bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward a valid definition of gout flare: Results of consensus exercises using delphi methodology and cognitive mapping
Authors: Taylor W. J. , Shewchuk R. , Saag K. G. , Schumacher H. R. , Singh J. A. , Grainger R. , Edwards N. L. , Bardin T. , Waltrip R. W. , Simon L. S. , Burgos‐Vargas R.
Published: March 2009

Objective

To identify, in people known to have gout, the testable, key components of a standard definition of gout flare for use in clinical research.

Methods

Consensus methodology was used to identify key elements of a gout flare. Two Delphi exercises were conducted among different groups of rheumatologists. A cognitive mapping technique among 9 gout experts with hierarchical cluster analysis provided a framework to guide the panel discussion, which identified the final set of items that should be tested empirically.

Results

From the Delphi exercises, 21 items were presented to the expert panel. Cluster analysis and multidimensional scaling showed that these items clustered into 5 concepts (joint inflammation, severity of symptoms, stereotypical nature, pain, and gout archetype) distributed along 2 dimensions (objective to subjective features and general features to specific features of gout). Using this analysis, expert panel discussion generated a short list of potential features: joint swelling, joint tenderness, joint warmth, severity of pain, patient global assessment, time to maximum pain, time to complete resolution of pain, an acute‐phase marker, and functional impact of the episode.

Conclusion

A short list of features has been identified and now requires validation against a patient‐ and physician‐defined gout flare in order to determine the best combination of features.
The association of quadriceps strength with the knee adduction moment in medial knee osteoarthritis
Authors: Lim Boon‐Whatt , Kemp Georgina , Metcalf Ben , Wrigley Tim V. , Bennell Kim L. , Crossley Kay M. , Hinman Rana S.
Published: March 2009

Objective

To investigate the relationship between quadriceps strength and the peak knee adduction moment during walking in medial tibiofemoral osteoarthritis (OA), and whether varus malalignment influences this relationship.

Methods

Maximum isometric quadriceps strength at 60° flexion relative to body mass and the peak knee adduction moment during walking were assessed in 184 community volunteers with medial knee OA. Mechanical knee alignment was determined either directly from full‐leg radiograph or extrapolated from anatomic alignment on knee radiograph using regression equations. Pearson's correlation coefficient was used to assess the association between quadriceps strength and peak knee adduction moment. The independent relationship between quadriceps strength and peak knee adduction moment, and the impact of varus malalignment on this relationship, was assessed using multiple regression analyses with and without adjustment for covariates.

Results

Quadriceps strength was not significantly associated with peak knee adduction moment (r = 0.14, P = 0.059). Neither quadriceps strength (b = 0.25, P = 0.142) nor the interaction between quadriceps strength and varus malalignment (b = −0.01, P = 0.693) significantly contributed to the variance in peak knee adduction moment. Results were unchanged with the inclusion of covariates.

Conclusion

No significant association was observed between quadriceps strength and the peak knee adduction moment, and the severity of varus malalignment did not influence the relationship. Results suggest that clinicians should not be concerned that patients with knee OA and stronger quadriceps are more likely to demonstrate a higher knee adduction moment.
A retrospective seven‐year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at university college london hospital: The first fifty patients
Authors: Lu Tim Y.‐T. , Ng Kristine P. , Cambridge Geraldine , Leandro Maria J. , Edwards Jonathan C. W. , Ehrenstein Michael , Isenberg David A.
Published: March 2009

Objective

To describe the 6‐month clinical outcome and the long‐term safety profile of B cell depletion therapy (BCDT) in 50 patients with active systemic lupus erythematosus (SLE), who were nonresponsive or poorly responsive to conventional immunosuppression.

Methods

All except 4 of 50 patients with active SLE received 1 gm of rituximab, 750 mg of cyclophosphamide, and 100–250 mg of methylprednisolone, administered on 2 occasions 2 weeks apart, to achieve B cell depletion. Clinical outcome was assessed using the British Isles Lupus Assessment Group (BILAG) activity index and serial serologic measurements of disease activity. Remission was defined as a change from a BILAG A or B score to a C or D score in every organ system. Partial remission was a change from a BILAG A or B score to a C or D score in at least 1 system, but with the persistence of 1 score of A or B in another system. No improvement was defined as a BILAG A or B score that remained unchanged after treatment.

Results

Of the 45 patients available for followup at 6 months, 19 patients (42%) achieved remission, and 21 patients (47%) reached partial remission after 1 cycle of BCDT (mean followup 39.6 months). BCDT resulted in a decrease in median global BILAG scores from 12 to 5 (P < 0.0001) and median anti–double‐stranded DNA antibody titers from 106 to 42 IU/ml (P < 0.0001), and an increase in the median C3 level from 0.81 to 0.95 mg/liter (P < 0.02) at 6 months. Five serious adverse events were observed.

