bluuebunny/crossref_metadata_2025 huggingface dataset:
“High‐Tech”‐Anwendungen von supramolekularen nanostrukturierten Gelmaterialien – von der regenerativen Medizin bis hin zu elektronischen Bauelementen
Authors: Hirst Andrew R. , Escuder Beatriu , Miravet Juan F. , Smith David K.
Published: September 2008

Die Nanofabrikation wird sehr wahrscheinlich Teil vieler Technologien im 21. Jahrhundert sein. Dabei bietet die chemische Synthese einen effizienten Ansatz zur Herstellung von molekularen Strukturen, die sich zu funktionellen Nanoarchitekturen organisieren. Ein starkes Interesse an selbstorganisierenden niedermolekularen Gelbildnern führte zu Kenntnissen über nichtkovalente Wechselwirkungen und Packungsparameter bei der Gelbildung. Die Moleküle bauen hierarchische supramolekulare Strukturen auf, was sich makroskopisch in der Bildung eines Gels ausdrückt. Eine Variation der Molekülstruktur kann die Organisation der Nanostrukturen bestimmen und dadurch spezifische Materialeigenschaften hervorbringen. Durch eine Kombination von supramolekularer Chemie, Materialwissenschaft und Biomedizin konnten anwendungsspezifische Materialien entwickelt werden. Auf dem Gebiet von regenerativer Medizin und Gewebezüchtung waren molekulare Gele als nanostrukturierte Gerüste zur Nachzüchtung von Nervenzellen in vivo erfolgreich, und die Aussicht auf den Einsatz von selbstorganisierten Fasern als eindimensionale Leiter in Gelmaterialien hat großes Interesse an der Nanoelektronik hervorgerufen.
High‐Tech Applications of Self‐Assembling Supramolecular Nanostructured Gel‐Phase Materials: From Regenerative Medicine to Electronic Devices
Authors: Hirst Andrew R. , Escuder Beatriu , Miravet Juan F. , Smith David K.
Published: September 2008

It is likely that nanofabrication will underpin many technologies in the 21st century. Synthetic chemistry is a powerful approach to generate molecular structures that are capable of assembling into functional nanoscale architectures. There has been intense interest in self‐assembling low‐molecular‐weight gelators, which has led to a general understanding of gelation based on the self‐assembly of molecular‐scale building blocks in terms of non‐covalent interactions and packing parameters. The gelator molecules generate hierarchical, supramolecular structures that are macroscopically expressed in gel formation. Molecular modification can therefore control nanoscale assembly, a process that ultimately endows specific material function. The combination of supramolecular chemistry, materials science, and biomedicine allows application‐based materials to be developed. Regenerative medicine and tissue engineering using molecular gels as nanostructured scaffolds for the regrowth of nerve cells has been demonstrated in vivo, and the prospect of using self‐assembled fibers as one‐dimensional conductors in gel materials has captured much interest in the field of nanoelectronics.
High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging
Authors: Werner Eric J. , Datta Ankona , Jocher Christoph J. , Raymond Kenneth N.
Published: September 2008

The desire to improve and expand the scope of clinical magnetic resonance imaging (MRI) has prompted the search for contrast agents of higher efficiency. The development of better agents requires consideration of the fundamental coordination chemistry of the gadolinium(III) ion and the parameters that affect its efficacy as a proton relaxation agent. In optimizing each parameter, other practical issues, such as solubility and in vivo toxicity, must also be addressed, making the attainment of safe, high‐relaxivity agents a challenging goal. This Minireview presents recent advances in the field, with an emphasis on gadolinium(III) hydroxypyridinone chelate complexes.
Proteomic characterization of mouse cartilage degradation in vitro
Authors: Wilson Richard , Belluoccio Daniele , Little Christopher B. , Fosang Amanda J. , Bateman John F.
Published: September 2008

Objective

To develop proteomics to analyze mouse cartilage degradation and correlate transcriptional and translational responses to catabolic stimuli.

Methods

Proteomic techniques were used to analyze catabolism in mouse femoral head cartilage. Using specific methods to prepare cartilage extracts and conditioned media for 2‐dimensional polyacrylamide gel electrophoresis and subsequent tandem mass spectrometry, we identified novel proteins and fragments released into the media of control, interleukin‐1α (IL‐1α)–treated, and all‐trans‐retinoic acid (RetA)–treated explants. Fluorescence 2‐dimensional difference gel electrophoresis was used to quantify protein expression changes. We also measured changes in messenger RNA (mRNA) expression to distinguish transcriptional and posttranslational regulation of released proteins.

Results

Differentially abundant proteins in the media of control and treated explants included fragments of thrombospondin 1 and connective tissue growth factor. IL‐1α stimulated release of the cartilage degeneration marker matrix metalloproteinase 3, as well as proteins with uncharacterized roles in cartilage pathology, such as neutrophil gelatinase–associated lipocalin. RetA stimulated release of the extracellular matrix proteins cartilage oligomeric matrix protein, link protein, and matrilin‐3 into the media, which was accompanied by a dramatic reduction in the corresponding mRNA transcript levels. Gelsolin, which has been implicated in cytoskeletal reorganization in arthritis synovial fibroblasts but has not been previously associated with cartilage pathology, was regulated by IL‐1α and RetA.

