bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rituximab is effective in the treatment of refractory ophthalmic Wegener's granulomatosis
Authors: Taylor Simon R. J. , Salama Alan D. , Joshi Lavnish , Pusey Charles D. , Lightman Susan L. 
Published: April 2009

AbstractObjectiveTo investigate the efficacy of rituximab in patients with refractory ophthalmic Wegener's granulomatosis (WG).MethodsData from 10 consecutive patients with refractory ophthalmic WG treated with rituximab were retrospectively reviewed. In all patients, the ophthalmic disease was driving treatment decisions, and disease activity had persisted despite standard immunosuppressive treatment. Patients had refractory scleritis (n = 3), orbital granulomas causing optic nerve compromise (n = 4), or a combination of both conditions (n = 3). All patients had been treated with at least 3 different immunosuppressive agents, and 5 patients had previously been treated with tumor necrosis factor α blockade. Rituximab was administered intravenously in 2 doses, 2 weeks apart, in combination with standard treatment. Disease activity was monitored clinically by an interdisciplinary approach, including disease activity scoring, immunodiagnostics, and magnetic resonance imaging, as well as by corresponding reductions in the required dose of conventional medication.ResultsA beneficial response to treatment with rituximab was seen in all 10 patients, including induction of clinical remission. In all patients, the peripheral blood B cell count fell to zero during treatment with rituximab. Titers of classic antineutrophil cytoplasmic antibodies fell in association with B cell counts, and this reduction was correlated with improved clinical findings.ConclusionIn contrast to previous observations, this study showed that treatment with rituximab was associated with clinical improvement in patients with refractory ophthalmic WG.
The high prevalence of knee osteoarthritis in a rural Chinese population: The Wuchuan osteoarthritis study
Authors: Kang Xiaozheng , Fransen Marlene , Zhang Yuqing , Li Hu , Ke Yan , Lu Ming , Su Steve , Song Xiongying , Guo Yong , Chen Jie , Niu Jingbo , Felson David , Lin Jianhao 
Published: April 2009

AbstractObjectiveTo estimate the prevalence of radiographic and symptomatic knee osteoarthritis (OA) in a remote rural region of northern China, and compare them with those reported in Beijing and with data from the Framingham (Massachusetts) cohort.MethodsA population‐based cross‐sectional survey was conducted among 1,030 residents of Wuchuan County, Inner Mongolia, age ≥50 years. Survey participants, mostly farmers reporting heavy physical occupational activity, completed an interviewer‐based questionnaire, and bilateral weight‐bearing posteroanterior semiflexed knee radiographs were obtained.ResultsWhereas the overall prevalence of radiographic knee OA was similar to that demonstrated in the Beijing OA study, men in Wuchuan had approximately double the prevalence of severe radiographic knee OA (prevalence ratio [PR] 2.5, 95% confidence interval [95% CI] 1.6–3.8) and symptomatic knee OA (PR 1.9, 95% CI 1.3–2.9). Women in Wuchuan also had a higher prevalence of both severe radiographic (PR 1.4, 95% CI 1.0–2.0) and symptomatic knee OA (PR 1.6, 95% CI 1.2–2.1) compared with their Beijing counterparts. The prevalence of bilateral OA and lateral compartment disease were 2–3 times higher in both Chinese cohorts compared with estimates from the Framingham OA study.ConclusionThe prevalence of symptomatic knee OA in rural areas of China is much higher than reported from urban regions of China or in the Framingham cohort. The higher representation of bilateral and lateral compartment disease in China suggests a unique phenotype to OA. These findings will be useful for guiding the distribution of future health care resources and preventive strategies. This article was published online on April 29, 2009. The incorrect figure was published for Figure 1. This notice is included in the online and print versions to indicate that both have been corrected.
Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis
Authors: Maksymowych W. P. , Inman R. D. , Gladman D. D. , Reeve J. P. , Pope A. , Rahman P. 
Published: April 2009

