bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mesencephalic Reticular Formation as a Conduit for Primate Collicular Gaze Control: Tectal Inputs to Neurons Targeting the Spinal Cord and Medulla
Authors: Perkins Eddie , Warren Susan , May Paul J.
Published: July 2009

The superior colliculus (SC), which directs orienting movements of both the eyes and head, is reciprocally connected to the mesencephalic reticular formation (MRF), suggesting the latter is involved in gaze control. The MRF has been provisionally subdivided to include a rostral portion, which subserves vertical gaze, and a caudal portion, which subserves horizontal gaze. Both regions contain cells projecting downstream that may provide a conduit for tectal signals targeting the gaze control centers which direct head movements. We determined the distribution of cells targeting the cervical spinal cord and rostral medullary reticular formation (MdRF), and investigated whether these MRF neurons receive input from the SC by the use of dual tracer techniques in Macaca fascicularis monkeys. Either biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin was injected into the SC. Wheat germ agglutinin conjugated horseradish peroxidase was placed into the ipsilateral cervical spinal cord or medial MdRF to retrogradely label MRF neurons. A small number of medially located cells in the rostral and caudal MRF were labeled following spinal cord injections, and greater numbers were labeled in the same region following MdRF injections. In both cases, anterogradely labeled tectoreticular terminals were observed in close association with retrogradely labeled neurons. These close associations between tectoreticular terminals and neurons with descending projections suggest the presence of a trans‐MRF pathway that provides a conduit for tectal control over head orienting movements. The medial location of these reticulospinal and reticuloreticular neurons suggests this MRF region may be specialized for head movement control. Anat Rec, 292:1162–1181, 2009. © 2009 Wiley‐Liss, Inc.
Effect of Hypoxia and Aging on PKC δ‐Mediated SC‐35 Phosphorylation in Rat Myocardial Tissue
Authors: Cataldi Amelia , Zingariello Maria , Rapino Monica , Zara Susi , Daniele Franca , Di Giulio Camillo , Antonucci Adriano
Published: July 2009

Nuclear speckles, which are sites of pre‐mRNA splicing and/or assembly components, are diffusely distributed throughout the nucleoplasm. They are composed of splicing factors (SFs), including SC‐35, which are nuclear proteins that remove introns (noncoding sequences in the genes) from precursor mRNA molecules, to form mature RNA, which will be transported to the cytoplasm, site of protein synthesis and activation. In light of such evidences, here we report that hypoxia modulates in vivo SC‐35 SF phosphorylation via protein kinase C (PKC) δ in young rat heart. Trichrome Mallory staining and TUNEL analysis along with immunohistochemistry and Western blotting have been performed on left ventricles excised from young and old rats exposed to intermittent hypoxia. Although young hypoxic myocardial cells appear smaller than normoxic cells, connective and endothelial components increase, SC‐35 phosphorylation is particularly evident in the endothelium and paralleled by an increased expression of vascular endothelial growth factor (VEGF). In addition, SC‐35 and PKC δ coimmunoprecipitation occurs, suggesting that SC‐35 phosphorylation could be PKC δ‐mediated and that hypoxic young heart needs to counteract the damage through a process of neoangiogenesis involving such SF. Even though the levels of SC‐35 and PKC δ are high, the similar response disclosed by normoxic and hypoxic old rat hearts (both showing a fibrotic organization, similar endothelial components and VEGF levels) could be due to the existence of an impaired oxygen sensing mechanism and thus to a low rate of angiogenesis. Anat Rec, 292:1135–1142, 2009. © 2009 Wiley‐Liss, Inc.
An Embryonic Staging Table for In Ovo Development of Eublepharis macularius, the Leopard Gecko
Authors: Wise Patrick A.D. , Vickaryous Matthew K. , Russell Anthony P.
Published: July 2009

Squamates constitute a major vertebrate radiation, representing almost one‐third of all known amniotes. Although speciose and morphologically diverse, they remain poorly represented in developmental studies. Here, we present an embryonic staging table of in ovo development for the basal gekkotan Eublepharis macularius (the leopard gecko) and advocate this species as a laboratory‐appropriate developmental model. E. macularius, is a hardy and tractable species of relatively large body size (with concomitantly relatively large eggs and embryos), that is widely available and easy to maintain and propagate. Additionally, E. macularius displays a body plan appropriate to the study of the plesiomorphic quadrupedal condition of early pentadactylous terrestrial amniotes. Although not unexpected, it is worth noting that the morphological events characterizing limb development in E. macularius are comparable with those described for the avian Gallus gallus. Therefore, E. macularius holds great promise as a model for developmental studies focusing on pentadactyly and the formation of digits. Furthermore, it is also attractive as a developmental model because it demonstrates temperature‐dependent sex determination. The staging table presented herein is based on an all‐female series and represents the entire 52 day in ovo period. Overall, embryogenesis of E. macularius is similar to that of other squamates in terms of developmental stage attained at the time of oviposition, patterns of limb and pharyngeal arch development, and features of the appearance of scalation and pigmentation, indicative of a conserved developmental program. Anat Rec, 292:1198–1212, 2009. © 2009 Wiley‐Liss, Inc.
A Reevaluation of the Unusual Abdominal Musculature of Squamate Reptiles (Reptilia: Squamata)
Authors: Bhullar Bhart‐Anjan S.
Published: July 2009

