bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: Findings in a multicenter, prospective, randomized, open‐label, parallel‐group clinical trial
Authors: Ginzler Ellen M. , Wofsy David , Isenberg David , Gordon Caroline , Lisk Laura , Dooley Mary‐Anne
Published: December 2009

Objective

To assess the effect of mycophenolate mofetil compared with intravenous pulses of cyclophosphamide on the nonrenal manifestations of lupus nephritis.

Methods

Patients with active lupus nephritis (renal biopsy class III, IV, or V) were recruited for the study (n = 370) and treated with mycophenolate mofetil (target dosage 3 gm/day) or intravenous cyclophosphamide (0.5–1.0 gm/m2/month), plus tapered prednisone, for 24 weeks. Nonrenal outcomes were determined using measures of whole body disease activity, including the British Isles Lupus Assessment Group (BILAG) disease activity index, the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and immunologic variables.

Results

Both treatments were effective on whole body disease activity in the systems examined, as indicated by changes in the classic BILAG index. With either treatment, remission was induced, notably in the mucocutaneous, musculoskeletal, cardiovascular/respiratory, and vasculitis systems, and flares were rare, as measured by the SELENA–SLEDAI. Levels of complement C3, C4, and CH50 and titers of anti–double‐stranded DNA antibodies were normalized after treatment with either mycophenolate mofetil or intravenous cyclophosphamide.

Conclusion

In addition to the efficacy of both treatments on the renal system, this analysis showed that remission could also be induced in other systems. There was no clear difference in efficacy between mycophenolate mofetil and intravenous cyclophosphamide in ameliorating either the renal or nonrenal manifestations. Mycophenolate mofetil is, therefore, a suitable alternative to cyclophosphamide for the treatment of renal and nonrenal disease manifestations in patients with biopsy‐proven lupus nephritis.
Rapid and sustained improvement in bone and cartilage turnover markers with the anti–interleukin‐6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: Results from a substudy of the multicenter double‐blind, placebo‐controlled trial of tocilizumab in inadequate responders to methotrexate alone
Authors: Garnero Patrick , Thompson Elizabeth , Woodworth Thasia , Smolen Josef S.
Published: December 2009

Objective

To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double‐blind, placebo‐controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response to MTX.

Methods

Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10–25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N‐terminal propeptide of type I collagen [PINP]), bone resorption (C‐terminal crosslinking telopeptide of type I collagen [CTX‐I] and C‐terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N‐terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX‐II]), and matrix metalloproteinase 3 (MMP‐3) were measured at baseline and at weeks 4, 16, and 24.

Results

TCZ induced marked dose‐dependent reductions in PIIANP, HELIX‐II, and MMP‐3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX‐I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ‐treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX‐II, and MMP‐3 levels as compared with ACR50 nonresponders.

Conclusion

TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP‐3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate‐to‐severe RA.
The transcription factor Fra‐2 regulates the production of extracellular matrix in systemic sclerosis
Authors: Reich Nicole , Maurer Britta , Akhmetshina Alfiya , Venalis Paulius , Dees Clara , Zerr Pawel , Palumbo Katrin , Zwerina Jochen , Nevskaya Tatiana , Gay Steffen , Distler Oliver , Schett Georg , Distler Jörg H. W.
Published: December 2009

Objective

Fra‐2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra‐2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra‐2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra‐2 induces fibrosis.

Methods

Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra‐2–transgenic and wild‐type mice. The expression of Fra‐2 in SSc patients and in animal models of SSc was analyzed by real‐time polymerase chain reaction and immunohistochemistry. Fra‐2, transforming growth factor β (TGFβ), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small‐molecule inhibitors.

Results

Fra‐2–transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra‐2 was up‐regulated in SSc patients and in different mouse models of SSc. Stimulation with TGFβ and platelet‐derived growth factor (PDGF) significantly increased the expression of Fra‐2 in SSc fibroblasts and induced DNA binding of Fra‐2 in an ERK‐dependent manner. Knockdown of Fra‐2 potently reduced the stimulatory effects of TGFβ and PDGF and decreased the release of collagen from SSc fibroblasts.