Conclusion

BCDT is an effective treatment for patients with active SLE whose disease has failed to respond to standard immunosuppressive therapy. Although the safety profile of BCDT is favorable, ongoing monitoring is required.
Health‐related quality of life of patients with juvenile dermatomyositis: Results from the paediatric rheumatology international trials organisation multinational quality of life cohort study
Authors: Apaz Maria Teresa , Saad‐Magalhães Claudia , Pistorio Angela , Ravelli Angelo , de Oliveira sato Juliana , Marcantoni Maria Beatriz , Meiorin Silvia , Filocamo Giovanni , Pilkington Clarissa , Maillard Susan , Al‐Mayouf Sulaiman , Prahalad Sampath , Fasth Anders , Joos Rik , Schikler Kenneth , Mozolova Dagmar , Landgraf Jeanne M. , Martini Alberto , Ruperto Nicolino
Published: March 2009

Objective

To investigate the health‐related quality of life (HRQOL) change over time, as measured by the Child Health Questionnaire (CHQ), and its determinants in patients with active juvenile dermatomyositis (DM).

Methods

We assessed patients with juvenile DM at both baseline and 6 months of followup, and healthy children age ≤18 years. Potential determinants of poor HRQOL included demographic data, physician's and parent's global assessments, muscle strength, functional ability as measured by the Childhood Health Assessment Questionnaire (C‐HAQ), global disease activity assessments, and laboratory markers.

Results

A total of 272 children with juvenile DM and 2,288 healthy children were enrolled from 37 countries. The mean ± SD CHQ physical and psychosocial summary scores were significantly lower in children with juvenile DM (33.7 ± 11.7 versus 54.6 ± 4.1) than in healthy children (45.1 ± 9.0 versus 52 ± 7.2), with physical well‐being domains being the most impaired. HRQOL improved over time in responders to treatment and remained unchanged or worsened in nonresponders. Both physical and psychosocial summary scores decreased with increasing levels of disease activity, muscle strength, and parent's evaluation of the child's overall well‐being. A C‐HAQ score >1.6 (odds ratio [OR] 5.06, 95% confidence interval [95% CI] 2.03–12.59), child's overall well‐being score >6.2 (OR 5.24, 95% CI 2.27–12.10), and to a lesser extent muscle strength and alanine aminotransferase level were the strongest determinants of poor physical well‐being at baseline. Baseline disability and longer disease duration were the major determinants for poor physical well‐being at followup.

Conclusion

We found that patients with juvenile DM have a significant impairment in their HRQOL compared with healthy peers, particularly in the physical domain. Physical well‐being was mostly affected by the level of functional impairment.
Association of physical performance with muscle strength and hip range of motion in hip osteoarthritis
Authors: Pua Yong‐Hao , Wrigley Tim V. , Collins Marnie , Cowan Sallie M. , Bennell Kim L.
Published: March 2009

Objective

To examine whether the associations of physical performance with isometric hip and knee extensors strength and passive hip flexion and internal rotation range of motion (ROM) are nonlinear in community‐dwelling adults with hip osteoarthritis (OA).

Methods

Participants were 100 adults (mean age 62 years) with radiographically confirmed hip OA. Physical performance measures included gait speed test and timed stair tests. Piecewise regression models of muscle strength and hip ROM on physical performance measures were used to identify possible breakpoints. Receiver operating characteristic (ROC) curve analysis was used to identify participants with functionally inadequate (≤1.0 meters/second) gait speed and optimal cut points were identified.

Results

Muscle strength and hip ROM were nonlinearly associated with stair measures but not with gait speed measures. The optimal breakpoints and ROC‐derived cut points were 1.8–2.5Nm/kg for knee extensors, 1.5–2.1Nm/kg for hip extensors, 25–26° for hip internal rotation ROM, and 109–115° for hip flexion ROM. Muscle strength breakpoints increased monotonically with increasing movement demand.

Conclusion

In individuals with hip OA, the associations between physical performance and measures of muscle strength and hip ROM are less straightforward than previously assumed. These breakpoints and ROC‐derived cut points may be useful in identifying individuals for whom interventions that improve muscle strength or hip ROM would be most beneficial.
Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: A randomized placebo‐controlled study
Authors: Norby Gudrun E. , Holme Ingar , Fellström Bengt , Jardine Alan , Cole Edward , Abedini Sadollah , Holdaas Hallvard
Published: March 2009

Objective

Patients with systemic lupus erythematosus (SLE), with or without end‐stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE.

Methods

Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double‐blind, placebo‐controlled study of the effect of fluvastatin (40–80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5–6‐year trial, and then invited to continue in a 2‐year open‐label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7–8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures.

Results

Fluvastatin reduced low‐density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3–40%), from a mean ± SD of 4.0 ± 0.9 mmoles/liter to 2.8 ± 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7–27.5%), from 6.4 ± 0.9 mmoles/liter to 5.1 ± 1.1 mmoles/liter. Compared with placebo‐treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9–119.4], P = 0.064).

Conclusion

Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.
Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: A randomized, double‐blind, placebo‐controlled trial
Authors: Khanna Dinesh , Clements Philip J. , Furst Daniel E. , Korn Joseph H. , Ellman Michael , Rothfield Naomi , Wigley Fredrick M. , Moreland Larry W. , Silver Richard , Kim Youn H. , Steen Virginia D. , Firestein Gary S. , Kavanaugh Arthur F. , Weisman Michael , Mayes Maureen D. , Collier David , Csuka Mary E. , Simms Robert , Merkel Peter A. , Medsger Thomas A. , Sanders Martin E. , Maranian Paul , Seibold James R.
Published: March 2009

Objective

A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 μg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double‐blind, placebo‐controlled clinical trial to compare placebo with 10 μg/kg/day and 25 μg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate‐to‐severe SSc.