Conclusion

In this first analysis of mouse cartilage degradation and protein release using proteomics, we identified proteins and fragments, some of which represent novel candidate biomarkers for cartilage degradation. Applying these proteomic techniques to wild‐type and genetically modified mouse cartilage will provide insights into the mechanisms of cartilage degeneration.
Modulation of peripheral B cell tolerance by CD72 in a murine model
Authors: Li Daniel Hsieh‐Hsin , Winslow Monte M. , Cao Thai M. , Chen Albert H. , Davis Corrine R. , Mellins Elizabeth D. , Utz Paul J. , Crabtree Gerald R. , Parnes Jane R.
Published: September 2008

Objective

B cells play a dominant role in the pathogenesis of several autoimmune diseases, including systemic lupus erythematosus. It is not well understood how B cell signaling contributes to autoantibody production. The goal of this study was to elucidate the role of CD72 in modulating B cell receptor (BCR)–mediated tolerogenic signaling and peripheral B cell tolerance.

Methods

A mouse model utilizing hen egg lysozyme (HEL) “anergic” B cells was studied. CD72‐deficient mice carrying the BCR‐specific IgHEL and/or soluble HEL (sHEL) transgenes were generated by breeding IgHEL‐transgenic MD4 mice and/or sHEL‐transgenic ML5 mice with congenic, CD72‐deficient C57BL/6J mice. Normal and anergic B cells were isolated for analyses of B cell signaling. Aged wild‐type and CD72‐deficient mice were also examined for autoimmune phenomena.

Results

In the absence of CD72, anergic B cells inappropriately proliferated and survived in response to stimulation with self antigen. Biochemical analyses indicated that in anergic B cells, CD72 dominantly down‐regulated BCR signaling to limit the antigen‐induced elevation in [Ca2+]i and the activation of NFATc1, NF‐κB, MAPK, and Akt. Mechanistically, CD72 was associated with, and regulated, the molecular adaptor Cbl‐b in anergic B cells, suggesting that Cbl‐b may play a role in mediating the negative effects of CD72 on BCR signaling. Moreover, in aged CD72‐deficient mice, spontaneous production of antinuclear and anti–double‐stranded DNA autoantibodies and features of lupus‐like autoimmune disease were observed.

Conclusion

CD72 is required to maintain B cell anergy and functions as a regulator of peripheral B cell tolerance. Thus, altered CD72 expression may play a role during the development of systemic lupus erythematosus.
Polymorphisms in the interleukin‐1 receptor antagonist and interleukin‐6 genes affect risk of osteolysis in patients with total hip arthroplasty
Authors: Gordon Andrew , Kiss‐Toth E. , Stockley Ian , Eastell Richard , Wilkinson J. Mark
Published: September 2008

Objective

To determine whether osteolysis after total hip arthroplasty (THA) is associated with common polymorphisms within the genes encoding the interleukin‐1 (IL‐1) family and IL‐6, and to determine whether polymorphisms that are associated with osteolysis affect in vitro messenger RNA (mRNA) expression in human peripheral blood mononuclear cells (PBMCs) in response to wear particles.

Methods

Unrelated white subjects of North European descent (n = 612) were recruited a mean of 11 years after cemented THA for primary osteoarthritis. Of these subjects, 272 had previous osteolysis and 340 had no radiographic evidence of osteolysis (control group). Genomic DNA was genotyped for the following single‐nucleotide polymorphisms (SNPs): IL1A +4845, IL1B +3954, IL1B –3737, IL1B –511, IL1RA +2018, IL6 –174, IL6 –572, and IL6 –597. In a subset of 60 subjects, PBMCs were extracted and stimulated with titanium particles and/or endotoxin, and cytokine mRNA expression was measured using quantitative real‐time reverse transcriptase–polymerase chain reaction.

Results

The odds ratio (OR) for osteolysis associated with carriage of the IL1RA +2018C allele was 0.66 (95% confidence interval [95% CI] 0.48–0.91) (P = 0.012). The remaining SNPs were not individually associated with osteolysis. The uncommon IL6 haplotype −174G/−572G/−597A (osteolysis group frequency 2.4%, control group frequency 0.8%) was associated with osteolysis (P = 0.02, calculated using Haploview software). The IL1RA +2018CC genotype was associated with increased mRNA expression compared with the +2018TT genotype in both unstimulated and stimulated PBMCs (P = 0.01 by analysis of variance, after Bonferroni correction).

