bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of COL10A1 induction during chondrogenesis of mesenchymal stem cells with demethylation of two CpG sites in the COL10A1 promoter
Authors: Zimmermann Peter , Boeuf Stéphane , Dickhut Andrea , Boehmer Sandra , Olek Sven , Richter Wiltrud
Published: August 2008

Objective

Human articular chondrocytes do not express COL10A1 and do not undergo hypertrophy except in close vicinity to subchondral bone. In contrast, chondrocytes produced in vitro from mesenchymal stem cells (MSCs) show premature COL10A1 expression and cannot form stable ectopic cartilage transplants, which indicates that they may be phenotypically unstable and not suitable for treatment of articular cartilage lesions. CpG methylation established during natural development may play a role in suppression of COL10A1 expression and hypertrophy in human articular chondrocytes. This study was undertaken to compare gene methylation patterns and expression of COL10A1 and COL2A1 in chondrocyte and MSC populations, in order to determine whether failed genomic methylation patterns correlate with an unstable chondrocyte phenotype after chondrogenesis of MSCs.

Methods

COL10A1 and COL2A1 regulatory gene regions were computationally searched for CpG‐rich regions. CpG methylation of genomic DNA from human articular chondrocytes, MSCs, and MSC‐derived chondrocytes was analyzed by Combined Bisulfite Restriction Analysis and by sequencing of polymerase chain reaction fragments amplified from bisulfite‐treated genomic DNA.

Results

The CpG island around the transcription start site of COL2A1 was unmethylated in all cell groups independent of COL2A1 expression, while 9 tested CpG sites in the sparse CpG promoter of COL10A1 were consistently methylated in human articular chondrocytes. Induction of COL10A1 expression during chondrogenesis of MSCs correlated with demethylation of 2 CpG sites in the COL10A1 promoter.

Conclusion

Our findings indicate that methylation‐based COL10A1 gene silencing is established in cartilage tissue and human articular chondrocytes. Altered methylation levels at 2 CpG sites of COL10A1 in MSCs and their demethylation during chondrogenesis may facilitate induction of COL10A1 as observed during in vitro chondrogenesis of MSCs.
Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish
Authors: McArdle Patrick F. , Parsa Afshin , Chang Yen‐Pei C. , Weir Matthew R. , O'Connell Jeffery R. , Mitchell Braxton D. , Shuldiner Alan R.
Published: August 2008

Objective

Uric acid is the primary end product of purine metabolism. Increased serum uric acid levels have been associated with gouty arthritis as well as with a variety of cardiovascular‐related phenotypes. This study was undertaken to investigate associations between uric acid levels and single‐nucleotide polymorphisms (SNPs).

Methods

A 500,000‐SNP genome‐wide association study of serum uric acid levels was performed in a cohort of Old Order Amish from Lancaster County, Pennsylvania.

Results

The scan confirmed a previously identified region on chromosome 4 to be strongly associated with uric acid levels (P = 4.2 × 10−11 for rs10489070). Followup genotyping revealed that a nonsynonymous coding SNP (Val253Ile; rs16890979) in GLUT9 was most strongly associated with uric acid levels, with each copy of the minor allele associated with a decrease of 0.47 mg/dl in the uric acid level (95% confidence interval 0.31–0.63 [P = 1.43 × 10−11]). The effect of this variant tended to be stronger in women than in men (P = 0.16 for sex–genotype interaction). The genotype effect was not modified by the inclusion of several cardiovascular risk factors, suggesting that GLUT9 is directly related to uric acid homeostasis. The SNP identified in the genome‐wide scan in the Amish population (rs10489070) was also significantly associated with gout in the Framingham Heart Study (P = 0.004).

Conclusion

Our findings indicate that GLUT9, which is expressed in the kidney, may be a novel regulator of uric acid elimination and that a common nonsynonymous variant in this gene contributes to abnormalities in uric acid homeostasis and gout.
Distinct topography of erosion and new bone formation in achilles tendon enthesitis: Implications for understanding the link between inflammation and bone formation in spondylarthritis
Authors: McGonagle Dennis , Wakefield Richard J. , Tan Ai Lyn , D'Agostino Maria Antonietta , Toumi Hechmi , Hayashi Koji , Emery Paul , Benjamin Michael
Published: August 2008

Objective

This study combined ultrasonography of the Achilles tendon enthesis at different stages of spondylarthritis (SpA) with microanatomic studies of normal cadaveric entheses, with the aim of exploring the relationship between bone erosion and new bone formation in enthesitis.

Methods

Thirty‐seven patients with SpA and Achilles tendon enthesitis (20 with early SpA and 17 with chronic SpA) and 10 normal control subjects underwent ultrasound scanning. The presence of bone erosion and spur formation was recorded at 3 sites: the proximal and distal halves of the enthesis and the adjacent calcaneal superior tuberosity. Parallel histologic analysis was performed on cadaveric Achilles tendon entheses to determine whether regional variations in bone density and trabecular architecture in relation to fibrocartilage distribution are related to disease patterns.

Results

Bone erosion in patients with early SpA occurred at either the proximal insertion or the superior tuberosity (11 of 20 patients; P < 0.001 versus distal enthesis). Very small spurs, which were present almost exclusively at the distal enthesis, were evident in patients with early SpA and in normal control subjects. However, large spurs were evident distally only in patients with chronic SpA (9 of 17 patients, compared with none of 20 patients with early SpA; P < 0.0001). Histologic studies showed that aged normal individuals had small spurs at the corresponding location. The bone‐to‐marrow ratio was also significantly lower in the regions prone to erosions (P < 0.05).

