bluuebunny/crossref_metadata_2025 huggingface dataset:
Initiation of the alternative pathway of murine complement by immune complexes is dependent on N‐glycans in IgG antibodies
Authors: Banda Nirmal K. , Wood Allyson K. , Takahashi Kazue , Levitt Brandt , Rudd Pauline M. , Royle Louise , Abrahams Jodie L. , Stahl Gregory L. , Holers V. Michael , Arend William P.
Published: September 2008

Objective

Collagen antibody–induced arthritis in mice exhibits a requirement for amplification by the alternative pathway of complement. Although the alternative pathway is activated by spontaneous hydrolysis, it is not known whether this pathway can also be initiated directly by IgG antibodies in immune complexes (ICs). IgG lacking terminal sialic acid and galactose (G0 IgG) can activate the lectin pathway of complement, but it is not known if G0 IgG can also activate the classical or alternative pathway. The purpose of this study was to examine the mechanism of initiation of the alternative pathway of complement by ICs.

Methods

We used adherent ICs containing bovine type II collagen (CII) and 4 monoclonal antibodies (mAb) to CII (adCII‐IC). C3 activation was measured in the presence of sera from wild‐type C57BL/6 mice or from mice deficient in informative complement components. The mAb were used intact or after enzyme digestion to create G0 IgG or to completely remove the N‐glycan.

Results

Both the classical and alternative pathways, but not the lectin pathway, mediated C3 activation induced by the adCII‐IC. Mannose inhibited the alternative pathway–mediated C3 activation but had no effect on the classical pathway, and N‐glycans in IgG were required by the alternative pathway but not the classical pathway. Both the classical and alternative pathways mediated C3 activation induced by G0 IgG. Mannose‐binding lectin bound avidly to G0 IgG, but lectin pathway–mediated C3 activation was only slightly increased by G0 IgG.

Conclusion

The alternative pathway of complement is capable of initiating C3 activation induced by adCII‐IC and requires the presence of N‐glycans on the IgG. G0 IgG activates both the classical and alternative pathways more strongly than the lectin pathway.
Junctional adhesion molecule C mediates leukocyte adhesion to rheumatoid arthritis synovium
Authors: Rabquer Bradley J. , Pakozdi Angela , Michel James E. , Gujar Bansari S. , Haines G. Kenneth , Imhof Beat A. , Koch Alisa E.
Published: September 2008

Objective

Leukocyte infiltration into the rheumatoid arthritis (RA) synovium is a multistep process in which leukocytes leave the bloodstream and invade the synovial tissue (ST). Leukocyte transendothelial migration and adhesion to RA ST requires adhesion molecules on the surface of endothelial cells and RA ST fibroblasts. This study was undertaken to investigate the role of junctional adhesion molecule C (JAM‐C) in mediating leukocyte recruitment and retention in the RA joint.

Methods

Immunohistologic analysis was performed on RA, osteoarthritis (OA), and normal ST samples to quantify JAM‐C expression. Fibroblast JAM‐C expression was also analyzed using Western blotting, cell surface enzyme‐linked immunosorbent assay, and immunofluorescence. To determine the role of JAM‐C in leukocyte retention in the RA synovium, in vitro and in situ adhesion assays and RA ST fibroblast transmigration assays were performed.

Results

JAM‐C was highly expressed by RA ST lining cells, and its expression was increased in OA ST and RA ST endothelial cells compared with normal ST endothelial cells. JAM‐C was also expressed on the surface of OA ST and RA ST fibroblasts. Furthermore, we demonstrated that myeloid U937 cell adhesion to both OA ST and RA ST fibroblasts and to RA ST was dependent on JAM‐C. U937 cell migration through an RA ST fibroblast monolayer was enhanced in the presence of neutralizing antibodies against JAM‐C.

Conclusion

Our results highlight the novel role of JAM‐C in recruiting and retaining leukocytes in the RA synovium and suggest that targeting JAM‐C may be important in combating inflammatory diseases such as RA.
Disrupted brain–immune system–joint communication during experimental arthritis
Authors: del Rey Adriana , Wolff Christine , Wildmann Johannes , Randolf Anke , Hahnel Anja , Besedovsky Hugo O. , Straub Rainer H.
Published: September 2008

Objective

To explore the hypothesis that, in parallel with alterations in the hypothalamus–pituitary–adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the course of arthritis development induced by type II collagen. This hypothesis was based on evidence that acute inflammatory processes induce cytokine expression in the brain and affect neuronal activity. We also studied whether depletion of hypothalamic noradrenaline can affect peripheral joint disease.

Methods

Hypothalamic cytokine gene expression and neurotransmitter concentration, parameters of inflammation, and joint innervation were evaluated during arthritis development in rats induced by injection of type II collagen in Freund's incomplete adjuvant. Noradrenergic neurons in the brain were depleted with 6‐hydroxydopamine.

