bluuebunny/crossref_metadata_2025 huggingface dataset:
Driving Anger Scale, French Adaptation: Further Evidence of Reliability and Validity
Authors: Villieux Arnaud , Delhomme Patricia
Published: August 2008

This study was conducted to provide further evidence of reliability and validity for the Driving Anger Scale, French version. A sample of 202 drivers, ages 18–25 years, completed the scale and the general Trait Anger scale from NEO Personality Inventory-Revised. Factor analysis indicated five factors similar to those found in the original U.S. version. The ‘Traffic Obstructions’ and ‘Slow Driving' factors have been slightly modified, and ‘Discourtesy’ was abandoned. Positive correlations were observed between scores on the Trait-Anger scale from the NEO Personality Inventory-Revised and the Driving Anger Scale ( r = .41) and with its factors (from .24 to .38), except for ‘Illegal Driving’. The internal consistency of the Driving Anger Scale was acceptable for the total score (α = .82) and for factors ranged from .74 to .80. This French version can be preliminarily recommended for the assessment of driving anger in France among young drivers.
Preliminary Report of a Validation Study of Instrumental Activities of Daily Living in a Greek Sample
Authors: Theotoka Ioulia , Kapaki Elisabeth , Vagenas Vasileios , Ilias Ioannis , Paraskevas George P. , Liappas Ioannis
Published: August 2008

To validate the Instrumental Activities of Daily Living in Greek, 44 men ( M age = 70.5 yr., SD = 7.2) and 58 women ( M age = 68.4, SD = 9.2), outpatients of memory clinics, were studied. Sex differences in the item responses were evaluated. Reliability assessed as Cronbach alpha was .84, while validity was assessed by correlation of .77 with the Mini-Mental State Examination. 21 men and 20 women had moderate to severe dementia, with Mini-Mental State Examination scores < 20. The results show that this Greek language version can be effectively used in Greece.
Analysis of the Efficacy of Possessions in Boys' 16-And-Under Basketball Teams: Differences between Winning and Losing Teams
Authors: Ortega Enrique , Palao José Manuel , Gómez Miguel ángel , Lorenzo Alberto , Cárdenas David
Published: August 2008

The purpose of this study was to analyze the ball possessions of winning and losing basketball teams in formative years (16 years and under). The sample was 3,897 ball possessions from 24 games of the boys' 16-and-under finals of the Andalusion Championship, Spain. The variables studied were game outcome, participation, and the initiation and end of each ball possession. Winning teams used more fast breaks and fewer set offenses in their ball possessions. Winning teams had shorter ball possessions and more passes and participating players. Dynamic game styles are necessary in youth basketball, focusing on continuously off-balancing the opponent through fast breaks and a high number of passes in set offenses.
Omni Scale Rating of Perceived Exertion at Ventilatory Breakpoint by Direct Observation of Children's Kinematics
Authors: Robertson Robert J. , Goss Fredric L. , Aaron Deborah J. , Utter A. C. , Nagle E.
Published: August 2008

Direct kinematic observation was used to measure ratings of perceived exertion at the ventilatory breakpoint (RPE-Vpt) in 10- to 14-yr.-old girls ( n = 22) and boys ( n = 22). RPE for the overall body, legs, and chest were simultaneously estimated by a trained observer and self-rated by a subject during treadmill exercise using the Children's OMNI-Walk/Run Scale. Subjects' heart rate and oxygen consumption were measured during each minute of exercise. Vpt for the girls and boys, respectively, were 64.2 and 66.5% VO2 max. RPE-Vpt ranged from 6.0 to 6.5 Overall, 7.1 to 7.6 Legs, and 5.0 to 5.5 Chest for both the observation and self-rating procedures. Responses indicated (a) RPE-Vpt (Overall, Legs, Chest) did not differ ( p>.05) between the observer and self-rating procedures and (b) Observer RPE-Vpt-Legs was greater ( p<.05) than RPE-Vpt-Chest. Findings validated direct kinematic observation to code group-normalized RPE-Vpt for girls and boys performing treadmill exercise.
Testing the Finno-Ugrian Suicide Hypothesis: Replication and Refinement with Regional Suicide Data from Eastern Europe
Authors: Voracek Martin , Loibl Lisa Mariella , Kandrychyn Siarhei
Published: August 2008

Multiple lines of evidence indicate specific genetic contributions to suicidal behavior. In particular, geographic studies support the Finno-Ugrian Suicide Hypothesis, i.e., genetic differences between populations may partially account for geographic patterns of suicide prevalence. Specifically, within Europe the high suicide-rate nations constitute a contiguous J-shaped belt. The present research replicated and extended 2003 findings of Voracek, Fisher, and Marušič with new data. Across 37 European nations, an interaction term of squared latitude multiplied with longitude (quantifying the J-shaped belt) accounted for 32% of the cross-national variance in total suicide rates alone, while latitude accounted merely for 18% of variance over and above those. Refined analysis included regional data from countries critical for testing the hypothesis (89 regions of Belarus, western Russia, and the Ukraine) and yielded an even more clear-cut pattern (56% and 3.5%, respectively). These results are consistent with the Finno-Ugrian Suicide Hypothesis. Study limitations and directions for further research are discussed.
Contextual Interference Effects in Learning Volleyball Skills
Authors: Zetou Eleni , Michalopoulou Maria , Giazitzi Katerina , Kioumourtzoglou Efthimis
Published: August 2008