Conclusion

We demonstrate that Fra‐2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFβ and PDGF. Since transgenic overexpression of Fra‐2 causes not only fibrosis but also vascular disease, Fra‐2 might be an interesting novel candidate for molecular‐targeted therapies for SSc.
Long‐term efficacy of the interleukin‐1 receptor antagonist anakinra in ten patients with neonatal‐onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome
Authors: Neven Bénédicte , Marvillet Isabelle , Terrada Celine , Ferster Alice , Boddaert Nathalie , Couloignier Vincent , Pinto Graziella , Pagnier Anne , Bodemer Christine , Bodaghi Bahram , Tardieu Marc , Prieur Anne Marie , Quartier Pierre
Published: December 2009

Objective

Cryopyrin‐associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases. Neonatal‐onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement. CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin‐1 (IL‐1) processing. Anakinra, an IL‐1 receptor antagonist, has been shown to be an effective treatment; however, data on long‐term efficacy and safety have been sparse. This study was undertaken to assess the long‐term efficacy and safety of anakinra treatment in patients with NOMID/CINCA syndrome.

Methods

We retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007.

Results

There were 10 patients with NOMID/CINCA syndrome who had been treated with anakinra. The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years. They had been followed up for 26–42 months. Sustained efficacy in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved. The dosage of anakinra required for efficacy ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest. Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment. Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed. No effect on overgrowth arthropathy was observed. Adverse events consisted of mild injection‐site reactions.

Conclusion

The present results indicate that anakinra treatment is effective over the long term in NOMID/CINCA syndrome. However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.
ANTI‐CD3 therapy expands the numbers of CD4+ and CD8+ treg cells and induces sustained amelioration of collagen‐induced arthritis
Authors: Notley Clare A. , McCann Fiona E. , Inglis Julia J. , Williams Richard O.
Published: December 2009

Objective

To assess the therapeutic potential of anti‐CD3 monoclonal antibodies (mAb) for rheumatoid arthritis, using collagen‐induced arthritis as an animal model.

Methods

Arthritis was induced in DBA/1 mice by immunization with type II collagen. After disease onset, a single injection of anti‐CD3 mAb (20 μg/mouse) was administered, and arthritis severity was monitored over a 10‐day period.

Results

Anti‐CD3 mAb treatment resulted in a sustained reduction in disease activity, which was associated with an increase in the proportion of naturally occurring CD4+CD25+FoxP3+ regulatory T (Treg) cells and the generation of a population of CD8+CD25+FoxP3+ Treg cells. Anti‐CD3 mAb treatment did not alter the capacity of CD4+ Treg cells to suppress effector T cell proliferation and interferon‐γ (IFNγ) production in vitro. However, CD4+ Treg cells from both anti‐CD3 mAb–treated and control mice were unable to suppress interleukin‐17 (IL‐17) production. In contrast, CD8+ Treg cells induced by anti‐CD3 therapy suppressed IL‐17 production as well as CD4+ T cell proliferation and IFNγ production.

Conclusion

These results show that anti‐CD3 mAb treatment has important therapeutic potential for rheumatoid arthritis and has the capacity to generate antiarthritic CD8+ Treg cells and expand the relative numbers of CD4+ Treg cells.
Evaluation of the efficacy and safety of terguride in patients with fibromyalgia syndrome: Results of a twelve‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study
Authors: Distler Oliver , Eich Wolfgang , Dokoupilova Eva , Dvorak Zdenek , Fleck Martin , Gaubitz Markus , Hechler Manfred , Jansen Jan‐Peter , Krause Andreas , Bendszus Martin , Pache Lothar , Reiter Rudolf , Müller‐Ladner Ulf
Published: December 2009

Objective

To assess the efficacy and safety of terguride, a partial dopamine agonist, in patients with fibromyalgia syndrome (FMS).

Methods

In a 12‐week, multicenter, double‐blind, placebo‐controlled, parallel‐group study, 99 patients were randomized at a ratio of 2 to 1 to receive terguride or placebo. Over 21 days, the dosage was titrated to a maximum daily dose of 3 mg of terguride or placebo, and this fixed dosage was continued over 9 weeks. The primary efficacy variable was the intensity of pain (100‐mm visual analog scale). Secondary efficacy variables included the Fibromyalgia Impact Questionnaire (FIQ) score, the tender point score (TPS), and the Hamilton Depression Scale (HDS) score. During the study, patients were evaluated for the presence of cervical spine stenosis by magnetic resonance imaging (MRI).

Results

No significant differences in the change in pain intensity, FIQ score, TPS, or HDS score between baseline and 12 weeks were observed in the terguride group as compared with the placebo group. Cervical spine stenosis was detected in 22% of the patients. Only patients with cervical spine stenosis responded to terguride treatment. FIQ scores improved significantly (per‐protocol analysis), and pain intensity, the TPS score, and the HDS score showed a trend toward improvement in the terguride group as compared with the placebo group. Terguride treatment was safe. Only those adverse events already known to be side effects of terguride were observed. Premature termination of the study in patients receiving terguride (26%) occurred predominantly during up‐titration and in the absence of comedication for treatment of nausea.