Results

Transiently increased corticosterone levels, followed by increased adrenaline levels and hypothalamic interleukin‐1β (IL‐1β) and IL‐6 overexpression were observed only during the induction phase of the disease. Hypothalamic noradrenaline content was increased during the symptomatic phase and was paralleled by a gradual loss of noradrenergic fibers in the joints. The positive correlation between hypothalamic IL‐1β expression and noradrenaline content in control groups was not observed in rats in which arthritis developed. Depletion of hypothalamic noradrenergic neurons when arthritis was established did not affect the course of the disease.

Conclusion

The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate a disruption in communication between afferent immune messages to the central nervous system and 2 main efferent antiinflammatory pathways under control of the brain during collagen‐induced arthritis.
Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system
Authors: Inglis Julia J. , McNamee Kay E. , Chia Shi‐Lu , Essex David , Feldmann Marc , Williams Richard O. , Hunt Stephen P. , Vincent Tonia
Published: September 2008

Objective

OA is the most common joint disease, affecting 10–15% of people over 60 years of age. However, up to 40% of individuals with radiologic damage are asymptomatic. The purpose of this study was to assess the role of the endogenous opioid system in delaying the onset of pain in a murine model of osteoarthritis (OA).

Methods

Osteoarthritis was induced by transection of the medial meniscotibial ligament. Pain was assessed by monitoring weight distribution and activity. At various times postsurgery, the opioid receptor antagonists naloxone or peripherally restricted naloxone methiodide were administered, and pain was assessed. Levels of the μ‐opioid receptor were assessed in the nerves innervating the joint by real‐time reverse transcription–polymerase chain reaction analysis.

Results

As in human disease, significant joint damage occurred in mice before the onset of pain. To assess whether delayed pain was partly the result of increased endogenous opioid function, naloxone or naloxone methiodide was administered. Both opioid receptor antagonists led to pain onset 4 weeks earlier than in vehicle‐treated mice, indicating a role of the peripheral opioid system in masking OA pain. The expression of the μ‐opioid receptor in the peripheral nerves supplying the joint was transiently increased in naloxone‐responsive mice.

Conclusion

These findings indicate that a temporal induction of μ‐opioid receptors in the early stages of OA delays the onset of pain. This is of clinical relevance and may contribute to the assessment of patients presenting with pain late in the disease. Furthermore, it may point to a mechanism by which the body blocks pain perception in moderate states of tissue damage, allowing an increased chance of survival.
Feasibility of a tetracycline‐binding method for detecting synovial fluid basic calcium phosphate crystals
Authors: Rosenthal Ann K. , Fahey Mark , Gohr Claudia , Burner Todd , Konon Irina , Daft Laureen , Mattson Eric , Hirschmugl Carol , Ryan Lawrence M. , Simkin Peter
Published: September 2008

Objective

Basic calcium phosphate (BCP) crystals are common components of osteoarthritis (OA) synovial fluid. Progress in understanding the role of these bioactive particles in clinical OA has been hampered by difficulties in their identification. Tetracyclines stain calcium phosphate mineral in bone. The aim of this study was to investigate whether tetracycline staining might be an additional or alternative method for identifying BCP crystals in synovial fluid.

Methods

A drop of oxytetracycline was mixed with a drop of fluid containing synthetic or native BCP, calcium pyrophosphate dihydrate (CPPD), or monosodium urate (MSU) crystals and placed on a microscope slide. Stained and unstained crystals were examined by light microscopy, with and without a portable broad‐spectrum ultraviolet (UV) pen light. A small set of characterized synovial fluid samples were compared by staining with alizarin red S and oxytetracycline. Synthetic BCP crystals in synovial fluid were quantified fluorimetrically using oxytetracycline.

Results

After oxytetracycline staining, synthetic and native BCP crystals appeared as fluorescent amorphous aggregates under UV light. Oxytetracycline did not stain CPPD or MSU crystals or other particulates. Oxytetracycline staining had fewer false‐positive test results than did alizarin red S staining and could provide estimates of the quantities of synthetic BCP crystals in synovial fluid.

Conclusion

With further validation, oxytetracycline staining may prove to be a useful adjunct or alternative to currently available methods for identifying BCP crystals in synovial fluid.
Immunoglobulin gene polymorphisms are susceptibility factors in clinical and autoantibody subgroups of the idiopathic inflammatory myopathies
Authors: O'Hanlon Terrance P. , Rider Lisa G. , Schiffenbauer Adam , Targoff Ira N. , Malley Karen , Pandey Janardan P. , Miller Frederick W.
Published: September 2008

Objective

To investigate possible associations of GM and KM markers with adult and juvenile forms of the idiopathic inflammatory myopathies (IIMs) in Caucasian and African American patients.

Methods

We performed serologic analyses of polymorphic determinants associated with immunoglobulin gamma heavy chains (GM) and kappa light chains (KM) in large populations of Caucasian patients (n= 514 [297 adults and 217 children]) and African American patients (n = 123 [73 adults and 50 children]) with IIM representing the major clinical and autoantibody groups.