The abdominal muscles of lizards and snakes (Squamata) have been the subject of periodic attention from anatomists, embryologists, and systematists. Until now, the presence of a superficial portion of the m. rectus abdominis, named the m. rectus abdominis lateralis, has been considered a key synapomorphy of the clade Autarchoglossa, which includes all extant squamates save Gekkota and Iguania. However, the precise anatomical relations of the m. rectus abdominis lateralis have never been fully investigated. Here, I show that the m. rectus abdominis lateralis is present in Iguania. Its absence in Gekkota represents rare gross anatomical support for recent molecular‐structure‐based hypotheses of squamate relationships placing geckoes as sister to the remaining squamates. Where present, it is the most superficial trunk muscle, exterior to the m. obliquus externus. The separation of the m. rectus abdominis lateralis from the m. rectus abdominis occurs as the m. obliquus externus aponeurosis and part of the m. obliquus internus aponeurosis emerge superficially to form the outer portion of the rectus sheath. In Autarchoglossa, the contralateral mm. recti abdomines laterales meet at the midline and are attached to the imbricae of the transverse scale rows characteristic of the clade, suggesting developmental, functional, and evolutionary association. Because the m. rectus abdominis lateralis is sometimes continuous with the pectoralis, its exclusive association with the m. rectus abdominis is questionable. It may be a neomorphic layer that is part of the abaxial developmental system, comprising those muscles whose connective tissue is largely derived from lateral plate as opposed to somatic mesoderm. Anat Rec, 292:1154–1161, 2009. © 2009 Wiley‐Liss, Inc.
Architecture of the Blood‐Spleen Barrier in the Soft‐Shelled Turtle, Pelodiseus Sinensis
Authors: Bao Hui‐Jun , Li Mei‐Ying , Wang Jiang , Qin Jun‐Hui , Xu Chun‐Sheng , Hei Nai‐Nan , Yang Ping , Gandahi J.A. , Chen Qiu‐Sheng
Published: July 2009

The soft‐shelled turtle, Pelodiseus sinensis, and its spleen section showing carbon particles of injected Indian ink mainly in the ellipsoid which composed the blood‐spleen barrier. See Bao et al, on page 1079, in this issue. Anatomical Record 292:1079–1087.
The role of neutrophil apoptosis in juvenile‐onset systemic lupus erythematosus
Authors: Midgley Angela , McLaren Zoe , Moots Robert J. , Edwards Steven W. , Beresford Michael W.
Published: July 2009

Objective

Accumulation of apoptotic cells may lead to the development of systemic lupus erythematosus (SLE) through a breakdown in immune tolerance. Altered neutrophil apoptosis may contribute to nuclear autoantigen exposure, ultimately leading to autoantibody generation. This study aimed to determine whether neutrophil apoptosis is altered in patients with juvenile‐onset SLE as compared with controls.

Methods

Apoptosis was measured in neutrophils from patients with juvenile‐onset SLE (n = 12), adult‐onset SLE (n = 6), and pediatric patients with inflammatory (n = 12) and noninflammatory (n = 12) conditions. Annexin V staining and flow cytometry were used to determine neutrophil apoptosis. Proapoptotic and antiapoptotic proteins were measured in sera and in neutrophil cell lysates.

Results

Neutrophil apoptosis was significantly increased in patients with juvenile‐onset SLE as compared with the noninflammatory controls at time 0. Incubation of neutrophils with sera from patients with juvenile‐onset SLE further increased neutrophil apoptosis as compared with incubation with sera from pediatric controls. Concentrations of TRAIL and FasL were significantly increased in sera from patients with juvenile‐onset SLE, whereas interleukin‐6, tumor necrosis factor α, and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) were significantly decreased. Addition of GM‐CSF to sera from patients with juvenile‐onset SLE significantly decreased neutrophil apoptosis as compared with juvenile‐onset SLE sera alone. The expression of proapoptotic proteins (caspase 3, Fas, and FADD) was elevated in juvenile‐onset SLE neutrophils, whereas the expression of antiapoptotic proteins (cellular inhibitor of apoptosis 1 and 2 and X‐linked inhibitor of apoptosis) was decreased. Neutrophil apoptosis correlated with biomarkers of disease activity (erythrocyte sedimentation rate and double‐stranded DNA concentration) and the British Isles Lupus Assessment Group disease activity score.