Conclusion

The IL1RA +2018C allele is associated with a decreased risk of osteolysis after THA and with increased IL‐1 receptor antagonist mRNA expression in vitro. An uncommon haplotype within the promoter region of the gene for IL‐6 is positively associated with osteolysis.
Spinal interleukin‐1β in a mouse model of arthritis and joint pain
Authors: Fiorentino Paolo M. , Tallents Ross H. , Miller Jen‐Nie H. , Brouxhon Sabine M. , O'Banion M. Kerry , Puzas J. Edward , Kyrkanides Stephanos
Published: September 2008

Objective

Pain from arthritis has been associated with peripheral sensitization of primary sensory afferents and the development of inflammation at the dorsal horns. This study was undertaken to determine whether the role of spinal interleukin‐1β (IL‐1β) in central processing of pain is important in the development of arthritis.

Methods

Col1‐IL‐1βXATmice and GFAP‐IL‐1βXATmice were injected with the feline immunodeficiency virus (FIV) (Cre) vector in the right and left temporomandibular joints (TMJs), or in the cisterna magna, respectively, to induce IL‐1β expression in the dorsal horns of the spinal horn. To inhibit intrathecal IL‐1 receptor type I (IL‐1RI) signaling, FIV(IL‐1Ra) vector was injected into the cisterna magna of Col1‐IL‐1βXATmice. The effects of IL‐1RI receptor inhibition in GFAP‐IL‐1βXATmice were studied in the GFAP‐IL‐1βXAT–IL‐1RI−/−compound mouse model. Neuroinflammatory, sensory, and behavioral changes were evaluated in conjunction with arthritic changes in the TMJ, assessed by histopathologic and immunohistochemical analyses.

Results

Induction of an osteoarthritis‐like condition in the TMJ in the Col1‐IL‐1βXATmouse model resulted in up‐regulation of murine IL‐1β at the dorsal horns. Moreover, intrathecal inhibition of IL‐1RI in Col1‐IL‐1βXATmice with arthritis led to amelioration of joint pathology and attenuation of the attendant joint pain. Overexpression of spinal IL‐1β in the recently developed GFAP‐IL‐1βXATsomatic mosaic model of neuroinflammation led to development of arthritis‐like pathology accompanied by increased pain‐like behavior.

Conclusion

Our results indicate that joint pathology and pain are dependent on spinal IL‐1β, and suggest the presence of a bidirectional central nervous system–peripheral joints crosstalk that may contribute to the development, expansion, and exacerbation of arthritis.
Evidence for a pathogenetic role of interleukin‐18 in cutaneous lupus erythematosus
Authors: Wang Dong , Drenker Melanie , Eiz‐Vesper Britta , Werfel Thomas , Wittmann Miriam
Published: September 2008

Objective

Cutaneous manifestations are the most common clinical features of lupus erythematosus (LE). The aim of this study was to analyze differences in the inflammatory response of keratinocytes from patients with cutaneous LE (CLE) compared with healthy controls.

Methods

Keratinocytes from LE patients and controls were cultured from epidermal stem cells of the hair follicle of anagen head hairs. Functional responses of keratinocytes to cytokine stimulation were determined by flow cytometry and enzyme‐linked immunosorbent assay. Biopsy samples of lesional skin were analyzed by immunohistochemistry.

Results

Keratinocytes from CLE patients expressed higher levels of IL‐18 receptor on their cell surface in response to tumor necrosis factor α (TNFα) or interferon‐γ stimulation. In response to IL‐18 stimulation, these cells produced large amounts of TNFα. Of note, in the presence of IL‐18, CLE keratinocytes failed to express IL‐12. IL‐12 has previously been shown to protect keratinocytes from ultraviolet irradiation–induced apoptosis. Keratinocytes from LE patients were more prone to die upon exposure to IL‐18, and this increased apoptosis was abrogated by blockade of endogenously produced TNFα as well as by the addition of exogenous IL‐12. IL‐18 was highly expressed in biopsy samples of lesional skin from CLE patients.

Conclusion

Our results demonstrate an intrinsic difference in the inflammatory response of keratinocytes and indicate an autocrine feedback loop involving TNFα, IL‐18, and IL‐12 family members. Our results suggest that IL‐18 may occupy an important position in the cytokine hierarchy in CLE, indicating the potential benefit of a local agent that blocks IL‐18 activity in the treatment of the manifestations of CLE.
Expression of the CD85j (leukocyte Ig‐like receptor 1, Ig‐like transcript 2) receptor for class I major histocompatibility complex molecules in idiopathic inflammatory myopathies
Authors: Schleinitz Nicolas , Cognet Celine , Guia Sophie , Laugier‐Anfossi Fanny , Baratin Myriam , Pouget Jean , Pelissier Jean‐Francois , Harle Jean‐Robert , Vivier Eric , Figarella‐Branger Dominique
Published: September 2008

Objective

Expression of class I major histocompatibility complex (MHC) molecules on the surface of muscle cells is a biologic feature of idiopathic inflammatory myopathies (IIM). Class I MHC–transgenic mouse models support a causative role for class I MHC expression by muscle cells in the pathogenesis of IIM. The muscle lesions are characterized by leukocyte infiltration. We undertook this study to analyze the expression in muscle lesions of various class I MHC–specific receptors on leukocytes and natural killer (NK) cells.