Results

For Caucasian patients with dermatomyositis (DM), the Gm 3 23 5,13 phenotype was a risk factor in both adults (odds ratio [OR] 2.2, corrected P [Pcorr] = 0.020) and children (OR 2.2, Pcorr = 0.0013). Of interest, the GM 13 allotype was a risk factor for juvenile DM in both Caucasian subjects (OR 3.9, Pcorr < 0.0001) and African American subjects (OR 4.8, Pcorr = 0.033). However, the Gm 1,3,17 5,13,21 phenotype was a risk factor for juvenile DM in Caucasian subjects but not African American subjects. Among the IIM autoantibody groups, Gm 3 23 5,13 was a risk factor in Caucasian adults with anti–Jo‐1 autoantibodies (OR 3.4, Pcorr = 0.0031), while the GM 3 allotype was protective in adults with anti–threonyl–transfer RNA synthetase or anti–U RNP autoantibodies (OR 0.1, Pcorr = 0.047 and OR 0.2, Pcorr = 0.034, respectively). In contrast, GM 6 was a risk factor in African American adults with anti–signal recognition particle autoantibodies (OR 7.5, Pcorr = 0.041).

Conclusion

These data suggest that polymorphic alleles of GM and KM loci are differentially associated with IIM subgroups defined by age, ethnicity, clinical features, and autoantibody status, and expand the list of immune response genes that are possibly important in the pathogenesis of myositis.
The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients
Authors: Chinoy H. , Platt H. , Lamb J. A. , Betteridge Z. , Gunawardena H. , Fertig N. , Varsani H. , Davidson J. , Oddis C. V. , McHugh N. J. , Wedderburn L. R. , Ollier W. E. R. , Cooper R. G.
Published: September 2008

Objective

To examine single‐nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase N22 gene (PTPN22) and to study the relationship between PTPN22 and the HLA region in patients with idiopathic inflammatory myopathies (IIMs).

Methods

PTPN22 SNPs were assessed in a large, cross‐sectional, case–control study from the UK involving patients with adult or juvenile IIM, comprising patients with polymyositis (PM) (n = 114), dermatomyositis (DM) (n = 102), myositis associated with another connective tissue disease (myositis–CTD overlap syndrome) (n = 64), or juvenile DM (n = 101), in comparison with 748 control subjects. Seventeen PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis‐specific/myositis‐associated autoantibodies (MSAs/MAAs) was performed by radioimmunoprecipitation.

Results

A significant association was noted between the R620W variant (rs2476601) and IIM (corrected P [Pcorr] = 0.0009 versus controls), and specifically with the clinical subgroup of PM (Pcorr = 0.003 versus controls). A weaker association was noted with juvenile DM (Pcorr = 0.009 versus controls). No significant associations were noted after stratification by serologic subgroups. The association with the R620W variant was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM.

Conclusion

The R620W variant is a significant risk factor for IIM, independent of the HLA 8.1 haplotype. Unlike that in the HLA region, risk is not increased in individuals possessing MSAs/MAAs. These results are further evidence that the PTPN22 gene confers autoimmune susceptibility.
Reactivation of rheumatoid arthritis after pregnancy: Increased phagocyte and recurring lymphocyte gene activity
Authors: Häupl Thomas , ØStensen Monika , Grützkau Andreas , Radbruch Andreas , Burmester Gerd‐R. , Villiger Peter M.
Published: September 2008

Objective

Pregnancy is associated with reduced disease activity in rheumatoid arthritis (RA) and frequently with disease exacerbation after delivery. This study was undertaken to generate a systematic overview of the molecular mechanisms related to disease remission and postpartum reactivation.

Methods

Transcriptomes of peripheral blood mononuclear cells (PBMCs) were generated from RA patients and healthy women by transcription profiling during the third trimester and 24 weeks after delivery. For functional interpretation, signatures of highly purified immune cells as well as Kyoto Encyclopedia of Genes and Genomes pathway annotations were used as a reference.

Results

Only minor differences in gene expression in PBMCs during pregnancy were found between RA patients and controls. In contrast, RA postpartum profiles presented the most dominant changes. Systematic comparison with expression signatures of monocytes, T cells, and B cells in healthy donors revealed reduced lymphocyte and elevated monocyte gene activity during pregnancy in patients with RA and in controls. Monocyte activity decreased after delivery in controls but persisted in RA patients. Furthermore, analysis of 32 immunologically relevant cellular pathways demonstrated a significant additional activation of genes related to adhesion, migration, defense of pathogens, and cell activation, including Notch, phosphatidylinositol, mTOR, Wnt, and MAPK signaling, in RA patients postpartum.

Conclusion

Our findings indicate that innate immune functions play an important role in postpartum reactivation of arthritis. However, this may depend not only on the monocyte itself, but also on the recurrence of lymphocyte functions postpartum and thus on a critical interaction between both arms of the immune system.
Epigallocatechin‐3‐gallate diminishes CCL2 expression in human osteoblastic cells via up‐regulation of phosphatidylinositol 3‐Kinase/Akt/Raf‐1 interaction: A potential therapeutic benefit for arthritis
Authors: Lin Sze‐Kwan , Chang Hao‐Hueng , Chen Yunn‐Jy , Wang Chih‐Chiang , Galson Deborah L. , Hong Chi‐Yuan , Kok Sang‐Heng
Published: September 2008

Objective

To assess the effects of epigallocatechin‐3‐gallate (EGCG) on oncostatin M (OSM)–induced CCL2 synthesis and the associated signaling pathways in human osteoblastic cells. The therapeutic effect of EGCG on collagen‐induced arthritis (CIA) in rats was also studied.