Conclusion

Our data demonstrate an imbalance in proapoptotic and antiapoptotic factors in both neutrophils and sera from patients with juvenile‐onset SLE. This imbalance results in increased neutrophil apoptosis in these patients. Correlations with markers of disease activity indicate that altered neutrophil apoptosis in juvenile‐onset SLE patients may play a pathogenic role in this condition.
Golimumab, a human anti–tumor necrosis factor α monoclonal antibody, injected subcutaneously every four weeks in methotrexate‐naive patients with active rheumatoid arthritis: Twenty‐four–week results of a phase III, multicenter, randomized, double‐blind, placebo‐controlled study of golimumab before methotrexate as first‐line therapy for early‐onset rheumatoid arthritis
Authors: Emery Paul , Fleischmann Roy M. , Moreland Larry W. , Hsia Elizabeth C. , Strusberg Ingrid , Durez Patrick , Nash Peter , Amante Eric Jason B. , Churchill Melvin , Park Won , Pons‐Estel Bernardo Antonio , Doyle Mittie K. , Visvanathan Sudha , Xu Weichun , Rahman Mahboob U.
Published: July 2009

Objective

To assess the safety and efficacy of golimumab in methotrexate (MTX)–naive patients with active rheumatoid arthritis (RA).

Methods

MTX‐naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1).

Results

An intent‐to‐treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P = 0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P = 0.049) and between group 3 (40.5%; P = 0.038) but not group 4 (36.5%; P = 0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound −5.2%; predefined delta value for noninferiority −10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively.

Conclusion

Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX‐naive patients, with no unexpected safety concerns.
Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long‐term methotrexate treatment
Authors: Stamp Lisa K. , O'Donnell John L. , Chapman Peter T. , Zhang Mei , Frampton Christopher , James Jill , Barclay Murray L.
Published: July 2009

Objective

Methotrexate (MTX) is the most commonly used disease‐modifying antirheumatic drug (DMARD) in the management of rheumatoid arthritis (RA). MTX is transported into cells, where additional glutamate moieties are added and it is retained as MTX polyglutamates (MTXGlu [referred to as a group as MTXGlun]). There is large interpatient variability in MTXGlunconcentrations. This study was undertaken to determine nongenetic factors that influence red blood cell (RBC) MTXGlunconcentrations in patients receiving long‐term stable low‐dose oral MTX.

Methods

One hundred ninety‐two patients receiving long‐term oral MTX for the treatment of RA were recruited. Trough MTXGlunconcentrations were measured by high‐performance liquid chromatography. Univariate analysis was performed to determine variables influencing MTXGlunconcentrations. Backward stepwise multivariate regression analysis was done to determine variables that affect individual MTXGlunconcentrations; variables withPvalues of <0.1 in the univariate analysis for any MTXGlunwere included.

Results

Univariate analysis revealed that increased age, lower estimated glomerular filtration rate (GFR), higher MTX dosage, longer duration of MTX treatment, and use of prednisone were associated with significantly higher MTXGlunconcentrations. Smokers had significantly lower concentrations of MTXGlu3, MTXGlu3–5, and MTXGlu1–5. Sex, rheumatoid factor and anti–cyclic citrullinated peptide status, RBC folate level, and body mass index had no significant effect on MTXGlunlevels. Concomitant use of other DMARDs was associated with lower MTXGlu2levels, and treatment with nonsteroidal antiinflammatory drugs was associated with lower MTXGlu3and MTXGlu1–5concentrations. Multivariate regression analysis revealed that age, MTX dosage, and estimated GFR were the major determinants of MTXGlunconcentrations.

Conclusion

Large interpatient variability in MTXGlunconcentrations can be explained, at least in part, by a combination of factors, particularly age, MTX dosage, and renal function. There are complex interactions between smoking, RBC folate levels, and concentrations of MTXGlun.
A polymorphism within IL21R confers risk for systemic lupus erythematosus
Authors: Webb Ryan , Merrill Joan T. , Kelly Jennifer A. , Sestak Andrea , Kaufman Kenneth M. , Langefeld Carl D. , Ziegler Julie , Kimberly Robert P. , Edberg Jeffrey C. , Ramsey‐Goldman Rosalind , Petri Michelle , Reveille John D. , Alarcón Graciela S. , Vilá Luis M. , Alarcón‐Riquelme Marta E. , James Judith A. , Gilkeson Gary S. , Jacob Chaim O. , Moser Kathy L. , Gaffney Patrick M. , Vyse Timothy J. , Nath Swapan K. , Lipsky Peter , Harley John B. , Sawalha Amr H.
Published: July 2009

Objective

Interleukin‐21 (IL‐21) is a member of the type I cytokine superfamily that has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL‐21 receptor (IL‐21R) is reduced in the B cells of patients with systemic lupus erythematosus (SLE), while serum IL‐21 levels are increased both in lupus patients and in some murine lupus models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to SLE. The aim of this study was to examine the genetic association between single‐nucleotide polymorphisms (SNPs) within IL21R and SLE.

Methods

We genotyped 17 SNPs in the IL21R gene in 2 large cohorts of lupus patients (a European‐derived cohort and a Hispanic cohort) and in ethnically matched healthy controls.

Results

We identified and confirmed the association between rs3093301 within the IL21R gene and SLE in the 2 cohorts (meta‐analysis odds ratio 1.16 [95% confidence interval 1.08–1.25], P = 1.0 × 10−4).