Conclusion

Bone erosion in association with Achilles tendon enthesitis in SpA is anatomically uncoupled from bone formation—the 2 processes are topographically and temporally distinct. We thus conclude that disease patterns in SpA are related to normal enthesis structure and biomechanics.
Proteomic analysis in monocytes of antiphospholipid syndrome patients: Deregulation of proteins related to the development of thrombosis
Authors: López‐Pedrera Chary , Cuadrado Maria José , Herández Vanessa , Buendïa Paula , Aguirre Maria Angeles , Barbarroja Nuria , Torres Luis Arïstides , Villalba José Manuel , Velasco Francisco , Khamashta Munther
Published: August 2008

Objective

Antiphospholipid antibodies (aPL) are closely related to the development of thrombosis, but the exact mechanism(s) leading to thrombotic events remains unknown. In this study, using proteomic techniques, we evaluated changes in protein expression of monocytes from patients with antiphospholipid syndrome (APS) related to the pathophysiology of the syndrome.

Methods

Fifty‐one APS patients were included. They were divided into 2 groups: patients with previous thrombosis, and patients with recurrent spontaneous abortion. As controls, we studied patients with thrombosis but without aPL, and age‐ and sex‐matched healthy subjects.

Results

The proteins that were more significantly altered among monocytes from APS patients with thrombosis (annexin I, annexin II, protein disulfide isomerase, Nedd8, RhoA proteins, and Hsp60) were functionally related to the induction of a procoagulant state as well as to autoimmune‐related responses. Proteins reported to be connected to recurrent spontaneous abortion (e.g., fibrinogen and hemoglobin) were also determined to be significantly deregulated in APS patients without thrombosis. In vitro treatment with IgG fractions purified from the plasma of APS patients with thrombosis changed the pattern of protein expression of normal monocytes in the same way that was observed in vivo for monocytes from APS patients with thrombosis.

Conclusion

For the first time, proteomic analysis has identified novel proteins that may be involved in the pathogenic mechanisms of APS, thus providing potential new targets for pathogenesis‐based therapies for the disease.
Vav/Phospholipase Cγ2–mediated control of a neutrophil‐dependent murine model of rheumatoid arthritis
Authors: Cremasco Viviana , Graham Daniel B. , Novack Deborah V. , Swat Wojciech , Faccio Roberta
Published: August 2008

Objective

Accumulating evidence indicates an important role of neutrophils in the development of rheumatoid arthritis (RA). Recruitment of neutrophils to the joint space and release of proteolytic enzymes can exacerbate tissue damage and the inflammatory response related to RA. Engagement of β2 integrin and subsequent activation of downstream signaling have been shown to be fundamental for activation of neutrophil effector functions. The aim of this study was to test the hypothesis that Vav and phospholipase Cγ2 (PLCγ2), two molecules involved in integrin signaling, are required for arthritis generation and neutrophil activation in a mouse model of arthritis.

Methods

Arthritis was induced in wild‐type (WT), Vavnull, and PLCγ2−/− mice using the K/BxN serum–transfer model. Neutrophil function was assessed by analyses of adhesion, spreading, and degranulation on integrin‐dependent substrates. Regulation of integrin signaling was determined by analyzing the phosphorylation of Pyk‐2, Src, and ERK.

Results

Vavnull and PLCγ2−/− mice were protected from inflammation and bone erosion in the K/BxN serum–transfer model of arthritis. Mechanistically, Vav and PLCγ2 control neutrophils mediated spreading and degranulation on integrin‐dependent substrates. Consequently, the Vav/PLCγ2 axis, acting downstream of the integrin receptor, modulated the activation of Pyk‐2, Src, and ERK.

Conclusion

Our findings show that Vav cooperates with PLCγ2 in modulating neutrophil activation downstream of the integrin receptor. This study identifies a Vav/PLCγ2‐dependent signaling pathway as a possible therapeutic target for the treatment of inflammation and bone disruption in arthritis.
Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis
Authors: Nile Christoper J. , Read Robert C. , Akil Mohammed , Duff Gordon W. , Wilson Anthony G.
Published: August 2008

Objective

Genetic variation in the gene for interleukin‐6 (IL‐6) contributes to the pathogenesis of inflammatory arthritis, but the role, if any, of epigenetic variability has not been reported. The aims of this study were to compare the DNA methylation status of the IL6 promoter in rheumatoid arthritis (RA) patients and control subjects and to study the effects on gene expression.

Methods

Genomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) obtained from RA patients and healthy controls. Macrophages from healthy controls were isolated and stimulated with lipopolysaccharide (LPS). Methylation status was determined using bisulfite genomic sequencing and IL6 messenger RNA (mRNA) levels by quantitative polymerase chain reaction. Gel shift assays were performed with methylated or unmethylated probes and HeLa cell nuclear extract.

Results

The proximal CpG motifs (–666 to +27) were predominantly unmethylated and the upstream motifs (–1099 to –1001) were highly methylated in PBMCs from patients and controls. Methylation of individual CpG motifs was similar, except at –1099C, which was less methylated in the patients than in the controls (58% versus 98%; P = 1 × 10−6). To test whether this observation might relate to gene regulation, LPS‐stimulated macrophages were grouped according to their IL6 mRNA stimulation index (SI). The level of methylation at –1099C was significantly lower in the group with high (SI >75) compared with the group with low (SI <10) induced mRNA levels (71% versus 93%; P = 0.007). Gel shift assays revealed decreased protein binding to the –1099C unmethylated probe.

