 6 healthy controls were either immunostained with anti–PGP 9.5 and anti‐nNOS antibodies or analyzed by semiquantitative reverse transcription–polymerase chain reaction and Western blotting.ResultsImmunohistochemical and biochemical data showed a decrease in PGP 9.5 and nNOS innervation and in their messenger RNA (mRNA) levels in lcSSc and dcSSc skin. In the edematous phase of SSc, a light alteration in cutaneous innervation was initiated and slowly progressed into the sclerotic phase, becoming most evident in the atrophic phase. Levels of nNOS mRNA were significantly lower between the edematous phase and the sclerotic phase in both dcSSc and lcSSc skin, which was attributable to the earlier occurrence of more severe pathologic alterations.ConclusionTotal cutaneous innervation and nNOS innervation slowly disappear in the skin of SSc patients. Expression of nNOS depends on the severity of tissue damage in SSc, and increased synthesis of NO also contributes to this process. It remains to be determined whether the changes in cutaneous innervation are due to the disease itself or whether these changes contribute to the pathogenesis and evolution of SSc.
Ultrasonographic and radiographic results from a two‐year controlled trial of immediate or one‐year–delayed addition of infliximab to ongoing methotrexate therapy in patients with erosive early rheumatoid arthritis
Authors: Taylor P. C. , Steuer A. , Gruber J. , McClinton C. , Cosgrove D. O. , Blomley M. J. K. , Marsters P. A. , Wagner C. L. , Maini R. N. 
Published: December 2005

AbstractObjectiveTo compare the impact of immediate and delayed introduction of anti–tumor necrosis factor therapy on inflammation and structural damage in methotrexate (MTX)–treated patients with early rheumatoid arthritis (RA).MethodsTwenty‐four patients with erosive early RA (duration <3 years) who were receiving MTX were randomized to receive infliximab 5 mg/kg or placebo infusions at weeks 0, 2, and 6, and then every 8 weeks through week 46. Beginning at week 54 and thereafter, all patients received infliximab 5 mg/kg. Metacarpophalangeal joints were scanned using high‐frequency ultrasonography and power Doppler imaging. Radiographs were evaluated using the modified Sharp/van der Heijde scoring system.ResultsFrom baseline to week 54, total synovial thickness was significantly improved in the infliximab + MTX group compared with the placebo + MTX group (median reduction 95.8% versus 37.5%; P = 0.005), as was the total color Doppler area (CDA; vascularity assessment) (median reduction 100% and 47.1%, respectively; P = 0.025). From week 0 to week 110, no significant between‐group difference was observed in the change from baseline for total synovial thickening or the total CDA. At week 54, greater progression in the Sharp/van der Heijde score was apparent in patients receiving placebo + MTX compared with those receiving infliximab + MTX. Although radiographic progression in the placebo + MTX group was greatly reduced in the second year (after initiation of infliximab therapy), marked differences were observed between the infliximab + MTX group (median change in the Sharp/van der Heijde score 4.0) and the placebo + MTX group (median change 14.5) from baseline to week 110 (P = 0.076).ConclusionThe results indicate that the efficacy of 2 years of combination therapy with infliximab + MTX for inhibiting cumulative structural damage was superior to that of 1 year of treatment with MTX alone followed by the addition of infliximab.
The impact of a diagnosis of fibromyalgia on health care resource use by primary care patients in the UK: An observational study based on clinical practice
Authors: Hughes Gwenda , Martinez Carlos , Myon Eric , Taïeb Charles , Wessely Simon 
Published: December 2005