AbstractObjectiveAlterations in antigen processing have been proposed to play a significant role in the pathogenesis of ankylosing spondylitis (AS). A non–major histocompatibility complex gene encoding an endoplasmic reticulum aminopeptidase, ERAP1, has been implicated recently. This study assessed 13 coding single‐nucleotide polymorphisms (SNPs) from 5 genes involved in antigen processing (ERAP1, TAP1, TAP2, LMP2, and LMP7) in 3 Canadian cohorts of patients with AS, to address the possibility of gene interactions in disease susceptibility.MethodsThe study involved 992 AS cases and 1,437 controls from 3 centers (472 cases and 451 controls from Alberta, 138 cases and 392 controls from Newfoundland, and 382 cases and 594 controls from Toronto). Most of the patients with AS and healthy, unrelated controls were Caucasians of northern European descent. Single‐marker and haplotype associations were determined using an allelic likelihood ratio test in UNPHASED, version 3.0.12, and the WHAP program, respectively. P values for significance of haplotype associations were calculated using a permutation test.ResultsA specific ERAP1 haplotype, rs27044/10050860/30187‐CCT, was strongly associated with increased risk of AS in all 3 case–control cohorts (pooled odds ratio [OR] 1.81, 95% confidence interval [95% CI] 1.46–2.24; P = 7 × 10−8), while a second specific ERAP1 haplotype, rs30187/26618/26653‐CTG, reduced the disease risk (pooled OR 0.77, 95% CI 0.67–0.88; P = 9 × 10−5). Significant associations were also noted for 3 ERAP1 SNP variants (rs10050860, rs30187, and rs26653), although no significant haplotype interaction between ERAP1 and TAP/LMP loci was evident.ConclusionThese data indicate that an AS disease locus may reside on a specific ERAP1 haplotype, and its effect is not multiplicative with contributions from TAP and LMP genes.
Premature atherosclerosis in pediatric systemic lupus erythematosus: Risk factors for increased carotid intima‐media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort
Authors: Schanberg Laura E. , Sandborg Christy , Barnhart Huiman X. , Ardoin Stacy P. , Yow Eric , Evans Gregory W. , Mieszkalski Kelly L. , Ilowite Norman T. , Eberhard Anne , Levy Deborah M. , Kimura Yukiko , von Scheven Emily , Silverman Earl , Bowyer Suzanne L. , Punaro Lynn , Singer Nora G. , Sherry David D. , McCurdy Deborah , Klein‐Gitelman Marissa , Wallace Carol , Silver Richard , Wagner‐Weiner Linda , Higgins Gloria C. , Brunner Hermine I. , Jung Lawrence , Soep Jennifer B. , Reed Ann ,   Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators
Published: April 2009

AbstractObjectiveTo evaluate risk factors for subclinical atherosclerosis in a population of patients with pediatric systemic lupus erythematosus (SLE).MethodsIn a prospective multicenter study, a cohort of 221 patients underwent baseline measurements of carotid intima‐media thickness (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess the thickness of the bilateral common carotid arteries and the mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT, which were examined in multivariable linear regression modeling.ResultsBased on the mean‐mean common or the mean‐max CIMT as the dependent variable, univariable analysis showed significant associations of the following variables with increased CIMT: increasing age, longer SLE duration, minority status, higher body mass index (BMI), male sex, increased creatinine clearance, higher lipoprotein(a) level, proteinuria, azathioprine treatment, and prednisone dose. In multivariable modeling, both azathioprine use (P = 0.005 for the mean‐mean model and P = 0.102 for the mean‐max model) and male sex (P < 0.001) were associated with increases in the mean‐max CIMT. A moderate dosage of prednisone (0.15–0.4 mg/kg/day) was associated with decreases in the mean‐max CIMT (P = 0.024), while high‐dose and low‐dose prednisone were associated with increases in the mean‐mean common CIMT (P = 0.021) and the mean‐max CIMT (P = 0.064), respectively. BMI (P < 0.001) and creatinine clearance (P = 0.031) remained associated with increased mean‐mean common CIMT, while increasing age (P < 0.001) and increasing lipoprotein(a) level (P = 0.005) were associated with increased mean‐max CIMT.ConclusionTraditional as well as nontraditional risk factors were associated with increased CIMT in this cohort of patients in the APPLE trial. Azathioprine treatment was associated with increased CIMT. The relationship between CIMT and prednisone dose may not be linear.
The α7 nicotinic acetylcholine receptor on fibroblast‐like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation
Authors: Maanen Marjolein A. Van , Stoof Susanne P. , Zanden Esmerij P. Van Der , Jonge Wouter J. De , Janssen Richard A. , Fischer David F. , Vandeghinste Nick , Brys Reginald , Vervoordeldonk Margriet J. , Tak Paul P. 
Published: April 2009