Methods

We generated a panel of cell transfectants to control the immunofluorescence analysis of class I MHC receptor expression. We then analyzed the expression of CD158 (killer cell Ig‐like receptors [KIRs]) and CD85j (leukocyte Ig‐like receptor 1, Ig‐like transcript 2) on muscle sections prepared from 14 patients with IIM (5 with dermatomyositis [DM], 5 with polymyositis [PM], and 4 with sporadic inclusion body myositis [IBM]).

Results

We could not detect the presence of NK cells in inflammatory lesions. However, the class I MHC receptor CD85j, but no KIRs, was expressed by inflammatory cells infiltrating muscle lesions in IIM.

Conclusion

CD85j is expressed in PM and sporadic IBM at the sites of partial invasion and in DM in perivascular inflammation, paving the way for dissecting the role of CD85j in the pathogenesis of inflammatory myopathies.
Vascular endothelial growth factor is highly expressed in muscle tissue of patients with polymyositis and patients with dermatomyositis
Authors: Grundtman Cecilia , Tham Emma , Ulfgren Ann‐Kristin , Lundberg Ingrid E.
Published: September 2008

Objective

To investigate the expression of vascular endothelial growth factor (VEGF) in muscle biopsy specimens and serum from patients with polymyositis and patients with dermatomyositis compared with that in healthy control subjects.

Methods

Muscle biopsy specimens from 33 patients with polymyositis or dermatomyositis and 15 healthy control subjects and serum samples from 56 patients and 56 healthy control subjects were analyzed. Patients were categorized into 3 groups, depending on disease duration and the presence or absence of inflammatory infiltrates. The expression of VEGF and the vessel marker CD31 in muscle was analyzed by immunohistochemistry, the expression of VEGF messenger RNA (mRNA) was analyzed by in situ hybridization, and serum levels of VEGF were determined by enzyme‐linked immunosorbent assay.

Results

Patients with polymyositis or dermatomyositis in the early or chronic phase without inflammatory infiltrates had a decreased total number of capillaries compared with healthy individuals. In patients with early disease without inflammatory infiltrates, the number of VEGF‐expressing muscle fibers was increased compared with that in control subjects, whereas VEGF expression was unchanged in the chronic phase of disease. In patients with established disease with inflammatory infiltrates, total VEGF expression was high compared with that in healthy control subjects. In healthy control subjects, VEGF was expressed in endothelial cells and in occasional muscle fibers. VEGF mRNA was expressed in muscle fibers in both healthy individuals and patients. The level of serum VEGF was significantly increased in patients compared with control subjects.

Conclusion

Our observations support a role of VEGF in the early phases of polymyositis and dermatomyositis. A reduced number of capillaries could lead to induction of VEGF expression in muscle fibers. Furthermore, differences in molecular expression during certain phases of disease may help in the development of specific therapeutic algorithms in the treatment of myositis.
Tumor necrosis factor α drives cadherin 11 expression in rheumatoid inflammation
Authors: Vandooren Bernard , Cantaert Tineke , Borg Mariëtte Ter , Noordenbos Troy , Kuhlman Rodger , Gerlag Daniëlle , Bongartz Tim , Reedquist Kris , Tak Paul P. , Baeten Dominique
Published: September 2008

Objective

Cadherin 11 expressed on fibroblast‐like synoviocytes (FLS) plays a key role in normal synovial architecture. The purpose of this study was to examine the expression of cadherin 11 in human synovitis.

Methods

Cadherin 11 expression in synovial biopsy samples from patients with various types of arthritis and in lung biopsy samples from patients with interstitial pneumonitis (IP) was examined by immunostaining. The regulation of cadherin 11 expression in human FLS was assessed by quantitative reverse transcription–polymerase chain reaction analysis and Western blotting. Therapeutic modulation of synovial cadherin 11 was assessed before and after effective antiinflammatory therapy.

Results

Abundant staining for cadherin 11 was seen in the intimal lining layer and the synovial sublining in inflamed tissues, with discrete staining in noninflammatory osteoarthritic (OA) tissues. The pattern and degree of immunostaining were similar in tissues from patients with rheumatoid arthritis (RA), nonpsoriatic spondylarthritis (SpA), psoriatic arthritis (PsA), and inflammatory OA. Clear staining for cadherin 11 was also observed in lung tissues from RA‐associated IP and idiopathic IP patients, but was very limited in normal lung tissue. Cadherin 11 staining correlated strongly with the degree of inflammatory infiltration of the tissue, as well as with the C‐reactive protein level and the erythrocyte sedimentation rate in RA patients. In vitro, cadherin 11 expression by FLS was consistently up‐regulated by tumor necrosis factor α (TNFα) at the protein, but not the messenger RNA, level. Cadherin 11 staining in vivo was strongly down‐regulated by prednisone treatment in RA patients and by TNFα blockade in SpA patients.