Conclusion

Our findings indicate that IL21R is a novel susceptibility gene for SLE.
Naturopathic treatment of rotator cuff tendinitis among Canadian postal workers: A randomized controlled trial
Authors: Szczurko Orest , Cooley Kieran , Mills Edward J. , Zhou Qi , Perri Dan , Seely Dugald
Published: July 2009

Objective

To explore the effectiveness of naturopathic care (NC) on rotator cuff tendinitis using a prospective randomized clinical trial design.

Methods

Canadian postal workers with rotator cuff tendinitis for a duration of >6 weeks were randomized to receive NC (n = 43) or standardized physical exercises (PEs; n = 42) over 12 weeks. Participants in the NC group received dietary counseling, acupuncture, and Phlogenzym (2 tablets 3 times/day). The PE intervention group received passive, active‐assisted, and active range of motion exercises and matched placebo. The primary outcome measure was the Shoulder Pain and Disability Index (SPADI), and secondary outcomes were the pain visual analog scale (VAS), Short Form 36 (SF‐36), Measure Yourself Medical Outcomes Profile (MYMOP), and shoulder maximal range of motion. Participants and assessors were blinded to group and placebo allocation.

Results

Seventy‐seven participants (87%) completed ≥8 weeks of the trial. Final total SPADI scores decreased by 54.5% (P < 0.0001) in the NC group and by 18% (P = 0.0241) in the PE group. Between‐group differences in changes to SPADI scores showed statistically significant decreases in shoulder pain and disability in the NC group compared with the PE group (P < 0.0001). Significant differences between groups were also observed in the pain VAS, MYMOP, SF‐36, and shoulder extension, flexion, and abduction, with the NC group showing superiority in each outcome. No serious adverse reactions were observed.

Conclusion

NC and PE provided significant improvements, with greater improvement in shoulder function in the NC group compared with the PE group. Statistically significant improvements in quality of life measures were observed in the NC group as compared with the PE group.
Health‐related quality of life in systemic sclerosis: A systematic review
Authors: Hudson Marie , Thombs Brett D. , Steele Russell , Panopalis Pantelis , Newton Evan , Baron Murray ,   Canadian Scleroderma Research Group
Published: July 2009

Objective

A number of studies (all n <200) have assessed health‐related quality of life (HRQOL) in patients with systemic sclerosis (SSc), but no systematic review of the effect of SSc on HRQOL has been done. The objective of this study was to systematically review the literature on HRQOL in SSc measured using the Medical Outcomes Trust Short Form 36 (SF‐36).

Methods

A comprehensive search was conducted in August 2007 using Medline, CINAHL, and EMBase to identify original research studies reporting SF‐36 scores of SSc patients. Selected studies were reviewed and characteristics of the study samples and SF‐36 data were extracted. Bayesian meta‐analysis and meta‐regression were performed to obtain pooled estimates of SF‐36 physical component summary (PCS) and mental component summary (MCS) scores for all patients as well as by limited and diffuse disease status.

Results

Twelve data sets with a total of 1,127 SSc patients were included in the systematic review. HRQOL was impaired in patients with SSc, with pooled SF‐36 PCS scores being more than 1 SD below the general population (38.3; 95% credible interval [95% CI] 35.2, 41.5) and pooled SF‐36 MCS scores being ∼0.5 SDs below the general population (46.6; 95% CI 44.2, 49.1). SF‐36 PCS scores were 3.5 points (95% CI −1.0, 8.0) lower in patients with diffuse compared with limited disease.

Conclusion

This study provides robust evidence of the presence and magnitude of impairment in HRQOL in patients with SSc. Although the impairment appears greater in physical health, mental health impairment is also reported.
Profiling microRNA expression in bovine articular cartilage and implications for mechanotransduction
Authors: Dunn Walter , DuRaine Grayson , Reddi A. Hari
Published: July 2009

Objective

Articular cartilage is an avascular tissue with precise polarity and organization comprising 3 distinct functional zones: the surface, middle, and deep zones. Each zone has a different gene expression pattern that plays a specific role in articular cartilage development and maintenance. MicroRNA (miRNA) are small noncoding gene products that play an important regulatory role in determining cell differentiation and function. The purpose of this study was to test our hypothesis that miRNA expression profiles in the different articular cartilage zones as well as between regions subjected to different levels of weight‐bearing stresses are unique.

Methods

Using an miRNA microarray approach in conjunction with quantitative reverse transcription–polymerase chain reaction, we identified miRNA in bovine articular cartilage that were differentially expressed in the different functional zones and in the anterior weight‐bearing and posterior non–weight‐bearing regions of the medial femoral condyle (M1 and M4, respectively).

Results

We identified miRNA‐221 and miR‐222 as part of a subset of differentially expressed miRNA that were up‐regulated in articular cartilage in the anterior, M1, greater weight‐bearing location. Additionally, miR‐126, miR‐145, and miR‐335 were down‐regulated in monolayers of tissue‐cultured chondrocytes as compared with levels determined directly from intact native cartilage.