The aim of this study was to examine the contextual interference effect on learning three volleyball skills. Participants were 26 novice female volleyball players ( M age = 12.4 yr., SD = 1.2). They were assigned into two groups, Low Interference ( n = 13) and High Interference ( n = 13). Two practice schedules were used: blocked (Low Interference) and random (High Interference). The training period lasted for 10 weeks and included 2 training sessions of 75 min. each per week. The pretest was performed before the first training session, the posttest was performed after the completion of the last training period, and the retention test was performed two weeks after the posttest. A 2 (Groups) × 3 (Measurement Periods) analysis of variance with repeated measures indicated significant improvement in performance between pre- and posttests for both High Interference and Low Interference groups for the three skills included in this study. There was no significant main effect of group or interaction effect of group and measure. These findings suggest that either blocked or random practice could be effectively used in learning of volleyball skills by unskilled children.
Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen‐induced arthritis: Evidence of a neuronal target
Authors: Boettger Michael K. , Hensellek Susanne , Richter Frank , Gajda Mieczyslaw , Stöckigt Renate , von Banchet Gisela Segond , Bräuer Rolf , Schaible Hans‐Georg
Published: August 2008

Objective

The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor α (TNFα) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy.

Methods

Locomotor and pain‐related behavior and histology were assessed in rats with chronic antigen‐induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent Aδ fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan‐induced inflammation).

Results

In rats with AIA, both etanercept and infliximab significantly decreased inflammation‐induced locomotor and pain‐related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI‐ and TNFRII‐like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint.

Conclusion

Overall, these data show the pronounced antinociceptive effects of TNFα neutralization, thus suggesting that reduction of the effects of TNFα on pain fibers themselves significantly contributes to pain relief.
Anti‐DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients
Authors: Hahn Bevra H. , Anderson Marissa , Le Elizabeth , Cava Antonio La
Published: August 2008

Objective

Treg cells oppose autoreactive responses in several autoimmune diseases, and their frequency is reduced in systemic lupus erythematosus (SLE). In murine lupus models, treatment with anti‐DNA Ig–based peptides can expand the number of Treg cells in vivo. This study was undertaken to test the possibility that functional human Treg cells can be induced by exposure to anti‐DNA Ig–based peptides.

Methods

Peripheral blood mononuclear cells were isolated from 36 lupus patients and 32 healthy individuals matched for ethnicity, sex, and age. Short‐term culture experiments in the presence of several independent stimuli including anti‐DNA Ig peptides were followed by flow cytometric analysis for identification of CD4+,CD25high T cells, cell sorting for in vitro suppression assays, and analysis of correlations between the expression of forkhead box P3 (FoxP3) and serologic and clinical characteristics of the SLE patients.

Results

The number of in vitro CD4+,CD25high T cells increased after culture with anti‐DNA Ig peptides in the SLE patients, but not in the controls. The expanded CD4+,CD25high T cells required FoxP3 for cell contact–mediated suppression of proliferation and interferon‐γ production in target CD4+,CD25− T cells. The induction of FoxP3 in SLE Treg cells occurred only in seropositive patients, and was correlated with anti‐DNA and IgG serum titers.

Conclusion

These results suggest a new modality to reverse the functional deficit of Treg cells in SLE patients with positive autoimmune serology, and identify a new strategy to enhance immunoregulatory T cell activity in human SLE.
The arthritis severity locusCia5dis a novel genetic regulator of the invasive properties of synovial fibroblasts
Authors: Laragione Teresina , Brenner Max , Mello Adriana , Symons Marc , Gulko Pércio S.
Published: August 2008

Objective

The synovial fibroblast, or fibroblast‐like synoviocyte (FLS), has a central role in pannus invasion and destruction of cartilage and bone in rheumatoid arthritis (RA). However, regulation of the FLS remains incompletely understood. The aim of this study was to determine whether the invasive properties of FLS are genetically regulated by arthritis severity loci.

Methods

DA rats (arthritis susceptible) and rat strains congenic for arthritis‐protective intervals were studied. Primary FLS cell lines were generated from each strain and used in a well‐established FLS invasion model through a collagen‐rich barrier. Cells or culture supernatants were analyzed for gene expression, activity of different matrix metalloproteinases (MMPs), cytoskeleton integrity, and cell proliferation.

Results

The median number of FLS from DA.F344(Cia5d) rats that invaded through the collagen‐rich barrier was reduced 86.5% compared with the median number of invading FLS from DA rats. Histologic examination showed that DA.F344(Cia5d) rats preserved a normal joint without pannus, hyperplasia, or erosions. FLS from DA.F344(Cia5d) rats produced significantly lower levels of active MMP‐2 compared with FLS from DA rats, but the levels of proMMP‐2 and MMP‐2 messenger RNA in DA.F344(Cia5d) rats were similar to those in DA rats. Treatment of FLS from DA rats with an MMP‐2 inhibitor reduced cell invasion to a level similar to that in DA.F344(Cia5d) rats, demonstrating that MMP‐2 activity accounted for the difference between FLS from these 2 strains. Analysis of MMP‐2–activating pathways revealed increased levels of soluble membrane type 1 (MT1)–MMP in DA rats compared with DA.F344(Cia5d) rats.