Conclusion

Cadherin 11 expression is regulated by mediators of inflammation, such as TNFα. Since cadherin 11 plays an important role in cartilage destruction in experimental arthritis, down‐modulation of cadherin 11 by potent antiinflammatory therapies in humans with arthritis may contribute to halting cartilage damage.
The effects of total knee arthroplasty on physical functioning in the older population
Authors: George Linda K. , Ruiz David , Sloan Frank A.
Published: September 2008

Objective

Clinical research provides convincing evidence that total knee arthroplasty (TKA) is safe and improves joint‐specific outcomes. However, higher‐level functioning associated with self care and independent living has not been studied. Furthermore, most previous studies of the effects of TKA relied on relatively small clinical samples. We undertook this study to estimate the effects of TKA on 3 levels of physical functioning in a national sample of older adults.

Methods

Data were obtained from the Medicare Current Beneficiary Survey from 1992 to 2003. Medicare claims data identified participants with osteoarthritis of the knee who received TKA (n = 259) or no TKA (n = 1,816). Propensity scores were used to match treatment and no‐treatment groups according to demographic characteristics, comorbid conditions, and baseline functioning. Three levels of physical functioning were examined as outcomes of TKA. These levels were represented by items on the Nagi Disability Scale, the Instrumental Activities of Daily Living (IADL) Scale, and the Activities of Daily Living (ADL) Scale. These items were measured after TKA and at comparable intervals for the no‐treatment group. Average treatment effects were calculated for relevant Nagi Disability Scale, IADL Scale, and ADL Scale tasks.

Results

Between baseline and outcome assessments, TKA recipients improved on all 3 levels of physical functioning; the no‐treatment group declined. Statistically significant average treatment effects for TKA were observed for one or more tasks for each measure of physical functioning.

Conclusion

TKA is associated with sizeable improvements in 3 levels of physical functioning among elderly Medicare beneficiaries.
Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis
Authors: Dass Shouvik , Rawstron Andy C. , Vital Edward M. , Henshaw Karen , McGonagle Dennis , Emery Paul
Published: September 2008

Objective

In rheumatoid arthritis (RA), B cell depletion occurs in all patients treated with rituximab, but the clinical responses to rituximab are variable. A highly sensitive assay was used to test the hypothesis that B cell depletion is variable, and that incomplete depletion leads to a poorer outcome.

Methods

Sixty patients with active RA unresponsive to anti–tumor necrosis factor agents received two 1‐gram infusions of rituximab. B cell numbers were measured by highly sensitive flow cytometry before and after each infusion and at 3‐month intervals thereafter. A reduction in B cell levels below 0.0001 × 109/liter was defined as complete depletion (compared with 0.05 × 109/liter by conventional cytometry). Clinical responses were measured using the European League Against Rheumatism (EULAR) criteria.

Results

At 6 months, 92% of patients had a moderate‐to‐good clinical response according to the EULAR criteria. B cells were detected in 63% of patients after the first infusion of rituximab (median level 0.0009 × 109/liter [range <0.0001–0.0015 × 109/liter), and these patients had poorer clinical outcomes than patients with complete depletion. At 9 months, 82% of patients with complete depletion had a moderate‐to‐ good EULAR response, compared with 43% of those with partial depletion (P = 0.01). At 12 months, 59% of complete responders had a moderate‐to‐good EULAR response, compared with 21% of those with partial depletion (P = 0.01). Patients in whom B cells were depleted only after the second infusion did no better than those in whom depletion was never complete and had poorer clinical outcomes than those in whom depletion was initially complete.

Conclusion

This study is the first to show, using a highly sensitive analysis, that rituximab therapy is associated with variable diminution in B cell numbers. A lack of complete depletion of B cells after 1 infusion was associated with a poorer outcome.
Interactions of T helper cells with fibroblast‐like synoviocytes: Up‐regulation of matrix metalloproteinases by macrophage migration inhibitory factor from both Th1 and Th2 cells
Authors: Schurigt Uta , Pfirschke Christina , Irmler Ingo M. , Hückel Marion , Gajda Mieczyslaw , Janik Tobias , Baumgrass Ria , Bernhagen Jürgen , Bräuer Rolf
Published: September 2008

Objective

Interactions of immune cells, such as activated T helper cells, with fibroblast‐like synoviocytes (FLS) play a crucial role in the joint destruction during human rheumatoid arthritis (RA). This study was undertaken to investigate the expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) by T helper cells, and to assess the role of MIF in overexpression of matrix metalloproteinases (MMPs) in cocultures of FLS from arthritic mice with either Th1 or Th2 cells.