Conclusion

Terguride treatment did not improve pain, the FIQ score, the TPS, or the HDS score in the total study population. However, a subgroup of patients with cervical spine stenosis seemed to benefit from terguride treatment.
Response of Th17 cells to a citrullinated arthritogenic aggrecan peptide in patients with rheumatoid arthritis
Authors: von Delwig Alexei , Locke James , Robinson John H. , Ng Wan‐Fai
Published: December 2009

Objective

Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disease. However, the autoantigens that play an important role in the development of RA remain unclear. The aim of this study was to investigate whether T cells specific for citrullinated epitopes from self proteins are present in patients with RA.

Methods

Peripheral blood mononuclear cells (PBMCs) from 28 RA patients and 18 healthy controls were stimulated with citrullinated or noncitrullinated aggrecan peptide Agg84–103, and proliferative and cytokine responses were assessed using 3H‐thymidine incorporation assay, enzyme‐linked immunosorbent assay, and intracellular cytokine analysis.

Results

A proliferative response to the citrullinated aggrecan peptide was detected in >60% of RA patients but not in healthy controls. Furthermore, citrullinated aggrecan peptide–stimulated PBMCs from RA patients produced high levels of the proinflammatory cytokine interleukin‐17 (IL‐17), accompanied by an induction of IL‐17+CD4+ T cells. In contrast, PBMCs from RA patients and healthy controls exhibited no response to stimulation with the noncitrullinated aggrecan peptide.

Conclusion

Proinflammatory T cell responses to stimulation with a citrullinated arthritogenic aggrecan peptide were detected in RA patients but not in healthy individuals, suggesting a role for these autoantigen‐specific T cells in the pathogenesis of RA. Our results suggest that the lack of response to the noncitrullinated analog peptide not only implicates the citrulline residue in T cell recognition but also highlights the potential value of citrullinated aggrecan peptide–specific responses as biomarkers of RA. To our knowledge, this is the first study to demonstrate the presence of citrullinated antigen–specific T cells in human RA.
Effect of long‐term belimumab treatment on b cells in systemic lupus erythematosus: Extension of a phase II, double‐blind, placebo‐controlled, dose‐ranging study
Authors: Jacobi Annett M. , Huang Weiqing , Wang Tao , Freimuth William , Sanz Inaki , Furie Richard , Mackay Meggan , Aranow Cynthia , Diamond Betty , Davidson Anne
Published: December 2009

Objective

To understand the effects of long‐term BLyS inhibition in human systemic lupus erythematosus (SLE).

Methods

Seventeen patients with SLE who were enrolled in a clinical trial of belimumab, a BLyS‐specific inhibitor, plus standard of care therapy were studied. Phenotypic analysis of lymphocytes was performed using flow cytometry. Circulating antibody‐secreting cells were enumerated using enzyme‐linked immunospot assay. Serum was analyzed by enzyme‐linked immunosorbent assay using an antibody that recognizes products of the VH4–34 gene. Lymphocyte counts, Ig levels, and anti–double‐stranded DNA antibody levels were available as part of the clinical trial analyses.

Results

Samples were collected on days 0, 84, 168, 365, and 532 and after day 730. The total number of B cells started to decrease from baseline between days 84 and 168. This was due to a decrease in naive and transitional B cells. CD27+IgD+ memory B cells and plasmablasts decreased only after 532 days, whereas CD27+IgD− memory B cells were not affected, and there were no changes in T cells. Serum IgM levels began to decline between days 84 and 168, but there were no changes in serum levels of IgG, IgG anti‐DNA antibodies, or VH4–34 antibodies during the study. SLE patients had more IgM‐, IgG‐, and autoantibody‐producing B cells than did normal controls on day 0. There was only a modest decrease in the frequency of total IgM‐producing, but not IgG‐producing, cells on days 365 and 532, consistent with the phenotypic and serologic data.

Conclusion

Our data confirm the dependence of newly formed B cells on BLyS for survival in humans. In contrast, memory B cells and plasma cells are less susceptible to selective BLyS inhibition.
Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry
Authors: Hetland Merete Lund , Christensen Ib Jarle , Tarp Ulrik , Dreyer Lene , Hansen Annette , Hansen Ib Tønder , Kollerup Gina , Linde Louise , Lindegaard Hanne M. , Poulsen Uta Engling , Schlemmer Annette , Jensen Dorte Vendelbo , Jensen Signe , Hostenkamp Gisela , ØStergaard Mikkel
Published: December 2009

Objective

To compare tumor necrosis factor α inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response.