Conclusion

These data represent the first evidence for a genetic component in the regulation of FLS invasion. A gene located within theCia5dinterval accounts for this effect and operates via the regulation of soluble MT1‐MMP production and MMP‐2 activation. These observations suggest novel potential pathways for prognostication and therapy.
Association of the IRF5 risk haplotype with high serum interferon‐α activity in systemic lupus erythematosus patients
Authors: Niewold Timothy B. , Kelly Jennifer A. , Flesch Marie H. , Espinoza Luis R. , Harley John B. , Crow Mary K.
Published: August 2008

Objective

A haplotype of the interferon regulatory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon‐α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity.

Methods

IFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single‐nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data.

Results

SLE patients with risk/risk and risk/neutral IRF5 genotypes had higher serum IFNα activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNα levels was driven largely by SLE patients who were positive for either anti–RNA binding protein (anti‐RBP) or anti–double‐stranded DNA (anti‐dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was independently associated with high serum IFNα in this autoantibody group. We found no difference in IFNα activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody.

Conclusion

The IRF5 SLE risk haplotype is associated with higher serum IFNα activity in SLE patients, and this effect is most prominent in patients positive for either anti‐RBP or anti‐dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.
Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis
Authors: Kinloch Andrew , Lundberg Karin , Wait Robin , Wegner Natalia , Lim Ngee Han , Zendman Albert J. W. , Saxne Tore , Malmstr Vivianne , Venables Patrick J.
Published: August 2008

Objective

To examine synovial fluid as a site for generating citrullinated antigens, including the candidate autoantigen citrullinated α‐enolase, in rheumatoid arthritis (RA).

Methods

Synovial fluid was obtained from 20 patients with RA, 20 patients with spondylarthritides (SpA), and 20 patients with osteoarthritis (OA). Samples were resolved using sodium dodecyl sulfate–polyacrylamide gel electrophoresis, followed by staining with Coomassie blue and immunoblotting for citrullinated proteins, α‐enolase, and the deiminating enzymes peptidylarginine deiminase type 2 (PAD‐2) and PAD‐4. Proteins from an RA synovial fluid sample were separated by 2‐dimensional electrophoresis, and each protein was identified by immunoblotting and mass spectrometry. Antibodies to citrullinated α‐enolase peptide 1 (CEP‐1) and cyclic citrullinated peptide 2 were measured by enzyme‐linked immunosorbent assay.

Results

Citrullinated polypeptides were detected in the synovial fluid from patients with RA and patients with SpA, but not in OA samples. Alpha‐enolase was detected in all of the samples, with mean levels of 6.4 ng/μl in RA samples, 4.3 ng/μl in SpA samples, and <0.9 ng/μl in OA samples. Two‐dimensional electrophoresis provided evidence that the α‐enolase was citrullinated in RA synovial fluid. The citrullinating enzyme PAD‐4 was detected in samples from all 3 disease groups. PAD‐2 was detected in 18 of the RA samples, in 16 of the SpA samples, and in none of the OA samples. Antibodies to CEP‐1 were found in 12 of the RA samples (60%), in none of the SpA samples, and in 1 OA sample.

Conclusion

These results highlight the importance of synovial fluid for the expression of citrullinated autoantigens in inflammatory arthritis. Whereas the expression of citrullinated proteins is a product of inflammation, the antibody response remains specific for RA.
A pilot study to evaluate the safety and efficacy of the long‐acting interleukin‐1 inhibitor rilonacept (interleukin‐1 trap) in patients with familial cold autoinflammatory syndrome
Authors: Goldbach‐Mansky Raphaela , Shroff Sharukh D. , Wilson Mildred , Snyder Christopher , Plehn Sara , Barham Beverly , Pham Tuyet‐Hang , Pucino Frank , Wesley Robert A. , Papadopoulos Joanne H. , Weinstein Steven P. , Mellis Scott J. , Kastner Daniel L.
Published: August 2008

Objective

Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin‐1β (IL‐1β), which is associated with cold‐induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL‐1 Trap), a long‐acting IL‐1 receptor fusion protein, in patients with FCAS.

Methods

Five patients with FCAS were studied in an open‐label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage‐escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high‐sensitivity C‐reactive protein [hsCRP], serum amyloid A [SAA], and IL‐6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values.

Results

In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute‐phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well‐tolerated. Weight gain in 2 patients was noted. No study drug–related serious adverse events were seen.

Conclusion

In this study, we present 2‐year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.
The chemokine receptors CXCR1/CXCR2 modulate antigen‐induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature
Authors: Coelho Fernanda M. , Pinho Vanessa , Amaral Flávio A. , Sachs Daniela , Costa Vívian V. , Rodrigues David H. , Vieira Angélica T. , Silva Tarcília A. , Souza Daniele G. , Bertini Riccardo , Teixeira Antônio L. , Teixeira Mauro M.
Published: August 2008

Objective

The chemokine receptors CXCR1 and CXCR2 play a role in mediating neutrophil recruitment and neutrophil‐dependent injury in several models of inflammation. We undertook this study to investigate the role of these receptors in mediating neutrophil adhesion, subsequent migration, and neutrophil‐dependent hypernociception in a murine model of monarticular antigen‐induced arthritis (AIA).