Conclusion

In conclusion, miR‐222 expression patterns in articular cartilage are higher in the weight‐bearing anterior medial condyle as compared with the posterior non–weight‐bearing medial condyle. Thus, miR‐222 might be a potential regulator of an articular cartilage mechanotransduction pathway. These data implicate miRNA in the maintenance of articular cartilage homeostasis and are therefore targets for articular cartilage tissue engineering and regenerative medicine.
Regulation of plasminogen activator inhibitor 1 expression in human osteoarthritic chondrocytes by fluid shear stress: Role of protein kinase Cα
Authors: Yeh Chih‐Chang , Chang Hsin‐I , Chiang Jui‐Kun , Tsai Wang‐Ting , Chen Li‐Ming , Wu Chean‐Ping , Chien Shu , Chen Cheng‐Nan
Published: July 2009

Objective

To test a fluid flow system for the investigation of the influence of shear stress on expression of plasminogen activator inhibitor 1 (PAI‐1) in human osteoarthritic (OA) articular chondrocytes (from lesional and nonlesional sites) and human SW‐1353 chondrocytes.

Methods

Human SW‐1353 chondrocytes and OA and normal human articular chondrocytes were cultured on type II collagen–coated glass plates under static conditions or placed in a flow chamber to form a closed fluid‐circulation system for exposure to different levels of shear stress (2–20 dyn/cm2). Real‐time polymerase chain reaction was used to analyze PAI‐1 gene expression, and protein kinase C (PKC) inhibitors and small interfering RNA were used to investigate the mechanism of shear stress–induced signal transduction in SW‐1353 and OA (lesional and nonlesional) articular chondrocytes.

Results

There was a significant reduction in PAI‐1 expression in OA chondrocytes obtained from lesional sites compared with those obtained from nonlesional sites. In SW‐1353 chondrocytes subjected to 2 hours of shear flow, moderate shear stresses (5 and 10 dyn/cm2) generated significant PAI‐1 expression, which was regulated through PKCα phosphorylation and Sp‐1 activation. These levels of shear stress also increased PAI‐1 expression in articular chondrocytes from nonlesional sites and from normal healthy cartilage through the activation of PKCα and Sp‐1 signal transduction, but no effect of these levels of fluid shear stress was observed on OA chondrocytes from lesional sites.

Conclusion

OA chondrocytes from lesional sites and those from nonlesional sites of human cartilage have differential responses to shear stress with regard to PAI‐1 gene expression, and therefore diverse functional consequences can be observed.
Amelioration of alphavirus‐induced arthritis and myositis in a mouse model by treatment with bindarit, an inhibitor of monocyte chemotactic proteins
Authors: Rulli Nestor E. , Guglielmotti Angelo , Mangano Giorgina , Rolph Michael S. , Apicella Claudia , Zaid Ali , Suhrbier Andreas , Mahalingam Suresh
Published: July 2009

Objective

Alphaviruses such as chikungunya virus, Sindbis virus, o'nyong‐nyong virus, Mayaro virus, and Ross River virus (RRV), are commonly associated with arthralgias and overt arthritides worldwide. Understanding the processes by which arthritogenic viruses cause disease is a prerequisite in the quest for better treatments. In this regard, we have recently established that monocyte/macrophages are mediators of alphavirus‐induced arthritis in mice. We hypothesized that chemokines associated with monocyte/macrophage recruitment may play an important role in disease. The aim of the present investigations was to determine whether bindarit, an inhibitor of monocyte chemotactic protein (MCP) synthesis, could ameliorate alphavirus‐induced rheumatic disease in mice.

Methods

Using our recently developed mouse model of RRV‐induced arthritis, which has many characteristics of RRV disease (RRVD) in humans, the effects of bindarit treatment on RRVD in mice were determined via histologic analyses, immunohistochemistry, flow cytometry, real‐time polymerase chain reaction analysis, enzyme‐linked immunosorbent assay, and electrophoretic mobility shift assay.

Results

Bindarit‐treated RRV‐infected mice developed mild disease and had substantially reduced tissue destruction and inflammatory cell recruitment as compared with untreated RRV‐infected mice. The virus load in the tissues was not affected by bindarit treatment. Bindarit exhibited its activity by down‐regulating MCPs, which in turn led to inhibition of cell infiltration and lower production of NF‐κB and tumor necrosis factor α, which are involved in mediating tissue damage.

Conclusion

Our data support the use of inhibitors of MCP production in the treatment of arthritogenic alphavirus syndromes and suggest that bindarit may be useful in treating RRVD and other alphavirus‐induced arthritides in humans.
Sera from anti–Jo‐1–positive patients with polymyositis and interstitial lung disease induce expression of intercellular adhesion molecule 1 in human lung endothelial cells
Authors: Helmers Sevim Barbasso , Englund Pernilla , Engström Marianne , Åhlin Erik , Fathi Maryam , Janciauskiene Sabina , Heimbürger Mikael , Rönnelid Johan , Lundberg Ingrid E.
Published: July 2009

Objective

To investigate whether sera or purified IgG from patients with polymyositis (PM) and patients with dermatomyositis (DM), with or without interstitial lung disease (ILD), can activate endothelial cells (ECs).

