bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel drug‐based Fe(III) heterochelates: synthetic, spectroscopic, thermal and in‐vitro antibacterial significance
Authors: Jani D.H. , Patel H.S. , Keharia H. , Modi C.K.
Published: November 2009

A series of novel heterochelates of the type [Fe(An)(L)(H2O)2]•mH2O [where H2An = 4,4′‐(arylmethylene)bis(3‐methyl‐1‐phenyl‐4,5‐dihydro‐1H‐pyrazol‐5‐ol); aryl = 4‐nitrophenyl, m = 1 (H2A1); 4‐chlorophenyl, m = 2 (H2A2); phenyl, m = 2 (H2A3); 4‐hydroxyphenyl, m = 2 (H2A4); 4‐methoxyphenyl, m = 2 (H2A5); 4‐hydroxy‐3‐methoxyphenyl, m = 1.5 (H2A6); 2‐nitrophenyl, m = 1.5 (H2A7); 3‐nitrophenyl, m = 0.5 (H2A8); p‐tolyl, m = 1 (H2A9) and HL = 1‐cyclopropyl‐6‐fluoro‐4‐oxo‐7‐(piperazin‐1‐yl)‐1,4‐dihydroquinoline‐3‐carboxylic acid] were investigated. They were characterized by elemental analysis (FT‐IR, 1H‐ & 13C‐NMR, and electronic) spectra, magnetic measurements and thermal studies. The FAB‐mass spectrum of [Fe(A3)(L)(H2O)2]•2H2O was determined. Magnetic moment and reflectance spectral studies revealed that an octahedral geometry could be assigned to all the prepared heterochelates. Ligands (H2An) and their heterochelates were screened for their in‐vitro antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Serratia marcescens bacterial strains. The kinetic parameters such as order of reaction (n), the energy of activation (Ea), the pre‐exponential factor (A), the activation entropy (ΔS#), the activation enthalpy (ΔH#) and the free energy of activation (ΔG#) are reported. Copyright © 2009 John Wiley & Sons, Ltd.
Modeling the need for hip and knee replacement surgery. Part 2. Incorporating census data to provide small‐area predictions for need with uncertainty bounds
Authors: Judge Andy , Welton Nicky J. , Sandhu Jat , Ben‐Shlomo Yoav
Published: November 2009

Objective

To develop methods to produce small‐area estimates of need for hip and knee replacement surgery to inform local health service planning.

Methods

Multilevel Poisson regression modeling was used to estimate rates of need for hip/knee replacement by age, sex, deprivation, rurality, and ethnic mix using a nationally representative population‐based survey (the English Longitudinal Study of Ageing, n = 11,392 people age ≥50 years). Estimates of need from the regression model were then combined with stratified census population counts to produce small‐area predictions of need. Uncertainty in the predictions was obtained by taking a Bayesian simulation‐based approach using WinBUGS software. This allows correlations in parameter estimates to be appropriately incorporated in the credible intervals for the small‐area predictions.

Results

Small‐area estimates of need for hip/knee replacement have been produced for wards and districts in England. Rates of need are adjusted for the sociodemographic characteristics of an area and include 95% credible intervals. Need for hip/knee replacement varies geographically, dependant on the sociodemographic characteristics of an area.

Conclusion

For the first time, small‐area estimates of need for hip/knee replacement surgery have been produced together with estimates of uncertainty to inform local health planning. The methodologic approach described here could be reproduced in other countries and for other disease indicators. Further research is required to combine small‐area estimates of need with provision to determine whether there is equitable access to care.
The New York City Rheumatology Objective Structured Clinical Examination: Five‐year data demonstrates its validity, usefulness as a unique rating tool, objectivity, and sensitivity to change
Authors: Berman Jessica R. , Lazaro Deana , Fields Theodore , Bass Anne R. , Weinstein Elena , Putterman Chaim , Dwyer Edward , Krasnokutsky Svetlana , Paget Stephen A. , Pillinger Michael H.
Published: November 2009

Objective

Traditional means of testing rheumatology fellows do not adequately assess some skills that are required to practice medicine well, such as humanistic qualities, communication skills, or professionalism. Institution of the New York City Rheumatology Objective Structured Clinical Examination (ROSCE) and our sequential 5 years of experience have provided us with a unique opportunity to assess its usefulness and objectivity as a rheumatology assessment tool.

Methods

Prior to taking the examination, all of the fellows were rated by their program directors. Fellows from the participating institutions then underwent a multistation patient‐interactive examination observed and rated by patient actors and faculty raters. Assessments were recorded by all of the participants using separate but overlapping sets of instruments testing the Accreditation Council of Graduate Medical Education (ACGME) core competencies of patient care, interpersonal and communication skills, professionalism, and overall medical knowledge.

Results

Although the program directors tended to rate their fellows more highly than the ROSCE raters, typically there was agreement between the program directors and the ROSCE faculty in distinguishing between the highest‐ and lowest‐ performing fellows. The ROSCE faculty and patient actor assessments of individual trainees were notable for a high degree of concordance, both quantitatively and qualitatively.

Conclusion

The ROSCE provides a unique opportunity to obtain a patient‐centered assessment of fellows' ACGME‐mandated competencies that traditional knowledge‐based examinations, such as the rheumatology in‐service examination, cannot measure. The ability of the ROSCE to provide a well‐rounded and objective assessment suggests that it should be considered an important component of the rheumatology training director's toolbox.
A patient's perspective on multidisciplinary treatment gain for fibromyalgia: An indicator for pre‐post treatment effects?
Authors: van Koulil Saskia , Kraaimaat Floris W. , van Lankveld Wim , van Riel Piet L. C. M. , Evers Andrea W. M.
Published: November 2009

Objective

Increasing attention is devoted to the patient's perspective in clinical research and practice. However, the relationship between the patient's view on treatment progress and standardized pre‐post changes in health outcomes is not well understood. The objective of this study was to investigate whether the patient's perception of treatment gain converges with pre‐post treatment effects of a multidisciplinary treatment as assessed by standardized self‐report measures.

Methods

During a tailored multidisciplinary treatment for fibromyalgia, validated self‐report questionnaires were assessed at baseline and posttreatment on the outcome measures of pain, functional disability, fatigue, anxiety, and negative mood. In addition, the participants were asked to fill in a questionnaire at the end of the treatment assessing the patient's perception of improvement on core outcomes, as well as satisfaction and usefulness of the treatment.

Results

Moderate to relatively high correlations were found between the patient's perception of improvement and pre‐post changes on the physical outcomes, in contrast to small or nonsignificant correlations for psychological outcomes. In addition, satisfaction and usefulness were significantly related to pre‐post changes on physical outcomes, but no relationship was found with respect to psychological outcomes.

Conclusion

Results suggest that the patient's perception of treatment gain and pre‐post changes in outcomes during treatment assess different aspects of the patient's treatment progress, particularly with regard to psychological functioning. Future research on clinical improvements should consider the patient's perception of treatment gain as an independent and clinically relevant outcome, in addition to standardized trial data of pre‐post assessments of health outcomes.
A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first‐degree relatives of probands with RA
Authors: Kolfenbach Jason R. , Deane Kevin D. , Derber Lezlie A. , O'Donnell Colin , Weisman Michael H. , Buckner Jane H. , Gersuk Vivian H. , Wei Shan , Mikuls Ted R. , O'Dell James , Gregersen Peter K. , Keating Richard M. , Norris Jill M. , Holers V. Michael
Published: November 2009

Objective

To describe a large, multicenter prospective cohort study of first‐degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the use of such a study in investigating the natural history of RA development.

Methods

A total of 1,058 FDRs, none of whom met the American College of Rheumatology criteria for RA, were enrolled in a prospective study investigating genetic and environmental influences on the development of RA‐related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit were described for these FDRs, and the relationship was examined between genetic factors, autoantibodies, inflammation, and joint disease.

Results

Fifty‐five percent of the FDRs had ≥1 copy of the shared epitope, 20% had ≥1 copy of the PTPN22 polymorphism, and ∼16% were positive for rheumatoid factor (RF; including isotypes) and/or anti–cyclic citrullinated peptide antibody. IgM‐RF positivity is associated with ≥1 tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% CI] 1.27–4.89; P < 0.01) and elevated C‐reactive protein (CRP) levels (OR 5.31, 95% CI 1.45–19.52; P = 0.01).

Conclusion

FDRs without RA demonstrate high prevalences of genetic risk factors and RA‐related autoantibodies. Additionally, an RF association with tender joints and elevated CRP levels suggests that autoantibodies are a valid intermediate marker of RA‐related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic and epidemiologic factors and the development of RA‐related autoimmunity.
Identification of undiagnosed inflammatory arthritis in a community health fair screen
Authors: Deane Kevin D. , Striebich Christopher C. , Goldstein Barbara L. , Derber Lezlie A. , Parish Mark C. , Feser Marie L. , Hamburger Elaine M. , Brake Stacey , Belz Cindy , Goddard James , Norris Jill M. , Karlson Elizabeth W. , Holers V. Michael
Published: November 2009

Objective

To identify individuals with undiagnosed inflammatory arthritis (IA) and rheumatoid arthritis (RA) in a community health fair screen, and to establish in a health fair setting the diagnostic accuracy of combinations of the Connective Tissue Disease Screening Questionnaire (CSQ) and autoantibody testing for IA.

Methods

Screening for IA/RA was performed at health fair sites using a combination of the CSQ, joint examination, rheumatoid factor, and anti–cyclic citrullinated peptide (anti‐CCP) antibody testing. IA was defined as ≥1 swollen joint suggestive of synovitis on joint examination by a trained clinician.

Results

Six hundred one subjects were screened; 51.0% participated because of joint symptoms (pain, stiffness, or swelling). Eighty‐four subjects (14.0%) had ≥1 swollen joint, designated as IA on joint examination. Of the 601 subjects screened, 9 (1.5%) had IA and met ≥4 of 7 American College of Rheumatology criteria for RA but had no prior diagnosis of RA, and 15 (2.5%) had IA and RF and/or anti‐CCP positivity, suggesting early RA. The diagnostic accuracy of combinations of the CSQ and autoantibody testing for the identification of IA yielded maximal sensitivity, specificity, and positive and negative predictive values of 95.3%, 99.2%, 71.4%, and 97.7%, respectively.

Conclusion

Health fair screening may be an effective approach for the identification of individuals with undiagnosed IA/RA. A combination of the CSQ and autoantibody testing alone has clinically useful diagnostic accuracy for the detection of IA. Decisions regarding which methodology to use for future health fair IA/RA screening will depend on goals of screening and funding.
The importance of allocation concealment and patient blinding in osteoarthritis trials: A meta‐epidemiologic study
Authors: Nüesch Eveline , Reichenbach Stephan , Trelle Sven , Rutjes Anne W. S. , Liewald Katharina , Sterchi Rebekka , Altman Douglas G. , Jüni Peter
Published: November 2009

Objective

To evaluate the association of adequate allocation concealment and patient blinding with estimates of treatment benefits in osteoarthritis trials.

Methods

We performed a meta‐epidemiologic study of 16 meta‐analyses with 175 trials that compared therapeutic interventions with placebo or nonintervention control in patients with hip or knee osteoarthritis. We calculated effect sizes from the differences in means of pain intensity between groups at the end of followup divided by the pooled SD and compared effect sizes between trials with and trials without adequate methodology.

Results

Effect sizes tended to be less beneficial in 46 trials with adequate allocation concealment compared with 112 trials with inadequate or unclear concealment of allocation (difference −0.15; 95% confidence interval [95% CI] −0.31, 0.02). Selection bias associated with inadequate or unclear concealment of allocation was most pronounced in meta‐analyses with large estimated treatment benefits (P for interaction < 0.001), meta‐analyses with high between‐trial heterogeneity (P = 0.009), and meta‐analyses of complementary medicine (P = 0.019). Effect sizes tended to be less beneficial in 64 trials with adequate blinding of patients compared with 58 trials without (difference −0.15; 95% CI −0.39, 0.09), but differences were less consistent and disappeared after accounting for allocation concealment. Detection bias associated with a lack of adequate patient blinding was most pronounced for nonpharmacologic interventions (P for interaction < 0.001).

Conclusion

Results of osteoarthritis trials may be affected by selection and detection bias. Adequate concealment of allocation and attempts to blind patients will minimize these biases.
Ambulatory visit utilization in a national, population‐based sample of adults with osteoarthritis
Authors: Cisternas Miriam G. , Yelin Edward , Katz Jeffrey N. , Solomon Daniel H. , Wright Elizabeth A. , Losina Elena
Published: November 2009

Objective

To estimate the proportion of adults with osteoarthritis (OA) seeing various medical providers and ascertain factors affecting the likelihood of a patient seeing an OA specialist.

Methods

We used data from the Medical Expenditures Panel Survey, a stratified random sample of the noninstitutionalized civilian population. We classified adults as having symptomatic OA if their medical conditions included at least 1 occurrence of the International Classification of Diseases, Ninth Revision Clinical Modification, codes 715, 716, or 719, and if they reported joint pain, swelling, or stiffness during the previous 12 months. For the purpose of our analysis, we defined rheumatologists, orthopedists, and physical therapists as OA specialists. We first estimated the proportion of OA individuals seen by OA specialists and other health care providers in a 1‐year period. We then used logistic regression to estimate the impact of demographic and clinical factors on the likelihood of an individual seeing an OA specialist.

Results

A total of 9,933 persons met the definition of OA, representing 22.5 million adults in the US. Of these persons, 92% see physicians during the year, 34% see at least 1 OA specialist, 25% see an orthopedist, 11% see a physical therapist, and 6% see a rheumatologist. Higher educational attainment, having more comorbidities, and residing in the northeastern US are significant positive predictors for a patient seeing an OA specialist. Significant negative predictors for seeing an OA specialist are being unmarried but previously married and having no health insurance.

Conclusion

Most adults with OA do not visit OA specialists. Those without insurance and with lower levels of education are less likely to see these specialists.
Understanding the lack of understanding: Invalidation from the perspective of the patient with fibromyalgia
Authors: Kool Marianne B. , van Middendorp Henriët , Boeije Hennie R. , Geenen Rinie
Published: November 2009

Objective

Patients with fibromyalgia have difficulty with the invisibility and medically unexplained character of the syndrome. Disbelief, lack of acceptance, and stigmatization by their spouse, family, colleagues, the health care system, and society are key issues in their lives. Nevertheless, the components of this phenomenon that we term “invalidation” are not clear. The aim of our study was to identify the definition and structure of invalidation as perceived by patients with fibromyalgia.

Methods

A hierarchical cluster analysis was applied to examine everyday invalidation experiences of patients with fibromyalgia. Ninety‐four statements about invalidation that were derived from interviews and a card‐sorting (Q‐sort) technique provided the input for this cluster analysis.

Results

The hierarchical structure of invalidation showed a higher‐order distinction between statements reflecting “discounting” and “understanding.” Discounting was subdivided into the components “denying” and “patronizing” (consisting of “lecturing” and “overprotecting”). Understanding was subdivided into “supporting” and “acknowledging.” These higher‐order constructs were further subdivided into 15 lower‐order clusters that reflected cognitive, affective, and behavioral aspects of invalidation.

Conclusion

Invalidation as perceived by patients with fibromyalgia includes active negative social responses (denying, lecturing, and overprotecting) as well as a lack of positive social responses (supporting and acknowledging) with respect to the patient and the condition of the patient. This definition of invalidation provides a basis to quantify invalidation and to study its impact on symptom severity, quality of life, therapy adherence, therapy outcome, and other important aspects of fibromyalgia.
Patient responsibility for medical decision making and risky treatment options
Authors: Fraenkel Liana , Peters Ellen
Published: November 2009

Objective

Studies have shown that increasing patient participation in decision making decreases utilization of risky procedures. It has been demonstrated that risk perception is increased under conditions that emphasize volition, or the act of choosing. The objective of this study was to examine whether emphasizing volition increases patients' risk perception and decreases their willingness to accept risk.

Methods

Consecutive patients attending outpatient clinic appointments viewed a video in which a physician described the availability of a new medication associated with a rare risk of a serious side effect. Patients' willingness to accept treatment and worry about the risk of the serious side effect were measured under 2 different conditions: one that minimized patient involvement and the one that maximized patient involvement in the decision‐making process.

Results

The willingness of the subject to take the proposed medication was lower (mean ± SD 4.2 ± 3.7 versus 5.3 ± 3.7; P < 0.001) and their worry about the risk of the adverse event was greater in the high compared with the low involvement condition (mean ± SD 6.1 ± 3.7 versus 5.5 ± 3.8; P < 0.001).

Conclusion

Increasing patient responsibility in medical decision making may decrease the patient's willingness to accept risky treatment options.
Caspase 1–independent activation of interleukin‐1β in neutrophil‐predominant inflammation
Authors: Guma Monica , Ronacher Lisa , Liu‐Bryan Ru , Takai Shinji , Karin Michael , Corr Maripat
Published: November 2009

Objective

Interleukin‐1β (IL‐1β) is a key cytokine linked to the pathogenesis of acute arthritis. Caspase 1, neutrophil elastase, and chymase all process proIL‐1β to its biologically active form. This study was undertaken to examine the potential contributions of each of these proteases in experimental models of inflammatory arthritis.

Methods

Caspase 1–deficient (Casp1−/−) and wild‐type (WT) mice were tested for their response to arthritogenic K/BxN serum transfer for induction of arthritis or injection of monosodium urate monohydrate (MSU) crystals for induction of peritonitis. All mice were prophylactically treated with inhibitors of neutrophil elastase or chymase. Arthritic paws were tested for the presence of IL‐1β protein by enzyme‐linked immunosorbent assay and Western blotting. Neutrophils and mast cells from WT and mutant mice were tested for their ability to secrete IL‐1β after in vitro stimulation, in the presence of protease inhibitors.

Results

Casp1−/− and WT mice developed paw swelling to the same extent in the K/BxN serum transfer–induced arthritis model. MSU crystal injection into Casp1−/− mice also resulted in neutrophil influx and production of measurable peritoneal IL‐1β protein. Both of these responses were attenuated with neutrophil elastase inhibitors. K/BxN serum transfer–induced arthritis was also reduced by treatment with a chymase inhibitor. Casp1−/− neutrophils and mast cells, when exposed to MSU crystals, secreted similar amounts of IL‐1β protein upon in vitro stimulation with lipopolysaccharide, albeit at lower levels than that secreted by WT cells. Elastase and chymase inhibitors reduced the amount of IL‐1β released by these cells.

Conclusion

The production of IL‐1β by neutrophils and mast cells is not exclusively dependent on caspase 1, and other proteases can compensate for the loss of caspase 1 in vivo. These pathways might therefore compromise the caspase 1–targeted therapies in neutrophil‐predominant arthritis.
The FAS −670A>G polymorphism influences susceptibility to systemic sclerosis phenotypes
Authors: Broen J. , Gourh P. , Rueda B. , Coenen M. , Mayes M. , Martin J. , Arnett F. C. , Radstake T. R. D. J.
Published: November 2009

Objective

To investigate the possible role of the FAS −670A>G functional polymorphism in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype.

Methods

A total of 2,900 SSc patients and 3,186 healthy controls were included in this study. We analyzed the genotype and allele frequencies of the FAS −670A>G polymorphism in 9 distinct ethnic cohorts, including 6 cohorts of European ancestry (a Spanish cohort of 228 SSc patients and 265 controls, a Dutch cohort of 203 SSc patients and 277 controls, a German cohort of 313 SSc patients and 247 controls, an Italian cohort of 323 SSc cases and 89 controls, a British cohort of 269 SSc patients, and a Swedish cohort of 182 patients) and 3 distinct ethnic cohorts from the US (a cohort of 1,047 white patients and 692 controls, a cohort of 159 Hispanic patients and 137 controls, and a cohort of 176 black SSc patients and 194 controls). Genotyping was performed using a TaqMan 5′ allelic discrimination assay.

Results

In the British, Italian, and American white cohorts we observed an association of the FAS −670G allele with limited cutaneous SSc (lcSSc) (odds ratios [ORs] 1.25, 1.43, and 1.18, respectively). A meta‐analysis comprising all 9 cohorts revealed an association of both the FAS −670G allele (OR 1.10) and the FAS −670GG genotype (OR 1.13) with the lcSSc phenotype. In a meta‐analysis including only white subjects, both the FAS −670G allele and the FAS −670GG genotype remained associated with lcSSc (allele OR 1.12; genotype OR 1.16). In addition, a recessive model of the −670GG genotype exhibited a strong association with SSc, lcSSc, and anticentromere antibody–positive lcSSc (OR 1.23, OR 1.33, and OR 1.45, respectively).

Conclusion

Our data show that the FAS −670A>G polymorphism plays a role in lcSSc susceptibility. A similar trend has been observed in other autoimmune diseases.
Increased tibiofemoral cartilage contact deformation in patients with anterior cruciate ligament deficiency
Authors: Van de Velde Samuel K. , Bingham Jeffrey T. , Hosseini Ali , Kozanek Michal , DeFrate Louis E. , Gill Thomas J. , Li Guoan
Published: November 2009

Objective

To investigate the in vivo cartilage contact biomechanics of the tibiofemoral joint following anterior cruciate ligament (ACL) injury.

Methods

Eight patients with an isolated ACL injury in 1 knee, with the contralateral side intact, participated in the study. Both knees were imaged using a specific magnetic resonance sequence to create 3‐dimensional models of knee bone and cartilage. Next, each patient performed a lunge motion from 0° to 90° of flexion as images were recorded with a dual fluoroscopic system. The three‐dimensional knee models and fluoroscopic images were used to reproduce the in vivo knee position at each flexion angle. With this series of knee models, the location of the tibiofemoral cartilage contact, size of the contact area, cartilage thickness at the contact area, and magnitude of the cartilage contact deformation were compared between intact and ACL‐deficient knees.

Results

Rupture of the ACL changed the cartilage contact biomechanics between 0° and 60° of flexion in the medial compartment of the knee. Compared with the contralateral knee, the location of peak cartilage contact deformation on the tibial plateaus was more posterior and lateral, the contact area was smaller, the average cartilage thickness at the tibial cartilage contact area was thinner, and the resultant magnitude of cartilage contact deformation was increased. Similar changes were observed in the lateral compartment, with increased cartilage contact deformation from 0° to 30° of knee flexion in the presence of ACL deficiency.

Conclusion

ACL deficiency alters the in vivo cartilage contact biomechanics by shifting the contact location to smaller regions of thinner cartilage and by increasing the magnitude of the cartilage contact deformation.
Expression of the dermatomyositis autoantigen Mi‐2 in regenerating muscle
Authors: Mammen Andrew L. , Casciola‐Rosen Livia A. , Hall John C. , Christopher‐Stine Lisa , Corse Andrea M. , Rosen Antony
Published: November 2009

Objective

Autoantibodies against the chromatin remodeler Mi‐2 are found in a distinct subset of patients with dermatomyositis (DM). Previous quantitative immunoblotting experiments demonstrated that Mi‐2 protein levels are up‐regulated in DM muscle. This study was undertaken to define the population of cells expressing high levels of Mi‐2 in DM muscle and to explore the regulation and functional role of Mi‐2 during muscle regeneration.

Methods

The expression of Mi‐2 was analyzed by immunofluorescence microscopy in human muscle biopsy specimens. In an experimental mouse model, cardiotoxin was used to induce muscle injury and repair, and expression of Mi‐2 during muscle regeneration was studied in this model by immunofluorescence and immunoblotting analyses. In addition, a cell culture system of muscle differentiation was utilized to artificially modulate Mi‐2 levels during proliferation and differentiation of myoblasts.

Results

In human DM muscle tissue, increased Mi‐2 expression was found preferentially in the myofibers within fascicles affected by perifascicular atrophy, particularly in the centralized nuclei of small perifascicular muscle fibers expressing markers of regeneration. In injured mouse muscle tissue, Mi‐2 levels were dramatically and persistently up‐regulated during muscle regeneration in vivo. Premature silencing of Mi‐2 with RNA interference in vitro resulted in accelerated myoblast differentiation.

Conclusion

Expression of Mi‐2 is markedly up‐regulated during muscle regeneration in a mouse model of muscle injury and repair. It is also up‐regulated in human DM myofibers expressing markers of regeneration. Results of the in vitro studies indicate that this protein may play a role in modulating the kinetics of myoblast differentiation. Our findings thus suggest that high levels of Mi‐2 expression in muscle biopsy tissue from patients with DM reflect the presence of incompletely differentiated muscle cells.
MLN3897 plus methotrexate in patients with rheumatoid arthritis: Safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double‐blind, placebo‐controlled, randomized, proof‐of‐concept study
Authors: Vergunst Clarissa E. , Gerlag Danielle M. , von Moltke Lisa , Karol Michael , Wyant Tim , Chi Xuedong , Matzkin Ellen , Leach Timothy , Tak Paul P.
Published: November 2009

Objective

To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX).

Methods

In this phase IIa, proof‐of‐concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for ≥6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1–83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897‐treated group compared with that in the placebo‐treated group.

Results

MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent‐to‐treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897‐treated patients and placebo‐treated patients (35% versus 33%, respectively;P= 0.72). Results were similar for the per‐protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (≥90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1α internalization assay).

Conclusion

MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.
Associations between the American College of Rheumatology pediatric response measures and the continuous measures of disease activity used in adult rheumatoid arthritis: A secondary analysis of clinical trial data from children with Polyarticular‐Course Juvenile Idiopathic Arthritis
Authors: Ringold Sarah , Chon Yun , Singer Nora G.
Published: November 2009

Objective

To measure associations between the American College of Rheumatology (ACR) pediatric criteria for improvement and the continuous measures of disease activity used for rheumatoid arthritis in adult patients with polyarticular‐course juvenile idiopathic arthritis (JIA).

Methods

In this retrospective analysis of 2 etanercept trials, disease activity was calculated at baseline, 3 months, and 6 months using the Disease Activity Score (DAS), the DAS based on 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). The ACR pediatric response and the European League Against Rheumatism (EULAR) response were also determined for the 3‐month and 6‐month evaluations. Data were analyzed in 94 patients with JIA independent of the treatment arm. Correlation coefficients between measures were calculated for each visit. The areas under the receiver operating characteristic curve (AUC of ROC) were calculated to assess the discriminative properties of the scores for the ACR pediatric response measures.

Results

The mean DAS, DAS28, CDAI score, and SDAI score were 3.7, 4.7, 30.8, and 36.4, respectively, at baseline, corresponding to high levels of disease activity (CDAI/SDAI) or moderate levels of disease activity (DAS/DAS28). At 3 months, the mean scores corresponded to low (DAS/DAS28) or moderate (CDAI/SDAI) disease activity. At 6 months, the mean scores corresponded to low disease activity (DAS/DAS28/CDAI) or moderate disease activity (SDAI). Most children met the criteria for a good or moderate EULAR response at 3 months and 6 months. The correlation between continuous outcome measures and each pediatric core set component was moderate to very good. The AUC of ROC values for each measure were high (range 0.76–0.98).

Conclusion

Good correlation and discriminative abilities were seen between the DAS, DAS28, CDAI, and SDAI for the ACR pediatric criteria for improvement. These disease activity measures may be useful for research and clinical care in polyarticular‐course JIA.
Insurer and out‐of‐pocket costs of osteoarthritis in the US: Evidence from national survey data
Authors: Kotlarz Harry , Gunnarsson Candace L. , Fang Hai , Rizzo John A.
Published: November 2009

Objective

Osteoarthritis (OA) is a major debilitating disease affecting ∼27 million persons in the US. Yet, the financial costs to patients and insurers remain poorly understood. The purpose of this study was to quantify by multivariate analyses the relationships between OA and annual health care expenditures borne by patients and insurers.

Methods

Data from the Medical Expenditure Panel Survey (MEPS) for the years 1996–2005 were used. MEPS is a large, nationally representative US database that includes information on health care expenditures, medical conditions, health insurance status, and sociodemographic characteristics. Individual and nationally aggregated cost estimates are provided.

Results

OA was found to contribute substantially to health care expenditures. Among women, OA increased out‐of‐pocket (OOP) expenditures by $1,379 per annum (2007 dollars) and insurer expenditures by $4,833. Among men, OA increased OOP expenditures by $694 per annum and insurer expenditures by $4,036. Given the high prevalence of OA, the aggregate effects on health care expenditures were very large. OA raised aggregate annual medical care expenditures by $185.5 billion. Of that amount, insurer expenditures were $149.4 billion and OOP expenditures were $36.1 billion. Because of the greater prevalence of OA in women and their more intensive use of health care, total expenditures for this group accounted for $118 billion, or almost two‐thirds of the total increase in health care expenditures resulting from OA.

Conclusion

The health care cost burden associated with OA is quite large for all groups examined and is disproportionately higher for women. Although insurers bear the brunt of treatment costs for OA, the OOP costs are also substantial.
Glucocorticoids increase α5 integrin expression and adhesion of synovial fibroblasts but inhibit ERK signaling, migration, and cartilage invasion
Authors: Lowin Torsten , Straub Rainer H. , Neumann Elena , Bosserhoff Anja , Vogel Corinna , Moissl Christine , Anders Sven , Müller‐Ladner Ulf , Schedel Jörg
Published: November 2009

Objective

In rheumatoid arthritis (RA), integrins mediate cell adhesion, migration, and invasion, and their expression is regulated by cytokines and growth factors. The aim of this study was to investigate whether hormones such as cortisol or other steroids can influence integrin expression and function in the synovial cells of patients with RA.

Methods

We performed immunofluorescence and fluorescence‐activated cell sorting analyses to quantify surface integrin levels. Adhesion and migration assays were performed to study the function of synovial fibroblasts (SFs). ERK activation was measured by cellular activation of a signaling enzyme‐linked immunosorbent assay. Invasion of SFs into cartilage was determined in the SCID mouse coimplantation model of RA in vivo.

Results

In RA, expression of integrin subunits α5, αv, and β1 was higher at the site of invasion compared with the sublining zone. Testosterone and 17β‐estradiol had no influence on integrin levels, but cortisol up‐regulated expression of the α5 subunit in a time‐dependent and dose‐dependent manner. In addition, cortisol increased the adhesion of SFs to fibronectin and inhibited ERK signaling upon integrin activation or upon stimulation with tumor necrosis factor. Small interfering RNA or a neutralizing antibody to α5 integrin increased SF migration, indicating that up‐regulated α5 integrin is responsible for an immobile phenotype. In addition, in the SCID mouse model, SF invasion into cartilage was attenuated by glucocorticoid treatment in vivo.

Conclusion

Glucocorticoids increase integrin expression and the adhesion of cells to fibronectin, inhibit ERK signaling, and down‐regulate the invasiveness of SFs in vivo. This study demonstrates that an important antiinflammatory aspect of glucocorticoids is regulating the expression and function of α5 integrin.
Serum levels of proinflammatory cytokines interleukin‐1β, interleukin‐6, and tumor necrosis factor α in mixed cryoglobulinemia
Authors: Antonelli Alessandro , Ferri Clodoveo , Ferrari Silvia Martina , Ghiri Emiliano , Goglia Fernando , Pampana Alessandro , Bruschi Fabrizio , Fallahi Poupak
Published: November 2009

Objective

No single previous study has evaluated serum levels of the proinflammatory cytokines interleukin‐1β (IL‐1β), IL‐6, and tumor necrosis factor α (TNFα) in patients with hepatitis C virus–associated mixed cryoglobulinemia (HCV‐MC). This study was undertaken to evaluate serum levels of these cytokines in patients with HCV‐MC.

Methods

Serum IL‐1β, IL‐6, and TNFα were assayed in 43 patients with HCV‐MC, in 43 sex‐ and age‐matched patients with chronic HCV without cryoglobulinemia, and in 43 sex‐ and age‐matched controls.

Results

HCV‐MC patients showed significantly higher mean IL‐1β, IL‐6, and TNFα levels than did the controls (P < 0.01) or the HCV patients (P ≤ 0.04). Serum levels of IL‐6 and TNFα were significantly higher in HCV patients than in controls (P < 0.05).

Conclusion

Our findings demonstrate elevated serum levels of IL‐1β, IL‐6, and TNFα in patients with HCV‐MC. If the importance of IL‐1β and IL‐6 in the pathogenesis of MC is confirmed, these results will open the way for the evaluation of new therapies for MC.
HLA–DR alleles determine responsiveness to Borrelia burgdorferi antigens in a mouse model of self‐perpetuating arthritis
Authors: Iliopoulou Bettina Panagiota , Guerau‐De‐Arellano Mireia , Huber Brigitte T.
Published: November 2009

Objective

Arthritis is a prominent manifestation of Lyme disease, which is caused by infection with Borrelia burgdorferi (Bb). Chronic Lyme arthritis persisting even after antibiotic treatment is linked to HLA–DRB1*0401 (DR4) and related alleles. In contrast, patients whose Lyme arthritis resolves within 3 months postinfection show an increased frequency of HLA–DRB1*1101 (DR11). The aim of this study was to analyze the underlying mechanism by which HLA–DR alleles confer genetic susceptibility or resistance to antibiotic‐refractory Lyme arthritis.

Methods

We generated DR11‐transgenic (DR11‐Tg) mice on a murine MHCII−/− background and compared their immune response to Bb antigens with the response of DR4‐Tg mice after immunization with Bb outer surface protein A (OspA) or infection with live Bb.

Results

T cells from OspA‐immunized and Bb‐infected DR11‐Tg mice had defective production of interferon‐γ as compared with those from DR4‐Tg mice. In contrast, DR11‐Tg mice developed higher titers of anti‐OspA and anti‐Bb antibodies, respectively, than did DR4‐Tg mice. Consistent with this observation, we found that the Bb‐infected DR11‐Tg mice had a decreased spirochetal burden as compared with the DR4‐Tg mice, as measured by quantitative polymerase chain reaction.

Conclusion

This study provides direct evidence that in the presence of HLA–DR11, the immune response against Bb antigens is directed toward a protective antibody response. In contrast, an inflammatory Th1 response is induced in the presence of DR4. These observations offer an explanation for the differential genetic susceptibility of DR4+ and DR11+ individuals to the development of chronic Lyme arthritis and, eventually, the progression to antibiotic‐refractory Lyme arthritis.
Prevalence and clinical correlates of pruritus in patients with systemic sclerosis
Authors: Razykov Ilya , Thombs Brett D. , Hudson Marie , Bassel Marielle , Baron Murray ,   The Canadian Scleroderma Research Group
Published: November 2009

Objective

There are no studies of pruritus prevalence or clinical correlates in systemic sclerosis (SSc). The objectives of this study were to document the proportion of SSc patients with pruritus on most days, to determine when in the course of the disease pruritus is most prevalent, and to identify clinical correlates.

Methods

We performed a cross‐sectional, multicenter study of 400 SSc patients from the Canadian Scleroderma Research Group Registry ≥1 year after Registry enrollment. Patients indicated whether they experienced pruritus during the past month on most days and underwent clinical histories and medical examinations. Multiple logistic regression was used to assess the association between sociodemographic and clinical variables and pruritus.

Results

A total of 179 patients (45%) reported pruritus on most days, including 69% (11 of 16) among patients 1.0–1.9 years from onset of non‐Raynaud's symptoms, 41% (38 of 93) for 2.0–4.9 years, 47% (44 of 94) for 5.0–9.9 years, 43% (60 of 140) for 10.0–19.9 years, and 46% (26 of 57) for ≥20 years. In post hoc analysis, patients 1.0–1.9 years from disease onset were significantly more likely to report pruritus (P= 0.049). Patients with pruritus had significantly more skin involvement (P= 0.029), more gastrointestinal (GI) symptoms (P< 0.001), worse breathing problems (P= 0.001), worse Raynaud's symptoms (P= 0.002), and more severe finger ulcers (P= 0.009). Only the number of GI symptoms predicted pruritus in multiple logistic regression analysis (odds ratio 1.25, 95% confidence interval 1.13–1.37;P< 0.001).