Methods

AIA was induced by administration of antigen into the knee joint of previously immunized mice. Intravital microscopy studies were performed to assess leukocyte rolling and adhesion. Mechanical hypernociception was investigated using an electronic pressure meter. Neutrophil accumulation in the tissue was measured by counting neutrophils in the synovial cavity and assaying myeloperoxidase activity. Levels of tumor necrosis factor α (TNFα) and the chemokines CXCL1 and CXCL2 were quantified by enzyme‐linked immunosorbent assay. Histologic analysis was performed to evaluate the severity of arthritis and leukocyte infiltration.

Results

Antigen challenge in immunized mice induced production of TNFα, CXCL1, and CXCL2 and also resulted in neutrophil recruitment, leukocyte rolling and adhesion, and hypernociception. Treatment with reparixin or DF2162 (allosteric inhibitors of CXCR1/CXCR2) decreased neutrophil recruitment, an effect that was associated with marked inhibition of neutrophil adhesion. Drug treatment also inhibited TNFα production, hypernociception, and the overall severity of the disease in the tissue.

Conclusion

Blockade of CXCR1/CXCR2 receptors inhibits neutrophil recruitment by inhibiting the adhesion of neutrophils to synovial microvessels. As a consequence, there is decreased local cytokine production and reduced hypernociception, as well as ameloriation of overall disease in the tissue. These studies suggest a potential therapeutic role for the modulation of CXCR1/CXCR2 receptor signaling in the treatment of arthritis.
Genome‐wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility
Authors: Julià Antonio , Ballina Javier , Cañete Juan D. , Balsa Alejandro , Tornero‐Molina Jesus , Naranjo Antonio , Alperi‐López Mercedes , Erra Alba , Pascual‐Salcedo Dora , Barceló Pere , Camps Jordi , Marsal Sara
Published: August 2008

Objective

To identify new genes associated with susceptibility to rheumatoid arthritis (RA), using a 2‐stage genome‐wide association study.

Methods

Following a liability‐based study design, we analyzed 317,503 single‐nucleotide polymorphisms (SNPs) in 400 patients with RA and 400 control subjects. We selected a group of candidate SNPs for replication in an independent group of 410 patients with RA and 394 control subjects. Using data from the 3 previous genome‐wide association studies in RA, we also looked for genomic regions showing evidence of common association signals. Finally, we analyzed the presence of genome‐wide epistasis using the binary test implemented in the PLINK program.

Results

We identified several genomic regions showing evidence of genome‐wide association (P < 1 × 10 −5). In the replication analysis, we identified KLF12 SNP rs1324913 as the most strongly associated SNP (P = 0.01). In our study, we observed that this SNP showed higher significance than PTPN22 SNP rs2476601, in both the genome‐wide association studies and the replication analyses. Furthermore, the integration of our data with those from previous genome‐wide association studies showed that KLF12 and PTPRT are the unique loci that are commonly associated in 3 different studies (P = 0.004 and P = 0.002 for KLF12 in the Wellcome Trust Case Control Consortium study and the Brigham and Women's Rheumatoid Arthritis Sequential Study genome‐wide association study, respectively). The genome‐wide epistasis analysis identified several SNP pairs close to significance after multiple test correction.

Conclusion

The present genome‐wide association study identified KLF12 as a new susceptibility gene for RA. The joint analysis of our results and those from previous genome‐wide association studies showed genomic regions with a higher probability of being genuine susceptibility loci for RA.
An early sympathetic nervous system influence exacerbates collagen‐induced arthritis via CD4+CD25+ cells
Authors: Härle Peter , Pongratz Georg , Albrecht Julia , Tarner Ingo H. , Straub Rainer H.
Published: August 2008

Objective

Activation of the sympathetic nervous system (SNS) ameliorates collagen‐induced arthritis (CIA) in the late phase of the disease but aggravates it in the presymptomatic phase. The aim of the present study was to determine whether CD4+CD25+ T cells are influenced by the SNS of mice and play a disease‐modifying role in the early symptomatic phase of the disease.

Methods

We tested the effects of the SNS on arthritis by transferring CD4+CD25+ T cells from sympathectomized mice immunized with type II collagen and from immunized, SNS‐intact animals (controls). We further characterized transferred cells by studying forkhead box P3 (FoxP3) expression, cell proliferation, and cytokine secretion.

Results

Using anti–dopamine‐β‐hydroxylase antibodies for systemic sympathectomy, we noticed a time‐dependent disease amelioration (strongest when sympathectomy was performed 7 days before immunization, with no effect 30 days after immunization). When CD4+CD25+ T cells from immunized and sympathectomized animals were transferred into mice with CIA (on day 32), disease severity was reduced compared with that in controls. However, the number of CD4+CD25+FoxP3+ cells and the FoxP3 expression level in CD4+CD25+ cells were not changed by sympathectomy. In a mixed assay of donor CD4+CD25− and CD4+CD25+ cells, proliferation was reduced when cells from sympathectomized animals were studied. In the same assay, secretion of tumor necrosis factor, interleukin‐17 (IL‐17), IL‐10, and IL‐4 (not interferon‐γ) was markedly reduced when cells were taken from sympathectomized animals. Culture of CD4+CD25+ cells with norepinephrine (10−5M) for 24 hours before transfer worsened the arthritis.