Methods

Patients' sera were selected based on the presence or absence of anti–Jo‐1, anti‐SSA, or anti–U1 small nuclear RNP autoantibodies. The presence of autoantibodies was determined by line blot assays. Cultured human microvascular ECs derived from lung tissue (HMVEC‐L) were incubated with sera or purified IgG from 22 patients with PM, 7 patients with DM, and 10 healthy individuals as controls. Assessment of intercellular adhesion molecule 1 (ICAM‐1) expression was conducted by immunofluorescence (n = 22) and by cell‐based enzyme‐linked immunosorbent assay (ELISA) (n = 20). Serum levels of soluble ICAM‐1 (sICAM‐1) were determined by ELISA.

Results

Sera from PM patients with ILD who were positive for anti–Jo‐1 autoantibodies had a significantly stronger effect on the expression of ICAM‐1 by HMVEC‐L in comparison with sera from healthy controls and patients with other autoantibodies. Purified IgG did not induce ICAM‐1 expression. Higher serum levels of sICAM‐1 were found in patients with myositis compared with healthy controls.

Conclusion

EC activation with ICAM‐1 expression could contribute to the multiorgan involvement, including the development of myositis and ILD, in patients carrying anti–Jo‐1 autoantibodies. The EC‐activating factors are not the autoantibodies themselves, but might be systemic factors associated with these autoantibodies.
STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis
Authors: Dieudé P. , Guedj M. , Wipff J. , Ruiz B. , Hachulla E. , Diot E. , Granel B. , Sibilia J. , Tiev K. , Mouthon L. , Cracowski J.L. , Carpentier P.H. , Amoura Z. , Fajardy I. , Avouac J. , Meyer O. , Kahan A. , Boileau C. , Allanore Y.
Published: July 2009

Objective

Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT‐4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single‐nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5.

Methods

Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects.

Results

STAT4 rs7574865 was shown to be associated with SSc (P = 0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11–1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiplicatively increased 1.28‐fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86–3.99) for combinations of genotypes with ≥3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P = 2.2 × 10−4, OR 1.97, 95% CI 1.28–3.04).

Conclusion

Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc‐related fibrosing alveolitis.
Detection of coronary artery lesions and myocardial necrosis by magnetic resonance in systemic necrotizing vasculitides
Authors: Mavrogeni S. , Manoussakis M. N. , Karagiorga T. C. , Douskou M. , Panagiotakos D. , Bournia V. , Cokkinos D. V. , Moutsopoulos H. M.
Published: July 2009

Objective

Myocardium and coronary arteries can occasionally be affected in patients with systemic necrotizing vasculitides; however, such involvement has not been systematically assessed using cardiovascular magnetic resonance imaging (MRI).

Methods

Magnetic resonance angiography and contrast‐enhanced MRI were applied for the assessment of coronary arteries (the left anterior descending [LAD], left circumflex [LCx], and right coronary artery [RCA]) and myocardium, respectively, in 39 patients with vasculitis who were asymptomatic for cardiac disease (16 with microscopic polyangiitis [MPA], 11 with Wegener's granulomatosis [WG], 9 with Churg‐Strauss syndrome [CSS], and 3 with polyarteritis nodosa [PAN]). Data were compared with age‐matched disease‐control patients with rheumatoid arthritis (n = 20) or systemic lupus erythematosus (n = 13), and with healthy control individuals with normal coronaries (n = 40).

Results

Patients with MPA, WG, and PAN (but not with CSS) were found to display significantly increased maximal diameters of coronary arteries compared with healthy controls (for MPA and WG; P < 0.001 for LAD and RCA, and P < 0.01 for LCx) and with both disease‐control groups (for only MPA; P < 0.01 for LAD and RCA, and P < 0.05 for LCx). Fusiform coronary aneurysms were detected in patients with MPA (4/16) and PAN (2/3), whereas coronary ectasias were evident in patients with MPA (14/16) and WG (2/11). The presence of myocardial necrosis (by assessment of late gadolinium‐enhanced images) was identified only in patients with MPA (2/16) and CSS (3/8 studied).

Conclusion

Cardiovascular MRI assessment of patients with systemic vasculitis revealed coronary ectatic disease in the majority of patients with MPA and PAN, as well as in several patients with WG. Myocardial necrosis can be detected in MPA and CSS.
Efficacy and tolerability of rituximab with or without PEGylated interferon alfa‐2b plus ribavirin in severe hepatitis C virus–related vasculitis: A long‐term followup study of thirty‐two patients
Authors: Terrier Benjamin , Saadoun David , Sène Damien , Sellam Jérémie , Pérard Laurent , Coppéré Brigitte , Karras Alexandre , Blanc François , Buchler Matthias , Plaisier Emmanuelle , Ghillani Pascale , Rosenzwajg Michelle , Cacoub Patrice
Published: July 2009

Objective

To report on the long‐term followup of a cohort of patients with hepatitis C virus (HCV)–related vasculitis treated with rituximab with or without PEGylated interferon alfa‐2b (PEG–IFN alfa‐2b) plus ribavirin.