Methods

The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease‐modifying drugs, center, and functional status (Health Assessment Questionnaire score).

Results

Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52–2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28–2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82–1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63–2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15–1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20–1.80).

Conclusion

Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times.
Rheumatoid arthritis–specific autoantibodies to peptidyl arginine deiminase type 4 inhibit citrullination of fibrinogen
Authors: Auger Isabelle , Martin Marielle , Balandraud Nathalie , Roudier Jean
Published: December 2009

Objective

Autoantibodies to citrullinated proteins are specific for rheumatoid arthritis (RA) and recognize epitopes centered by citrulline, a posttranslationally modified form of arginine. Peptidyl arginine deiminase type 4 (PAD‐4), the enzyme that converts arginine into citrulline, is in itself a target for RA‐specific autoantibodies. This study was undertaken to assess whether anti–PAD‐4 autoantibodies interfere with citrullination in vitro in patients with RA, and to identify peptide targets of anti–PAD‐4 antibodies that can activate or inhibit citrullination.

Methods

To test whether autoantibodies to PAD‐4 influence citrullination, an in‐house citrullination assay was developed using purified autoantibodies to PAD‐4. To map B cell epitopes on PAD‐4, 65 overlapping 20‐mer peptides encompassing the entire PAD‐4 were analyzed for their reactivity in RA sera.

Results

Autoantibodies to PAD‐4 inhibited PAD‐4–mediated citrullination. Three linear peptides on PAD‐4 were recognized almost uniquely by PAD‐4 autoantibodies in the sera of patients with RA. One peptide was located in the N‐terminal, calcium‐binding domain of PAD‐4, while 2 other peptides were located in the C‐terminal, substrate‐binding domain of PAD‐4.

Conclusion

Autoantibodies to PAD‐4 inhibit in vitro citrullination of fibrinogen by PAD‐4. Most anti–PAD‐4–positive sera recognize peptides located both in the N‐terminal domain (211–290) and the C‐terminal domain (601–650) of PAD‐4.
Evidence that Dkk‐1 is dysfunctional in ankylosing spondylitis
Authors: Daoussis Dimitrios , Liossis Stamatis‐Nick C. , Solomou Elena E. , Tsanaktsi Anastasia , Bounia Konstadina , Karampetsou Maria , Yiannopoulos Georgios , Andonopoulos Andrew P.
Published: December 2009

Objective

Dkk‐1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk‐1 in ankylosing spondylitis (AS), a prototypical bone‐forming disease.

Methods

Serum Dkk‐1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme‐linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk‐1 to its receptor (low‐density lipoprotein receptor–related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti–Dkk‐1 monoclonal antibody, by Western immunoblotting.

Results

Serum Dkk‐1 levels were significantly increased in patients with AS (mean ± SEM 2,730 ± 135.1 pg/ml) as compared with normal subjects (P = 0.040), patients with RA (P = 0.020), and patients with PsA (P = 0.049). Patients with AS receiving anti–tumor necrosis factor α (anti‐TNFα) treatment had significantly higher serum Dkk‐1 levels than patients with AS not receiving such treatment (P = 0.007). Patients with AS studied serially prior to and following anti‐TNFα administration exhibited a significant increase in serum Dkk‐1 levels (P = 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk‐1 blockade significantly enhanced Wnt signaling in control serum–treated, but not AS serum–treated, Jurkat T cells.

Conclusion

Our findings indicate that in patients with AS, circulating bone formation–promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk‐1–mediated inhibition.
Lack of effect of a single injection of human C‐reactive protein on murine lupus or nephrotoxic nephritis
Authors: Carlucci Francesco , Terence Cook H. , Garg Abhilok , Pepys Mark B. , Botto Marina
Published: December 2009

Objective

It has been reported that a single dose of human C‐reactive protein (CRP) can prevent and reverse the renal damage in murine models of spontaneous lupus, as well as the rapid‐onset immune complex disease induced in the accelerated nephrotoxic nephritis (ANTN) model. This study was undertaken to attempt to replicate these observations using a highly purified and fully characterized human CRP preparation.

Methods

(NZB × NZW)F1 (NZB/NZW) mice were treated with a single 200‐μg subcutaneous injection of CRP or control reagents either before disease onset at 4 months of age or when high‐grade proteinuria was present at 7 months of age. Mice were monitored at least monthly for proteinuria and autoantibody levels. ANTN was induced by preimmunizing C57BL/6 mice with sheep IgG, followed 5 days later by injection of sheep anti‐mouse glomerular basement membrane antibody and CRP or control reagents. Renal disease was assessed by regular urinalysis and histologic evaluation.