AbstractObjectiveTo investigate the impact of a diagnosis of fibromyalgia (FM) in clinical practice on health care resource use in the UK.MethodsRates of visits, prescriptions, referral, and diagnostic testing were estimated in patients who had been diagnosed as having FM between 1998 and March 2003 in UK primary care and compared with those in matched controls. Rates were calculated in 6‐month intervals from 10 years before until 4 years after the FM diagnosis.ResultsPatients (2260) were newly diagnosed as having FM; 81.3% were women. Their mean age was 49 years. FM patients had considerably higher rates of visits, prescriptions, and testing from at least 10 years prior to diagnosis compared with controls. By the time of diagnosis, FM patients had 25 visits and 11 prescriptions per year compared with 12 visits and 4.5 prescriptions per year in controls. Visit rates were highest for depression, followed by fatigue, chest pain, headache, and sleep disturbance. Following diagnosis, visits for most symptoms and health care use markers declined, but within 2–3 years, most visits rose to levels at or higher than those at diagnosis.ConclusionPrimary care patients who had been diagnosed as having FM reported higher rates of illness and health care resource use for at least 10 years prior to their diagnosis, which suggests that illness behavior may play a role. Being diagnosed as having FM may help patients cope with some symptoms, but the diagnosis has a limited impact on health care resource use in the longer term, possibly because there is little effective treatment.
Transforming growth factor β1 in the pathogenesis of autoimmune congenital complete heart block: Lesson from twins and triplets discordant for the disease
Authors: Cimaz Rolando , Orietta Borghi Maria , Gerosa Maria , Biggioggero Martina , Raschi Elena , Meroni Pier Luigi 
Published: December 2005

AbstractObjectiveClinical evidence and experimental evidence suggest that anti‐Ro/La autoantibodies are necessary but not sufficient for the development of congenital complete heart block (CCHB). Maternal, fetal, and environmental factors may also contribute to heart damage in CCHB. The aim of our study was to investigate polymorphisms of transforming growth factor β1 (TGFβ1) and tumor necrosis factor α (TNFα) genes in twins and triplets discordant for CCHB whose mothers are anti‐Ro/La positive.MethodsWe studied 2 families in which 1 of the mothers gave birth to triplets and the other gave birth to twins. Only 1 child in each family was affected by CCHB, although 1 of the triplets had incomplete heart block. We analyzed TNFα and TGFβ1 polymorphisms in the 2 babies with CCHB and their siblings. TNFα polymorphisms at the promoter region and TGFβ1 polymorphisms at codons 10 and 25 were determined using polymerase chain reaction–restriction fragment length polymorphism analysis. In addition, the production of TGFβ1 and TNFα by resting or mitogen‐stimulated peripheral blood mononuclear cells in cell culture supernatants was evaluated by enzyme‐linked immunosorbent assay.ResultsThe profibrotic TGFβ1 genotype was detected in the twin with CCHB but not in the healthy twin, while all of the triplets displayed the same TGFβ1 genotype at codon 10. Peripheral blood mononuclear cells from the children with CCHB displayed higher spontaneous and mitogen‐stimulated TGFβ1 secretion than was observed in their siblings. No differences regarding TNFα polymorphisms and secretion of TNFα were observed.ConclusionThe results of this study suggest that, besides anti‐Ro/La autoantibodies, a fetal profibrotic response might contribute to the development of CCHB, but additional pathogenic mechanism(s) are also likely to play a role.
Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF‐κB/Rel proteins via the p38 mitogen‐activated protein kinase pathway, and of the MEK‐1/ERK pathway
Authors: López‐Pedrera Chary , Buendía Paula , José Cuadrado Maria , Siendones Emilio , Angeles Aguirre Maria , Barbarroja Nuria , Montiel‐Duarte Cristina , Torres Antonio , Khamashta Munther , Velasco Francisco 
Published: December 2005

AbstractObjectiveAntiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL). In patients with primary APS, expression of tissue factor (TF) on the surface of monocytes is increased, which may contribute to thrombosis in these patients. However, the intracellular mechanisms involved in aPL‐mediated up‐regulation of TF on monocytic cells are not understood. This study was undertaken to investigate the intracellular signals induced by aPL that mediate TF activation in monocytes from APS patients.MethodsWe analyzed, both in vivo and in vitro, aPL interactions with proteins that have signaling functions, including mitogen‐activated protein kinases (MAP kinases) and NF‐κB/Rel proteins.ResultsIn vivo studies demonstrated significantly higher levels of both TF messenger RNA and TF protein in monocytes from APS patients compared with controls. At the molecular level, increased proteolysis of IκBα and activation of NF‐κB were observed. Constitutive activation of both p38 and ERK‐1 MAP kinases was also found. Treatment of normal monocytes with aPL activated ERK‐1 and p38 MAP kinases, as well as the IκB/NF‐κB pathway, in a dose‐dependent manner. NF‐κB activation and IκBα degradation induced by aPL were inhibited by the NF‐κB inhibitor SN50 and the p38 MAP kinase inhibitor SB203580, thus suggesting crosstalk between these pathways. However, the MEK‐1/ERK inhibitor PD98059 did not affect aPL‐induced NF‐κB binding activity. TF expression induced by aPL was significantly inhibited by combined treatment with the 3 inhibitors.ConclusionOur results suggest that aPL induces TF expression in monocytes from APS patients by activating, simultaneously and independently, the phosphorylation of MEK‐1/ERK proteins, and the p38 MAP kinase–dependent nuclear translocation and activation of NF‐κB/Rel proteins.
Production of a novel class of polyreactive pathogenic autoantibodies in BXD2 mice causes glomerulonephritis and arthritis
Authors: Hsu Hui‐Chen , Zhou Tong , Kim Helen , Barnes Stephen , Yang PingAr , Wu Qi , Zhou Juling , Freeman Bruce A. , Luo Ming , Mountz John D. 
Published: December 2005

AbstractObjectiveThe BXD2 mouse strain spontaneously develops glomerulonephritis and erosive arthritis. The goal of this study was to identify the antigenic target proteins and epitopes and to unravel the mechanisms by which the related conditions arise in BXD2 mice.MethodsIndividual hybridomas isolated from the spleen of a 10‐month‐old BXD2 mouse were injected intraperitoneally into nonautoimmune mice for evaluation of pathogenicity of each autoantibody. Autoantigens were immunoprecipitated with the pathogenic autoantibody L3A4. Autoantigens were identified using enzyme‐linked immunosorbent assay, Western blotting, 2‐dimensional gel electrophoresis, and matrix‐assisted laser desorption ionization–time‐of‐flight mass spectrometry (MS) and tandem MS. Antigenic epitopes were determined using a high‐throughput epitope mapping method.ResultsThe production of autoantibodies in BXD2 mice occurred in an orderly progression, with peak levels of autoantibodies to nitrotyrosine (NT)–modified enolase, Ro, α‐actin, and heat‐shock proteins (HSPs) preceding peak levels of antihistone, anti‐DNA, and rheumatoid factor. Two monoclonal autoantibodies, L3A4 and T56G10, were identified that could induce immune complexes, renal disease, and/or arthritis. Both L3A4 and T56G10 were polyreactive, and each reacted with separate sets of autoantigens. The antigenic targets of L3A4 consisted of NT‐modified enolase, ATP5b, α‐actin, and Hsp70 family proteins including Hspa5 and Hsp74. The antigenic epitopes of NT‐modified enolase and Hspa5 exhibited sequence homology and cross‐reactivity, suggesting that epitope spreading may occur through a molecular mimicry mechanism.ConclusionThe polyreactivity of autoantibodies that target a novel class of autoantigens may enable these autoantibodies to induce erosive arthritis or glomerulonephritis either by direct pathogenic mechanisms or indirectly via Fc or immune complex deposition.
Spondylarthritis‐associated and non–spondylarthritis‐associated B27 subtypes differ in their dependence upon tapasin for surface expression and their incorporation into the peptide loading complex
Authors: Goodall Jane C. , Ellis Lou , Hill Gaston J. S. 
Published: December 2005

AbstractObjectiveB27 subtypes associated with susceptibility to ankylosing spondylitis (AS), and those reported not to be associated with AS, are found to differ in the amino acids that are known in other HLA class I molecules to alter the requirements for tapasin and incorporation into the peptide loading complex. The purpose of this study was to examine the behavior of B*2704 and B*2705 in comparison with B*2706 and B*2709 during early events in HLA class I antigen expression, and determine if their behavior correlates with disease association.MethodsCell lines with nonfunctional tapasin were transiently transfected with different B27 subtypes and their site‐directed mutants, and surface expression analyzed by flow cytometry. The association with the peptide loading complex was determined by immunoprecipitation of heterodimeric transporter‐associated peptide and analysis of coprecipitated B27.ResultsAmino acids at positions 114, 116, and 152 in the different B27 subtypes were shown to perform key roles in defining a requirement for interaction with tapasin. Not all disease‐associated alleles were expressed optimally in the absence of tapasin; furthermore, dependence on tapasin for cell surface expression did not correlate with disease association. Although B*2706, which is not associated with disease, exhibited a number of properties different from those of the disease‐associated subtypes, these properties were not displayed by the non–disease‐associated allele B*2709.ConclusionThese results indicate that the ability to exhibit optimal cell surface expression in the absence of tapasin is not a prerequisite for susceptibility to AS.
Toll‐like receptor 9 signaling protects against murine lupus
Authors: Wu Xiaobo , Peng Stanford L. 
Published: December 2005

