Support from the UK Department of Health through its Health Technology Assessment Programme and Arthritis Research

ABSTRACT. Objective. Our aim was to determine areal bone mineral density (BMD a ) and disease-related factors linked with BMD a in adults with a history of juvenile idiopathic arthritis (JIA). Methods. Men and women with a history of JIA attending a young adult rheumatology clinic in Newcastle, UK, underwent dual energy x-ray absorptiometry (DEXA) of the lumbar spine and total hip. Information was obtained about disease duration and subtype, previous treatment including corticosteroid and methotrexate therapy, and large-joint replacement. Subjects completed the modified Health Assessment Questionnaire (HAQ). Blood was taken for assessment of C-reactive protein, erythrocyte sedimentation rate, and rheumatoid factor (RF). Results. Seventy-one women and 16 men, mean age 28.7 and 31.4 years, and mean disease duration 20.6 and 24.0 years, respectively, were studied. Mean BMD a was 0.982 (Z-score = -0.328; 95% CI -0.657, 0.001) and 1.028 g/cm 2 (Z-score = -0.251; 95% CI -1.266, 0.764) in women and men, respectively, at the spine and 0.817 (Z-score = -0.542; 95% CI -0.975, -0.109) and 0.857 g/cm 2 (Z-score = -0.176; 95% CI -2.323, 1.971) at the hip. After adjusting for age and sex, increasing HAQ score was associated with both lower spine BMD a and hip BMD a . Compared with patients with oligoarticular disease, those with enthesitis-related arthritis had higher BMD a at the spine, while those with extended oligoarticular and polyarticular RF-negative disease had lower hip BMD a . Oral corticosteroids and the presence of a large-joint replacement were associated with lower BMD a at both the spine and hip. Conclusion. There was a trend toward low BMD a in women with a history of JIA. These patients may be at risk of the complications of osteoporosis including fragility fractures and should be considered for targeted preventive measures. (First Release June 15 2011

Weight reduction is not a major reason for improvement in rheumatoid arthritis from lacto-vegetarian, vegan or Mediterranean diets

OBJECTIVES: Several investigators have reported that clinical improvements of patients with rheumatoid arthritis (RA), from participating in therapeutic diet intervention studies, have been accompanied by loss of body weight. This has raised the question whether weight reduction per se can improve RA. In order to test this hypothesis, three previously conducted diet intervention studies, comprising 95 patients with RA, were pooled. Together with Age, Gender, and Disease Duration, change during the test period in body weight, characterised dichotomously as reduction or no reduction (dichoΔBody Weight), as well as Diet (dichotomously as ordinary diet or test diet), were the independent variables. Dependent variables were the difference (Δ) from baseline to conclusion of the study in five different disease outcome measures. ΔESR and ΔPain Score were both characterised numerically and dichotomously (improvement or no improvement). ΔAcute Phase Response, ΔPhysical Function, and ΔTender Joint Count were characterised dichotomously only. Multiple logistic regression was used to analyse associations between the independent and the disease outcome variables. RESULTS: Statistically significant correlations were found between Diet and three disease outcome variables i.e. ΔAcute-Phase Response, ΔPain Score, and ΔPhysical Function. Δ Body Weight was univariately only correlated to ΔAcute-Phase Response but not significant when diet was taken into account. CONCLUSION: Body weight reduction did not significantly contribute to the improvement in rheumatoid arthritis when eating lacto-vegetarian, vegan or Mediterranean diets

Crystal Structure of Escherichia coli CusC, the Outer Membrane Component of a Heavy Metal Efflux Pump

Background: While copper has essential functions as an enzymatic co-factor, excess copper ions are toxic for cells, necessitating mechanisms for regulating its levels. The cusCBFA operon of E. coli encodes a four-component efflux pump dedicated to the extrusion of Cu(I) and Ag(I) ions. Methodology/Principal Findings: We have solved the X-ray crystal structure of CusC, the outer membrane component of the Cus heavy metal efflux pump, to 2.3 A ˚ resolution. The structure has the largest extracellular opening of any outer membrane factor (OMF) protein and suggests, for the first time, the presence of a tri-acylated N-terminal lipid anchor. Conclusions/Significance: The CusC protein does not have any obvious features that would make it specific for metal ions, suggesting that the narrow substrate specificity of the pump is provided by other components of the pump, most likely by the inner membrane component CusA