AbstractObjectiveRecent studies have suggested an important role for neurotransmitters as modulators of inflammation. Therefore, we undertook this study to investigate the expression of the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) and its function in rheumatoid arthritis (RA).MethodsThe potential role of the α7nAChR in modulating proinflammatory cytokine expression in fibroblast‐like synoviocytes (FLS) was identified by screening an adenoviral short hairpin RNA (Ad.shRNA) library. An α7‐specific antibody was used for immunohistochemistry, and fluorescein isothiocyanate–labeled α‐bungarotoxin, which binds specifically to the α7nAChR, was used for immunofluorescence. Gene expression in FLS was determined by quantitative polymerase chain reaction with primers specific for the α7nAChR. In addition, we analyzed messenger RNA (mRNA) expression of dupα7, a variant α7 transcript. Next, we studied the functional role of the α7nAChR in RA FLS by examining the effects of α7‐specific agonists on the production of interleukin‐6 (IL‐6) and IL‐8 by activated FLS.ResultsA screen using an Ad.shRNA library against 807 transcripts revealed that a specific α7nAChR shRNA potently modulated IL‐8 and matrix metalloproteinase expression in FLS. The α7nAChR was expressed in the inflamed synovium from RA patients, predominantly in the intimal lining layer. We found α7nAChR expression at both the mRNA and protein level in cultured RA FLS. FLS also constitutively expressed dupα7 mRNA. Specific α7nAChR agonists reduced tumor necrosis factor α–induced IL‐6 and IL‐8 production by FLS.ConclusionThe α7nAChR and its dupα7 variant are expressed in RA synovium, where they may play a critical role in regulating inflammation. Targeting the α7nAChR could provide a novel antiinflammatory approach to the treatment of RA.
Induction of the expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents
Authors: Wermuth Peter J. , del Galdo Francesco , Jiménez Sergio A. 
Published: April 2009

AbstractObjectiveNephrogenic systemic fibrosis (NSF) is a severe fibrosing disorder occurring in patients with renal insufficiency. The majority of patients with this disorder have documented exposure to magnetic resonance imaging contrast agents containing Gd. The purpose of this study was to examine the effects of gadolinium diethylenetriaminepentaacetic acid bismethylamide (Gd[DTPA‐BMA]; Omniscan) as compared with Gd‐DTPA and GdCl3 on the expression and production of cytokines and growth factors by normal human peripheral blood monocytes in vitro and to examine whether conditioned media from Gd‐exposed peripheral blood monocytes could induce a profibrotic phenotype in dermal fibroblasts.MethodsNormal human peripheral blood monocytes isolated by Ficoll‐Hypaque gradient centrifugation and plastic adherence were incubated with various concentrations of Gd[DTPA‐BMA], Gd‐DTPA, or GdCl3. Gene expression of interleukins 4, 6, and 13, interferon‐γ, tumor necrosis factor α, transforming growth factor β, connective tissue growth factor, and vascular endothelial growth factor were assessed by real‐time polymerase chain reaction (PCR) analysis. Production and secretion of cytokines and growth factors by Gd compound–exposed monocytes was quantified by enzyme‐linked immunosorbent assay proteome multiplex arrays. The effects of conditioned media from the Gd compound–exposed monocytes on the phenotype of normal human dermal fibroblasts were examined by real‐time PCR and Western blotting.ResultsThe 3 Gd‐containing compounds stimulated the expression and production of numerous cytokines and growth factors by normal human peripheral blood monocytes. Conditioned media from these cells induced a profibrotic phenotype in normal human dermal fibroblasts.ConclusionThe 3 Gd‐containing compounds studied induce potent cellular responses in normal human peripheral blood monocytes, which may participate in the development of tissue fibrosis in NSF.
Methylation status of CpG islands in the promoter regions of signature genes during chondrogenesis of human synovium–derived mesenchymal stem cells
Authors: Ezura Yoichi , Sekiya Ichiro , Koga Hideyuki , Muneta Takeshi , Noda Masaki 
Published: April 2009