Conclusion

The SNS increases disease severity in the early phase of symptomatic CIA by stimulating several proinflammatory aspects of CD4+CD25+ T cells.
Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis
Authors: Kadri A. , Ea H. K. , Bazille C. , Hannouche D. , Lioté F. , Cohen‐Solal M. E.
Published: August 2008

Objective

To characterize bone microarchitectural changes and to test the hypothesis that disrupting local cytokine equilibrium could modify cartilage degradation in a murine model of experimental osteoarthritis (OA).

Methods

Ten‐week‐old male C57BL/6 mice underwent medial meniscectomy of their right knees and a sham operation of their left knees. The mice received intraperitoneal injections of osteoprotegerin (OPG) (10 mg/kg), interleukin‐1 receptor antagonist (IL‐1Ra) (100 mg/kg), or phosphate buffered saline for 6 weeks. The microarchitecture of the trabecular bone, the OA score, and expression of ADAMTS‐4 and ADAMTS‐5 were assessed. Proteoglycan release was measured in cartilage explant cultures in the presence of IL‐1Ra and OPG.

Results

In the meniscectomized knees, bone volume/tissue volume (BV/TV) was lower, whereas trabecular separation, the OA score, and aggrecanase expression were higher than in the sham‐operated knees. After treatment with OPG, BV/TV was significantly increased and trabecular separation was reduced in the knees that underwent meniscectomy. The OA score and the number of ADAMTS‐positive cells were significantly decreased by treatment with OPG but were not affected by IL‐1Ra. Moreover, OPG did not directly reduce the release of proteoglycans from cartilage explant cultures.

Conclusion

In an experimental model of OA, meniscectomy induced bone loss and cartilage degradation at 6 weeks. Systemic administration of OPG prevented bone and cartilage degradation in vivo but had no effect on cartilage in vitro. These data collectively indicate that bone could be a contributor in the early stages of OA pathogenesis. They further suggest that disruption of RANKL/OPG balance might result in the degradation of cartilage subjected to mechanical loading. Specific targeting of the bone cytokine network might help to prevent OA.
The mouse mast cell–restricted tetramer‐forming tryptases mouse mast cell protease 6 and mouse mast cell protease 7 are critical mediators in inflammatory arthritis
Authors: McNeil H. Patrick , Shin Kichul , Campbell Ian K. , Wicks Ian P. , Adachi Roberto , Lee David M. , Stevens Richard L.
Published: August 2008

Objective

Increased numbers of mast cells (MCs) that express β tryptases bound to heparin have been detected in the synovium of patients with rheumatoid arthritis (RA). The corresponding tryptases in mice are mouse MC protease 6 (mMCP‐6) and mMCP‐7. Although MCs have been implicated in RA and some animal models of arthritis, no direct evidence for a MC‐restricted tryptase in the pathogenesis of inflammatory arthritis has been shown. We created transgenic mice that lack heparin and different combinations of mMCP‐6 and mMCP‐7, to evaluate the roles of MC‐restricted tryptase–heparin complexes in an experimental model of arthritis.

Methods

The methylated bovine serum albumin/interleukin‐1β (mBSA/IL‐1β) experimental protocol was used to induce inflammatory monarthritis in different mouse strains. Mice were killed at the time of peak disease on day 7, and histochemical methods were used to assess joint pathology.

Results

Arthritis was induced in the knee joints of mBSA/IL‐1β–treated mMCP‐6+/mMCP‐7− and mMCP‐6−/mMCP‐7+ C57BL/6 mice, and numerous activated MCs that had exocytosed the contents of their secretory granules were observed in the diseased mice. In contrast, arthritis was markedly reduced in heparin‐deficient mice and in mMCP‐6−/mMCP‐7− C57BL/6 mice.

Conclusion

MC‐derived tryptase–heparin complexes play important roles in mBSA/IL‐1β–induced arthritis. Because mMCP‐6 and mMCP‐7 can compensate for each other in this disease model, the elimination of both tryptases is necessary to reveal the prominent roles of these serine proteases in joint inflammation and destruction. Our data suggest that the inhibition of MC‐restricted tryptases could have therapeutic potential in the treatment of RA.
Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes
Authors: Cillero‐Pastor Berta , Caramés Beatriz , Lires‐Deán Marcos , Vaamonde‐García Carlos , Blanco Francisco J. , López‐Armada María J.
Published: August 2008

Objective

Mitochondrial alterations play a key role in the pathogenesis of osteoarthritis (OA). This study evaluated a potential role of mitochondrial respiratory chain (MRC) dysfunction in the inflammatory response of normal human chondrocytes.

Methods

Commonly used inhibitors of the MRC were utilized to induce mitochondrial dysfunction in normal human chondrocytes. Levels of prostaglandin E2 (PGE2) protein and expression of cyclooxygenase 2 (COX‐2) and COX‐1 messenger RNA (mRNA) and protein were analyzed. To identify the underlying mechanisms responsible for PGE2 liberation, reactive oxygen species (ROS) were measured. Inhibitors of ROS, including vitamin E, and inhibitors of mitochondrial Ca2+ and NF‐κB were used to test their effects on the MRC.