Conclusion

These data suggest that methylation of a single CpG in the IL6 promoter region may affect IL6 gene regulation and may play a role in the pathogenesis of RA.
Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis
Authors: Landau Dan‐Avi , Rosenzwajg Michelle , Saadoun David , Trébeden‐Negre Hélène , Klatzmann David , Cacoub Patrice
Published: August 2008

Objective

Mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder associated with chronic hepatitis C virus (HCV) infection. We previously reported that MC vasculitis is associated with a quantitative defect of peripheral blood regulatory T cells. The aim of this study was to prospectively evaluate the evolution of this defect during the course of antiviral treatment.

Methods

Treg cell frequencies and numbers were analyzed in 131 patients with chronic HCV infection (including 66 with MC vasculitis) and 20 healthy volunteer donors. Measurements were taken before, during, and after treatment with PEGylated interferon alfa‐2b plus ribavirin.

Results

At baseline, patients with MC vasculitis had a significantly lower frequency and number of Treg cells than did patients without MC vasculitis. Complete remission of MC vasculitis following antiviral treatment was associated with a significant increase in Treg cell levels compared with baseline. In contrast, Treg cell levels in nonresponders or partial responders, which did not differ from those in complete responders at baseline, remained unchanged over the course of the study.

Conclusion

The strong positive correlation between clinical responses and Treg cell levels provides further support for the central role of Treg cells in the pathogenesis of HCV‐induced MC vasculitis and emphasizes the dual role of Treg cells in chronic HCV infection: while Treg cells may hinder viral elimination, they also limit autoimmune injury.
Natural killer cell degeneration exacerbates experimental arthritis in mice via enhanced interleukin‐17 production
Authors: Lo Cherry Kam Chun , Lam Queenie Lai Kwan , Sun Lingyun , Wang Shengjun , Ko King‐Hung , Xu Huaxi , Wu Chang‐You , Zheng Bo‐Jian , Lu Liwei
Published: August 2008

Objective

An altered phenotype and dysfunction of natural killer (NK) cells have been observed in patients with rheumatoid arthritis. The aim of this study was to determine whether dysregulated NK cells contribute to the pathogenesis of experimental arthritis.

Methods

For initiation of collagen‐induced arthritis (CIA), DBA/1J mice were immunized with type II collagen in Freund's adjuvant. Control mice were immunized with adjuvant alone. NK cells from the blood, spleens, and bone marrow of immunized mice were analyzed by flow cytometry. Levels of interleukin‐17 (IL‐17) secretion and autoantibody production were measured by enzyme‐linked immunosorbent assays. Immunized mice in which NK cells were depleted by anti–asialo GM1antibody treatment were assessed for the development of CIA. Moreover, sorting‐purified NK cells from both mice with CIA and control mice were analyzed for cytokine gene expression.

Results

We observed markedly reduced frequencies of NK cells in the blood and spleens of mice with CIA compared with the frequencies in adjuvant‐treated control mice. Upon NK cell depletion, immunized mice displayed an early onset of arthritis with more severe clinical symptoms, which correlated with increased plasma cell generation and autoantibody production. Moreover, a substantially increased number of IL‐17–secreting cells in synovial tissue and more pronounced joint damage were observed. Freshly isolated NK cells from mice with CIA showed markedly reduced expression of interferon‐γ (IFNγ). Furthermore, coculture of normal NK cells and CD4+ T cells revealed that NK cells strongly suppressed production of Th17 cells via their IFNγ production.

Conclusion

These results suggest that NK cells play a protective role in the development of experimental arthritis, an effect that is possibly mediated by suppressing Th17 cell generation via IFNγ production.
Prevention of murine antiphospholipid syndrome by BAFF blockade
Authors: Kahn Philip , Ramanujam Meera , Bethunaickan Ramalingam , Huang Weiqing , Tao Haiou , Madaio Michael P. , Factor Stephen M. , Davidson Anne
Published: August 2008

Objective

This study was undertaken to determine whether BAFF blockade can be used to prevent or treat antiphospholipid syndrome in a mouse model.

Methods

Eight‐ and 12‐week‐old (NZW × BXSB)F1 mice were treated with BAFF‐R‐Ig or TACI‐Ig alone or in addition to a short course of CTLA‐4Ig. Mice were monitored for thrombocytopenia and proteinuria. Sera were tested for anticardiolipin antibodies (aCL), BAFF levels, and levels of soluble vascular cell adhesion molecule and E‐selectin. Mice were killed at 17, 22, or 32 weeks of age, and kidneys and hearts were subjected to histologic examination. Spleen cells were phenotyped and enzyme‐linked immunospot assays for autoantibody‐producing B cells were performed.

Results

Both BAFF‐R‐Ig and TACI‐Ig prevented disease onset and significantly prolonged survival. Treated mice had significantly smaller spleens than controls, with fewer B cells and fewer activated and memory T cells. BAFF blockade did not prevent the development of aCL, and there was only a modest delay in the development of thrombocytopenia. However, treated mice had significantly less nephritis and myocardial infarcts than did controls.

Conclusion

Our findings suggest that aCL are generated in the germinal center, which is relatively independent of BAFF. Effector function of antiplatelet antibodies was only modestly affected by BAFF blockade. In contrast, myocardial infarctions were prevented, suggesting that triggering of thromboses requires both autoantibodies and mediators of inflammation. Similarly, renal damage requires both immune complexes and effector cells. The dissociation between autoantibody production and inflammation that may occur with B cell–depleting therapies underscores the role of B cells as effector cells in the autoimmune response.
Association of body fat with C‐reactive protein in rheumatoid arthritis
Authors: Giles Jon T. , Bartlett Susan J. , Andersen Ross , Thompson Richard , Fontaine Kevin R. , Bathon Joan M.
Published: August 2008

Objective

The serum C‐reactive protein (CRP) concentration is commonly used in rheumatoid arthritis (RA) as a surrogate marker of systemic inflammation, presumably induced by synovitis. However, other tissues, such as adipose tissue, can induce CRP production. This study was undertaken to explore the associations between measures of adiposity and CRP levels in RA.