Methods

CCL2 and c‐Fos messenger RNA expression was analyzed by Northern blotting. The modulating effects of EGCG on the activation of Raf‐1, Akt, and phosphatidylinositol 3‐kinase (PI 3‐kinase) were examined by coimmunoprecipitation, Western blotting, and PI 3‐kinase activity assay. Interactions between c‐Fos and CCL2 promoter were evaluated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. The effect of EGCG on CIA in rats was examined clinically and immunohistochemically.

Results

EGCG inhibited OSM‐stimulated CCL2 expression in primary human osteoblasts and MG‐63 cells. In MG‐63 cells, EGCG alleviated the OSM‐induced phosphorylation of Raf‐1 at Ser338 but restored the dephosphorylation of Raf‐1 at Ser259. EGCG increased the activity of PI 3‐kinase, the level of phosphorylated Akt (Ser473), and binding between Raf‐1 and active Akt. EMSA and ChIP assay revealed that EGCG attenuated activator protein 1 (AP‐1)–CCL2 promoter interaction, possibly by reducing c‐Fos synthesis. Codistribution of CD68+ macrophages and CCL2+ osteoblasts in osteolytic areas was obvious in the CIA model. Administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the amount of CCL2‐synthesizing osteoblasts.

Conclusion

By stimulating PI 3‐kinase activity, EGCG promoted Akt/Raf‐1 crosstalk, resulting in decreased AP‐1 binding to CCL2 promoter, and finally reduced CCL2 production in osteoblasts. EGCG alleviated the severity of CIA, probably by suppressing CCL2 synthesis in osteoblasts to diminish macrophage infiltration. Our data support the therapeutic potential of EGCG on arthritis.
Neutrophil dysfunction in a family with a SAPHO syndrome–like phenotype
Authors: Ferguson Polly J. , Lokuta Mary A. , El‐Shanti Hatem I. , Muhle Leah , Bing Xinyu , Huttenlocher Anna
Published: September 2008

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) is an inflammatory disorder of the bone, skin, and joints. We describe a family with multiple affected members who segregate a SAPHO syndrome–like phenotype, and we report the results of neutrophil studies and candidate gene analysis. We obtained written informed consent and a family history and reviewed medical records. We collected DNA and sequenced candidate genes, and we performed functional studies on neutrophils isolated from the proband and her mother. The pedigree segregated chronic osteomyelitis and cutaneous inflammation in a pattern that suggested an autosomal‐dominant disorder. No coding sequence mutations were detected in PSTPIP1, PSTPIP2, LPIN2, SH3BP2, or NCF4. Analysis of neutrophil function in the proband, including nitroblue tetrazolium tests, myeloperoxidase assays, neutrophil chemotaxis, and neutrophil chemotaxis assays, revealed no identifiable abnormalities. However, an abnormality in the luminol, but not the isoluminol, respiratory burst assays following stimulation with phorbol myristate acetate (PMA) was detected in neutrophils isolated from the affected proband. Internal oxidant production was also reduced in the proband and her mother when neutrophils were treated with fMLP with or without platelet‐activating factor, PMA alone, or tumor necrosis factor α alone. This family segregates a disorder characterized by chronic inflammation of the skin and bone. Functional differences in neutrophils exist between affected individuals and controls. The biologic significance of this defect remains unknown. Identification of the gene defect will help identify an immunologic pathway that, when dysregulated, causes inflammation of the skin and bone.
Induction of osteoclast‐associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis
Authors: Herman Sonja , Müller Ruediger B. , Krönke Gerhard , Zwerina Jochen , Redlich Kurt , Hueber Axel J. , Gelse Holger , Neumann Elena , Müller‐Ladner Ulf , Schett Georg
Published: September 2008

Objective

Osteoclast‐associated receptor (OSCAR) is a newly identified osteoclast‐specific receptor and is of key importance in the process of osteoclast costimulation. This study was undertaken to define the role of costimulation in osteoclast differentiation during inflammatory arthritis.

Methods

OSCAR expression was assessed in the synovium and peripheral blood monocytes of patients with rheumatoid arthritis (RA), and associations with disease activity were assessed. Serum levels of OSCAR were determined by enzyme‐linked immunosorbent assay. In vitro osteoclast assays were performed to characterize the role of OSCAR in human osteoclastogenesis. Cytokine regulation of OSCAR was investigated by reverse transcriptase–polymerase chain reaction.

Results

OSCAR was expressed by osteoclasts at the erosion front and by mononuclear cells around synovial microvessels. Flow cytometry revealed enhanced expression of OSCAR in peripheral blood monocytes of RA patients as compared with healthy controls. OSCAR expression was correlated with disease activity and acute‐phase reactant concentrations. Serum levels of soluble OSCAR were lower in RA patients than in healthy controls. Monocytes with high OSCAR expression exhibited an enhanced potential to differentiate into osteoclasts. Tumor necrosis factor α was identified as the main inducer of OSCAR expression in monocytes.