AbstractObjectiveHuman synovium–derived mesenchymal stem cells (MSCs) can efficiently differentiate into mature chondrocytes. It has been suggested that DNA methylation is one mechanism that regulates human chondrogenesis; however, the methylation status of genes related to chondrogenic differentiation is not known. The purpose of this study was to investigate the CpG methylation status in human synovium–derived MSCs during experimental chondrogenesis, with a view toward potential therapeutic use in osteoarthritis.MethodsHuman synovium–derived MSCs were subjected to chondrogenic pellet culture for 3 weeks. The methylation status of 12 regions in the promoters of 10 candidate genes (SOX9, RUNX2, CHM1, FGFR3, CHAD, MATN4, SOX4, GREM1, GPR39, and SDF1) was analyzed by bisulfite sequencing before and after differentiation. The expression levels of these genes were analyzed by real‐time reverse transcription–polymerase chain reaction. Methylation status was also examined in human articular cartilage.ResultsBisulfite sequencing analysis indicated that 10 of the 11 CpG‐rich regions analyzed were hypomethylated in human progenitor cells before and after 3 weeks of pellet culture, regardless of the expression levels of the genes. The methylation status was consistently low in SOX9, RUNX2, CHM1, CHAD, and FGFR3 following an increase in expression upon differentiation and was low in GREM1 and GPR39 following a decrease in expression upon chondrogenesis. One exceptional instance of a differentially methylated CpG‐rich region was in a 1‐kb upstream sequence of SDF1, the expression of which decreased upon differentiation. Paradoxically, the hypermethylation status of this region was reduced after 3 weeks of pellet culture.ConclusionThe DNA methylation levels of CpG‐rich promoters of genes related to chondrocyte phenotypes are largely kept low during chondrogenesis in human synovium–derived MSCs.
MicroRNA‐124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast‐like synoviocytes from patients with rheumatoid arthritis
Authors: Nakamachi Yuji , Kawano Seiji , Takenokuchi Mariko , Nishimura Kunihiro , Sakai Yoshitada , Chin Takaaki , Saura Ryuichi , Kurosaka Masahiro , Kumagai Shunichi 
Published: April 2009

AbstractObjectiveTo elucidate the role of microRNA (miRNA) in the pathogenesis of rheumatoid arthritis (RA), we analyzed synoviocytes from RA patients for their miRNA expression.MethodsSynoviocytes derived from surgical specimens obtained from RA patients were compared with those obtained from osteoarthritis (OA) patients for their expression of a panel of 156 miRNA with quantitative stem‐loop reverse transcription–polymerase chain reaction. The miRNA whose expression decreased or increased in RA synoviocytes as compared with OA synoviocytes were identified, and their target genes were predicted by computer analysis. We used an in vitro system of enhancing the expression of specific miRNA by transfection of precursors into synoviocytes, and then we performed proliferation, cell cycle, and apoptosis assays, as well as enzyme‐linked immunosorbent assays for cytokine production. The effects of transfection on predicted target protein and messenger RNA (mRNA) were then examined by Western blot analysis and luciferase reporter assay.ResultsWe found that miR‐124a levels significantly decreased in RA synoviocytes as compared with OA synoviocytes. Transfection of precursor miR‐124a into RA synoviocytes significantly suppressed their proliferation and arrested the cell cycle at the G1 phase. We identified a putative consensus site for miR‐124a binding in the 3′‐untranslated region of cyclin‐dependent kinase 2 (CDK‐2) and monocyte chemoattractant protein 1 (MCP‐1) mRNA. Induction of miR‐124a in RA synoviocytes significantly suppressed the production of the CDK‐2 and MCP‐1 proteins. Luciferase reporter assay demonstrated that miR‐124a specifically suppressed the reporter activity driven by the 3′‐untranslated regions of CDK‐2 and MCP‐1 mRNA.ConclusionThe results of this study suggest that miR‐124a is a key miRNA in the posttranscriptional regulatory mechanisms of RA synoviocytes.
Generalized Wegener's granulomatosis in an immunocompetent adult after cytomegalovirus mononucleosis and bacterial urinary tract infection
Authors: Varani Stefania , Mastroianni Antonio , Frascaroli Giada , Tammik Charlotte , Rahbar Afsar , Christensson Marta , Rossini Giada , Landini Maria Paola , Söderberg‐Nauclér Cecilia 
Published: April 2009

AbstractHuman cytomegalovirus (HCMV) is frequently detected in autoimmune diseases, but its role in such disorders is poorly understood. Herein we describe the case of a young woman who developed generalized Wegener's granulomatosis (WG) after HCMV mononucleosis and urinary tract infection. During mononucleosis, the patient had extraordinarily high plasma levels of proinflammatory cytokines such as interleukin‐5 and lymphotoxin α, autoantibodies, and a higher blood level of viral DNA than were found in other immunocompetent patients infected with HCMV or healthy controls. Active HCMV replication was detected after the onset of vasculitis, and HCMV genomes or antigens were found in blood, urine, and inflammatory lesions on the kidney. Thus, HCMV may have triggered or exacerbated inflammation and autoimmunity in this case of WG.
Down‐regulation of myeloid cell leukemia 1 by epigallocatechin‐3‐gallate sensitizes rheumatoid arthritis synovial fibroblasts to tumor necrosis factor α–induced apoptosis
Authors: Ahmed Salahuddin , Silverman Matthew D. , Marotte Hubert , Kwan Kevin , Matuszczak Natalie , Koch Alisa E. 
Published: April 2009