Methods

Men and women ages 18–70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 μg/kg/day or 25 μg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28.

Results

The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo.

Conclusion

Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.
Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis
Authors: Faurschou Mikkel , Mellemkjaer Lene , Sorensen Inge Juul , Svalgaard Thomsen Bjarne , Dreyer Lene , Baslund Bo
Published: March 2009

Objective

Experimental studies indicate that patients with Wegener's granulomatosis (WG) experience accelerated atherosclerosis. The purpose of this study was to investigate whether the occurrence of overt ischemic heart disease (IHD) is increased in WG.

Methods

A total of 293 WG patients were included in the study. Information on all hospitalizations for IHD in Denmark from 1977 to 2006 was obtained from the Danish National Hospital Register. The WG patients were compared with the Danish background population with respect to rates of hospitalization for clinical manifestations of IHD after the date of vasculitis diagnosis by calculating standardized ratios of observed to expected (O:E) events.

Results

Sixty‐three first IHD events were registered in the WG group during the 2,482 patient‐years of followup, corresponding to a significantly increased O:E ratio for IHD of 1.9 (95% confidence interval [95% CI] 1.4–2.4). A significantly increased risk was found for acute myocardial infarction (MI) (O:E ratio 2.5 [95% CI 1.6–3.7]), but not for angina pectoris (O:E ratio 1.3 [95% CI 0.7–2.1]). In analyses stratified according to the time between the diagnosis of vasculitis and the cardiovascular event, increased O:E ratios were found for IHD and acute MI occurring <5.0 years after WG diagnosis (2.1 [95% CI 1.4–3.0] for IHD and 3.6 [95% CI 2.0–5.9] for acute MI) and for IHD occurring ≥10.0 years after WG diagnosis (2.2 [95% CI 1.3–3.4]). Significantly increased O:E ratios for IHD and acute MI were found in patients who were ≥50.0 years of age at the time of diagnosis of WG, in male patients, and in patients who received high cumulative doses of cyclophosphamide.

Conclusion

Compared with the background population, WG patients seem to experience an increased number of both early and late cardiovascular events due to IHD.
Association between anti–cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis
Authors: López‐Longo Francisco Javier , Oliver‐Miñarro Desamparados , de la Torre Inmaculada , González‐Díaz de Rábago Eugenia , Sánchez‐Ramón Silvia , Rodríguez‐Mahou Margarita , Paravisini Alexandra , Monteagudo Indalecio , González Carlos‐Manuel , GarCía‐Castro Marta , Casas María Dolores , Carreño Luis
Published: March 2009

Objective

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease that may not always be related to the presence of traditional cardiovascular risk factors. The aim of this study was to determine if anti–cyclic citrullinated peptide (anti‐CCP) antibodies are associated with cardiovascular disease in patients with RA.

Methods

Anti‐CCP antibodies were determined by enzyme‐linked immunosorbent assay in the earliest serum sample available from 937 patients with a diagnosis of RA. We studied the relationship between anti‐CCP antibodies with traditional cardiovascular risk factors and cardiovascular events.

Results

We found positive anti‐CCP antibodies (>25 units/ml) in 672 patients (71.7%). There was no association between the anti‐CCP antibodies and cardiovascular risk factors such as smoking, hypertension, dyslipidemia, being overweight, or diabetes mellitus. However, patients who had positive anti‐CCP antibodies experienced more frequent ischemic heart disease (6.5% versus 2.6%; odds ratio [OR] 2.58, 95% confidence interval [95% CI] 1.17–5.65) and had higher mortality rates (11.2% versus 6.8%; OR 1.72, 95% CI 1.01–2.91). Similar results were obtained when we considered anti‐CCP titers 20‐fold higher (>500 units/ml). Multivariable analysis showed that ischemic heart disease is independently associated with positive anti‐CCP antibodies (OR 2.8, 95% CI 1.19–6.56; P = 0.009).

Conclusion

Anti‐CCP antibodies in patients with RA are independently associated with the development of ischemic heart disease.
Clinical and imaging efficacy of infliximab in HLA–B27–Positive patients with magnetic resonance imaging–determined early sacroiliitis
Authors: Barkham Nick , Keen Helen I. , Coates Laura C. , O'Connor Philip , Hensor Elizabeth , Fraser Alexander D. , Cawkwell Lorna S. , Bennett Alexander , McGonagle Dennis , Emery Paul
Published: March 2009

Objective

To evaluate the efficacy of infliximab in HLA–B27–positive patients with magnetic resonance imaging (MRI)–determined early sacroiliitis, using both clinical and MRI assessments.

Methods

Forty patients with recent‐onset inflammatory back pain, as assessed by the Calin criteria, HLA–B27 positivity, clinical disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), pain and morning stiffness, and magnetic resonance imaging (MRI)–determined sacroiliac joint bone edema were randomized in a double‐blind manner to receive infliximab 5 mg/kg or placebo at 0, 2, 6, and 12 weeks. MRI scans were performed at baseline and 16 weeks and scored by 2 observers (blinded to both the order of the scans and to treatment group), using the Leeds scoring system. Clinical assessments included the BASDAI, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL) instrument, the ASsessment in Ankylosing Spondylitis International Working Group criteria (ASAS) for improvement, and markers of inflammation.