Results

CRP treatment of NZB/NZW mice, either early or late in the disease, had no effect on proteinuria, autoantibody titers, or survival. CRP administration did not reduce renal injury or alter disease in the ANTN model. Human serum amyloid P component, a pentraxin protein that is very closely related to CRP, similarly had no effect.

Conclusion

Our completely negative observations do not confirm that human CRP has reproducible antiinflammatory or immunomodulatory effects in these murine models, nor do they support the suggestion that CRP might be useful for therapy of lupus or immune complex–mediated nephritis.
Efficacy and safety of rituximab in moderately‐to‐severely active systemic lupus erythematosus: The randomized, double‐blind, phase ii/iii systemic lupus erythematosus evaluation of rituximab trial
Authors: Merrill Joan T. , Neuwelt C. Michael , Wallace Daniel J. , Shanahan Joseph C. , Latinis Kevin M. , Oates James C. , Utset Tammy O. , Gordon Caroline , Isenberg David A. , Hsieh Hsin‐Ju , Zhang David , Brunetta Paul G.
Published: December 2009

Objective

B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately‐to‐severely active extrarenal SLE.

Methods

Patients entered with ≥1 British Isles Lupus Assessment Group (BILAG) A score or ≥2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182.

Results

In the intent‐to‐treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty‐three percent of the patients had ≥1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG‐defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab.

Conclusion

The EXPLORER trial enrolled patients with moderately‐to‐severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.
Anti–neuropilin‐1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis
Authors: Kong Jin‐Sun , Yoo Seung‐Ah , Kim Jung‐Wook , Yang Seung‐Pil , Chae Chi‐Bom , Tarallo Valeria , Falco Sandro De , Ryu Sung‐Ho , Cho Chul‐Soo , Kim Wan‐Uk
Published: December 2009

Objective

To delineate the role of neuropilin‐1 (NP‐1), a vascular endothelial growth factor receptor (VEGFR), in rheumatoid inflammation and to determine whether blockade of NP‐1 could suppress synoviocyte survival and angiogenesis.

Methods

VEGF111–165 peptide, which encompasses the NP‐1 binding domain of VEGF165, was generated by cleaving VEGF165 with plasmin. The effect of this peptide on the interaction between VEGF165 and its receptor was determined by 125I‐VEGFR binding assay. Assays to determine synoviocyte apoptosis, adhesion, and migration were performed in the presence of VEGF165 and/or the peptide. VEGF165‐induced angiogenesis was assessed by measuring the proliferation, tube formation, and wounding migration of endothelial cells (ECs). Mice were immunized with type II collagen to induce experimental arthritis.

Results

VEGF111–165 peptide specifically inhibited the binding of 125I‐VEGF165 to NP‐1 on rheumatoid synoviocytes and ECs. The peptide eliminated the VEGF165‐mediated increase in synoviocyte survival and activation of p‐ERK and Bcl‐2. The peptide also completely inhibited a VEGF165‐induced increase in synoviocyte adhesion and migration. In addition, the anti–NP‐1 peptide blocked VEGF165‐stimulated proliferation, capillary tube formation, and wounding migration of ECs in vitro. VEGF165‐induced neovascularization in a Matrigel plug in mice was also blocked by treatment with the peptide. Finally, subcutaneous injection of anti–NP‐1 peptide suppressed arthritis severity and autoantibody formation in mice with experimental arthritis and inhibited synoviocyte hyperplasia and angiogenesis in arthritic joints.

Conclusion

Anti–NP‐1 peptide suppressed VEGF165‐induced increases in synoviocyte survival and angiogenesis, and thereby blocked experimental arthritis. Our findings suggest that anti–NP‐1 peptide could be useful in alleviating chronic arthritis.
Tayler instability of toroidal magnetic fields in MHD Taylor‐Couette flows
Authors: Rüdiger G. , Schultz M.
Published: December 2009

The nonaxisymmetric Tayler instability (TI) of toroidal magnetic fields due to axial electric currents is studied for conducting incompressible fluids between two infinitely long corotating cylinders. For given Reynolds number of rotation the magnetic Prandtl number Pm of the liquid conductor and the ratio of the cylinder's rotation rates are the free parameters. It is shown that for resting cylinders the critical Hartmann number for instability does not depend on Pm hence the TI also exists in the limit Pm → 0. By rigid rotation the instability is suppressed where for Pm = 1 the rotational quenching takes its maximum. Rotation laws with negative shear (i.e. dΩ /dR < 0) strongly destabilize the toroidal field if the rotation is not too fast. In galaxies with their quadrupolar magnetic field geometry this effect could have drastic implications. For sufficiently high Reynolds numbers of rotation, however, the TI completely disappears. For the considered magnetic constellation the superrotation laws support the rotational stabilization. The angular momentum transport of the instability is anticorrelated with the shear so that an eddy viscosity can be defined which proves to be positive.