Conclusion

These data suggest that the osteoclast costimulation pathway is activated in RA. OSCAR is induced in monocytes of RA patients, facilitating their differentiation into osteoclasts and bone resorption.
Induction of an osteoarthritis‐like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice
Authors: Wu Qiuqian , Kim Kyung‐Ok , Sampson Erik R. , Chen Di , Awad Hani , O'Brien Todd , Puzas J. Edward , Drissi Hicham , Schwarz Edward M. , O'Keefe Regis J. , Zuscik Michael J. , Rosier Randy N.
Published: September 2008

Objective

To determine whether Smurf2, an E3 ubiquitin ligase known to inhibit transforming growth factor β (TGFβ) signaling, is expressed in human osteoarthritic (OA) cartilage and can initiate OA in mice.

Methods

Human OA cartilage was obtained from patients undergoing knee arthroplasty. Samples were graded histologically using the Mankin scale and were examined immunohistochemically for Smurf2 expression. A transgene driven by the collagen 2α1 promoter was used to overexpress Smurf2 in mice. Smurf2 overexpression in mouse sternal chondrocytes was confirmed by reverse transcription–polymerase chain reaction and Western blotting. Changes in articular cartilage area, chondrocyte number, and chondrocyte diameter were assessed histomorphometrically using OsteoMeasure software. Alterations in type X collagen and matrix metalloproteinase 13 (MMP‐13) in articular chondrocytes were examined by in situ hybridization and immunohistochemistry, respectively. Joint bone phenotypes were evaluated by microfocal computed tomography. The effects of Smurf2 overexpression on TGFβ signaling were examined using a luciferase‐based reporter and immunoprecipitation/Western blotting.

Results

Human OA cartilage strongly expressed Smurf2 as compared with nonarthritic human cartilage. By 8 months of age, Smurf2‐transgenic mice exhibited decreased articular cartilage area, fibrillation, clefting, eburnation, subchondral sclerosis, and osteophytes. Increased expression of type X collagen and MMP‐13 were also detected in articular cartilage from transgenic mice. Transgenic sternal chondrocytes showed reduced TGFβ signaling as well as decreased expression and increased ubiquitination of pSmad3.

Conclusion

Smurf2 is up‐regulated during OA in humans, and Smurf2‐transgenic mice spontaneously develop an OA‐like phenotype that correlates with decreased TGFβ signaling and increased pSmad3 degradation. Overall, these results suggest a role of Smurf2 in the pathogenesis of OA.
The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from the glucosamine/chondroitin arthritis intervention trial
Authors: Sawitzke Allen D. , Shi Helen , Finco Martha F. , Dunlop Dorothy D. , Bingham Clifton O. , Harris Crystal L. , Singer Nora G. , Bradley John D. , Silver David , Jackson Christopher G. , Lane Nancy E. , Oddis Chester V. , Wolfe Fred , Lisse Jeffrey , Furst Daniel E. , Reda Domenic J. , Moskowitz Roland W. , Williams H. James , Clegg Daniel O.
Published: September 2008

Objective

Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA.

Methods

A 24‐month, double‐blind, placebo‐controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline.

Results

The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW.

Conclusion

At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.
Family factors, emotional functioning, and functional impairment in juvenile fibromyalgia syndrome
Authors: Kashikar‐Zuck Susmita , Lynch Anne M. , Slater Shalonda , Graham T. Brent , Swain Nicole F. , Noll Robert B.
Published: September 2008

Objective

Family factors and emotional functioning can play an important role in the ability of adolescents with juvenile primary fibromyalgia syndrome (JPFS) to cope with their condition and function in their everyday lives. The primary objectives of this study were to determine 1) whether adolescents with JPFS and their caregivers differed from healthy age‐matched comparison peers and their caregivers in terms of emotional distress and functional impairment; 2) whether there were any differences in the family environment of adolescents with JPFS compared with healthy comparison peers; and 3) which individual‐, caregiver‐, and family‐level variables were associated with functional impairment in adolescents with JPFS.

Methods

Participants were 47 adolescents with JPFS recruited from a pediatric rheumatology clinic and 46 comparison peers without chronic illness matched for age, sex, and race. Participants and their caregivers (all mothers) completed a battery of standardized measures administered in their homes.

Results

Adolescents with JPFS had greater internalizing and externalizing symptoms than healthy comparison peers. Mothers of adolescents with JPFS reported twice as many pain conditions and significantly greater depressive symptoms than mothers of comparison peers. The JPFS group also had poorer overall family functioning and more conflicted family relationships. In adolescents with JPFS, maternal pain history was associated with significantly higher functional impairment.

Conclusion

Increased distress and chronic pain are evident in families of adolescents with JPFS, and family relationships are also impacted. Implications for child functional impairment and the need for inclusion of caregivers in treatment are discussed.
Activity limitations and compensatory mechanism use following limited wrist fusion
Authors: Bialocerkowski Andrea E.
Published: September 2008

Objective

To document the activity limitations experienced by patients who had undergone a 4‐corner wrist fusion, and the compensatory mechanisms they use in daily life.