Results

The mean reduction in the total MRI score from week 0 to week 16 was significantly greater in infliximab‐treated patients compared with placebo‐treated patients (P = 0.033). On average, significantly more lesions resolved in the infliximab group (P < 0.001), while significantly more new lesions developed in the placebo group (P = 0.004). Significantly greater improvement in the infliximab group versus the placebo group was also observed for changes from week 0 to week 16 in the BASDAI (P = 0.002), BASFI (P = 0.004), and ASQoL (P = 0.007) scores. Responses according to the ASAS criteria for 40% improvement, the ASAS criteria for 20% improvement in 5 of 6 domains, and ASAS partial remission were achieved by 61%, 44%, and 56% of infliximab‐treated patients, respectively. Infliximab was well tolerated, and no serious adverse events were observed.

Conclusion

Infliximab was an effective therapy for early sacroiliitis, providing a reduction in disease activity by week 16. This study is the first to show that infliximab is effective for reducing clinical and imaging evidence of disease activity in patients with MRI‐determined early axial spondylarthritis.
Opposing effects of HLA–DRB1*13 alleles on the risk of developing anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis
Authors: Lundström Emeli , Källberg Henrik , Smolnikova Marina , Ding Bo , Rönnelid Johan , Alfredsson Lars , Klareskog Lars , Padyukov Leonid
Published: March 2009

Objective

The effect of non–shared epitope HLA–DRB1 alleles on rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate the effects of several HLA–DRB1 alleles, independent of the shared epitope, on the risk of developing anti–citrullinated protein antibody (ACPA)–positive or ACPA‐negative RA in a large case–control study.

Methods

HLA typing for the DRB1 gene was performed in 1,352 patients with RA and 922 controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated.

Results

DRB1*13 was found to protect against ACPA‐positive RA when stratifying for the shared epitope and using a dominant genetic model (RR 0.41 [95% CI 0.26–0.64]). Furthermore, DRB1*13 neutralized the effect of the shared epitope in ACPA‐positive RA (RR 3.91 [95% CI 3.04–5.02] in patients who had the shared epitope but not DRB1*13, and RR 1.22 [95% CI 0.81–1.83] in patients with both the shared epitope and DRB1*13, as compared with patients negative for both the shared epitope and DRB1*13). However, we did not replicate the previous published risk of ACPA‐negative RA conferred by DRB1*03 when a dominant genetic model was used (RR 1.29 [95% CI 0.91–1.82]). Similarly, no significant effect of DRB1*03 on RR for ACPA‐negative RA was seen using the recessive genetic model (RR 1.18 [95% CI 0.6–2.4]). In contrast, the combination of DRB1*03 and DRB1*13 was significantly associated with increased risk of developing ACPA‐negative RA (RR 2.07 [95% CI 1.17–3.67]).

Conclusion

Our findings indicate that the DRB1*13 allele plays a dual role in the development of RA, by protecting against ACPA‐positive RA but, in combination with DRB1*03, increasing the risk of ACPA‐negative RA.
In vitro spontaneous osteoclastogenesis of human peripheral blood mononuclear cells is not crucially dependent on T lymphocytes
Authors: Vandooren Bernard , Melis Lode , Veys Eric M. , Tak Paul P. , Baeten Dominique
Published: March 2009

Objective

In vitro spontaneous osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) is increased in diseases with excessive bone loss. The purpose of this study was to reassess the role of T lymphocytes in this process.

Methods

Fresh or cryopreserved PBMCs obtained from healthy subjects and from patients with rheumatoid arthritis, psoriatic arthritis, and non‐psoriatic spondylarthritis were cultured at high density and stained for tartrate‐resistant acid phosphatase (TRAP). Resorption of mineralized matrix was assessed by a dentin disc assay. CD14+ monocytes and CD3+ T cells were selected using magnetically labeled antibodies.

Results

Numerous multinucleated, TRAP+, dentin‐resorbing osteoclasts developed spontaneously from fresh PBMCs from healthy individuals. This process was abrogated by T cell depletion and was restored by exogenous macrophage colony‐stimulating factor (M‐CSF) and RANKL, indicating the important role of T cells in spontaneous osteoclastogenesis in vitro. Using physiologic freezing and thawing as a model for the activation of PBMCs, spontaneous osteoclastogenesis was significantly increased in cryopreserved versus fresh cells. Under these conditions, spontaneous osteoclastogenesis was not dependent on T lymphocytes, since it was not influenced by T cell depletion and persisted in purified CD14+ cell cultures supplemented with M‐CSF and RANKL. In contrast to studies with fresh PBMCs, spontaneous osteoclastogenesis under these conditions did not appear to be clearly different between healthy subjects and patients with arthritis.

Conclusion

Spontaneous osteoclastogenesis in vitro is dependent on T lymphocytes or on the direct activation of monocytic cells, depending on the test conditions. This variability warrants better validation of the relevance of this functional test for in vivo osteoclastogenesis.
Measuring finger joint cartilage by ultrasound as a promising alternative to conventional radiograph imaging
Authors: Möller Burkhard , Bonel Harald , Rotzetter Marianne , Villiger Peter M. , Ziswiler Hans‐rudolf
Published: March 2009

Objective

To evaluate the reliability and validity of a novel ultrasound (US) imaging method to measure metacarpophalangeal (MCP) and proximal interphalangeal (PIP) finger joint cartilage.