Conclusion

Pruritus is common in SSc and is independently associated with GI symptoms. Focused research on sources of pruritus and its management in SSc is needed.
DNA hypomethylation in rheumatoid arthritis synovial fibroblasts
Authors: Karouzakis Emmanuel , Gay Renate E. , Michel Beat A. , Gay Steffen , Neidhart Michel
Published: November 2009

Objective

Rheumatoid arthritis synovial fibroblasts (RASFs) are phenotypically activated and aggressive. We undertook this study to investigate whether the intrinsic activation of RASFs is due to global genomic hypomethylation, an epigenetic modification.

Methods

Global genomic hypomethylation was assessed by immunohistochemistry, flow cytometry, and L1 promoter bisulfite sequencing. The levels of Dnmt1 were determined in synovial tissue and cultured SFs by Western blotting before and after treatment with cytokines and growth factors. Normal SFs were treated for 3 months with a nontoxic dose of the DNA hypomethylation drug 5‐azacytidine (5‐azaC), and changes in gene expression were revealed using complementary DNA arrays. The phenotypic changes were confirmed by flow cytometry.

Results

In situ and in vitro, RASF DNA had fewer 5‐methylcytosine and methylated CG sites upstream of an L1 open‐reading frame than did DNA of osteoarthritis SFs, and proliferating RASFs were deficient in Dnmt1. Using 5‐azaC, we reproduced the activated phenotype of RASFs in normal SFs. One hundred eighty‐six genes were up‐regulated >2‐fold by hypomethylation, with enhanced protein expression. These included growth factors and receptors, extracellular matrix proteins, adhesion molecules, and matrix‐degrading enzymes. The hypomethylating milieu induced irreversible phenotypic changes in normal SFs, which resembled those of the activated phenotype of RASFs.

Conclusion

DNA hypomethylation contributes to the chronicity of RA and could be responsible for the limitation of current therapies.
Specifically modified osteopontin in rheumatoid arthritis fibroblast‐like synoviocytes supports interaction with B cells and enhances production of interleukin‐6
Authors: Take Yasuhiro , Nakata Ken , Hashimoto Jun , Tsuboi Hideki , Nishimoto Norihiro , Ochi Takahiro , Yoshikawa Hideki
Published: November 2009

Objective

Osteopontin (OPN) is expressed by fibroblast‐like synoviocytes (FLS) in rheumatoid arthritis (RA), but its pathologic role is still obscure. The present study was undertaken to analyze the role of OPN in RA by focusing on its effects on cell–cell interactions between FLS and B lymphocytes.

Methods

FLS obtained from 10 patients with RA and 10 non‐RA subjects and a B lymphocyte cell line were studied. The characteristics of OPN expression by FLS were analyzed by Western blotting, immunoprecipitation, and immunofluorescence studies. In cocultures of FLS and B lymphocytes, the effects of OPN on adhesion of B lymphocytes to FLS and the consequent production of interleukin‐6 (IL‐6) were analyzed in experiments involving overexpression and knockdown of OPN and inhibitory studies with an OPN‐blocking antibody. In vivo, the expression of OPN in RA synovium was examined by immunohistochemistry.

Results

A specifically modified 75‐kd form of OPN was predominantly expressed in RA FLS, and this was associated with expression of >200‐kd thrombin‐cleaved OPN that was crosslinked with fibronectin and localized on the surface of the FLS. In FLS–B lymphocyte cocultures, 75‐kd OPN–positive FLS produced a significantly higher amount of IL‐6 than did 75‐kd OPN–negative FLS. When the FLS were separated from B lymphocytes or cultured alone, the production of IL‐6 was low and was not significantly different between these 2 culture conditions. Moreover, OPN overexpression enhanced production of IL‐6 in 75‐kd OPN–positive FLS–B lymphocyte cocultures. Addition of the OPN‐blocking antibody inhibited the adhesion of B lymphocytes to FLS. Immunohistochemical analyses revealed that localization of IL‐6–positive cells coincided with the sites at which OPN and B lymphocytes were colocalized.

Conclusion

Specifically modified 75‐kd OPN was expressed by RA FLS. This form of OPN affected FLS–B lymphocyte interactions by supporting the adhesion of B lymphocytes to FLS and enhancing the production of IL‐6.
Interferon‐α mediates suppression of C‐reactive protein: Explanation for muted C‐reactive protein response in lupus flares?
Authors: Enocsson Helena , Sjöwall Christopher , Skogh Thomas , Eloranta Maija‐Leena , Rönnblom Lars , Wetterö Jonas
Published: November 2009

Objective

C‐reactive protein (CRP) is synthesized by hepatocytes in response to interleukin‐6 (IL‐6) during inflammation. Despite raised IL‐6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon‐α (IFNα), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP.

Methods

The interference of all 12 IFNα subtypes with CRP promoter activity induced by IL‐6 and IL‐1β was studied in a CRP promoter– and luciferase reporter–transfected human hepatoma cell line, Hep‐G2. CRP secretion by primary human hepatocytes was analyzed by enzyme‐linked immunosorbent assay.

Results

CRP promoter activity was inhibited by all single IFNα subtypes, as well as by 2 different mixtures of biologically relevant IFNα subtypes. The most prominent effect was seen using a leukocyte‐produced mixture of IFNα (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFNα was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep‐G2 proliferation/viability were not affected by IFNα.

Conclusion

The current study demonstrates that IFNα is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up‐regulated IFNα and a muted CRP response during SLE disease flares. Given the fundamental role of both IFNα and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.