Methods

MIF expression by in vitro–polarized murine Th1 and Th2 cells was determined using 2 different generation protocols. FLS were isolated from the inflamed joints of mice with antigen‐induced arthritis. MMP expression was analyzed in cocultures of the FLS with T helper cell subsets. Effects of MIF were blocked by a neutralizing anti‐MIF antibody. In addition, analyses were performed on cocultures of either Th1 or Th2 cells with FLS from MIF‐deficient mice.

Results

Both Th1 and Th2 cells expressed high quantities of MIF. MMPs were overexpressed by FLS after coculture with both Th1 and Th2 cells. Activated T helper cells were more effective than resting cells. Neutralization of MIF by an anti‐MIF antibody led to a marked reduction in MMP expression in Th1‐ and Th2‐stimulated FLS. T helper cells generated from MIF‐deficient mice exhibited a T helper cell–specific cytokine profile comparable with that in wild‐type cells, except in the expression of MIF, but showed an impaired ability to stimulate MMP expression in FLS.

Conclusion

MIF is an important Th1 and Th2 cell–derived proinflammatory cytokine that stimulates MMP expression in FLS from arthritic mice, and therefore inhibition of MIF might be a promising target for novel therapeutic strategies in human RA.
Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase
Authors: Lundberg Karin , Kinloch Andrew , Fisher Benjamin A. , Wegner Natalia , Wait Robin , Charles Peter , Mikuls Ted R. , Venables Patrick J.
Published: September 2008

Objective

To map the antibody response to human citrullinated α‐enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross‐reactivity with bacterial enolase.

Methods

Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme‐linked immunosorbent assay (ELISA) for reactivity with citrullinated α‐enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross‐reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross‐reactivity with bacterial enolase was investigated by immunoblotting.

Results

An immunodominant peptide, citrullinated α‐enolase peptide 1, was identified. Antibodies to this epitope were observed in 37–62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine‐containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated α‐enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2 = 0.803, P < 0.0001). Affinity‐purified antibodies to the human peptide cross‐reacted with citrullinated recombinant P gingivalis enolase.

Conclusion

We have identified an immunodominant epitope in citrullinated α‐enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross‐reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.
Nonspherical femoral head shape (pistol grip deformity), neck shaft angle, and risk of hip osteoarthritis: A case–control study
Authors: Doherty Michael , Courtney Philip , Doherty Sally , Jenkins Wendy , Maciewicz Rose A. , Muir Kenneth , Zhang Weiya
Published: September 2008

Objective

To determine whether 2‐dimensional measures of femoral head shape and angle are associated with hip osteoarthritis (OA).

Methods

We compared cases with symptomatic radiographic hip OA with asymptomatic controls with no radiographic hip OA. On anteroposterior pelvis radiographs, we measured “pistol grip deformity” for each hip (visually categorized as nonspherical, indeterminate, or spherical), the femoral head–to–femoral neck ratio as an interval measure of femoral head shape, and the femoral neck shaft angle. The relative risk of hip OA associated with each feature was estimated using odds ratios (ORs) and 95% confidence intervals (95% CIs), adjusted for possible confounders using a logistic regression model.

Results

Of 1,007 cases, 965 had definite radiographic hip OA; of 1,123 controls, 1,111 had no radiographic OA. The prevalence of pistol grip deformity in at least 1 hip was 3.61% in controls and 17.71% in cases (OR 6.95 [95% CI 4.64–10.41]), and the prevalence of abnormal femoral head–to–femoral neck ratio in at least 1 hip was 3.70% in controls and 24.27% in cases (OR 12.08 [95% CI 8.05–18.15]). The risk of hip OA increased as the femoral head–to–femoral neck ratio decreased (P for trend < 0.001) and with each extreme of neck shaft angle (P < 0.05). In cases with unilateral hip OA, the prevalence of abnormal femoral head–to–femoral neck ratio in the unaffected hip was 2 times greater than that in controls (OR 1.82 [95% CI 1.07–3.07]); in contrast, an abnormally low, but not abnormally high, neck shaft angle was more common in unaffected hips than in controls (OR 1.79 [95% CI 1.03–3.14]).

Conclusion

Our findings indicate that pistol grip deformity is associated with hip OA. The increased prevalence of pistol grip deformity and an abnormally low neck shaft angle in unaffected hips of cases with unilateral OA suggests that they are risk factors for development of hip OA. However, both a nonspherical head shape and an increase in neck shaft angle may occur as a consequence of OA.
Interleukin‐6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease‐modifying antirheumatic drugs: The tocilizumab in combination with traditional disease‐modifying antirheumatic drug therapy study
Authors: Genovese Mark C. , McKay James D. , Nasonov Evgeny L. , Mysler Eduardo F. , da Silva Nilzio A. , Alecock Emma , Woodworth Thasia , Gomez‐Reino Juan J.
Published: September 2008

Objective

To examine the efficacy and safety of the humanized anti–interleukin‐6 receptor antibody tocilizumab combined with conventional disease‐modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA).

Methods

A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double‐blind, placebo‐controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks.