Methods

We examined 48 patients with rheumatoid arthritis (RA), 18 patients with osteoarthritis (OA), 24 patients with unclassified arthritis of the finger joints, and 34 healthy volunteers. The proximal cartilage layer of MCP and PIP joints for fingers 2–5 was bilaterally visualized from a posterior view, with joints in ∼90° flexion. Cartilage thickness was measured with integrated tools on static images. External validity was assessed by measuring radiologic joint space width (JSW) and a numeric joint space narrowing (JSN) score in patients with RA.

Results

Precise measurement was possible for 97.5% of MCP and 94.2% of PIP joints. Intraclass correlation coefficients for bilateral total joint US scores were 0.844 (95% confidence interval [95% CI] 0.648–0.935) for interobserver comparisons and 0.928 (95% CI 0.826–0.971) for intraobserver comparisons (using different US devices). The US score correlated with JSN for both hands (adjusted R2 = 0.513, P < 0.001) and JSW of the same finger joints (adjusted R2 = 0.635, P < 0.001). Reduced cartilage shown by US allowed discrimination of early symptomatic OA versus early RA and healthy joints. In patients with RA, US scores correlated with duration of treatment‐resistant, progressive RA.

Conclusion

The US method of direct visualization and quantification of cartilage in MCP and PIP joints is objective, reliable, valid, and can be useful for diagnostic purposes in patients with arthritis.
Amphoteric liposomes enable systemic antigen‐presenting cell–directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis
Authors: Andreakos Evangelos , Rauchhaus Una , Stavropoulos Athanassios , Endert Gerold , Wendisch Volkmar , Benahmed Amina S. , Giaglis Stavros , Karras James , Lee Sam , Gaus Hans , Bennett C. Frank , Williams Richard O. , Sideras Paschalis , Panzner Steffen
Published: March 2009

Objective

Mediation of RNA interference by oligonucleotides constitutes a powerful approach for the silencing of genes involved in the pathogenesis of inflammatory disease, but in vivo application of this technique requires effective delivery to immune cells and/or sites of inflammation. The aim of the present study was to develop a new carrier system to mediate systemic administration of oligonucleotides to rheumatoid arthritis (RA) joints, and to develop an antisense oligonucleotide (ASO)–based approach to interfere with CD40–CD154 interactions in an experimental model of RA.

Methods

A novel liposomal carrier with amphoteric properties, termed Nov038, was developed and assessed for its ability to systemically deliver an ASO directed against CD40 (CD40‐ASO). Male DBA/1 mice with collagen‐induced arthritis were treated with Nov038‐encapsulated CD40‐ASO, and the effects of treatment on various parameters of disease activity, including clinical score, paw swelling, lymph node responses, and inflammatory cytokine production in the joints, were assessed.

Results

Nov038 was well tolerated, devoid of immune‐stimulatory effects, and efficacious in mediating systemic oligonucleotide delivery to sites of inflammation. In mice with collagen‐induced arthritis, Nov038 enabled the therapeutic administration of CD40‐ASO and improved established disease, while unassisted CD40‐ASO was ineffective, and anti–tumor necrosis factor α (anti‐TNFα) treatment was less effective in this model. Nov038/CD40‐ASO efficacy was attributed to its tropism for monocyte/macrophages and myeloid dendritic cells (DCs), resulting in rapid down‐regulation of CD40, inhibition of DC antigen presentation, and reduction in collagen‐specific T cell responses, as well as decreased levels of TNFα, interleukin‐6 (IL‐6), and IL‐17 in arthritic joints.

Conclusion

Amphoteric liposomes represent a novel carrier concept for systemic and antigen‐presenting cell–targeted oligonucleotide delivery with clinical applicability and numerous potential applications, including target validation in vivo and inflammatory disease therapeutics. Moreover, Nov038/CD40‐ASO constitutes a potent alternative to monoclonal antibody–based approaches for interfering with CD40–CD40L interactions.
On the estimation of the heavy‐tail exponent in time series using the max‐spectrum
Authors: Stoev Stilian A. , Michailidis George
Published: March 2009

This paper addresses the problem of estimating the tail index α of distributions with heavy, Pareto‐type tails for dependent data, that is of interest in the areas of finance, insurance, environmental monitoring and teletraffic analysis. A novel approach based on the max self‐similarity scaling behavior of block maxima is introduced. The method exploits the increasing lack of dependence of maxima over large size blocks, which proves useful for time series data.

We establish the consistency and asymptotic normality of the proposed max‐spectrum estimator for a large class ofm‐dependent time series, in the regime of intermediate block‐maxima. In the regime of large block‐maxima, we demonstrate the distributional consistency of the estimator for a broad range of time series models including linear processes. The max‐spectrum estimator is a robust and computationally efficient tool, which provides a novel time‐scale perspective to the estimation of the tail exponents. Its performance is illustrated over synthetic and real data sets. Copyright © 2009 John Wiley & Sons, Ltd.
Falling and explosive, dormant, and rising markets via multiple‐regime financial time series models
Authors: Chen Cathy W. S. , Gerlach Richard H. , Lin Ann M. H.
Published: March 2009

A multiple‐regime threshold nonlinear financial time series model, with a fat‐tailed error distribution, is discussed and Bayesian estimation and inference are considered. Furthermore, approximate Bayesian posterior model comparison among competing models with different numbers of regimes is considered which is effectively a test for the number of required regimes. An adaptive Markov chain Monte Carlo (MCMC) sampling scheme is designed, while importance sampling is employed to estimate Bayesian residuals for model diagnostic testing. Our modeling framework provides a parsimonious representation of well‐known stylized features of financial time series and facilitates statistical inference in the presence of high or explosive persistence and dynamic conditional volatility. We focus on the three‐regime case where the main feature of the model is to capturing of mean and volatility asymmetries in financial markets, while allowing an explosive volatility regime. A simulation study highlights the properties of our MCMC estimators and the accuracy and favourable performance as a model selection tool, compared with a deviance criterion, of the posterior model probability approximation method. An empirical study of eight international oil and gas markets provides strong support for the three‐regime model over its competitors, in most markets, in terms of model posterior probability and in showing three distinct regime behaviours: falling/explosive, dormant and rising markets. Copyright © 2009 John Wiley & Sons, Ltd.
Teaching local area networking in a secure virtual environment
Authors: Steffen G. D. , Abu‐Mulaweh H. I.
Published: March 2009

Space, cost, and security are major concerns associated with the local area network teaching/learning process. Teaching even the most basic networking techniques requires a minimum of two computers per student with additional systems for more involved experiments. The overhead and space requirements become quite staggering for large class sizes. The students, just learning and unaware, can furthermore be susceptible to outside intrusion or cause accidental adverse affects upon the network to which they attach. Teaching local area networking in a virtual environment can reduce space, cost, and security concerns. This article addresses the setup of a virtual environment, managing multiple student environments, properly securing virtual machines, and laboratory experiments in virtual environments. © 2009 Wiley Periodicals, Inc. Comput Appl Eng Educ 18: 547–554, 2010; View this article online at wileyonlinelibrary.com; DOI 10.1002/cae.20228
Computer‐aided tool for teaching mechanical clutch systems design
Authors: Muñoz‐Abella B. , Álvarez‐Caldas C. , Rubio L.
Published: March 2009

This paper describes an educational computer application—MecClutch—focused on teaching the design process of mechanical clutches and their operational conditions to Mechanical Engineering students. The software is divided into three sections: (1) multimedia files, pictures, and videos, produced in order to teach the working of the mechanism, (2) theoretical information related to mechanical clutches, and (3) interactive problems that allow to design a mechanical clutch and test changes in operational conditions when varying the value of critical design parameters. This software has become a very useful tool for undergraduate Mechanical Engineering students in compliment to theoretical classes or alone, as a self‐study tool. © 2009 Wiley Periodicals, Inc. Comput Appl Eng Educ 19: 493–500, 2011
Investigation of the Ion Storage/Transfer Behavior in an Electrical Double‐Layer Capacitor by Using Ordered Microporous Carbons as Model Materials
Authors: Nishihara Hirotomo , Itoi Hiroyuki , Kogure Taichi , Hou Peng‐Xiang , Touhara Hidekazu , Okino Fujio , Kyotani Takashi
Published: March 2009

Ordered microporous carbon: The mechanism of an electrical double‐layer capacitor containing zeolite‐templated carbons as model microporous materials was investigated in detail (see figure). Its three‐dimensionally ordered and connected micropores were found to greatly reduce ion‐transfer resistance and, therefore, exhibited a high rate performance.

magnified image

An ordered microporous carbon, which was prepared with zeolite as a template, was used as a model material to understand the ion storage/transfer behavior in electrical double‐layer capacitor (EDLC). Several types of such zeolite‐templated carbons (ZTCs) with different structures (framework regularity, particle size and pore diameter) were prepared and their EDLC performances were evaluated in an organic electrolyte solution (1 M Et4NBF4/propylene carbonate). Moreover, a simple method to evaluate a degree of wettability of microporous carbon with propylene carbonate was developed. It was found that the capacitance was almost proportional to the surface area and this linearity was retained even for the carbons with very high surface areas (>2000 m2 g−1). It has often been pointed out that thin pore walls limit capacitance and this usually gives rise to the deviation from linearity, but such a limitation was not observed in ZTCs, despite their very thin pore walls (a single graphene, ca. 0.34 nm). The present study clearly indicates that three‐dimensionally connected and regularly arranged micropores were very effective at reducing ion‐transfer resistance. Despite relatively small pore diameter ZTCs (ca. 1.2 nm), their power density remained almost unchanged even though the particle size was increased up to several microns. However, when the pore diameter became smaller than 1.2 nm, the power density was decreased due to the difficulty of smooth ion‐transfer in such small micropores.
Semiparametric inference for survival models with step process covariates
Authors: Hanson Timothy , Johnson Wesley , Laud Purushottam
Published: March 2009

The authors consider Bayesian methods for fitting three semiparametric survival models, incorporating time‐dependent covariates that are step functions. In particular, these are models due to Cox [Cox (1972)Journal of the Royal Statistical Society, Series B, 34, 187–208], Prentice & Kalbfleisch and Cox & Oakes [Cox & Oakes (1984)Analysis of Survival Data, Chapman and Hall, London]. The model due to Prentice & Kalbfleisch [Prentice & Kalbfleisch (1979)Biometrics, 35, 25–39], which has seen very limited use, is given particular consideration. The prior for the baseline distribution in each model is taken to be a mixture of Polya trees and posterior inference is obtained through standard Markov chain Monte Carlo methods. They demonstrate the implementation and comparison of these three models on the celebrated Stanford heart transplant data and the study of the timing of cerebral edema diagnosis during emergency room treatment of diabetic ketoacidosis in children. An important feature of their overall discussion is the comparison of semi‐parametric families, and ultimate criterion based selection of a family within the context of a given data set. The Canadian Journal of Statistics 37: 60–79; © 2009 Statistical Society of Canada
Log‐rank permutation tests for trend: saddlepointp‐values and survival rate confidence intervals
Authors: Abd‐Elfattah Ehab F. , Butler Ronald W.
Published: March 2009

Supposep + 1 experimental groups correspond to increasing dose levels of a treatment and all groups are subject to right censoring. In such instances, permutation tests for trend can be performed based on statistics derived from the weighted log‐rank class. This article uses saddlepoint methods to determine the mid‐P‐values for such permutation tests for any test statistic in the weighted log‐rank class. Permutation simulations are replaced by analytical saddlepoint computations which provide extremely accurate mid‐P‐values that are exact for most practical purposes and almost always more accurate than normal approximations. The speed of mid‐P‐value computation allows for the inversion of such tests to determine confidence intervals for the percentage increase in mean (or median) survival time per unit increase in dosage. The Canadian Journal of Statistics 37: 5‐16; 2009 © 2009 Statistical Society of Canada
Discrete‐time survival trees
Authors: Bou‐hamad Imad , Larocque Denis , Ben‐Ameur Hatem , Mâsse Louise C. , Vitaro Frank , Tremblay Richard E.
Published: March 2009

Tree‐based methods are frequently used in studies with censored survival time. Their structure and ease of interpretability make them useful to identify prognostic factors and to predict conditional survival probabilities given an individual's covariates. The existing methods are tailor‐made to deal with a survival time variable that is measured continuously. However, survival variables measured on a discrete scale are often encountered in practice. The authors propose a new tree construction method specifically adapted to such discrete‐time survival variables. The splitting procedure can be seen as an extension, to the case of right‐censored data, of the entropy criterion for a categorical outcome. The selection of the final tree is made through a pruning algorithm combined with a bootstrap correction. The authors also present a simple way of potentially improving the predictive performance of a single tree through bagging. A simulation study shows that single trees and bagged‐trees perform well compared to a parametric model. A real data example investigating the usefulness of personality dimensions in predicting early onset of cigarette smoking is presented. The Canadian Journal of Statistics 37: 17‐32; 2009 © 2009 Statistical Society of Canada
Tulp3 is a critical repressor of mouse hedgehog signaling
Authors: Cameron Don A. , Pennimpede Tracie , Petkovich Martin
Published: March 2009

Precise regulation of the morphogen sonic hedgehog (Shh) and modulation of the Shh signaling pathway is required for proper specification of cell fate within the developing limbs and neural tube, and resultant tissue morphogenesis. Tulp3 (tubby‐like protein 3) is a protein of unknown function which has been implicated in nervous system development through gene knockout studies. We demonstrate here that mice lacking the Tulp3 gene develop abnormalities of both the neural tube and limbs consistent with improper regulation of Shh signaling. Tulp3−/− embryos show expansion of Shh target gene expression and display a ventralization of neural progenitor cells in the caudal neural tube. We further show that Tulp3−/−/Shh−/− compound mutant embryos resemble Tulp3 mutants, and express Shh target genes in the neural tube and limbs which are not expressed in Shh−/− embryos. This work uncovers a novel role for Tulp3 as a negative regulatory factor in the Hh pathway. Developmental Dynamics 238:1140–1149, 2009. © 2009 Wiley‐Liss, Inc.
IFN‐γ‐STAT1 signal regulates the differentiation of inducible Treg: Potential role for ROS‐mediated apoptosis
Authors: Chang Jae‐Hoon , Kim Yeon‐Jeong , Han Seung‐Hee , Kang Chang‐Yuil
Published: March 2009

Regulatory CD4+ T cells are important for the homeostasis of immune cells, and their absence correlates with autoimmune disorders. However, how the immune system regulates Treg homeostasis remains unclear. We found that IFN‐γ‐deficient‐mice had more forkhead box P3 (FOXP3+) cells than WT mice in all secondary lymphoid organs except the thymus. However, T‐bet‐ or IL‐4Rα‐deficient mice did not show a similar increase. In vitro differentiation studies showed that conversion of naïve T cells into FOXP3+ cells (neo‐generated inducible Treg (iTreg)) by TGF‐β was significantly inhibited by IFN‐γ in a STAT‐1‐dependent manner. Moreover, an in vivo adoptive transfer study showed that inhibition of FOXP3+ iTreg generation by IFN‐γ was a T‐cell autocrine effect. This inhibitory effect of IFN‐γ on iTreg generation was significantly abrogated after N‐acetyl‐L‐cysteine treatment both in vitro and in vivo, indicating that IFN‐γ regulation of iTreg generation is dependent on ROS‐mediated apoptosis. Therefore, our results suggest that autocrine IFN‐γ can negatively regulate the neo‐generation of FOXP3+ iTreg through ROS‐mediated apoptosis in the periphery.
Synthesis, Characterization, and Catalytic Application of Aluminum Anilido‐Oxazolinate Complexes
Authors: Chen Chi‐Tien , Weng Han‐Jade , Chen Ming‐Tsz , Huang Chi‐An , Peng Kuo‐Fu
Published: March 2009