AbstractObjectiveHypomethylated CpG–containing DNA, which is recognized by Toll‐like receptor 9 (TLR‐9), has been strongly implicated in the pathogenesis of autoantibody‐mediated diseases such as systemic lupus erythematosus. This study was undertaken to determine the role of TLR‐9 in the MRL/+ and MRL/lpr models of murine lupus.MethodsTLR‐9–deficient MRL mice were generated by backcrossing a TLR‐9–deficient allele against the MRL backgrounds by a speed congenic technique. Parameters of murine lupus were examined by routine methods. Regulatory T cell activity was assessed by autologous mixed lymphocyte reaction (AMLR), an in vitro assay for autoreactivity.ResultsSurprisingly, TLR‐9–deficient animals of both the MRL/+ and the MRL/lpr backgrounds developed more severe lupus, as judged by anti‐DNA and rheumatoid factor autoantibodies, total serum Ig isotypes, lymphadenopathy, inflammatory infiltrates in the salivary gland and kidney, proteinuria, and mortality, in comparison with their TLR‐9–sufficient littermates. In vitro, regulatory T cells from TLR‐9–deficient animals were impaired in their ability to suppress the AMLR.ConclusionIn the MRL model of murine lupus, TLR‐9 signaling plays a protective role, perhaps by modulating the activity of regulatory T cells. These results contrast with findings of recent studies that implicate TLR‐9 in the pathogenesis of anti‐DNA responses, based in part on investigations in incompletely backcrossed TLR‐9–deficient MRL/lpr mice in vivo or transgenic B cells in vitro. The present results highlight the need for caution in the assessment of disease paradigms based on the study of isolated cell populations in vitro, as well as in vivo studies of knockout animals involving non‐ideal genetic models.
Prevention and reversal of nephritis in MRL/lpr mice with a single injection of C‐reactive protein
Authors: Rodriguez Wilfredo , Mold Carolyn , Marnell Lorraine L. , Hutt Julie , Silverman Gregg J. , Tran Dao , Du Clos Terry W. 
Published: December 2005

AbstractObjectiveC‐reactive protein (CRP) is an acute‐phase serum protein with binding reactivity to nuclear autoantigens and immunomodulatory function. The MRL/lpr mouse is an important model of human systemic lupus erythematosus (SLE). These mice develop high‐titer anti‐DNA antibodies and immune complex–mediated nephritis and exhibit progressive lymphadenopathy. The mortality rate among these mice is 50% by age 18–20 weeks; the most frequent cause of death is glomerulonephritis. The present study was undertaken to determine whether treatment of mice with CRP would affect the course of lupus nephritis.MethodsMRL/lpr mice were treated with a single 200‐μg injection of CRP at either age 6 weeks (before disease onset) or age 13 or 15 weeks (when proteinuria had reached high levels). Proteinuria was measured weekly, and levels of anti–double‐stranded DNA autoantibodies and blood urea nitrogen were determined monthly. Glomerular immune complex deposition and renal pathology were assessed in mice ages 15 weeks and 17 weeks.ResultsEarly CRP treatment markedly delayed the onset of proteinuria and lymphadenopathy, increased survival, and reduced levels of autoantibodies to DNA. Treatment of mice with active disease reversed proteinuria and prolonged survival. Renal disease was decreased in CRP‐treated mice, with a marked suppression of glomerular pathology, tubular degeneration, and interstitial inflammation, which correlated with the decrease in proteinuria and azotemia.ConclusionThese findings demonstrate that systemic suppression of autoimmunity is initiated by a single injection of CRP. Long‐term maintenance of CRP‐mediated protection was reversed by injection of an anti‐CD25 monoclonal antibody but not by macrophage depletion, suggesting that disease suppression is maintained by CD25‐bearing T cells.