Methods

Patients completed 2 copies of the Adelaide Questionnaire, a measure with a standardized section and an individualized section. The test–retest reliability of the questionnaire was evaluated.

Results

Twenty‐five patients were recruited to the study, and 21 completed both questionnaires. Excellent test–retest reliability was gained for both the standardized and individualized sections of the Adelaide Questionnaire.

Conclusion

Patients with 4‐corner wrist fusions report activity limitations following surgery, particularly with daily tasks that involve hand/forearm rotation and grip strength. Various compensatory mechanisms are used by the majority of patients. The impact of these mechanisms on activity limitations varies between patients, but often decreases impact of the activity limitations on everyday life.
Physical activity in adolescents with juvenile idiopathic arthritis
Authors: Lelieveld Otto T. H. M. , Armbrust Wineke , van Leeuwen Miek A. , Duppen Nienke , Geertzen Jan H. B. , Sauer Pieter J. J. , van Weert Ellen
Published: September 2008

Objective

To explore physical activity (PA) in adolescents with juvenile idiopathic arthritis (JIA) compared with a healthy population and to examine associations between PA and disease‐related factors.

Methods

Total energy expenditure (TEE), activity‐related energy expenditure (AEE), PA level, and PA pattern were assessed with a 3‐day activity diary. Aerobic capacity was assessed using a Symptom Limited Bicycle Ergometry test. Functional ability was assessed with the Childhood Health Assessment Questionnaire. Disease activity was assessed using Paediatric Rheumatology International Trials Organisation core set criteria. Overall well‐being was measured using a visual analog scale, and time since diagnosis was assessed by retrospective study from patients' charts. We used a cross‐sectional study design. Reference data were collected from healthy Dutch secondary school children.

Results

Thirty patients and 106 controls were included (mean ± SD age 17.0 ± 0.6 and 16.7 ± 0.9 years, respectively). TEE, AEE, and PA level were significantly lower in the JIA group. The JIA group spent more time in bed and less time on moderate to vigorous PA. Only 23% of the JIA patients met public health recommendations to perform ≥1 hour daily moderate to vigorous PA compared with 66% in the reference group. Higher PA was associated with higher levels of well‐being and maximal oxygen consumption.

Conclusion

Adolescents with JIA have low PA levels and are at risk of losing the benefits of PA. Low PA is not related to disease activity, and control over the disease does not restore previous PA levels. Interventions by pediatric rheumatologists are needed to increase PA levels in patients with JIA.
Living with a fluctuating illness of ankylosing spondylitis: A qualitative study
Authors: Mengshoel Anne Marit
Published: September 2008

Objective

To examine the relationship between illness fluctuations and how people with ankylosing spondylitis (AS) adapt to everyday life situations.

Methods

Twelve respondents, 8 women and 4 men, age 30–59 years with an AS duration of 6 months to 40 years participated in qualitative interviews. They were asked to give examples of how they lived their everyday life during good and bad times of illness. The text analyses consisted of familiarization with the content, identifying and coding meaningful statements, sorting them into categories, and condensing themes.

Results

Three different types of situations for those living with AS emerged from the analysis: ordinary life, slowed‐down life, and disrupted life. Ordinary life included managing symptoms by incorporating motion into everyday life routines and adjusting tasks in work situations, sports activities, home life, and social activities. During slowed‐down life, an acute or insidious onset of stiffness and fatigue occurred that could be reversed by slowing down ordinary life for a period of time. During disrupted life, the respondents were unable to cope with everyday life because of inexplicable and unmanageable intense, localized, or distributed pain.

Conclusion

By examining the relationships between illness and what people do to recover, 3 different life conditions were found: ordinary life, slowed‐down life, and disrupted life. Living with AS requires a continuous but varying process of normalization of symptoms and everyday life within the framework of these 3 illness conditions.
Arthritis disability and heart disease disability
Authors: Verbrugge Lois M. , Juarez Lucia
Published: September 2008

Objective

Arthritis is the most common health condition in midlife and late life, and heart disease is the leading cause of death. This article compares disability impacts of these 2 preeminent health problems.

Methods

Using data from the National Health Interview Survey Disability Supplement, we studied specific limitations and disabilities, accommodations used (buffers), and accommodations needed (barriers) for US population groups of adults with arthritis disability, heart disease disability, both arthritis and heart disease disability, and disability due to other conditions. Weights and complex SE adjusted for sample design. We hypothesized that arthritis disability is more extensive and troublesome than heart disease disability.

Results

People with arthritis disability had more numerous, longer, and more bothersome disabilities than people with heart disease disability. People with arthritis disability used more equipment and rehabilitation, whereas people with heart disease disability emphasized personal assistance, medications, and medical services. People with arthritis disability experienced more barriers and needs in activities and services. People with disabilities from both arthritis and heart disease were especially disadvantaged, with high levels of limitations and accommodations. People with disability from other conditions had the highest social participation, fewest disabilities, and most tailored accommodations of all groups.