Presence of Mycoplasma fermentans in the bloodstream of Mexican patients with rheumatoid arthritis and IgM and IgG antibodies against whole microorganism

<p>Abstract</p> <p>Background</p> <p>Increasing evidence incriminates bacteria, especially <it>Mycoplasma fermentans</it>, as possible arthritogenic agents in humans. The purpose of this study was to investigate <it>M. fermentans </it>in the bloodstream of patients with rheumatoid arthritis.</p> <p>Methods</p> <p>Two hundred and nineteen blood samples from patients with rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, and healthy individuals were screened by bacterial culture and direct PCR in order to detect mycoplasmas; IgM and IgG against <it>M. fermentans </it>PG18 were also detected by ELISA and Immunoblotting assays in patients with rheumatoid arthritis and healthy individuals.</p> <p>Results</p> <p>Blood samples from patients with antiphospholipid syndrome and healthy individuals were negative for mycoplasma by culture or direct PCR. In blood samples from patients with systemic lupus erythematosus were detected by direct PCR <it>M. fermentans </it>in 2/50 (2%), <it>M. hominis </it>in 2/50 (2%) and <it>U. urealyticum </it>in 1/50 (0.5%). In patients with RA <it>M. fermentans </it>was detected by culture in 13/87 blood samples and in 13/87 by direct PCR, however, there was only concordance between culture and direct PCR in six samples, so <it>M. fermentans </it>was detected in 20/87(23%) of the blood samples from patients with RA by either culture or PCR. Antibody-specific ELISA assay to <it>M. fermentans </it>PG18 was done, IgM was detected in sera from 40/87 patients with RA and in sera of 7/67 control individuals, IgG was detected in sera from 48/87 RA patients and in sera from 7/67 healthy individuals. Antibody-specific immunoblotting to <it>M. fermentans </it>PG18 showed IgM in sera from 35/87 patients with RA and in sera from 4/67 healthy individuals, IgG was detected in sera from 34/87 patients and in sera from 5/67 healthy individuals.</p> <p>Conclusion</p> <p>Our findings show that only <it>M. fermentans </it>produce bacteremia in a high percentage of patients with RA. This finding is similar to those reported in the literature. IgM and IgG against <it>M. fermentans </it>PG18 were more frequent in patients with RA than healthy individuals.</p

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report

Objective The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set. Methods Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis. Results The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach. Conclusion The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78048/1/27580_ftp.pd

2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative

Objective The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct “rheumatoid arthritis.” Results In the new criteria set, classification as “definite RA” is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct “rheumatoid arthritis.”Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78045/1/27584_ftp.pd

Redefining the timing and circumstances of the chicken's introduction to Europe and north-west Africa

This is the final version. Available on open access from Cambridge University Press via the DOI in this recordLittle is known about the early history of the chicken (Gallus gallus domesticus), including the timing and circumstances of its introduction into new cultural environments. To evaluate its spatio-temporal spread across Eurasia and north-west Africa, the authors radiocarbon dated 23 chicken bones from presumed early contexts. Three-quarters returned dates later than those suggested by stratigraphy, indicating the importance of direct dating. The results indicate that chickens did not arrive in Europe until the first millennium BC. Moreover, a consistent time-lag between the introduction of chickens and their consumption by humans suggests that these animals were initially regarded as exotica and only several centuries later recognised as a source of ‘food’.Arts and Humanities Research Council (AHRC)Natural Environment Research Council (NERC)Chair of Palaeoanatomy, LMU Munic

Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections

Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0×10−5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes

The Future of Rheumatoid Arthritis and Hand Surgery - Combining Evolutionary Pharmacology and Surgical Technique

Rheumatoid arthritis is a systemic autoimmune disease of uncertain aetiology, which is characterized primarily by synovial inflammation with secondary skeletal destructions

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB