bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of recreational fishing for elasmobranch conservation in the Great Barrier Reef Marine Park
Authors: Lynch Ann‐Maree J. , Sutton Stephen G. , Simpfendorfer Colin A.
Published: June 2009

309 Great Barrier Reef Marine Park recreational fishers were surveyed to examine recreational catch and harvest of elasmobranchs and to explore recreational fishers' handling behaviour and attitudes.

Elasmobranchs represented 6% of fishers' total catch of all fish (including released individuals), and 0.8% of fishers' total harvest (i.e. retained individuals) across all survey days. The majority of elasmobranchs caught by fishers were released, primarily because they were perceived as being inedible.

Recreational fishers' self‐reported handling and release behaviour for elasmobranchs is largely consistent with ‘best practice’ guidelines except that fishers had low use of circle hooks and barbless hooks, and a significant proportion (33%) reported using stainless steel hooks.

Most fishers had positive attitudes towards elasmobranchs, placing high importance on releasing sharks and rays in good condition (86%), high value on their existence (84%), and low value on catching them (63%).

Results indicate that post‐release mortality is probably the largest source of recreational fishing mortality of elasmobranchs in the Great Barrier Reef. Future research should be targeted at obtaining better estimates of species‐specific post‐release mortality levels, understanding how post‐release survival can be increased by changing fishing techniques or fisher behaviour, and developing more effective methods of engaging fishers in elasmobranch conservation. Copyright © 2009 John Wiley & Sons, Ltd.
Synthesis of Dimeric Quinazolin‐2‐one, 1,4‐Benzodiazepin‐2‐one, and Isoalloxazine Compounds as Inhibitors of Amyloid Peptides Association
Authors: Barthel Alexander , Trieschmann Lothar , Ströhl Dieter , Kluge Ralph , Böhm Gerald , Csuk René
Published: June 2009

The synthesis of dimeric compounds derived from quinazolin‐2‐one and 1,4‐benzodiazepin‐2‐one possessing a piperazine or homopiperazine spacer was investigated. In addition, a piperazine spacered bis‐isoalloxazine and a bis‐riboflavin compound were prepared and their ability to interrupt the association of prion proteins and Alzheimer‐specific Aβ peptides was investigated using a fast screening system based on flow cytometry. The bis‐isoalloxazine 14 was identified as a new lead structure.
Multi‐Component Synthesis of Dihydropyrimidines by Iodine Catalyst at Ambient Temperature and in‐vitro Antimycobacterial Activity
Authors: Zalavadiya Paresh , Tala Satish , Akbari Jignesh , Joshi Hitendra
Published: June 2009

An efficient and simple three‐component domino synthesis of some new dihydropyrimidines (DHPMs) from aromatic aldehydes, 1,3‐dicarbonyl compounds and N‐(3‐chloro‐4‐fluorophenyl)urea using molecular iodine as catalyst is described. The 1‐substituted dihydropyrimidines were isolated in good to excellent yields (78‐90%) within a short reaction time (4‐6 h) at ambient temperature. The biological evaluation revealed that the newly synthesized compounds (4a‐i and 5a‐i) exhibited moderate antimycobacterial activity against Mycobacterium tuberculosis H37 RV.
Synthesis and Cytotoxic Activity of Novel Amidine Analogues of Bis(2‐chloroethyl)amine
Authors: Bielawski Krzysztof , Bielawska Anna , Poplawska Bozena
Published: June 2009

Novel nitrogen mustard agents 7–12 involving 4‐(N,N‐bis(2‐chloroethyl)aminophenyl)propylamine linked to a 5‐(4‐N‐alkylamidinophenyl)‐2‐furancarboxylic acid moiety by the formation of an amide bond have been synthesized, characterized, and evaluated for their in‐vitro cytotoxic activity against MDA‐MB‐231 and MCF‐7 human breast cancer cells. Evaluation of the cytotoxicity of 7–12 employing a MTT assay and inhibition of [3H]thymidine incorporation into DNA demonstrated that these compounds exhibit remarkable cytotoxic effects in comparison with 4‐[bis(2‐chloroethyl)amino]benzenebutanoic acid. Compounds 7 and 9, which possess a cationic amidine and 4,5‐dihydro‐1H‐imidazol function moiety are approximately ten times more potent than 4‐[bis(2‐chloroethyl)amino]benzenebutanoic acid. The new compounds were evaluated as DNA topoisomerase II inhibitors. The cytotoxicity of the compounds 7–12 correlates with their DNA‐binding affinities and their relative potency as topoisomerase II inhibitors.
Benzothiazole Incorporated Barbituric Acid Derivatives: Synthesis and Anticonvulsant Screening
Authors: Siddiqui Nadeem , Ahsan Waquar
Published: June 2009

A series of 1‐(6‐substituted‐1,3‐benzothiazol‐2‐yl)‐3‐(substituted phenyl)hexahydro‐2,4,6‐pyrimidinetriones4a–twere synthesized starting from substituted anilines. These compounds contained two active anticonvulsant pharmacophores, benzothiazole and barbituric acid. Structures of the compounds were confirmed on the basis of different spectroscopic techniques. All the compounds were evaluated for their anticonvulsant activity. Three compounds4c,4d, and4sshowed promising anticonvulsant activities in Maximal Electroshock Seizure test (MES) and subcutaneous pentylenetetrazole test (scPTZ). They also displayed a wide safety profile when tested for the minimal motor impairment test.
Comparison of two methods of conducting the fit and strong! program
Authors: Seymour Rachel B. , Hughes Susan L. , Campbell Richard T. , Huber Gail M. , Desai Pankaja
Published: June 2009

Objective

Fit and Strong! is an award winning, evidence‐based, multiple‐component physical activity/behavior change intervention. It is a group‐ and facility‐based program that meets for 90 minutes 3 times per week for 8 weeks (24 sessions total). We originally tested Fit and Strong! using physical therapists (PTs) as instructors but have transitioned to using nationally certified exercise instructors (CEIs) as part of an effort to translate Fit and Strong! into community‐based settings, and have tested the impact of this shift in instruction type on participant outcomes.

Methods

We used a 2‐group design. The first 161 participants to sequentially enroll received instruction from PTs. The next 190 sequential enrollees received instruction from CEIs. All participants were assessed at baseline, at the conclusion of the 8‐week Fit and Strong! program, and at the 6‐month followup.

Results

We saw no significant differences by group on outcomes at 8 weeks or 6 months. Participants in both groups improved significantly with respect to lower‐extremity strength, aerobic capacity, pain, stiffness, and physical function. Significant differences favoring the PT‐led classes were seen on 2 of 5 mediators, self‐efficacy for exercise and barriers adherence efficacy. Participant evaluations rated both types of instruction equally highly, attendance was identical, and no untoward health events were observed or reported under either instruction mode.

Conclusion

Outcomes under the 2 types of instruction are remarkably stable. These findings justify the use of CEIs in the future to extend the reach of the Fit and Strong! program.
Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets
Authors: Griffin Thomas A. , Barnes Michael G. , Ilowite Norman T. , Olson Judyann C. , Sherry David D. , Gottlieb Beth S. , Aronow Bruce J. , Pavlidis Paul , Hinze Claas H. , Thornton Sherry , Thompson Susan D. , Grom Alexei A. , Colbert Robert A. , Glass David N.
Published: June 2009

Objective

To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent‐onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures.

Methods

Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second‐line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG‐U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance‐weighted discrimination normalization.

Results

Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup‐specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor β–inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets.

Conclusion

Gene expression signatures in PBMCs from patients with recent‐onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.
Anti‐DNA antibody induction of protein kinase C phosphorylation and fibronectin synthesis in human and murine lupus and the effect of mycophenolic acid
Authors: Yung Susan , Zhang Qing , Zhang Chen Zhu , Chan Kwok Wah , Lui Sing Leung , Chan Tak Mao
Published: June 2009

Objective

To examine fibronectin (FN) expression in human lupus nephritis and the effect of anti‐DNA antibodies on transforming growth factor β1 (TGFβ1) and FN synthesis in cultured human mesangial cells. The effects of mycophenolic acid (MPA) on this pathway, and the effects of mycophenolate mofetil (MMF) treatment in (NZB × NZW)F1/J mice were also studied.

Methods

Immunohistochemical analyses of renal biopsy samples from patients with active diffuse proliferative lupus nephritis were performed. Cultured human mesangial cells were incubated with human polyclonal anti‐DNA antibodies, with or without MPA. (NZB × NZW)F1/J mice with active nephritis were randomized to receive either MMF (100 mg/kg/day) or vehicle treatment for 12 weeks.

Results

Glomerular FN expression was increased in patients with lupus nephritis, and it colocalized with IgG deposition. Anti‐DNA antibodies induced protein kinase Cα (PKCα), PKCβI, and PKCβII activation, increased levels of bioactive TGFβ1, and increased FN synthesis in human mesangial cells (P < 0.001 for each comparison versus control conditions). Pretreatment of anti‐DNA antibodies with exogenous DNA reduced their cellular binding and abrogated their induction of TGFβ1 and FN synthesis. Inhibition of PKC activation in human mesangial cells prior to anti‐DNA antibody stimulation had no effect on cell proliferation, but resulted in significantly reduced antibody‐mediated TGFβ1 secretion and FN synthesis. MPA treatment down‐regulated PKCα, PKCβI, and PKCβII phosphorylation, reduced levels of TGFβ1 bioactivation, and decreased FN synthesis and deposition into the extracellular matrix. MMF treatment in (NZB × NZW)F1/J mice resulted in a reduction in glomerular IgG deposition, PKC activation, and FN expression, as well as an amelioration of proteinuria.

Conclusion

Human polyclonal anti‐DNA antibodies induce TGFβ1 and FN synthesis in human mesangial cells through PKC activation, which is inhibited by MPA.
Clinical and immunogenetic prognostic factors for radiographic severity in ankylosing spondylitis
Authors: Ward Michael M. , Hendrey Matthew R. , Malley James D. , Learch Thomas J. , Davis John C. , Reveille John D. , Weisman Michael H.
Published: June 2009

Objective

To improve prognostic ability in ankylosing spondylitis (AS), we sought to identify demographic, clinical, and immunogenetic characteristics associated with radiographic severity in a large cohort of patients.

Methods

Patients with AS for ≥20 years were enrolled in a cross‐sectional study (n = 398). Pelvic and spinal radiographs were scored using the Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI‐s), and radiographic severity was measured as the BASRI‐s/duration of AS. Clinical factors and HLA–B, DR, DQ, and DP alleles associated with the highest quartile of the distribution of radiographic severity were identified by first using random forests and then using multivariable logistic regression modeling. Similar procedures were used to identify factors associated with the lowest quartile of radiographic severity.

Results

Radiographic severity (being in the top quartile of BASRI‐s/duration of AS) was associated with older age at onset of AS (odds ratio [OR] 1.10 per year), male sex (OR 1.90), current smoker (OR 4.72), and the presence of HLA–B*4100 (OR 11.73), DRB1*0804 (OR 12.32), DQA1*0401 (OR 5.24), DQB1*0603 (OR 3.42), and DPB1*0202 (OR 23.36), whereas the presence of DRB1*0801 was strongly negatively associated (OR 0.03). Being in the lowest quartile of BASRI‐s/duration of AS was also less likely among those with an older age at onset of AS (OR 0.94 per year), men (OR 0.28), and current smokers (OR 0.29).

Conclusion

The accuracy of the prognosis of radiographic severity in AS is improved by knowing the age at disease onset, sex, smoking history, and the presence of HLA–B*4100, DRB1*0804, DQA1*0401, DQB1*0603, DRB1*0801, and DPB1*0202 alleles.
Anti–U11/U12 RNP antibodies in systemic sclerosis: A new serologic marker associated with pulmonary fibrosis
Authors: Fertig Noreen , Domsic Robyn T. , Rodriguez‐Reyna Tatiana , Kuwana Masataka , Lucas Mary , Medsger Thomas A. , Feghali‐Bostwick Carol A.
Published: June 2009

Objective

To characterize a new serum autoantibody in patients with systemic sclerosis (SSc) directed against U11/U12 RNP and to identify the clinical features associated with this autoantibody.

Methods

We identified autoantibodies directed against the U11/U12 RNP complex in sera of patients with SSc and confirmed antibody specificity by immunoprecipitation, reverse transcriptase–polymerase chain reaction, and Southern blotting. We determined the prevalence of these antibodies in SSc and their specificity for SSc. We compared anti–U11/U12 RNP autoantibody–positive and negative SSc patients on demographic, disease classification, clinical variables, and survival.

Results

We identified 33 patients with anti–U11/U12 RNP antibodies. In 2 consecutive series of SSc patients first seen at 10‐year intervals (1994–1995 and 2004–2005), the prevalence of anti–U11/U12 RNP antibody–positive patients was 15 of 462 (3.2%). Seventeen (52%) of these 33 patients had limited cutaneous involvement. All patients had Raynaud's phenomenon and 82% had gastrointestinal (GI) involvement. None had “intrinsic” pulmonary arterial hypertension. The most significant clinical difference between anti–U11/U12 antibody–positive and negative cohorts was the prevalence of lung fibrosis, which occurred in 79% of the anti–U11/U12 RNP antibody–positive patients versus 37% of the anti–U11/U12 RNP antibody–negative patients (P < 0.0001). GI involvement was also significantly increased in the anti–U11/U12 RNP antibody–positive group. Patients with anti–U11/U12 RNP antibodies and pulmonary fibrosis had a 2.25‐fold greater risk of death than anti–U11/U12 RNP negative patients with pulmonary fibrosis.

Conclusion

Anti–U11/U12 RNP antibodies are present in the sera of approximately 3% of patients with SSc and are a marker for lung fibrosis, which is often severe.
Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease‐modifying antirheumatic drugs: A clinical and imaging comparative study
Authors: Saleem Benazir , Brown Andrew K. , Keen Helen , Nizam Sharmin , Freeston Jane , Karim Zunaid , Quinn Mark , Wakefield Richard , Hensor Elizabeth , Conaghan Philip G. , Emery Paul
Published: June 2009

Objective

For patients with rheumatoid arthritis (RA) in remission who are receiving disease‐modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging‐detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging‐detected synovitis.

Methods

One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1–5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity.

Results

In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission.

Conclusion

In RA patients with disease in remission, imaging‐detected synovitis persists, with power Doppler activity seen in ≥48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging‐detected synovitis.
Spondylarthritis in HLA–B27/human β2‐microglobulin–transgenic rats is not prevented by lack of CD8
Authors: Taurog Joel D. , Dorris Martha L. , Satumtira Nimman , Tran Tri M. , Sharma Rohit , Dressel Ralf , van den Brandt Jens , Reichardt Holger M.
Published: June 2009

Objective

HLA–B27 predisposes to spondylarthritis by an unknown mechanism. A logical candidate mechanism is through recognition of B27 by CD8+ T cells. The purpose of this study was to examine the effects of a lack of CD8 on the spondylarthritis that develops in B27/human β2‐microglobulin (Huβ2m)–transgenic rats.

Methods

A missense mutation in the CD8a gene that causes a loss of CD8α expression was identified in offspring of a male Sprague‐Dawley rat that had been treated with the mutagen N‐ethyl‐N‐nitrosourea. The mutation was crossed into B27/Huβ2m‐transgenic lines on the Lewis background. CD8a–/– and CD8a+/– progeny were compared on a mixed SD‐LEW background as well as after at least 10 backcrosses to LEW rats. CD8 function was assessed by generating cytolytic T lymphocytes (CTLs) against allogeneic DA strain antigens.

Results

Homozygous mutant rats showed normal CD8a and CD8b messenger RNA levels but no detectable expression of either protein and an almost complete abrogation of the allogeneic CTL response. Two disease phenotypes previously observed in different B27/Huβ2m‐transgenic lines also occurred in the respective CD8a–/–‐transgenic rat lines. There was no significant difference in disease prevalence or severity between CD8a–/– rats and CD8a+/– rats.

Conclusion

All of the previously described disease manifestations in HLA–B27/Huβ2m‐transgenic rats arise in the absence of any functional CD8+ T cells. It thus seems unlikely that classic T cell recognition of HLA–B27 is of primary importance in this animal model. The possibility of a secondary role of a CD8‐dependent mechanism cannot be entirely excluded.
Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis
Authors: Hintzen Christoph , Quaiser Saskia , Pap Thomas , Heinrich Peter C. , Hermanns Heike M.
Published: June 2009

Objective

To investigate the molecular mechanisms of CCL13/monocyte chemoattractant protein 4 (MCP‐4) chemokine expression through proinflammatory cytokines in different primary human fibroblasts and the contribution of CCL13 to monocyte migration.

Methods

Using RNase protection assays and enzyme‐linked immunosorbent assays, we quantified the expression of CCL13 compared with that of CCL2/MCP‐1 in primary human fibroblasts. Boyden chamber assays were performed to determine the importance of CCL13 for migration of primary monocytes. Pharmacologic inhibitors as well as small interfering RNA knockdown approaches were used to investigate the signaling pathways regulating CCL13 expression.

Results

The interleukin‐6 (IL‐6)–type cytokine oncostatin M (OSM) was a powerful inducer of CCL13 expression in primary synovial fibroblasts from patients with rheumatoid arthritis (RA) as well as those from healthy control subjects but not in other types of fibroblasts. Neither IL‐6 nor tumor necrosis factor α could stimulate the expression of CCL13 in synovial fibroblasts; IL‐1β was a very weak inducer. Synovial fibroblasts from patients with RA constitutively produced low amounts of CCL13, which was partially dependent on constitutive production of OSM. By investigating the underlying molecular mechanism, we identified STAT‐5, ERK‐1/2, and p38 as critical factors involved in OSM‐dependent transcription and messenger RNA stabilization of CCL13.

Conclusion

In contrast to other prominent cytokines involved in the pathogenesis of RA, OSM can strongly up‐regulate the expression of CCL13, a chemokine recently identified in the synovial fluid of patients with RA. Despite potent OSM‐induced signal transduction in all types of fibroblasts analyzed, only synovial fibroblasts secreted CCL13, which might be indicative of tissue‐specific imprinting of different fibroblasts during development.
Development of a structured interview tool to help patients identify and solve rheumatic condition‐related work barriers
Authors: Allaire Saralynn , Keysor Julie J.
Published: June 2009

Objective

To develop a comprehensive and efficient assessment tool for rheumatic condition‐related work barriers and explore its use by physical and occupational therapists.

Methods

Literature on arthritis work barriers was examined, followed by the collection of qualitative data on work barriers from patients with rheumatic conditions. A tool called the Work Experience Survey‐Rheumatic Conditions (WES‐RC), which identifies barriers and facilitates the formation of solutions for barriers, was developed using this data. Ten physical and occupational therapists reviewed the initial version of the tool and provided qualitative data and the relevance of its use by therapists. Using this data, the WES‐RC was revised. The therapists then administered the WES‐RC to 20 patients. Quantitative data, qualitative data, and results of the administrative experience were collected from therapists after each administration. Relevant data were used to further revise the WES‐RC. Qualitative data were coded and themes developed by 2 readers and compared. Means and frequencies were used to describe the quantitative data.

Results

The WES‐RC addressed patients' work barriers quite well with a mean score of 8.7, on a scale of 1–10 where 10 = barriers completely covered, and administration time was reported as “about right” in 18 (90%) of 20 administrations. Eighty percent of the therapists' administration experiences were positive. Therapists reported barrier identification as easy, while solution formation was difficult in 45% of the administrations and judged insufficient in 35%.

Conclusion

The WES‐RC appears to be feasible for rheumatology patients and for use by physical and occupational therapists. Further study is needed to enhance effective solution formation.
Being careful: A grounded theory of emergent chronic knee problems
Authors: Maly Monica R. , Cott Cheryl A.
Published: June 2009

Objective

To gain insight into the prediagnostic stages of knee osteoarthritis (OA) and identify the process whereby people recognize and address emergent chronic knee problems.

Methods

Twenty‐six people (15 women, mean age 53.2 ± 7.4 years) participated in a grounded theory study. Ten participants had a recent diagnosis of knee OA, and 16 had no diagnosis. The undiagnosed participants self‐reported their symptoms, which had lasted at least 6 months and were consistent with knee OA. During semistructured, one‐on‐one interviews, participants reflected on the development and impact of their chronic knee problems. A constant comparative approach was used for analysis.

Results

Participants described uncertainty in understanding the meaning of intermittent knee symptoms for several years before becoming aware of the emergence of chronic knee problems. Once aware, participants engaged in a circular process of interpreting the meaning of knee symptoms and being careful. Being careful referred to the cycle of perceptions, intentions, and behaviors aimed at avoiding knee damage during physical activity. This cycle continued until participants experienced a disruption that challenged their participation in meaningful activities, at which time they decided to access health care.

Conclusion

As a new construct, being careful unifies the complex set of experiences and behaviors that describe how participants protected their knee during physical activity. Participants interpret the experiences associated with emerging knee problems through interactions with others. These interactions enhance the participants' self‐management, despite not having the benefits associated with diagnosis, such as justification for symptoms and formal assistance.
Hyperuricemia and risk of stroke: A systematic review and meta‐analysis
Authors: Kim Seo Young , Guevara James P. , Kim Kyoung Mi , Choi Hyon K. , Heitjan Daniel F. , Albert Daniel A.
Published: June 2009

Objective

To assess the association between hyperuricemia and risk of stroke incidence and mortality because hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but, to date, results from observational studies are conflicting.

Methods

A systematic review and meta‐analysis were conducted. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Prospective cohort studies were included only if they contained data on stroke incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the association of stroke incidence and mortality with serum uric acid levels were calculated.

Results

A total of 16 studies including 238,449 adults were eligible and abstracted. Hyperuricemia was associated with a significantly higher risk of both stroke incidence (6 studies; RR 1.41, 95% confidence interval [95% CI] 1.05, 1.76) and mortality (6 studies; RR 1.36, 95% CI 1.03, 1.69) in our meta‐analyses of unadjusted study estimates. Subgroup analyses of studies adjusting for known risk factors such as age, hypertension, diabetes mellitus, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence (4 studies; RR 1.47, 95% CI 1.19, 1.76) and mortality (6 studies; RR 1.26, 95% CI 1.12, 1.39). The pooled estimate of multivariate RRs did not differ significantly by sex.

Conclusion

Hyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future research is needed to determine whether lowering uric acid level has any beneficial effects on stroke.
Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways
Authors: Trouw L. A. , Haisma E. M. , Levarht E. W. N. , van der Woude D. , Ioan‐Facsinay A. , Daha M. R. , Huizinga T. W. J. , Toes R. E.
Published: June 2009

Objective

It has been suggested that anti–citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti–cyclic citrullinated peptide (anti‐CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.

Methods

We set up novel assays to analyze complement activation by anti‐CCP antibodies, using cyclic citrullinated peptide–coated plates, specific buffers, and normal and complement‐deficient sera as a source of complement.

Results

Anti‐CCP antibodies activated complement in a dose‐dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti‐CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.

Conclusion

Our findings indicate that anti‐CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement‐mediated damage in RA.
Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β through the NF‐κB and MAPK pathways in rheumatoid arthritis
Authors: Zheng Wenxin , Li Runsheng , Pan Heng , He Dongyi , Xu Rong , Guo Taylor B. , Guo Yajun , Zhang Jingwu Z.
Published: June 2009

Objective

Osteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP‐1) and macrophage inflammatory protein 1β (MIP‐1β), in RA.

Methods

Enzyme‐linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation.

Results

The effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP‐1 and MIP‐1β in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP‐1 or MIP‐1β in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP‐1 or MIP‐1β, and this effect could be blocked by an anti‐OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50–83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF‐κB and MAPK pathways, involving the activation of IKKβ, p38, and JNK.

Conclusion

These results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP‐1 and MIP‐1β.
Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women
Authors: Valdes Ana M. , Lories Rik J. , van Meurs Joyce B. , Kerkhof Hanneke , Doherty Sally , Hofman Albert , Hart Deborah J. , Zhang Feng , Luyten Frank P. , Uitterlinden Andre G. , Doherty Michael , Spector Tim D.
Published: June 2009

Objective

The ANP32A gene encodes a tumor suppressor molecule that plays a regulatory role in apoptosis and interferes with canonical Wnt signaling in vitro. We undertook this study to test whether genetic variation at ANP32A was associated with osteoarthritis (OA) in women.

Methods

Single‐nucleotide polymorphisms (SNPs) in the ANP32A gene were genotyped in 438 control women, 425 women with total knee replacements (TKRs), and 537 women with total hip replacements (THRs) from the Nottingham case–control study as well as in 820 women from the population‐based Chingford Study cohort for whom hip and knee radiographs were available. The most highly associated SNP was further tested in women from the Rotterdam Study (131 with THRs, 633 with knee OA, and 1,567 controls) and the TwinsUK Study cohort (67 with THRs, 43 with TKRs, and 358 controls), for a total of 2,170 patients with OA and 2,849 controls.

Results

The ANP32A transcript was abundantly expressed in normal and OA articular cartilage. Three SNPs in the ANP32A gene were significantly associated in Nottingham patients with hip OA, but not knee OA. One of these (rs7164503) was associated with hip and knee OA in the Chingford Study cohort and with THR in the TwinsUK Study cohort, but the association was not statistically significant in the Rotterdam Study. When we combined hip data from all 4 cohorts, we found that the minor allele of rs7164503 was associated with a significantly lower risk of hip OA (Mantel‐Haenszel odds ratio 0.67 [95% confidence interval 0.53–0.84], P < 3.8 × 10−4) and that a similar trend was observed for knee OA (Mantel‐Haenszel odds ratio 0.87 [95% confidence interval 0.73–1.01], P < 0.055).

Conclusion

Our results provide evidence suggesting that ANP32A is involved in the pathogenesis of OA of the hip.
Characterization and peripheral blood biomarker assessment of anti–Jo‐1 antibody–positive interstitial lung disease
Authors: Richards Thomas J. , Eggebeen Aaron , Gibson Kevin , Yousem Samuel , Fuhrman Carl , Gochuico Bernadette R. , Fertig Noreen , Oddis Chester V. , Kaminski Naftali , Rosas Ivan O. , Ascherman Dana P.
Published: June 2009

Objective

Using a combination of clinical, radiographic, functional, and serum protein biomarker assessments, this study was aimed at defining the prevalence and clinical characteristics of interstitial lung disease (ILD) in a large cohort of patients with anti–Jo‐1 antibodies.

Methods

A review of clinical records, pulmonary function test results, and findings on imaging studies determined the existence of ILD in anti–Jo‐1 antibody–positive individuals whose data were accumulated in the University of Pittsburgh Myositis Database from 1982 to 2007. Multiplex enzyme‐linked immunosorbent assays (ELISAs) for serum inflammation markers, cytokines, chemokines, and matrix metalloproteinases in different patient subgroups were performed to assess the serum proteins associated with anti–Jo‐1 antibody–positive ILD.

Results

Among the 90 anti–Jo‐1 antibody–positive individuals with sufficient clinical, radiographic, and/or pulmonary function data, 77 (86%) met the criteria for ILD. While computed tomography scans revealed a variety of patterns suggestive of underlying usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia, a review of the histopathologic abnormalities in a subset of patients undergoing open lung biopsy or transplantation or whose lung tissue was obtained at autopsy (n = 22) demonstrated a preponderance of UIP and diffuse alveolar damage. Analysis by multiplex ELISA yielded statistically significant associations between anti–Jo‐1 antibody–positive ILD and elevated serum levels of C‐reactive protein (CRP), CXCL9, and CXCL10, which distinguished this disease entity from idiopathic pulmonary fibrosis and anti–signal recognition particle antibody–positive myositis. Recursive partitioning further demonstrated that combinations of these and other serum protein biomarkers can distinguish these disease subgroups at high levels of sensitivity and specificity.

Conclusion

In this large cohort of anti–Jo‐1 antibody–positive individuals, the incidence of ILD approached 90%. Multiplex ELISA demonstrated disease‐specific associations between anti–Jo‐1 antibody–positive ILD and serum levels of CRP as well as the interferon‐γ–inducible chemokines CXCL9 and CXCL10, highlighting the potential of this approach to define biologically active molecules contributing to the pathogenesis of myositis‐associated ILD.
Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry
Authors: Tubach F. , Salmon D. , Ravaud P. , Allanore Y. , Goupille P. , Bréban M. , Pallot‐Prades B. , Pouplin S. , Sacchi A. , Chichemanian R. M. , Bretagne S. , Emilie D. , Lemann M. , Lorthololary O. , Mariette X.
Published: June 2009

Objective

Tuberculosis (TB) is associated with anti–tumor necrosis factor (anti‐TNF) monoclonal antibody (mAb) therapy, but whether this association is drug‐specific remains a concern. Our objective was to describe cases of TB associated with anti‐TNF mAb therapy, identify risk factors, and estimate the incidence.

Methods

We conducted an incidence study and a case–control analysis to investigate the risk of newly diagnosed TB associated with the use of anti‐TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti‐TNF mAb therapy for any indication; for each case, 2 patients treated with anti‐TNF agents served as control subjects.

Results

We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex‐ and age‐adjusted incidence rate of TB was 116.7 per 100,000 patient‐years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7–15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4–25.8] and SIR 29.3 [95% CI 20.3–42.4] versus SIR 1.8 [95% CI 0.7–4.3], respectively). In the case–control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6–69.0] and OR 17.1 [95% CI 3.6–80.6], respectively). Other risk factors were age, the first year of anti‐TNF mAb treatment, and being born in an endemic area.

Conclusion

The risk of TB is higher for patients receiving anti‐TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti‐TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.
The small ubiquitin‐like modifier mediates the resistance of prosthesis‐loosening fibroblast‐like synoviocytes against fas‐induced apoptosis
Authors: Meinecke Ingmar , Pap Géza , Mendoza Heidi , Drange Steffen , Ender Stephan , Strietholt Simon , Gay Renate E. , Seyfert Christine , Ink Barbara , Gay Steffen , Pap Thomas , Peters Marvin A.
Published: June 2009

Objective

To study the expression of small ubiquitin‐like modifier 1 (SUMO‐1) in aseptic loosening of prosthesis implants and to investigate its role in regulating the susceptibility of prosthesis‐loosening fibroblast‐like synoviocytes (FLS) to Fas‐induced apoptosis.

Methods

Specimens of aseptically loosened tissue were obtained at revision surgery, and the expression of SUMO‐1 was analyzed by in situ hybridization. SUMO‐1 levels in FLS were determined by quantitative polymerase chain reaction and Western blot analysis. Immunohistochemistry and confocal microscopy were used to study the subcellular localization of SUMO‐1. The functional role of SUMO‐1 in Fas‐induced apoptosis of prosthesis‐loosening FLS was investigated by small interfering RNA–mediated knockdown of SUMO‐1 and by gene transfer of the nuclear SUMO‐specific protease SENP1.

Results

SUMO‐1 was expressed strongly in aseptically loosened tissue and was found prominently at sites adjacent to bone. Prosthesis‐loosening FLS expressed levels of SUMO‐1 similar to the levels expressed by rheumatoid arthritis (RA) FLS, with SUMO‐1 being found mainly in promyelocytic leukemia protein nuclear bodies. Knockdown of SUMO‐1 had no effect on spontaneous apoptosis but significantly increased the susceptibility of prosthesis‐loosening FLS to Fas‐induced apoptosis. Gene transfer of the nuclear SUMO‐specific protease SENP1 reverted the apoptosis‐inhibiting effects of SUMO‐1.

Conclusion

These data suggest that SUMO‐1 is involved in the activation of both RA FLS and prosthesis‐loosening FLS by preventing these cells from undergoing apoptosis. Modification of nuclear proteins by SUMO‐1 contributes to the antiapoptotic effects of SUMO‐1 in prosthesis‐loosening FLS, providing evidence for the specific activation of sumoylation during their differentiation. Therefore, SUMO‐1 may be an interesting target for novel strategies to prevent aseptic prosthesis loosening.
Enthesis inflammation in recurrent acute anterior uveitis without spondylarthritis
Authors: Muñoz‐Fernández Santiago , de Miguel Eugenio , Cobo‐Ibáñez Tatiana , Madero Rosario , Ferreira Antonio , Hidalgo M. Ventura , Schlincker Armelle , Martín‐Mola Emilio
Published: June 2009

Objective

To investigate whether patients with idiopathic recurrent acute anterior uveitis (AAU) have enthesis alterations comparable with those in patients with spondylarthritis (SpA).

Methods

A blinded, controlled study of enthesis evident on ultrasound (US) examination was performed in 100 patients and controls classified into 5 groups, as follows: patients with confirmed SpA (group 1), patients with recurrent AAU who were positive for HLA–B27 and did not have SpA (group 2), patients with recurrent AAU who were negative for HLA–B27 and did not have SpA (group 3), patients with forms of uveitis other than those related to SpA (group 4), and healthy controls (group 5). In total, 12 enthesis locations were explored in each patient and control subject by 2 ultrasonographers who were blinded with regard to the diagnosis. A newly developed US method, the Madrid Sonography Enthesitis Index (MASEI), in which the diagnosis of SpA is determined as a cutoff score of 18 points, was used.

Results

A total of 1,200 entheses were explored by US in 100 patients and controls. The MASEI cutoff limit was met or exceeded by 81%, 55.6%, 40%, 10%, and 19% of the subjects in the 5 groups, respectively. The MASEI score was significantly higher in groups 1 and 2 than in groups 4 and 5. The differences between groups 1 and 3 were also found to be significant.

Conclusion

Our findings indicate that a high percentage of HLA–B27–positive patients with idiopathic recurrent AAU without features of SpA have enthesis lesions comparable with those seen in patients with SpA. These data suggest that patients with recurrent AAU, especially those who are HLA–B27 positive, have an abortive or incomplete form of SpA.
Changes in proximal femoral mineral geometry precede the onset of radiographic hip osteoarthritis: The study of osteoporotic fractures
Authors: Javaid M. K. , Lane N. E. , Mackey D. C. , Lui L.‐Y. , Arden N. K. , Beck T. J. , Hochberg M. C. , Nevitt M. C.
Published: June 2009

Objective

Radiographic hip osteoarthritis (RHOA) is associated with increased hip areal bone mineral density (aBMD). This study was undertaken to examine whether femoral geometry is associated with RHOA independent of aBMD.

Methods

Participants in the Study of Osteoporotic Fractures in whom pelvic radiographs had been obtained at visits 1 and 5 (mean 8.3 years apart) and hip dual x‐ray absorptiometry (DXA) had been performed (2 years after baseline) were included. Prevalent and incident RHOA phenotypes were defined as composite (osteophytes and joint space narrowing [JSN]), atrophic (JSN without osteophytes), or osteophytic (femoral osteophytes without JSN). Analogous definitions of progression were based on minimum joint space and total osteophyte score. Hip DXA scans were assessed using the Hip Structural Analysis program to derive geometric measures, including femoral neck length, width, and centroid position. Relative risks and 95% confidence intervals for prevalent, incident, and progressive RHOA per SD increase in geometric measure were estimated in a hip‐based analysis using multinomial logistic regression with adjustment for age, body mass index, knee height, and total hip aBMD.

Results

In 5,245 women (mean age 72.6 years), a wider femoral neck with a more medial centroid position was associated with prevalent and incident osteophytic and composite RHOA phenotypes (P < 0.05). Increased neck width and centroid position were associated with osteophyte progression (both P < 0.05). No significant geometric associations with atrophic RHOA were found.

Conclusion

Differences in proximal femoral bone geometry and spatial distribution of bone mass occur early in hip OA and predict prevalent, incident, and progressive osteophytic and composite phenotypes, but not the atrophic phenotype. These bone differences may reflect responses to loading occurring early in the natural history of RHOA.
Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis
Authors: Chia Shi‐Lu , Sawaji Yasunobu , Burleigh Annika , McLean Celia , Inglis Julia , Saklatvala Jeremy , Vincent Tonia
Published: June 2009

Objective

We have previously identified in articular cartilage an abundant pool of the heparin‐binding growth factor, fibroblast growth factor 2 (FGF‐2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF‐2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF‐2 suppresses interleukin‐1–driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF‐2 in murine cartilage.

Methods

Basal characteristics of the articular cartilage of Fgf2−/− and Fgf2+/+ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase–polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2−/− and Fgf2+/+ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF‐2 on OA progression was assessed in Fgf2−/− mice.

Results

Fgf2−/− mice were morphologically indistinguishable from wild‐type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2−/− mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2−/− mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF‐2. Increased disease in Fgf2−/− mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase.

Conclusion

These data identify FGF‐2 as a novel endogenous chondroprotective agent in articular cartilage.