We have also shown the possibility of laboratory TI experiments with a wide‐gap container filled with fluid metals like sodium or gallium. Even the effect of the rotational stabilization can be reproduced in the laboratory with electric currents of only a few kA (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Dynamics of the solar magnetic field from SOHO/MDI
Authors: Benevolenskaya E.E.
Published: December 2009

The investigation of the dynamics of magnetic fields from small scales to the large scales is very important for the understanding of the nature of solar activity. It is also the base for producing adequate models of the solar cycle with the purpose to predict the level of solar activity. Since December 1995 the Michelson Doppler Imager (MDI) on board of the Solar and Heliospheric Observatory (SOHO) provides full disk magnetograms and synoptic maps which cover the period of solar cycle 23 and the current minimum. In this paper, I review the following important topics with a focus on the dynamics of the solar magnetic field. The synoptic structure of the solar cycle; the birth of the solar cycle (overlapping cycles 23 and 24); the relationship of the photospheric magnetic activity and the EUV solar corona, polar magnetic fields and dynamo theory (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Convective dynamos in spherical wedge geometry
Authors: Käpylä P.J. , Korpi M.J. , Brandenburg A. , Mitra D. , Tavakol R.
Published: December 2009

Self‐consistent convective dynamo simulations in wedge‐shaped spherical shells are presented. Differential rotation is generated by the interaction of convection with rotation. Equatorward acceleration and dynamo action are obtained only for sufficiently rapid rotation. The angular velocity tends to be constant along cylinders. Oscillatory large‐scale fields are found to migrate in the poleward direction. Comparison with earlier simulations in full spherical shells and Cartesian domains is made (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The interstellar magnetic field near the Galactic center
Authors: Ferrière K.
Published: December 2009

We review the current observational knowledge of the interstellar magnetic field within ∼150 pc ofthe Galactic center. We also discuss the various theoretical scenarios that have been put forward to explain the existing observations. Our critical overview leads to two important conclusions: (1) The interstellar magnetic field near the GC is approximately poloidal on average in the diffuse intercloud medium and approximately horizontal in dense interstellar clouds. (2) In the general intercloud medium, the field is relatively weak and probably close to equipartition with cosmic rays (B ∼ (6–20) μ G), but there exist a number of localized filaments where the field is much stronger (some filaments could possibly have B ≳ 1 mG). In dense interstellar clouds, the field is probably rather strong, with typical values ranging between a few 0.1 mG and a few mG (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Influence of Ohmic diffusion on the excitation and dynamics of MRI
Authors: Korpi M.J. , Käpylä P.J. , Väisälä M.S.
Published: December 2009

In this paper we make an effort to understand the interaction of turbulence generated by the magnetorotational instability (MRI) with turbulence from other sources, such as supernova explosions (SNe) in galactic disks. First we perform a linear stability analysis (LSA) of non‐ideal MRI to derive the limiting value of Ohmic diffusion that is needed to inhibit the growth of the instability for different types of rotation laws. With the help of a simple analytical expression derived under first‐order smoothing approximation (FOSA), an estimate of the limiting turbulence level and hence the turbulent diffusion needed to damp the MRI is derived. Secondly, we perform numerical simulations in local cubes of isothermal nonstratified gas with external forcing of varying strength to see whether the linear result holds for more complex systems. Purely hydrodynamic calculations with forcing, rotation and shear are made for reference purposes, and as expected, non‐zero Reynolds stresses are found. In the magnetohydrodynamic calculations, therefore, the total stresses generated are a sum of the forcing and MRI contributions. To separate these contributions, we perform reference runs with MRI‐stable shear profiles (angular velocity increasing outwards), which suggest that the MRI‐generated stresses indeed become strongly suppressed as function of the forcing. The Maxwell to Reynolds stress ratio is observed to decrease by an order of magnitude as the turbulence level due to external forcing exceeds the predicted limiting value, which we interpret as a sign of MRI suppression. Finally, we apply these results to estimate the limiting radius inside of which the SN activity can suppress the MRI, arriving at a value of 14 kpc (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The origin of our galactic magnetic field
Authors: Kulsrud R.M.
Published: December 2009