Results

Antimycin A and oligomycin (inhibitors of mitochondrial complexes III and V, respectively) significantly increased the levels of PGE2 (mean ± SEM 505 ± 132 pg/50,000 cells and 288 ± 104 pg/50,000 cells, respectively, at 24 hours versus a basal level of 29 ± 9 pg/50,000 cells; P < 0.05) and increased the expression of COX‐2 at both the mRNA and protein levels. Expression of COX‐1 did not show any modulation with either inhibitor. Further experiments revealed that antimycin A and oligomycin induced a marked increase in the levels of ROS. Production of PGE2 and expression of COX‐2 protein were inhibited by antioxidants, vitamin E, and mitochondrial Ca2+ and NF‐κB inhibitors. The response to blockers of mitochondrial Ca2+ movement showed that ROS production was dependent on mitochondrial Ca2+ accumulation.

Conclusion

These results strongly suggest that, in human chondrocytes, the inhibition of complexes III and V of the MRC induces an inflammatory response, which could be especially relevant in relation to PGE2 production via mitochondrial Ca2+ exchange, ROS production, and NF‐κB activation. These data may prove valuable for a better understanding of the participation of mitochondria in the pathogenesis of OA.
Is imatinib mesylate a promising drug in systemic sclerosis?
Authors: van Daele P. L. A. , Dik W. A. , Thio H. B. , van Hal P. Th. W. , van Laar J. A. M. , Hooijkaas H. , van Hagen P. M.
Published: August 2008

A patient with therapy‐resistant and progressive systemic sclerosis (SSc) with pulmonary involvement who was treated with imatinib mesylate is described herein. Prior to treatment, pulmonary fibroblasts obtained from the patient were cultured and incubated with imatinib mesylate. Preincubation of the fibroblasts for 16 hours with 2.5 μg/ml imatinib mesylate efficiently abrogated platelet‐derived growth factor BB–induced fibroblast proliferation. Furthermore, transforming growth factor β1–induced type I collagen gene transcription was blocked. During treatment, the patient's pulmonary involvement stabilized and her skin tightness improved. To our knowledge, this is the first report of a patient with therapy‐refractory SSc responding to treatment with imatinib mesylate.
High ten‐year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: A population‐based cohort study
Authors: Kremers Hilal Maradit , Crowson Cynthia S. , Therneau Terry M. , Roger Veronique L. , Gabriel Sherine E.
Published: August 2008

Objective

To estimate the 10‐year absolute risk of cardiovascular (CV) events in newly diagnosed rheumatoid arthritis (RA) patients and the potential contribution of CV risk factors to absolute risk assessment.

Methods

A population‐based incidence cohort of RA patients (defined according to the American College of Rheumatology 1987 criteria) was assembled and compared with an age‐ and sex‐matched non‐RA cohort. Data were collected on CV risk factors and CV events. Cox regression models were used to estimate the 10‐year risk of a combined CV end point, adjusting for CV risk factors. Subjects were classified into 5 risk categories based on their 10‐year absolute risk.

Results

The absolute CV risk in RA patients was similar to that in non‐RA subjects who were 5–10 years older. The absolute risk varied substantially according to the presence of CV risk factors. The 10‐year absolute CV risk among 60–69‐year‐old RA patients with no risk factors was 16.8%, but rose to 60.4% if risk factors such as smoking, hypertension, dyslipidemia, diabetes, and obesity were present. Among RA patients with a low body mass index, in addition to the above risk factors, the 10‐year absolute CV risk rose to 86.2%.

Conclusion

More than half of the newly diagnosed RA patients who were 50–59 years of age and all of those >60 years of age had a >10% risk of CV disease within 10 years of their RA incidence and should be targeted for specific CV risk reduction strategies tailored to their personal risk profiles.
Cytokine‐controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: Fibroblast‐mediated pathologic bone resorption
Authors: Tunyogi‐Csapo Miklos , Kis‐Toth Katalin , Radacs Marianna , Farkas Balint , Jacobs Joshua J. , Finnegan Alison , Mikecz Katalin , Glant Tibor T.
Published: August 2008

Objective

To determine whether proinflammatory cytokine treatment or the complete absence of select cytokines modulates the expression of RANKL and osteoprotegerin (OPG) in synovial fibroblasts.

Methods

Fibroblasts were isolated from normal and rheumatoid human synovium and from normal or arthritic joints of wild‐type and cytokine gene–deficient (interleukin‐4–knockout [IL‐4 −/−] and interferon‐γ–knockout [IFNγ −/−]) mice. Fibroblasts were stimulated with proinflammatory cytokines (tumor necrosis factor α [TNFα], IL‐1β, and IL‐17) or antiosteoclastogenic cytokines (IL‐4 and IFNγ), alone or in combination, and the expression of RANKL and OPG was measured.

Results

Proinflammatory cytokine–stimulated fibroblasts from rheumatoid and arthritic mouse joints expressed higher levels of RANKL and OPG than those from normal joints. IL‐4 suppressed RANKL expression and increased OPG expression, IFNγ reduced the production of both RANKL and OPG, and IL‐17 had only a modest effect on the expression of RANKL or OPG. Additive effects of combination treatment (TNFα/IL‐17 or IL‐1β/IL‐17) were observed only in the human system. Extensive destruction was observed in the arthritic joints of IL‐4 −/− mice, with a corresponding upward shift of the RANKL:OPG ratios. However, an IL‐17 deficiency did not attenuate arthritis or reduce bone resorption.

Conclusion

Proinflammatory cytokines induce the expression of RANKL and OPG in both human and murine synovial fibroblasts. The RANKL:OPG ratios are shifted in favor of bone protection by IL‐4 treatment, and, to a lesser extent, by IFNγ treatment. Unexpectedly, an IL‐17 deficiency alone does not induce reduced inflammatory bone destruction. Our results suggest that synovial fibroblasts may significantly contribute to bone resorption through modulation of RANKL and OPG production in a cytokine‐rich milieu of inflamed joints.
Characterization of metalloprotease cleavage products of human articular cartilage
Authors: Zhen Eugene Y. , Brittain Isabelle J. , Laska Dennis A. , Mitchell Peter G. , Sumer Eren U. , Karsdal Morten A. , Duffin Kevin L.
Published: August 2008

Objective

To identify, characterize, and compare proteolysis peptide products generated by metalloprotease digests of human articular cartilage.

Methods

Human articular cartilage was digested by the addition of exogenous metalloproteases, including matrix metalloproteinases 2, 3, 8, 9, 12, and 13 and aggrecanases ADAMTS‐4 and ADAMTS‐5. Proteolyzed peptide products were identified by proteomics methods using mass spectrometry.

Results

Complete sequences of the peptides proteolyzed from human articular cartilage, including N‐ and C‐termini and hydroxylated posttranslational modifications, were determined. A wide variety of peptides, originating from types I, II, and III collagen, biglycan, prolargin, fibromodulin, fibronectin, decorin, cartilage oligomeric matrix protein, cartilage intermediate‐layer protein, megakaryocyte‐stimulating factor, mimecan, aggrecan, and lumican, was analyzed following metalloprotease digestion. Release of peptides varied as a function of time, enzyme specificity, and abundance. Specific type II collagen peptide biomarkers, including those containing the three‐quarter–length fragment cleavage site and those containing the domains for helical peptide of type II collagen and C‐telopeptide of type II collagen, were observed after release by selected proteases.

Conclusion

The use of intact cartilage instead of purified protein substrates in the assay allowed for the identification of novel potential substrates and cleavage sites for individual enzymes under more physiologically relevant conditions. Characterization of these cartilage matrix peptides may help in the development of pharmacodynamic biomarkers of cartilage degradation, and also may contribute to an understanding of the bioactive peptides important in chondrocyte signaling.
Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides
Authors: Jandus Camilla , Bioley Gilles , Rivals Jean‐Paul , Dudler Jean , Speiser Daniel , Romero Pedro
Published: August 2008

Objective

A distinct subset of proinflammatory CD4+ T cells that produce interleukin‐17 was recently identified. These cells are implicated in different autoimmune disease models, such as experimental autoimmune encephalomyelitis and collagen‐induced arthritis, but their involvement in human autoimmune disease has not yet been clearly established. The purpose of this study was to assess the frequency and functional properties of Th17 cells in healthy donors and in patients with different autoimmune diseases.

Methods

Peripheral blood was obtained from 10 psoriatic arthritis (PsA), 10 ankylosing spondylitis (AS), 10 rheumatoid arthritis (RA), and 5 vitiligo patients, as well as from 25 healthy donors. Synovial tissue samples from a separate group of patients were also evaluated (obtained as paraffin‐embedded sections). Peripheral blood cells were analyzed by multiparameter flow cytometry and immunohistochemistry. Cytokine production was examined by enzyme‐linked immunosorbent assay and intracellular cytokine staining using specific monoclonal antibodies. Synovial tissue was examined for infiltrating T cells by immunohistochemical analysis.

Results

We found increased numbers of circulating Th17 cells in the peripheral blood of patients with seronegative spondylarthritides (PsA and AS), but not in patients with RA or vitiligo. In addition, Th17 cells from the spondylarthritis patients showed advanced differentiation and were polyfunctional in terms of T cell receptor–driven cytokine production.

Conclusion

These observations suggest a role of Th17 cells in the pathogenesis of certain human autoimmune disorders, in particular the seronegative spondylarthritides.
Inhibition of experimental Sjögren's syndrome through immunization with HSP60 and its peptide amino acids 437–460
Authors: Delaleu Nicolas , Madureira Ana Carina , Immervoll Heike , Jonsson Roland
Published: August 2008

Objective

To investigate a potential immunomodulatory effect of the 60‐kd heat‐shock protein (Hsp60) on experimental spontaneous Sjögren's syndrome (SS).

Methods

Seven‐week‐old nonobese diabetic (NOD) mice were immunized with eukaryotic Hsp60 or an Hsp60‐derived peptide (amino acid residue [aa] 437–460). At 21 weeks of age, nondiabetic mice were investigated for salivary gland inflammation, exocrine function, and extraglandular disease manifestations. In addition, biomarker profiles comprising 87 analytes in serum and 75 in saliva were analyzed.