A family of aluminum complexes containing anilido‐oxazolinate ligands are described. Reactions of five anilido‐oxazolinate ligand precursors, HNPhTriMeOxa, HNPhDiiPrOxa, HNPhOMeOxa, HNPhSMeOxa, or HNPhOxa, with 1 molar equiv. of AlMe3 in toluene give the aluminum dimethyl complexes (NArOxa)AlMe2 [Ar = 2,4,6‐trimethylphenyl, (NPhTriMeOxa)AlMe2 (1); Ar = 2,6‐diisopropylphenyl, (NPhDiiPrOxa)AlMe2 (2); Ar = 2‐methoxyphenyl, (NPhOMeOxa)AlMe2 (3); Ar = 2‐methylthiophenyl, (NPhSMeOxa)AlMe2 (4); Ar = phenyl, (NPhOxa)AlMe2 (5), respectively]. The molecular structures are reported for compounds 1–4. Their catalytic activities toward the ring‐opening polymerization reactions of L‐lactide or ϵ‐caprolactone in the presence of BnOH are also under investigation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Reactivity of C,N‐Chelated Stannylene with Azobenzene
Authors: Padělková Zdeňka , Nechaev Mikhail S. , Lyčka Antonín , Holubová Jana , Zevaco Thomas A. , Růžička Aleš
Published: March 2009

The reactivity of a C,N‐chelated stannylene L2Sn [L = 2‐(Me2NCH2)C6H4] with azobenzene yielded two different products. In the case of reaction in diethyl ether at room temperature, the cyclic complex L2Sn–N(Ph)–N(Ph)–SnL2 was isolated. The second compound, isolated from the reaction in boiling THF, is the product of C–H activation and ortho‐metallation of azobenzene, the cyclic [2‐(SnL2)‐C6H4]–N–N–[C6H4‐2‐(SnL2)]. Byproducts in the second reaction are the free ligand (LH) and the cyclic complex L2Sn–(L)Sn–Sn(L)2–O(H). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Recent advances in the conversion of bioglycerol into value‐added products
Authors: Pagliaro Mario , Ciriminna Rosaria , Kimura Hiroshi , Rossi Michele , Della Pina Cristina
Published: March 2009

A versatile platform chemical and energy vector, bioglycerol from biodiesel manufacturing is increasingly finding new commercial applications. We report on some of the main achievements for converting glycerol into high‐value products and energy developed in the last two years, and conclude by providing an outlook on the evolving status of bioglycerol in the chemical industry.
Moisture barrier and physical properties of acetylated derivatives with increasing acetylation degree
Authors: Bourlieu Claire , Ferreira Mariana , Barea Bruno , Guillard Valérie , Villeneuve Pierre , Guilbert Stéphane , Gontard Nathalie
Published: March 2009

Four acetostearin products with increasing acetylation degree were synthesized by chemical interesterification followed by fractionation/blending stages. Their physical properties and functional barrier properties were studied and compared to the properties of technical tristearin. Increasing acetylation degree (AD) modified the triacylglycerols crystal habits and probably led to an increase in acyl chain fluidity, which induced, at macroscopic levels, a decrease in solid fat content (SFC), in melting point, in surface and bulk material hydrophobicity, and an increased moisture effective diffusivity. Water vapor permeability (WVP) coefficients of the materials were partially influenced by the AD factor, but also by the development of macroscopic cracks in lipids presenting high SFC. Acetylated stearin up to 47% (acetyl mol/mol of esterified chain) presented the lowest WVP at 20 °C resulting from an adequate balance between hydrophobicity and mechanical properties of the material.
NMR study of the lipid profile of mullet raw roe and bottarga
Authors: Scano Paola , Rosa Antonella , Locci Emanuela , Dessi M. Assunta , Lai Adolfo
Published: March 2009

Samples of mullet (Mugil cephalus) roes from two different fishing areas were studied by means of 1H, 13C and 31P NMR and GC techniques. The lipid fraction of unprocessed roes and that of the corresponding salted and dried commercial products “bottarga” were analyzed and the data compared. Roes of mullets from different origin showed different composition regarding mainly triacylglycerols, monounsaturated and n‐3 polyunsaturated fatty acids. The NMR spectra of processed roes, compared to those of the corresponding raw materials, showed a release of free fatty acids and the formation of other minor molecular components, such as free fatty alcohols, lysophospholipids, and diacylglycerols, thus indicating that hydrolytic processes were the main consequence of manufacturing. An increase of cholesterol ester concentration after processing was also detected. Through the analysis of the 31P NMR spectra, it was possible to follow the fate of the phospholipids and the formation of lysophospholipids induced by the salting and drying procedures.