AbstractObjectiveOverexpression of the antiapoptotic protein myeloid cell leukemia 1 (Mcl‐1) in rheumatoid arthritis (RA) synovial fibroblasts is a major cause of their resistance to tumor necrosis factor α (TNFα)–induced apoptosis. This study was undertaken to evaluate the efficacy of epigallocatechin‐3‐gallate (EGCG) in down‐regulating Mcl‐1 expression and its mechanism of RA synovial fibroblast sensitization to TNFα‐induced apoptosis.MethodsEGCG effects on cultured RA synovial fibroblast cell morphology, proliferation, and viability over 72 hours were determined by microscopy and a fluorescent cell enumeration assay. Caspase 3 activity was determined by a colorimetric assay. Western blotting was used to evaluate the apoptosis mediators poly(ADP‐ribose) polymerase (PARP), Mcl‐1, Bcl‐2, Akt, and nuclear translocation of NF‐κB.ResultsIn RA synovial fibroblasts, EGCG (5–50 μM) inhibited constitutive and TNFα‐induced Mcl‐1 protein expression in a concentration‐ and time‐dependent manner (P < 0.05). Importantly, EGCG specifically abrogated Mcl‐1 expression in RA synovial fibroblasts and affected Mcl‐1 expression to a lesser extent in osteoarthritis and normal synovial fibroblasts or endothelial cells. Inhibition of Mcl‐1 by EGCG triggered caspase 3 activity in RA synovial fibroblasts, which was mediated via down‐regulation of the TNFα‐induced Akt and NF‐κB pathways. Caspase 3 activation by EGCG also suppressed RA synovial fibroblast growth, and this effect was mimicked by Akt and NF‐κB inhibitors. Interestingly, Mcl‐1 degradation by EGCG sensitized RA synovial fibroblasts to TNFα‐induced PARP cleavage and apoptotic cell death.ConclusionOur findings indicate that EGCG itself induces apoptosis and further sensitizes RA synovial fibroblasts to TNFα‐induced apoptosis by specifically blocking Mcl‐1 expression and, hence, may be of promising adjunct therapeutic value in regulating the invasive growth of synovial fibroblasts in RA.
Altered mineralization of human osteoarthritic osteoblasts is attributable to abnormal type I collagen production
Authors: Couchourel Denis , Aubry Isabelle , Delalandre Aline , Lavigne Martin , Martel‐Pelletier Johanne , Pelletier Jean‐Pierre , Lajeunesse Daniel 
Published: April 2009

AbstractObjectiveBone tissue in osteoarthritis (OA) is composed of abundant undermineralized osteoid matrix. The aim of this study was to investigate the mechanisms responsible for this abnormal matrix, using in vitro OA subchondral osteoblasts.MethodsPrimary normal and OA osteoblasts were prepared from tibial plateaus. Phenotype was determined by alkaline phosphatase activity, and osteocalcin, osteopontin, prostaglandin E2 (PGE2), and transforming growth factor β1 (TGFβ1) were assessed by enzyme‐linked immunosorbent assay. Expression of COL1A1 and COL1A2 was determined by real‐time polymerase chain reaction. The production of type I collagen was determined by the release of its C‐terminal propeptide and Western blot analysis. In vitro mineralization was evaluated by alizarin red staining. Inhibition of TGFβ1 expression was performed using a small interfering RNA technique.ResultsMineralization of OA osteoblasts was reduced compared with mineralization of normal osteoblasts, even in the presence of bone morphogenetic protein 2 (BMP‐2). Alkaline phosphatase and osteocalcin levels were elevated in OA osteoblasts compared with normal osteoblasts, whereas osteopontin levels were similar. The COL1A1‐to‐COL1A2 messenger RNA ratio was 3‐fold higher in OA osteoblasts compared with normal osteoblasts, and the production of collagen by OA osteoblasts was increased. Because TGFβ1 inhibits BMP‐2–dependent mineralization, and because TGFβ1 levels are ∼4‐fold higher in OA osteoblasts than in normal osteoblasts, inhibiting TGFβ1 levels in OA osteoblasts corrected the abnormal COL1A1‐to‐COL1A2 ratio and increased alizarin red staining.ConclusionElevated TGFβ1 levels in OA osteoblasts are responsible, in part, for the abnormal ratio of COL1A1 to COL1A2 and for the abnormal production of mature type I collagen. This abnormal COL1A1‐to‐COL1A2 ratio generates a matrix that blunts mineralization in OA osteoblasts.