Results

In mice immunized with Hsp60 and aa 437–460, SS‐related histopathologic features were significantly reduced compared with NOD controls. In addition, 50% of Hsp60‐injected mice and 33% of aa 437–460–injected mice retained normal exocrine function. Both treatments induced similar changes in biomarker profiles. Notably, levels of circulating interferon‐γ–inducible 10‐kd protein (IP‐10) and eotaxin were decreased significantly after treatment. Anti–type 3 muscarinic acetylcholine receptor (anti‐M3R) IgG1, interleukin‐10, and leptin discriminated best between the different treatment groups. Successful prevention of hyposalivation was accompanied by quantitative alterations in 36 biomarkers, of which 19 mediators of inflammation declined to levels comparable with those found in BALB/c mice. Low secreted vascular endothelial growth factor A was the most accurate predictor of successful prevention of hyposalivation. Low salivary granulocyte chemotactic protein 2 was identified as the best predictor of normal secretory function across the strains.

Conclusion

Immunization with Hsp60 and its peptide aa 437–460 led to inhibition of SS in NOD mice. Comprehensive analyses revealed specific biomarker signatures capable of predicting treatment group and treatment outcome. Molecules involved in inflammatory chemotaxis, neovascularization, and regulatory pathways caused the differences displayed by the biomarker profiles.
Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis
Authors: Rego‐Pérez Ignacio , Fernández‐Moreno Mercedes , Fernández‐López Carlos , Arenas Joaquín , Blanco Francisco J.
Published: August 2008

Objective

Some studies indicate that the mitochondrion is implicated in osteoarthritis (OA). To test the hypothesis that mitochondrial DNA (mtDNA) haplogroups contribute to the prevalence and severity of knee OA, we analyzed the European mtDNA haplogroups in a Spanish population of patients with knee OA and healthy control subjects.

Methods

We combined the single‐base extension assay with the polymerase chain reaction–restriction fragment length polymorphism technique to obtain the different single‐nucleotide polymorphisms that characterize the European haplogroups in 457 patients with knee OA and 262 radiologic controls. Knee OA radiographs had previously been classified as grades 1–4 according to Kellgren/Lawrence (K/L) scoring system.

Results

Individuals carrying haplogroup J showed a significantly decreased risk of knee OA (odds ratio [OR] 0.460 [95% confidence interval (95% CI) 0.282–0.748], P = 0.002). In terms of K/L scores, patients carrying haplogroup J had a less severe progression of knee OA (OR 0.351 [95% CI 0.156–0.787], P = 0.012), while those carrying haplogroup U had a more severe progression (OR 1.788 [95% CI 1.094–2.922], P = 0.025).

Conclusion

People carrying haplogroup J may be at a lower risk of developing knee OA, and those carrying this haplogroup in whom knee OA does not develop may have a less severe progression of the disease. Patients with knee OA carrying haplogroup U may have a more severe progression of the disease. These results indicate that mtDNA haplogroups contribute to the pathogenesis of OA.
Efficient suppression of murine arthritis by combined anticytokine small interfering RNA lipoplexes
Authors: Khoury Maroun , Escriou Virginie , Courties Gabriel , Galy Anne , Yao Roseline , Largeau Céline , Scherman Daniel , Jorgensen Christian , Apparailly Florence
Published: August 2008

Objective

Blocking tumor necrosis factor (TNF) effectively inhibits inflammation and joint damage in rheumatoid arthritis (RA), but 40% of RA patients respond only transiently or not at all to the current anti‐TNF biotherapies. The purpose of this study was to develop an alternative targeted therapy for this subgroup of RA patients. As proof of concept, we tested the efficiency of an RNA interference (RNAi)–based intervention that targets proinflammatory cytokines in suppressing murine collagen‐induced arthritis (CIA).

Methods

Two synthetic short interfering RNA (siRNA) sequences were designed for each of the proinflammatory cytokines interleukin‐1 (IL‐1), IL‐6, and IL‐18. Their silencing specificity was assessed according to lipopolysaccharide‐induced messenger RNA expression in J774.1 mouse macrophages as compared with control siRNA. For in vivo administration, siRNA were formulated as lipoplexes with the RPR209120/DOPE liposome and a carrier DNA and were injected intravenously (0.5 mg/kg) into DBA/1 mice with CIA.

Results

Weekly injections of anti–IL‐1, anti–IL‐6, or anti–IL‐18 siRNA‐based lipoplexes significantly reduced the incidence and severity of arthritis, abrogating joint swelling and destruction of cartilage and bone, both in the preventative and the curative settings. The most striking therapeutic effect was observed when the 3 siRNA were delivered in combination. The siRNA lipoplex cocktail reduced all pathologic features of RA, including inflammation, joint destruction, and the Th1 response, and overall parameters of RA were improved as compared with anti‐TNF siRNA lipoplex–based treatment.

Conclusion

Our results present a novel option for in vivo RNAi‐based antiinflammatory immunotherapy. Our findings indicate that intravenous administration of a lipoplex cocktail containing several anticytokine siRNA is a promising novel antiinflammatory therapy for RA, as well as a useful and simple tool for understanding the pathophysiology of RA and for evaluating new therapeutic candidates.