A serious difficulty with the standard alpha‐omega theory of the origin of galactic magnetic fields involves the question of flux expulsion. This is intimately related to flux freezing. The alpha‐omega theory is shown in the context of the giant superbubble explosions that have a large impact on the physics of the interstellar medium. It is shown that superbubbles alone can duplicate the processes of the alpha‐omega dynamo and produce exponential growth of the galactic magnetic field. The possibility of the blow‐out of pieces of the magnetic field is discussed and it is shown that they have the potential to solve the flux‐expulsion problem. However, such an explanation must lead to apparent ‘gaps’ in the field in the galactic disc. These gaps are probably unavoidable in any dynamo theory and should have important observable consequences, one of which is an explanation for the escape of cosmic rays from the disc (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Fluctuation dynamo based on magnetic reconnections
Authors: Baggaley A.W. , Shukurov A. , Barenghi C.F. , Subramanian K.
Published: December 2009

We develop a new model of the fluctuation dynamo in which the magnetic field is confined to thin flux ropes advected by a multi‐scale flow which models turbulence. Magnetic dissipation occurs only via reconnections of flux ropes. The model is particularly suitable for rarefied plasma, such as the solar corona or galactic halos. We investigate the kinetic energy release into heat, mediated by dynamo action, both in our model and by solving the induction equation with the same flow. We find that the flux rope dynamo is more than an order of magnitude more efficient at converting mechanical energy into heat. The probability density of the magnetic energy released during reconnections has a power‐law form with the slope –3, consistent with the solar corona heating by nanoflares. We also present a nonlinear extension of the model. This shows that a plausible saturation mechanism of the fluctuation dynamo is the suppression of turbulent magnetic diffusivity, due to suppression of random stretching at the location of the flux ropes. We confirm that the probability distribution function of the magnetic line curvature has a power‐law form suggested by Schekochihin et al. (2002c). We argue, however, using our results that this does not imply a persistent folded structure of magnetic field, at least in the nonlinear stage (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The solar dynamo in the light of the distribution of various sunspot magnetic classes over butterfly diagram
Authors: Sokoloff D. , Khlystova A.I.
Published: December 2009

We present the data concerning the distribution of various sunspot magnetic classes over the solar butterfly diagram and discuss how this data can inform solar dynamo models. We use the statistics of sunspots that violate the Hale polarity law to estimate the ratio of the fluctuating and mean components of the toroidal magnetic field inside the solar convective zone. An analysis of the spatial distribution of bipolar, unipolar and complex sunspot groups in the context of simple dynamo models results in the conclusion that the mean toroidal field is relatively simple and maintains its shape during the course of the solar cycle (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Comparisons and connections between mean field dynamo theory and accretion disc theory
Authors: Blackman E.G.
Published: December 2009

The origin of large scale magnetic fields in astrophysical rotators, and the conversion of gravitational energy into radiation near stars and compact objects via accretion have been subjects of active research for a half century. Magnetohydrodynamic turbulence makes both problems highly nonlinear, so both subjects have benefitted from numerical simulations.However, understanding the key principles and practical modeling of observations warrants testable semi‐analytic mean field theories that distill the essential physics. Mean field dynamo (MFD) theory and alpha‐viscosity accretion disc theory exemplify this pursuit. That the latter is a mean field theory is not always made explicit but the combination of turbulence and global symmetry imply such. The more commonly explicit presentation of assumptions in 20th century textbook MFDT has exposed it to arguably more widespread criticism than incurred by 20th century alpha‐accretion theory despite complementary weaknesses. In the 21st century however, MFDT has experienced a breakthrough with a dynamical saturation theory that consistently agrees with simulations. Such has not yet occurred in accretion disc theory, though progress is emerging. Ironically however, for accretion engines, MFDT and accretion theory are presently two artificially uncoupled pieces of what should be a single coupled theory. Large scale fields and accretion flows are dynamically intertwined because large scale fields likely play a key role in angular momentum transport. I discuss and synthesize aspects of recent progress in MFDT and accretion disc theory to suggest why the two likely conspire in a unified theory (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Magnetohydrodynamic turbulence in a strongly magnetised plasma
Authors: Sridhar S.
Published: December 2009