Conclusion

Arthritis had higher and more extensive disability impact than heart disease. Both groups had more difficulty, buffers, and barriers in their lives than people disabled by other conditions. Therefore, arthritis and heart disease are premier conditions for disability attention and alleviation in the US population.
Compliance with biologic therapies for rheumatoid arthritis: Do patient out‐of‐pocket payments matter?
Authors: Curkendall S. , Patel V. , Gleeson M. , Campbell R. S. , Zagari M. , Dubois R.
Published: September 2008

Objective

To assess the impact of patient out‐of‐pocket (OOP) expenditures on adherence and persistence with biologics in patients with rheumatoid arthritis (RA).

Methods

An inception cohort of RA patients with pharmacy claims for etanercept or adalimumab during 2002–2004 was selected from an insurance claims database of self‐insured employer health plans (n = 2,285) in the US. Adherence was defined as medication possession ratio (MPR): the proportion of the 365 followup days covered by days supply. Persistence was determined using a survival analysis of therapy discontinuation during followup. Patient OOP cost was measured as the patient's coinsurance and copayments per week of therapy, and as the proportion of the total medication charges paid by the patient. Multivariate linear regression models of MPR and proportional hazards models of persistence were used to estimate the impact of cost, adjusting for insurance type and demographic and clinical variables.

Results

Mean ± SD OOP expenditures averaged $7.84 ± $14.15 per week. Most patients (92%) paid less than $20 OOP for therapy/week. The mean ± SD MPR was 0.52 ± 0.31. Adherence significantly decreased with increased weekly OOP (coeff = −0.0035, P < 0.0001) and with a higher proportion of therapy costs paid by patients (coeff = −0.8794, P < 0.0001), translating into ∼1 week of therapy lost per $5.50 increase in weekly OOP. Patients whose weekly cost exceeded $50 were more likely to discontinue than patients with lower costs (hazard ratio 1.58, P < 0.001).

Conclusion

Most patients pay less than $20/week for biologics, but a small number have high OOP expenses, associated with lower medication compliance. The adverse impact of high OOP costs on adherence, persistence, and outcomes must be considered when making decisions about increasing copayments.
Feasibility and effectiveness of an aerobic exercise program in children with fibromyalgia: Results of a randomized controlled pilot trial
Authors: Stephens Samantha , Feldman Brian M. , Bradley Nicolette , Schneiderman Jane , Wright Virginia , Singh‐Grewal Davinder , Lefebvre Arlette , Benseler Susanne M. , Cameron Bonnie , Laxer Ronald , O'brien Christine , Schneider Rayfel , Silverman Earl , Spiegel Lynn , Stinson Jennifer , Tyrrell Pascal N. , Whitney Kristi , Tse Shirley M. L.
Published: September 2008

Objective

To determine the feasibility of conducting a randomized controlled trial of a 12‐week exercise intervention in children with fibromyalgia (FM) and to explore the effectiveness of aerobic exercise on physical fitness, function, pain, FM symptoms, and quality of life (QOL).

Methods

FM patients ages 8–18 years were randomized to a 12‐week exercise intervention of either aerobics or qigong. Both groups participated in 3 weekly training sessions. Program adherence and safety were monitored at each session. Data were collected at 3 testing sessions, 2 prior to and 1 after the intervention, and included FM symptoms, function, pain, QOL, and fitness measures.

Results

Thirty patients participated in the trial. Twenty‐four patients completed the program; 4 patients dropped out prior to training and 2 dropped out of the aerobics program. Better adherence was reported in the aerobics group than in the qigong group (67% versus 61%). Significant improvements in physical function, functional capacity, QOL, and fatigue were observed in the aerobics group. Anaerobic function, tender point count, pain, and symptom severity improved similarly in both groups.

Conclusion

It is feasible to conduct an exercise intervention trial in children with FM. Children with FM tolerate moderate‐intensity exercise without exacerbation of their disease. Significant improvements in physical function, FM symptoms, QOL, and pain were demonstrated in both exercise groups; the aerobics group performed better in several measures compared with the qigong group. Future studies may need larger sample sizes to confirm clinical improvement and to detect differences in fitness in childhood FM.
The ergonomic assessment tool for arthritis: Development and pilot testing
Authors: Backman Catherine L. , Village Judy , Lacaille Diane
Published: September 2008

Objective

Ergonomic assessment and recommendations may help people with arthritis maintain employment; however, most ergonomic tools are designed to assess injury risk in the general population and are not specific to the needs of people with inflammatory arthritis (IA). Our objectives were to design and pilot test an ergonomic assessment tool for people with IA and to propose ergonomic modifications to prevent work loss and maintain at‐work productivity.

Methods

Relevant content was identified in a literature review by an interdisciplinary team. Respecting some clients' reluctance to disclose arthritis to employers, no work site visit was required. An initial assessment tool was reviewed by a 4‐person expert panel, revised and pretested with 13 adults with IA by 3 occupational therapists (OTs). The final tool, comprised of a self‐assessment, an interview guide, and a solutions summary, was used in a pilot test of a multifaceted program designed to prevent work loss and maintain at‐work productivity. One OT conducted all ergonomic consultations and followed up with phone calls at 1 month. Implementation of recommendations was evaluated at 3, 6, and 12 months.