Results

At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P < 0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28 <2.6), European League Against Rheumatism responses, and systemic markers such as the C‐reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy‐three percent of patients in the tocilizumab group had ≥1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3‐fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid‐lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported.

Conclusion

Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.
An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis
Authors: Brown A. K. , Conaghan P. G. , Karim Z. , Quinn M. A. , Ikeda K. , Peterfy C. G. , Hensor E. , Wakefield R. J. , O'Connor P. J. , Emery P.
Published: September 2008

Objective

Achieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal disease outcome. However, we have previously demonstrated a high prevalence of imaging‐detected synovial inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the long‐term significance of subclinical synovitis and its relationship to structural outcome.

Methods

We studied 102 RA patients receiving conventional treatment who had been judged by their consultant rheumatologist to be in remission, as well as 17 normal control subjects. Subjects underwent clinical, laboratory, functional, and quality of life assessments over 12 months. In addition to standard radiography of the hands and feet, imaging of the hands and wrists was performed with musculoskeletal ultrasonography (US) and conventional 1.5T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques.

Results

Despite their being in clinical remission, 19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage (P = 0.032, P < 0.001, and P = 0.002, respectively). Furthermore, there was a significant association between the musculoskeletal US PD score at baseline and structural progression over 12 months in totally asymptomatic metacarpophalangeal joints (P = 0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio 12.21, P < 0.001).

Conclusion

Subclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients in clinical remission who are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of disease status and the prediction of structural outcome.
Educational and occupational outcomes among young adults with juvenile idiopathic arthritis
Authors: Gerhardt Cynthia A. , McGoron Katie D. , Vannatta Kathryn , McNamara Kelly A. , Taylor Janalee , Passo Murray , Noll Robert B.
Published: September 2008

Objective

To examine educational and occupational outcomes among young adults with juvenile idiopathic arthritis (JIA) and peers during the transition from adolescence to emerging adulthood.

Methods

Families were recruited when children with JIA were 8–14 years old. At that time, each child with JIA was matched to a classmate of similar age, sex, and race for inclusion in a comparison group. For the current followup (12.64 years postdiagnosis), 45 participants with JIA, 46 peers, and their parents completed questionnaires soon after the young person's 18th birthday. Disease type and severity were rated by health care providers.

Results

Young adults with JIA and peers were similar on a variety of factors, including family background, scholastic and occupational self‐concept, and academic competence. The proportion of participants who graduated from high school, were working, and expressed plans to attend postsecondary education or seek employment was similar between groups. Disease type, initial severity, and time since diagnosis were generally not associated with indices of educational and occupational attainment.

Conclusion

Despite the challenge of having a chronic illness, young adults with JIA were similar to peers on numerous educational and occupational outcomes during the transition from adolescence to emerging adulthood. Interventions to assist academic or occupational functioning may not be necessary for all children with JIA, but additional research is needed to identify subgroups at risk for long‐term difficulties.
Effects of activity strategy training on pain and physical activity in older adults with knee or hip osteoarthritis: A pilot study
Authors: Murphy Susan L. , Strasburg Debra M. , Lyden Angela K. , Smith Dylan M. , Koliba Jessica F. , Dadabhoy Dina P. , Wallis Susan M.
Published: September 2008

Objective

To examine effects of activity strategy training (AST), a structured rehabilitation program taught by occupational therapists and designed to teach adaptive strategies for symptom control and engagement in physical activity (PA).

Methods

A randomized controlled pilot trial was conducted at 4 sites (3 senior housing facilities and 1 senior center) in southeastern, lower Michigan. Fifty‐four older adults with hip or knee osteoarthritis (mean ± SD age 75.3 ± 7.1 years) participated. At each site, older adults were randomly assigned to 1 of 2 programs: exercise plus AST (Ex + AST) or exercise plus health education (Ex + Ed). The programs involved 8 sessions over 4 weeks with 2 followup sessions over a 6‐month period, and were conducted concurrently within each site. Pain, total PA and PA intensity (measured objectively by actigraphy and subjectively by the Community Healthy Activities Model Program for Seniors questionnaire), arthritis self‐efficacy, and physical function were assessed at baseline and posttest.

Results

At posttest, participants who received Ex + AST had significantly higher levels of objective peak PA (P = 0.02) compared with participants who received Ex + Ed. Although not statistically significant, participants in Ex + AST tended to have larger pain decreases, increased total objective and subjective PA, and increased physical function. No effects were found for arthritis self‐efficacy.

Conclusion

Although participants were involved in identical exercise programs, participants who received AST tended to have larger increases in PA at posttest compared with participants who received health education. Future studies will be needed to examine larger samples and long‐term effects of AST.
Effect of the early use of the anti–tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis
Authors: Bejarano Victoria , Quinn Mark , Conaghan Philip G. , Reece Richard , Keenan Anne‐Maree , Walker David , Gough Andrew , Green Michael , McGonagle Dennis , Adebajo Ade , Jarrett Stephen , Doherty Sheelagh , Hordon Lesley , Melsom Richard , Unnebrink Kristina , Kupper Hartmut , Emery Paul
Published: September 2008

Objective

To compare work disability and job loss in early rheumatoid arthritis (RA) patients receiving adalimumab plus methotrexate (adalimumab + MTX) versus MTX alone.

Methods

In this multicenter, randomized, controlled trial, patients with RA for <2 years who had never taken MTX and who self‐reported work impairment were randomized to adalimumab + MTX or placebo + MTX for 56 weeks. Primary outcome was job loss of any cause and/or imminent job loss at or after week 16. Secondary outcomes included disease activity, function (Health Assessment Questionnaire [HAQ] score), and RA quality of life (RAQoL) questionnaire score. Work was evaluated with work diaries and the RA Work Instability Scale.

Results

Although job loss during the 56‐week study was significantly lower with adalimumab + MTX (14 of 75 patients) compared with MTX alone (29 of 73 patients; P = 0.005), the primary end point was not met (12 of 75 versus 20 of 73 patients; P = 0.092), likely owing to early drop out in the MTX group. There were significant improvements in American College of Rheumatology 20% response criteria, 28‐joint Disease Activity Score, ΔHAQ, ΔRAQoL, and working time lost in the adalimumab + MTX group. Twenty‐four serious adverse events were reported in 17 participants, with no differences between groups.

Conclusion

Adalimumab + MTX reduced job loss and improved productivity in early RA when compared with MTX alone, which supports the early use of anti–tumor necrosis factor therapy and suggests its cost efficacy.
Hand function and performance of daily activities in systemic lupus erythematosus
Authors: Johnsson Pia Malcus , Sandqvist Gunnel , Bengtsson Anders , Nived Ola
Published: September 2008

Objective

To investigate hand problems in patients with systemic lupus erythematosus (SLE) and to explore consequences on the ability to perform daily activities.

Methods

One hundred nine patients with SLE completed a questionnaire assessing hand problems in terms of deficits in body structures, e.g., joints, and body functions including pain, grip force, and other physiologic functions of the hand, the Health Assessment Questionnaire (HAQ), and the Simple hand test. Patients who stated problems in hand function answered questions about performance of daily activities and to what extent different deficits in body structures and body functions interfered.

Results

Seventy‐three percent of patients experienced hand problems and 42% reported interference with performance of daily activities. Problems from body structures of the hand were distributed relatively evenly over joints and tendons/muscles. Reduced grip force and activity‐induced pain were the most commonly reported problems in body functions. The most affected activity area was productivity, namely household tasks, work at home, work/study, and child care; least affected was self‐care. Reduced grip force followed by fumbling and pain were the most frequently reported body functions to create difficulties in performing daily activities. When comparing patients with and without difficulties in performing daily activities, there were significant differences in problems from tendons/muscles, joints in the thumb, reduced force, stiffness, fumbling, numbness/tingling, and the HAQ.

Conclusion

A majority of the study group had hand problems and almost half of the group experienced difficulties in performing daily activities due to SLE. The most affected activity area was productivity, where reduced grip force, fumbling, and pain were the most interfering body functions.
Association of body composition with disability in rheumatoid arthritis: Impact of appendicular fat and lean tissue mass
Authors: Giles Jon T. , Bartlett Susan J. , Andersen Ross E. , Fontaine Kevin R. , Bathon Joan M.
Published: September 2008

Objective

To explore the association of measures of body composition with disability in patients with rheumatoid arthritis (RA).

Methods

Patients with RA underwent total body dual‐energy x‐ray absorptiometry for measurement of total and regional body fat and lean mass. The associations of measures of fat and lean mass with disability, measured with the Health Assessment Questionnaire (HAQ), were explored for the total cohort and by sex, controlling for pertinent demographic, lifestyle, and RA disease and treatment covariates.

Results

We studied 197 subjects (118 women, 79 men). Median (interquartile range) HAQ score was 0.625 (0.125–1.25) and was significantly higher, indicating worse physical function, in women than in men. HAQ score was strongly correlated with depression, pain, RA duration, duration of morning stiffness, Disease Activity Score in 28 joints, radiographic damage scores, levels of physical and sedentary activities, and body composition, with increasing fat and decreasing lean mass associated with higher HAQ scores. Appendicular fat and lean mass demonstrated the strongest association per kilogram with HAQ. Mean HAQ score was 0.52 units higher for subjects in the highest versus the lowest quartile of appendicular fat mass (P < 0.001), and 0.81 units higher for subjects in the lowest versus the highest quartile of appendicular lean mass (P < 0.001). Adjusting for demographic and RA characteristics partially attenuated these associations. The joint associations of appendicular fat and lean mass on HAQ were additive without significant interaction.

Conclusion

Body composition, particularly the amount of fat and lean mass located in the arms and legs, is strongly associated with disability in RA patients.