Methods

The study group comprised 32 HCV RNA–positive patients with HCV‐related vasculitis: 20 patients were treated with rituximab and PEG–IFN alfa‐2b (9 of whom had not previously received antiviral treatment and 11 of whom had experienced disease resistance to or relapse with antiviral treatment), and 12 antiviral‐intolerant patients were treated with rituximab alone.

Results

Treatment with rituximab and PEG–IFN alfa‐2b plus ribavirin induced a complete clinical response and a partial clinical response in 80% and 15% of patients, respectively, a complete immunologic response and a partial immunologic response in 67% and 33% of patients, respectively, and a sustained virologic response in 55% of patients. Treatment with rituximab alone induced a complete clinical response and a partial clinical response in 58% and 9% of patients, respectively, and a complete immunologic response and a partial immunologic response in 46% and 36% of patients, respectively. B cell depletion was achieved in 96% of patients, and B cell recovery began after a median delay of 12 months. After a mean ± SD followup period of 23 ± 12 months, 22% of patients experienced a clinical relapse, and 34% of patients experienced an immunologic relapse. All relapses were associated with the absence of virologic control, and 78% of relapses were associated with B cell recovery. Six patients were re‐treated with rituximab. All 6 of these patients had a complete clinical response, 50% had a complete immunologic response, and 50% had a partial immunologic response. Rituximab was well tolerated overall.

Conclusion

Rituximab is an effective treatment of severe and/or refractory HCV‐related vasculitis. Relapses were consistently associated with the absence of virologic control. The clinical and immunologic efficacy of rituximab after repeated infusion appeared to be the same as that observed after induction therapy.
Accelerated development of aging‐associated and instability‐induced osteoarthritis in osteopontin‐deficient mice
Authors: Matsui Yuichiro , Iwasaki Norimasa , Kon Shigeyuki , Takahashi Daisuke , Morimoto Junko , Matsui Yutaka , Denhardt David T. , Rittling Susan , Minami Akio , Uede Toshimitsu
Published: July 2009

Objective

To investigate the role of osteopontin (OPN) in the development of osteoarthritis (OA) under in vivo and in vitro conditions.

Methods

Both instability‐induced and aging‐associated OA models were generated using OPN‐deficient (OPN−/−) and control wild‐type (WT) mice. An in vitro cartilage degradation model was also used, to evaluate the effect of OPN on proteoglycan loss from joint cartilage.

Results

OPN deficiency exacerbated both aging‐associated and instability‐induced OA. Both structural changes and an increased loss of proteoglycan from cartilage tissue were augmented in the absence of OPN. OPN deficiency also led to the induction of matrix metalloproteinase 13 (MMP‐13), which degrades a major component of the cartilage matrix protein type II collagen. Both the loss of proteoglycan and the induction of the collagen‐degrading enzyme MMP‐13 facilitated the development of OA.

Conclusion

OPN plays a pivotal role in the progression of both instability‐induced and aging‐associated spontaneous OA. OPN is a critical intrinsic regulator of cartilage degradation via its effects on MMP‐13 expression and proteoglycan loss.
Role of p53 in human chondrocyte apoptosis in response to shear strain
Authors: Hashimoto Shingo , Nishiyama Takayuki , Hayashi Shinya , Fujishiro Takaaki , Takebe Ken , Kanzaki Noriyuki , Kuroda Ryosuke , Kurosaka Masahiro
Published: July 2009

Objective

Chondrocyte apoptosis plays an important role in cartilage degeneration in osteoarthritis (OA), and mechanical injury to cartilage induces chondrocyte apoptosis. In response to DNA damage, p53 expression is up‐regulated, transcription activity is increased, and apoptosis signals are initiated. The p53‐regulated apoptosis‐inducing protein 1 (p53AIP‐1) is one of the p53‐regulated genes, and is activated in response to DNA damage. This study was undertaken to analyze p53 function after induction of apoptosis by shear strain in chondrocytes.

Methods

OA cartilage samples were obtained from subjects undergoing total knee replacement surgery, and normal cartilage samples were obtained from subjects undergoing surgery for femoral neck fracture. Chondrocytes were isolated from human cartilage and cultured. Expression of p53 and p53AIP in chondrocytes was detected by reverse transcriptase–polymerase chain reaction and Western blotting. Shear strain was introduced in normal human knee chondrocytes. To explore p53 function, normal human knee chondrocytes were pretreated with pifithrin‐α or p53 small interfering RNA (siRNA) before induction of shear strain. Chondrocyte apoptosis was detected by expression of cleaved caspase 9 with Western blotting and TUNEL staining. Expression of p53 and p53AIP‐1 was analyzed by Western blotting.

Results

OA and normal chondrocytes expressed p53. OA chondrocytes showed much higher expression of p53 and p53AIP‐1 than did normal chondrocytes. TUNEL‐positive cells and expression of p53, p53AIP‐1, and cleaved caspase 9 were increased by shear strain, but chondrocyte apoptosis was suppressed after pretreatment with pifithrin‐α or p53 siRNA.