Results

Nineteen women (mean age 51 years) with IA (mean disease duration 12 years) completed ergonomic assessments. A range of risks were identified and 87 recommendations were made (mean 4.5 per participant). At 1 year, 85% of recommendations had been implemented by 74% of the participants.

Conclusion

The Ergonomic Assessment Tool for Arthritis is a feasible and comprehensive process for identifying ergonomic job accommodations.
Are behavioral interventions for arthritis effective with minorities? Addressing racial and ethnic diversity in disability and rehabilitation
Authors: McIlvane Jessica M. , Baker Tamara A. , Mingo Chivon A. , Haley William E.
Published: September 2008

Objective

To determine whether research evaluating the effectiveness of behavioral interventions for arthritis demonstrates that these interventions are effective with, and appropriately utilized by, minority participants.

Methods

A systematic review was conducted of arthritis intervention research from 1997 to 2008. For each article, information was gathered on the percentage of participants who were from different racial/ethnic groups, whether interventions were shown to be effective for minority participants, whether differential attrition analyses were conducted, whether efforts were reported in minority recruitment and retention, and whether attempts were made to make interventions culturally appropriate.

Results

We identified 25 randomized intervention studies. Of these, only 2 reported on whether the intervention was similarly effective for white and black patients (equal effectiveness was found), and 6 studies reported examining differences in attrition by race (higher attrition in nonwhites was found in 1 study). Most studies did not report the percentage of participants from specific minority groups, and in many studies the percentage of minority participants was small. No studies reported making systematic efforts to assure that interventions were culturally appropriate for minority participants.

Conclusion

Minority patients with arthritis are at risk for higher levels of disability than white patients, but little is known about whether evidence‐based interventions for arthritis are effective for culturally diverse patients. In addition, minority patients appear to be underrepresented in intervention research, and too little attention has been paid to minority recruitment and assuring that interventions are culturally appropriate for diverse patients.
Impact of nervous system hyperalgesia on pain, disability, and quality of life in patients with knee osteoarthritis: A controlled analysis
Authors: Imamura Marta , Imamura Satiko Tomikawa , Kaziyama Helena H. S. , Targino Rosa Alves , Hsing Wu Tu , De Souza Luiz Paulo Marques , Cutait MArtin Mendonça , Fregni Felipe , Camanho Gilberto Luis
Published: September 2008

Objective

Refractory, disabling pain associated with knee osteoarthritis (OA) is usually treated with total knee replacement. However, pain in these patients might be associated with central nervous sensitization rather than peripheral inflammation and injury. We evaluated the presence of hyperalgesia in patients scheduled for a total knee replacement due to knee osteoarthritis with refractory pain, and we assessed the impact of pressure pain threshold measurements (PPT) on pain, disability, and quality of life of these patients.

Methods

Sixty‐two female patients were compared with 22 age‐matched healthy controls without reported pain for the last year. PPT was measured at the lower extremities subcutaneous dermatomes, over the vastus medialis, adductor longus, rectus femoris, vastus lateralis, tibialis anterior, peroneus longus, iliacus, quadratus lumborum and popliteus muscles and at the supraspinous ligaments from L1–L5, over the L5–S1 and S1–S2 sacral areas and at the pes anserinus bursae and patellar tendon.

Results

Patients with knee OA had significantly lower PPT over all evaluated structures versus healthy control subjects (P < 0.001). Lower PPT values were correlated with higher pain intensity, higher disability scores, and with poorer quality of life, except for the role‐emotional and general health status. Combined PPT values over the patellar tendon, at the S2 subcutaneous dermatome and at the adductor longus muscle were the best predictors for visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index pain scores.

Conclusion

Patients with pain due to osteoarthritis who were scheduled for total knee replacement showed hyperalgesia of nervous system origin that negatively impacted pain, knee functional capacity, and most aspects of quality of life.
The effect of cell fixation on the discrimination of normal and leukemia cells with laser tweezers Raman spectroscopy
Authors: Chan James W. , Taylor Douglas S. , Thompson Deanna L.
Published: September 2008

Laser tweezers Raman spectroscopy (LTRS) was used to characterize the effect of different chemical fixation procedures on the Raman spectra of normal and leukemia cells. Individual unfixed, paraformaldehyde‐fixed, and methanol‐fixed normal and transformed lymphocytes from three different cell lines were analyzed with LTRS. When compared to the spectra of unfixed cells, the fixed cell spectra show clear, reproducible changes in the intensity of specific Raman markers commonly assigned to DNA, RNA, protein, and lipid vibrations (e.g. 785, 1230, 1305, 1660 cm−1) in mammalian cells, many of which are important markers that have been used to discriminate between normal and cancer lymphocytes. Statistical analyses of the Raman data and classification using principal component analysis and linear discriminant analysis indicate that methanol fixation induces a greater change in the Raman spectra than paraformaldehyde. In addition, we demonstrate that the spectral changes as a result of the fixation process have an adverse effect on the accurate Raman discrimination of the normal and cancer cells. The spectral artifacts created by the use of fixatives indicate that the method of cell preparation is an important parameter to consider when applying Raman spectroscopy to characterize, image, or differentiate between different fixed cell samples to avoid potential misinterpretation of the data. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 132–139, 2009.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com