I present a review of incompressible magnetohydrodynamic (MHD) turbulence in a strongly magnetised plasma. The approach is phenomenological even where a more rigorous theory is available, so that a reader armed with paper, pencil and some determination may be able to work through most of the physics. The focus is on the inertial‐range spectra for very large (fluid and magnetic) Reynolds numbers. These theories of the inertial‐range are built on two important facts: (i) Kraichnan's insight that the turbulent cascades are a result of nonlinear interactions between oppositely directed wavepackets of Elsasser fields; (ii) these oppositely directed wavepackets do not exchange energy, but contribute only to changing each other's spatial structures. I begin with a description and critique of the Iroshnikov‐Kraichnan theory, and explore the fundamental departures necessitated by the anisotropic nature of the turbulence. Derivations of the inertial‐range spectra of four regimes of MHD turbulence – the balanced weak, balanced strong, imbalanced weak and the imbalanced strong cascades – are then presented. The need for studying the spectra of imbalanced turbulence when the waves on the outer scale have a short correlation time is briefly discussed (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Equatorial magnetic helicity flux in simulations with different gauges
Authors: Mitra D. , Candelaresi S. , Chatterjee P. , Tavakol R. , Brandenburg A.
Published: December 2009

We use direct numerical simulations of forced MHD turbulence with a forcing function that produces two different signs of kinetic helicity in the upper and lower parts of the domain. We show that the mean flux of magnetic helicity from the small‐scale field between the two parts of the domain can be described by a Fickian diffusion law with a diffusion coefficient that is approximately independent of the magnetic Reynolds number and about one third of the estimated turbulent magnetic diffusivity. The data suggest that the turbulent diffusive magnetic helicity flux can only be expected to alleviate catastrophic quenching at Reynolds numbers of more than several thousands. We further calculate the magnetic helicity density and its flux in the domain for three different gauges. We consider the Weyl gauge, in which the electrostatic potential vanishes, the pseudo‐Lorenz gauge, where the speed of light is replaced by the sound speed, and the ‘resistive gauge’ in which the Laplacian of the magnetic vector potential acts as a resistive term. We find that, in the statistically steady state, the time‐averaged magnetic helicity density and the magnetic helicity flux are the same in all three gauges (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Simple laminar dynamos
Authors: Moss D.
Published: December 2009

Although current interest in astrophysical dynamo theory is largely focussed on flows with both large‐ and small‐scale motions, historically the study of dynamos driven by laminar flows has been important. Some classical laminar flow dynamos are reviewed. These results were obtained in an asymptotic regime corresponding to small values of system parameters. Numerical simulations have since been used to extend these results outside of these asymptotic regimes; the asymptotic results remain useful approximations well outside of their formal regions of validity. By changing slightly the system geometries some interesting new results have recently been obtained The latter include the very simple “one‐roll” dynamo, with motions in a single meridional cell contained within a spherical volume of fluid, without differential rotation (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Magnetic fields in the early Universe
Authors: Subramanian K.
Published: December 2009

We give a pedagogical introduction to two aspects of magnetic fields in the early Universe. We first focus on how to formulate electrodynamics in curved space time, defining appropriate magnetic and electric fields and writing Maxwell equations in terms of these fields. We then specialize to the case of magnetohydrodynamics in the expanding Universe. We emphasize the usefulness of tetrads in this context. We then review the generation of magnetic fields during the inflationary era, deriving in detail the predicted magnetic and electric spectra for some models. We discuss potential problems arising from back reaction effects and from the large variation of the coupling constants required for such field generation (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Mean electromotive force proportional to mean flow in MILD turbulence
Authors: Rädler K.‐H. , Brandenburg A.
Published: December 2009

In mean‐field magnetohydrodynamics the mean electromotive force due to velocity and magnetic‐field fluctuations plays a crucial role. In general it consists of two parts, one independent of and another one proportional to the mean magnetic field. The first part may be nonzero only in the presence of mhd turbulence, maintained, e.g., by small‐scale dynamo action. It corresponds to a battery, which lets a mean magnetic field grow from zero to a finite value. The second part, which covers, e.g., theαeffect, is important for large‐scale dynamos. Only a few examples of the aforementioned first part of the mean electromotive force have been discussed so far. It is shown that a mean electromotive force proportional to the mean fluid velocity, but independent of the mean magnetic field, may occur in an originally homogeneous isotropic mhd turbulence if there are nonzero correlations of velocity and electric current fluctuations or, what is equivalent, of vorticity and magnetic field fluctuations. This goes beyond the Yoshizawa effect, which consists in the occurrence of mean electromotive forces proportional to the mean vorticity or to the angular velocity defining the Coriolis force in a rotating frame and depends on the cross‐helicity defined by the velocity and magnetic field fluctuations. Contributions to the mean electromotive force due to inhomogeneity of the turbulence are also considered. Possible consequences of the above findings for the generation of magnetic fields in cosmic bodies are discussed (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)