Conclusion

Our findings indicate that p53 and p53AIP‐1 play important roles in human chondrocyte apoptosis. Down‐regulation of p53 expression prevents cartilage from undergoing apoptosis introduced by shear strain.
European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus
Authors: Chung Sharon A. , Tian Chao , Taylor Kimberly E. , Lee Annette T. , Ortmann Ward A. , Hom Geoffrey , Graham Robert R. , Nititham Joanne , Kelly Jennifer A. , Morrisey Jean , Wu Hui , Yin Hong , Alarcón‐Riquelme Marta E. , Tsao Betty P. , Harley John B. , Gaffney Patrick M. , Moser Kathy L. , Manzi Susan , Petri Michelle , Gregersen Peter K. , Langefeld Carl D. , Behrens Timothy W. , Seldin Michael F. , Criswell Lindsey A.
Published: July 2009

Objective

To determine whether genetic substructure in European‐derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease.

Methods

SLE patients of European descent (n = 1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north–south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations.

Results

In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend = 0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh–low] 1.64, 95% confidence interval [95% CI] 1.13–2.35) and discoid rash (Ptrend = 0.014, ORhigh–low 1.93, 95% CI 0.98–3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend = 1.6 × 10−4, ORhigh–low 0.46, 95% CI 0.30–0.69) and anti–double‐stranded DNA autoantibodies (Ptrend = 0.017, ORhigh–low 0.67, 95% CI 0.46–0.96).

Conclusion

This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.
Delayed acquisition of somatic hypermutations in repopulated IGD+CD27+ memory B cell receptors after rituximab treatment
Authors: Muhammad Khalid , Roll Petra , Einsele Hermann , Dörner Thomas , Tony Hans‐Peter
Published: July 2009

Objective

Transient B cell depletion by rituximab has been used with clinical efficacy in the treatment of patients with rheumatoid arthritis (RA). Previous studies of B cell repopulation have shown long‐term numerical reduction in memory B cells. Non–class‐switched IgD+CD27+ memory B cells, in particular, repopulate slowly. This study was undertaken to determine whether mutational acquisition in individual B cell receptors in repopulating class‐switched and non–class‐switched memory B cells is affected by rituximab.

Methods

Cells obtained from 16 RA patients, 4 healthy donors, and 3 patients who underwent allogeneic stem cell transplantation (ASCT) were analyzed using single B cell sorting followed by nested polymerase chain reaction and Ig VH3 sequencing.

Results

There was a delayed acquisition of mutations in Ig receptors of IgD+ memory B cells over a period of 6 years after a single course of rituximab. One year after rituximab treatment, 84% of single repopulating IgD+CD27+ B cells were unmutated, and no highly mutated Ig receptors were found (compared with 52% before therapy). Over time, increasing numbers of mutations were detected. Even 6 years after rituximab treatment, however, mutations in IgD+ memory B cells were still significantly reduced. In contrast, class‐switched memory B cells repopulated with quantitatively normal mutations. In comparison, in patients undergoing ASCT, IgD+ memory cells repopulated earlier with higher mutations in Ig receptors.

Conclusion

Our data suggest that IgD+ memory B cells are particularly susceptible to the effects of rituximab, with delayed acquisition of mutations in their Ig receptors still evident 6 years after a single course of rituximab. Our findings indicate that these cells have different requirements for mutational acquisition compared with class‐switched memory B cells.
Longitudinal effect of vigorous physical activity on patella cartilage morphology in people without clinical knee disease
Authors: Teichtahl Andrew J. , Wluka Anita E. , Forbes Andrew , Wang Yuanyuan , English Dallas R. , Giles Graham G. , Cicuttini Flavia M.
Published: July 2009

Objective

There are few data concerning possible long‐term effects of physical activity on cartilage change in the patellofemoral compartment. We examined the effect of participation in vigorous physical activity on changes to patella cartilage over 2 years.

Methods

A total of 297 healthy adults ages 50–79 years with no history of knee injury or symptoms were recruited from an existing study. Physical activity data were obtained by questionnaire at baseline (2003–2004). Patella cartilage volume and defects were determined by magnetic resonance imaging at baseline (2003–2004) and followup (2006–2007).

Results

Participation in vigorous physical activity at baseline was associated with a reduced rate of patella cartilage volume loss (−21.2 mm3 per annum [95% confidence interval (95% CI) −41.5, −1.0; P = 0.04]) and a trend toward less risk of worsening patella cartilage defects (odds ratio 0.4; 95% CI 0.2, 1.1 [P = 0.07]) over the subsequent 2 years. In the subgroup with no significant patella cartilage defects at baseline (n = 192), participation in vigorous physical activity was associated with a reduced annual rate of patella cartilage volume loss (95% CI −53.8, −7.8; P = 0.03) and a trend for fewer new patella cartilage defects (95% CI 0.1, 1.1; P = 0.08). No significant relationships were found between vigorous physical activity and cartilage volume change or defect progression in the subgroup with prevalent patella cartilage defects at baseline.

Conclusion

These observations suggest that vigorous physical activity is beneficial to patellofemoral joints for people without preexisting cartilage damage. Weight‐bearing vigorous physical activity might, therefore, be useful in the prevention of patellofemoral osteoarthritis.