Methods

One hundred ninety‐six men and women with RA underwent anthropometric assessment and total body dual‐energy x‐ray absorptiometry for measurement of total and regional body fat and lean mass. The associations between measures of fat and lean mass and serum levels of CRP and interleukin‐6 (IL‐6) were determined in analyses stratified by sex, with adjustment for pertinent demographic, lifestyle, and RA disease and treatment covariates as well as for the potential modifying effects of articular activity and biologic pharmacotherapeutic agents.

Results

All measures of adiposity were significantly associated with the level of CRP in women, but not in men. In women, the measure of adiposity that showed the strongest association with the CRP level was truncal fat, in which, in adjusted analyses, each kilogram increase was associated with a 0.101‐unit increase in the logarithmically transformed CRP level (P < 0.001). Neither the level of articular activity nor the use of biologic agents significantly modified this association in women. However, in men, elevated articular involvement was associated with a decreasing CRP level as truncal fat increased. For all analyses, substitution of IL‐6 for CRP produced similar findings.

Conclusion

Adiposity is independently associated with CRP levels in women with RA, and thus may confound the estimation of RA disease activity when serum CRP concentration is used as a surrogate for systemic inflammation.
Decreased expression of caveolin 1 in patients with systemic sclerosis: Crucial role in the pathogenesis of tissue fibrosis
Authors: Galdo Francesco Del , Sotgia Federica , de Almeida Cecilia J. , Jasmin Jean‐Francois , Musick Megan , Lisanti Michael P. , Jiménez Sergio A.
Published: August 2008

Objective

Recent studies have implicated caveolin 1 in the regulation of transforming growth factor β (TGFβ) downstream signaling. Given the crucial role of TGFβ in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.

Methods

CAV1 expression in tissues was analyzed by immunofluorescence and confocal microscopy. The extent of tissue fibrosis in Cav1‐knockout mice was assessed by histologic/histochemical analyses and quantified by hydroxyproline assays. Cav1‐null and SSc fibroblast phenotypes and protein production were analyzed by real‐time polymerase chain reaction, immunofluorescence, Western blot, and multiplexed enzyme‐linked immunosorbent assay techniques. The effects of restoration of caveolin 1 function in SSc fibroblasts in vitro were also examined using a cell‐permeable recombinant CAV1 peptide.

Results

CAV1 was markedly decreased in the affected lungs and skin of SSc patients. Cav1‐knockout mice developed pulmonary and skin fibrosis. Down‐regulation of caveolin 1 was maintained in cultured SSc fibroblasts, and restoration of caveolin 1 function in vitro normalized their phenotype and abrogated TGFβ stimulation through inhibition of Smad3 activation.

Conclusion

Caveolin 1 appears to participate in the pathogenesis of tissue fibrosis in SSc. Restoration of caveolin 1 function by treatment with a cell‐permeable peptide corresponding to the CAV1 scaffolding domain may be a novel therapeutic approach in SSc.
Association of the STAT4 gene with increased susceptibility for some immune‐mediated diseases
Authors: Martínez A. , Varadé J. , Márquez A. , Cénit M. C. , Espino L. , Perdigones N. , Santiago J. L. , Fernández‐Arquero M. , de la Calle H. , Arroyo R. , Mendoza J. L. , Fernández‐Gutiérrez B. , de la Concha E. G. , Urcelay E.
Published: August 2008

Objective

The STAT4 gene encodes a transcription factor involved in the signaling pathways of several cytokines, including interleukin‐12 (IL‐12), the type I interferons, and IL‐23. Recently, the association of a STAT4 haplotype marked by rs7574865 with rheumatoid arthritis (RA) and systemic lupus erythematosus was reported. The aim of this study was to investigate the role of this STAT4 tagging polymorphism in other immune‐mediated diseases.

Methods

The study group comprised 2,776 consecutively recruited Spanish individuals: 575 with RA, 440 with multiple sclerosis, 700 with inflammatory bowel disease, 311 with type 1 diabetes, and 723 ethnically matched healthy control subjects. The STAT4 polymorphism rs7574865 was genotyped using a predesigned TaqMan assay. Allele and genotype frequencies in patients and control subjects were compared by chi‐square test.

Results

The association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin (for T versus G, P = 1.2 × 10−6, odds ratio [OR] 1.59, 95% confidence interval [95% CI] 1.31–1.92), and the association was described for the first time in both clinical forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis (for T versus G, P = 0.006, OR 1.29, 95% CI 1.07–1.55), and in type 1 diabetes mellitus (for T versus G, P = 0.008, OR 1.36, 95% CI 1.07–1.71). In contrast, the genotypic distribution of this polymorphism showed no difference between patients with multiple sclerosis and healthy control subjects (for T versus G, P = 0.83, OR 1.02, 95% CI 0.82–1.28).

Conclusion

The STAT4 gene is emerging as a novel common risk factor for diverse complex diseases.
Replication of the tumor necrosis factor receptor−associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family‐based study
Authors: Kurreeman F. A. S. , Rocha D. , Houwing‐Duistermaat J. , Vrijmoet S. , Teixeira V. H. , Migliorini P. , Balsa A. , Westhovens R. , Barrera P. , Alves H. , Vaz C. , Fernandes M. , Pascual‐Salcedo D. , Michou L. , Bombardieri S. , Radstake T. , van Riel P. , van de Putte L. , Lopes‐Vaz A. , Prum B. , Bardin T. , Gut I. , Cornelis F. , Huizinga T. W. J. , Petit‐Teixeira E. , Toes R. E. M. ,   European Consortium on Rheumatoid Arthritis Families
Published: August 2008

Objective

We recently showed, using a candidate gene approach in a case–control association study, that a 65‐kb block encompassing tumor necrosis factor receptor−associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case–control association studies, family‐based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family‐based approach.

Methods

A total of 1,356 western European white individuals from 452 “trio” families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay.

Results

We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2‐fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04–1.50).

Conclusion

Using a family‐based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.
Amino‐terminal fragment of the prohormone brain‐type natriuretic peptide in rheumatoid arthritis
Authors: Solus Joseph , Chung Cecilia P. , Oeser Annette , Avalos Ingrid , Gebretsadik Tebeb , Shintani Ayumi , Raggi Paolo , Sokka Tuulikki , Pincus Theodore , Stein C. Michael
Published: August 2008

Objective

Increased concentrations of N‐terminal pro–brain natriuretic peptide (NT‐proBNP) are associated with cardiovascular morbidity and mortality, but little is known about their relationship to chronic inflammation. Patients with rheumatoid arthritis (RA) have chronic inflammation, increased arterial stiffness, and accelerated coronary atherosclerosis. This study was undertaken to test the hypothesis that NT‐proBNP concentrations are elevated in patients with RA and are associated with coronary artery calcification and markers of inflammation.

Methods

In 159 patients with RA (90 with early RA and 69 with longstanding RA) without heart failure and 88 control subjects, serum concentrations of NT‐proBNP, interleukin‐6 (IL‐6), and tumor necrosis factor α (TNFα) were measured and coronary calcification was assessed. Associations between NT‐proBNP levels and the other parameters were investigated.

Results

NT‐proBNP concentrations were elevated in patients with longstanding RA (median 142.8 pg/ml [interquartile range 54.8–270.5]) and those with early RA (median 58.1 pg/ml [interquartile range 19.4–157.6]) compared with controls (18.1 [3.2–46.0]) (P < 0.001). In patients with RA, NT‐proBNP concentrations were associated with age (ρ = 0.35, P < 0.001), levels of IL‐6 (ρ = 0.33, P < 0.001), TNFα (ρ = 0.23, P = 0.003), and C‐reactive protein (CRP) (ρ = 0.21, P = 0.01), coronary calcium score (ρ = 0.30, P < 0.001), systolic blood pressure (ρ = 0.30, P < 0.001), and disease activity (ρ = 0.29, P < 0.001). After adjustment for age, race, and sex, the associations between NT‐proBNP concentrations and disease activity, TNFα, IL‐6, and CRP remained significant, but those with systolic blood pressure and coronary calcium score were attenuated.

Conclusion

NT‐proBNP concentrations are increased in patients with RA without clinical heart failure and may indicate subclinical cardiovascular disease and a chronic inflammatory state.
Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody–associated small‐vessel vasculitis: Comparison of two independent cohorts
Authors: Pagnoux Christian , Hogan Susan L. , Chin Hyunsook , Jennette J. Charles , Falk Ronald J. , Guillevin Loïc , Nachman Patrick H.
Published: August 2008

Objective

Predictors of treatment resistance and relapse have been identified in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis in the Glomerular Disease Collaborative Network (GDCN) in the southeastern US. This study was undertaken to evaluate the applicability of those predictors in an independent cohort followed up by the French Vasculitis Study Group.

Methods

Predictors of treatment resistance were evaluated using logistic regression models and reported as odds ratios (ORs) with 95% confidence intervals (95% CIs). Predictors of relapse were evaluated using Cox proportional hazards models and reported as hazard ratios (HRs) with 95% CIs. Models were controlled for age, sex, race, baseline serum creatinine level, and cyclophosphamide therapy.

Results

The French cohort (n = 434) and the GDCN cohort (n = 350) had similar median followup periods (44 months versus 45 months) and initial percentages of patients taking cyclophosphamide (82% versus 78%). The French cohort included more patients with proteinase 3 (PR3) ANCA (58% versus 40%), lung involvement (58% versus 49%), and upper respiratory tract involvement (62% versus 31%). Of the predictors of treatment resistance in the GDCN cohort (female sex, African American race, presence of myeloperoxidase ANCA, elevated creatinine level, and age), only age predicted treatment resistance in the French cohort (OR 1.32 per 10 years [95% CI 1.05–1.66]). Predictors of relapse in the GDCN cohort were PR3 ANCA (HR 1.77 [95% CI 1.11–2.82]), lung involvement (HR 1.68 [95% CI 1.10–2.57), and upper respiratory tract involvement (HR 1.58 [95% CI 1.00–2.48]), while predictors in the French cohort were PR3 ANCA (HR 1.66 [95% CI 1.15–2.39]) and lung involvement (HR 1.56 [95% CI 1.11–2.20]), but not upper respiratory tract involvement (HR 0.96 [95% CI 0.67–1.38]).

Conclusion

Our findings indicate that older age is a predictor of treatment resistance, and that PR3 ANCA and lung involvement are predictors of relapse in both cohorts. Discrepancies in predictors of treatment tract resistance may reflect differences in access to care, and differences in predictors of relapse may reflect variations in disease expression.
The distinct role of the Runx proteins in chondrocyte differentiation and intervertebral disc degeneration: Findings in murine models and in human disease
Authors: Sato Shingo , Kimura Ayako , Ozdemir Jerfi , Asou Yoshinori , Miyazaki Makiko , Jinno Tetsuya , Ae Keisuke , Liu Xiuyun , Osaki Mitsuhiko , Takeuchi Yasuhiro , Fukumoto Seiji , Kawaguchi Hiroshi , Haro Hirotaka , Shinomiya Ken‐Ichi , Karsenty Gerard , Takeda Shu
Published: August 2008

Objective

Runx2 is a transcription factor that regulates chondrocyte differentiation. This study was undertaken to address the role of the different Runx proteins (Runx1, Runx2, or Runx3) in chondrocyte differentiation using chondrocyte‐specific Runx–transgenic mice, and to study the importance of the QA domain of Runx2, which is involved in its transcriptional activation.

Methods

Runx expression was analyzed in the mouse embryo by in situ hybridization. Overexpression of Runx1, Runx2 (lacking the QA domain [ΔQA]), or Runx3 was induced in chondrocytes in vivo, to produce α(1)II‐Runx1, α(1)II‐Runx2ΔQA, and α(1)II‐Runx3 mice, respectively, for histologic and molecular analyses. Runx expression was also examined in an experimental mouse model of mechanical stress–induced intervertebral disc (IVD) degeneration and in human patients with IVD degeneration.

Results

Runx1 expression was transiently observed in condensations of mesenchymal cells, whereas Runx2 and Runx3 were robustly expressed in prehypertrophic chondrocytes. Similar to α(1)II‐Runx2 mice, α(1)II‐Runx2ΔQA and α(1)II‐Runx3 mice developed ectopic mineralization of cartilage, but this was less severe in the α(1)II‐Runx2ΔQA mice. In contrast, α(1)II‐Runx1 mice displayed no signs of ectopic mineralization. Surprisingly, α(1)II‐Runx1 and α(1)II‐Runx2 mice developed scoliosis due to IVD degeneration, characterized by an accumulation of extracellular matrix and ectopic chondrocyte hypertrophy. During mouse embryogenesis, Runx2, but not Runx1 or Runx3, was expressed in the IVDs. Moreover, both in the mouse model of IVD degeneration and in human patients with IVD degeneration, there was significant up‐regulation of Runx2 expression.

Conclusion

Each Runx protein has a distinct, yet overlapping, role during chondrocyte differentiation. Runx2 contributes to the pathogenesis of IVD degeneration.
The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: A cohort and nested case–control analysis
Authors: Wolfe Frederick , Michaud Kaleb
Published: August 2008

Objective

To determine the risk of myocardial infarction (MI) in patients with rheumatoid arthritis (RA) compared with that in patients with noninflammatory rheumatic disorders and to determine risk factors for MI in RA, the relationship between cardiovascular risk factors and corticosteroid use, and the relationship between RA treatment and MI.

Methods

We conducted a cohort study of MI in 17,738 patients with RA and 3,001 patients with noninflammatory rheumatic disorders who were assessed at 6‐month intervals between 1999 and July 2006. We evaluated treatment effect in a nested case–control study of RA participants who were matched by age, sex, study duration, and date of study entry.

Results

The covariate‐adjusted risk of first MI in RA versus that in noninflammatory rheumatic disorders was 1.9 (95% confidence interval 1.2–2.9) (P = 0.005). In RA, MI was predicted by age, sex, education level, hypertension, smoking, exercise, prior MI, diabetes, a comorbidity index, use of low‐dose aspirin and antilipemic agents, RA severity and treatment variables, and corticosteroid use. Except for obesity, predictors were of equal strength in RA and noninflammatory rheumatic disorders. The increased risk for MI in RA compared with that in noninflammatory rheumatic disorders lessened when corticosteroid users were excluded. Use of corticosteroids was associated with future development of diabetes and hypertension.

Conclusion

MI in RA is associated with demographic and cardiovascular risk factors and corticosteroid use. Study data support the hypothesis that RA activity causes MI and that corticosteroids are primarily a marker of RA activity. However, corticosteroids increase the risk of diabetes and hypertension and contribute to the overall risk of MI.
Physical activity levels in patients with early knee osteoarthritis measured by accelerometry
Authors: Farr Joshua N. , Going Scott B. , Lohman Timothy G. , Rankin Lucinda , Kasle Shelley , Cornett Michelle , Cussler Ellen
Published: August 2008

Objective

Physical activity (PA) is recommended for osteoarthritis (OA) management to reduce pain and improve function. The purpose of this study was to objectively assess the level and pattern of PA in male and female knee OA patients to determine adherence to Centers for Disease Control and Prevention/American College of Sports Medicine and Exercise and Physical Activity Conference recommendations for PA.

Methods

Early OA patients (n = 255, 76% women, mean ± SD age 54.6 ± 7.1 years, mean ± SD body mass index 27.8 ± 4.3 kg/m2) with Kellgren/Lawrence‐defined grade II (no higher) radiographic OA in at least 1 knee wore an accelerometer for 6–7 contiguous days. Light (LPA), moderate (MPA), and vigorous (VPA) PA intensities were defined as accelerometer recordings of 100–2,224, 2,225–5,950, and >5,950 counts per minute, respectively.

Results

Patients wore accelerometers for a mean ± SD of 6.8 ± 0.3 days and 13.8 ± 2.2 hours/day, and spent much more time (P < 0.001) in MPA (23.6 ± 17.2 minutes/day) than VPA (0.95 ± 3.5 minutes/day). Men spent significantly (P < 0.05) more time in all PA intensities than women. Only 30% of patients achieved recommended PA levels. The proportion of men (47%) achieving the recommendation was significantly (P = 0.04) higher than women (24%).

Conclusion

Knee OA patients accumulate little VPA and most (70%) do not achieve recommended levels for MPA or greater. New strategies to increase levels of PA in this population are needed.
Acupuncture for pain relief in patients with rheumatoid arthritis: A systematic review
Authors: Wang Chenchen , de Pablo Paola , Chen Xiaoyan , Schmid Christopher , McAlindon Timothy
Published: August 2008

Objective

To systematically review the efficacy of acupuncture on pain relief in patients with rheumatoid arthritis (RA).

Methods

We performed a comprehensive search of 12 western and Chinese databases and reference lists through March 2008. We included randomized controlled trials with pain as an end point, measured by tender joint count (TJC) or a pain scale. We also reviewed the effect of acupuncture on morning stiffness, erythrocyte sedimentation rate (ESR), and C‐reactive protein (CRP) level. Study quality was assessed by Jadad score. Differences between treatment groups were pooled as mean or median change (P value).

Results

Eight studies met eligibility criteria with a total of 536 subjects. There were 4 placebo‐controlled trials and 4 active‐controlled trials. Average study duration was 11 weeks. Mean ± SD acupuncture points and sessions were 11 ± 8 and 42 ± 62, respectively. Average duration of needle insertion was 24 minutes. Six studies reported a decrease in pain for acupuncture versus controls; the mean or median changes of acupuncture‐decreased TJC pain ranged from 1.5 to 6.5. In addition, 4 studies reported a significant reduction in morning stiffness (mean change −29 minutes), but the difference was nonsignificant versus controls. With regard to inflammatory markers, 5 studies observed a reduction in ESR (mean change −3.9 mm/hour) and 3 observed a CRP level reduction (mean change −2.9 mg/dl); only 1 study showed a significant difference for both ESR and CRP.

Conclusion

Despite some favorable results in active‐controlled trials, conflicting evidence exists in placebo‐controlled trials concerning the efficacy of acupuncture for RA. Rigorous and well‐controlled randomized trials are warranted.
A systematic review of instruments measuring foot function, foot pain, and foot‐related disability in patients with rheumatoid arthritis
Authors: van der Leeden Marike , Steultjens Martijn P. M. , Terwee Caroline B. , Rosenbaum Dieter , Turner Debbie , Woodburn Jim , Dekker Joost
Published: August 2008

Objective

To compose an inventory of instruments that have been described to measure foot function (i.e., pressure and/or gait parameters), foot pain, and foot‐related disability in rheumatoid arthritis (RA), and to investigate the clinimetric quality of these measures.

Methods

A systematic search was conducted in Medline, CINAHL, EMBase, and Sportdiscus. Standardized criteria, extended with levels of evidence, were applied to assess the quality of the clinimetric studies and the properties (i.e., reliability, validity, and responsiveness) of the described instruments.

Results

A variety of measurement instruments were identified. Only 16 instruments have been studied for their measurement properties in RA patients: 7 for assessing foot function, 3 for measuring foot‐related disability, and 6 for measuring both foot pain and foot‐related disability. Thirteen instruments were rated for reliability, of which 10 were rated positively on different levels of evidence. No positive rating for absolute measurement error was applicable for any of the tests. Internal consistency was reported for 7 instruments; 3 assigned a positive rating. For 2 instruments, Rasch analysis was used to assess the methodologic quality. A positive rating was reported for goodness‐of‐fit only, not for item calibration. Seven instruments were rated for construct validity, and 3 assigned a positive rating. Only 2 instruments were rated positively for responsiveness.

Conclusion

This review offers a basis for choosing the most appropriate instruments for measuring foot function, foot pain, and foot‐related disability in RA patients, both for clinical practice and for research. Further research on the quality of these measures is urgently needed.
Substitution of specialized rheumatology nurses for rheumatologists in the diagnostic process of fibromyalgia: A randomized controlled trial
Authors: Kroese M. E. A. L. , Schulpen G. J. C. , Bessems M. C. M. , Severens J. L. , Nijhuis F. J. , Geusens P. P. , Landewé R. B.
Published: August 2008

Objective

To evaluate the substitution of specialized rheumatology nurses for rheumatologists in diagnosing fibromyalgia (FM).

Methods

Referred patients with FM symptoms (n = 193) were randomized to a study group diagnosed by a specialized rheumatology nurse (SRN group, n = 97) or to a control group diagnosed by a rheumatologist (RMT group, n = 96). SRN patients were seen within 3 weeks by a nurse who took structured history and initiated routine laboratory tests. During a 5‐minute supervision session, the rheumatologist was informed by the nurse about medical history, performed a brief physical examination, and confirmed or rejected the nurse's diagnosis. RMT patients were seen by a rheumatologist after a regular waiting period of 3 months. Outcome measures were initial agreement between the nurse and rheumatologist in the SRN group, final diagnosis after 12–24 months of followup, patient satisfaction, and diagnostic costs.

Results

The mean waiting time after randomization was 2.8 and 12.1 weeks in the SRN and RMT groups, respectively. Eight RMT patients cancelled their appointments because of the waiting time. Excellent agreement (κ = 0.91) between rheumatologists and nurses was found. After 12–24 months of followup, none of the initial diagnoses were recalled in either group. SRN patients were significantly more satisfied than RMT patients. Mean diagnostic costs were lower in the SRN group (€219) than in the RMT group (€281) (95% uncertainty interval €−103, €−20).

Conclusion

Substituting specialized nurses for rheumatologists in the diagnostic process of FM is a trustworthy and successful approach that saves waiting time, provides greater patient satisfaction, and is cost‐effective.
Clinical course and prognosis of hand and wrist problems in primary care
Authors: Spies‐Dorgelo Marinda N. , van der Windt Daniëlle A. W. M. , Prins A. Pieter A. , Dziedzic Krysia S. , van der Horst Henriëtte E.
Published: August 2008

Objective

To describe the course of a new episode of hand and wrist problems in general practice and to identify predictors that are associated with poor outcome at short‐term and long‐term followup.

Methods

Patients consulting their general practitioner with hand or wrist problems (no prior consultation in the preceding 3 months) were sent a questionnaire at baseline and at 3, 6, and 12 months of followup. Potential predictors included sociodemographic variables, characteristics of the symptoms, physical activity, and psychosocial factors. General practitioners recorded information on symptoms, signs, and medical diagnosis. The main outcome measure was insufficient improvement of symptoms using the Symptom Severity Scale at short‐term (3 months) and long‐term (12 months) followup.

Results

Twenty‐three percent of patients reported complete recovery after 3 months, increasing to 42% at 1 year after first presentation. Higher probability of poor outcome at 3 months was associated with being female, low pain intensity at baseline, and lower personal control at baseline; at 12 months it was associated with older age, being female, reporting symptoms for >3 months at baseline, low scores on the coping strategy “reducing demands,” and a higher score on somatization. Discriminative ability of the models was moderate, with areas under the curve after bootstrapping of 0.60 and 0.69 at 3 and 12 months, respectively.

Conclusion

More than half of all patients reported residual symptoms at 1 year. Although poor outcome was difficult to predict, age, sex, duration of symptoms, and psychosocial factors were associated with poor outcome of hand and wrist problems.
Besonderheiten bei der Beurteilung des Ankündigungsverhaltens von Spannbetonbrü
Authors: Albertin‐Hummel Ursula , Brandt Bernd
Published: August 2008

Bezüglich eines Versagens sind ältere Brücken häufig den Bauwerken ohne Vorankündigung nach dem Riss‐vor‐Bruch‐Kriterium zuzuordnen. Die betreffenden Brücken bergen ein Versagensrisiko, das bei Brücken mit spannungsrisskorrosionsempfindlichem Spannstahl besonders groß ist.

Ergänzend zu den Besonderheiten bei der Beurteilung des Ankündigungsverhaltens von Spannbetonbrücken nach dem Riss‐vor‐Bruch‐Kriterium Teil I (Temperatur, Schnittgrößenumlagerung) werden weitere Untersuchungen zur Beurteilung des Restrisikos für den Bauherrn durchgeführt: Überlegungen hinsichtlich der Spanngliedanzahl und ‐größe sowie der möglichen Verkehrslastanteile dienen einer Bewertung der Gefährdung der einzelnen Brückenbauwerke. Anhand der verschiedenen Beurteilungskriterien werden Vorschläge zur weiteren Vorgehensweise bei gefährdeten Brücken gegeben. Hinweise für Bauwerksprüfungen gemäß DIN 1076 zum Erkennen von Rissen und Schäden aufgrund eines Versagens infolge Spannungsrisskorrosion werden vorgestellt.
Tragverhalten und Bemessung von eingemörtelten Bewehrungsstäben unter zyklischer Beanspruchung im ungerissenen und gerissenen Beton
Authors: Simons Isabelle , Eligehausen Rolf
Published: August 2008

Im folgenden Aufsatz werden Ergebnisse der an der Universität Stuttgart durchgeführten experimentellen und numerischen Parameterstudien im ungerissenen und gerissenen Beton mit einbetonierten und eingemörtelten Rippenstäben unter monotoner und zyklischer Beanspruchung dargestellt. Dabei wird das Verbundtragverhalten von eingemörtelten Stäben mit dem von einbetonierten Rippenstäben verglichen. Darauf aufbauend wird ein Zusammenhang zwischen dem Verbundtragverhalten bei monotoner und zyklischer Beanspruchung abgeleitet. Auf Basis der durchgeführten Untersuchungen wird abschließend ein vereinfachtes Bemessungskonzept für Bewehrungsanschlüsse mit eingemörtelten Rippenstäben vorgeschlagen, mit welchem das für Anwendungen im Stahlbetonbau geltende Sicherheitsniveau gewährleistet ist.
Der druckwasserdichte Anschluss an WU‐Bauwerke
Authors: Hohmann Rainer
Published: August 2008

Der druckwasserdichte Anschluss eines wasserundurchlässigen Bauwerks aus Beton an ein bestehendes Bauwerk stellt planerisch und ausführungstechnisch eine anspruchsvolle Aufgabe dar. Anschlussfugen finden sich in zahlreichen Bauwerken im Ingenieurbau, im Hoch‐ und Industriebau, im Wasser‐, Tief‐ und Tunnelbau. Lösungen müssen exakt auf die Randbedingungen der Fuge und die spezifischen Gegebenheiten des Objekts abgestimmt werden. Welche Systeme kommen als Abdichtung in Frage? Welche Fehler sollten bei der Planung und Ausführung möglichst vermieden werden? Welche Besonderheiten treten bei der Anschlussfuge zwischen einem Bauwerk mit Hautabdichtung und einem aus wasserundurchlässigem Beton auf? Der Beitrag bietet einen Überblick über die verschiedenen Möglichkeiten Anschlussfugen abzudichten.