The prevalence of giant cell arteritis and polymyalgia rheumatica in a UK primary care population

Background: To update community-based prevalence values for Polymyalgia Rheumatic (PMR) and Giant Cell Arteritis (GCA) using case record review supplemented by population survey and subsequent clinical review. Methods: Clinical data were obtained from case records of a large primary care practice in Norfolk, UK and reviewed for diagnoses of GCA and PMR. In addition postal survey was carried out to capture potentially undiagnosed cases within the practice population. Those screening positive for potential diagnoses of GCA and PMR were invited for clinical review. A cumulative prevalence estimate was subsequently calculated on those diagnosed within the GP practice and subsequently on those fulfilling the various published classification criteria sets. The date of the database lock and mail merge was March 2013. Results: Through detailed systematic review of 5,159 GP case records, 21 patients had a recorded diagnosis of GCA and 117 had PMR . No new cases were identified among 2,227 completed questionnaires returned from the population survey of a sample of 4,728. The resulting cumulative prevalence estimate in those aged ≥55 years meeting the ACR classification criteria set for GCA was 0.25% (95% CI 0.11% to 0.39%) and for five published criteria sets for PMR ranged from 0.91% to 1.53% (95% CI ranges 0.65%, 1.87%). The prevalence of both conditions was higher in women than in men and in older age groups. Conclusion: This study provides the first UK prevalence estimate of GCA and PMR in over 30 years and is the first to apply classification criteria sets

The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold

Activation of Toll-like receptors induces dimerization and the recruitment of the death domain (DD) adaptor protein MyD88 into an oligomeric post receptor complex termed the Myddosome. The Myddosome is a hub for inflammatory and oncogenic signaling and has a hierarchical arrangement with 6-8 MyD88 molecules assembling with exactly 4 of IRAK-4 and 4 of IRAK-2. Here we show that a conserved motif in IRAK-4 (Ser8-X-X-X-Arg12) is autophosphorylated and that the phosphorylated DD is unable to form Myddosomes. Furthermore a mutant DD with the phospho-mimetic residue Asp at this position is impaired in both signalling and Myddosome assembly. IRAK-4 Arg12 is also essential for Myddosome assembly and signalling and we propose that phosphorylated Ser8 induces the N-terminal loop to fold into an α-helix. This conformer is stabilised by an electrostatic interaction between phospho-Ser8 and Arg12 and would destabilise a critical interface between IRAK-4 and MyD88. Interestingly IRAK-2 does not conserve this motif and has an alternative interface in the Myddosome that requires Arg67, a residue conserved in paralogues, IRAK-1 and 3(M).This work was supported by program grants from the Wellcome Trust (WT081744/Z/06/Z) and the UK Medical Research Council (G1000133) to N.J.G. and C.E.B. and a Wellcome Investigator award to N.J.G. (WT100321/z/12/Z). AD was the recipient of a studentship award from GlaxoSmithKline. JG was supported by the German Cancer Research Center (DKFZ). ANRW was supported by the Else-Kröner-Fresenius-Stiftung, the German Research Foundation (Grant SFB685 “Immunotherapy”) and the University of Tübingen. PGM was supported by a Thuthuka Grant from the S. African NRF (TTK14060668443)

The comparative responsiveness of the EQ-5D and SF-6D to change in patients with inflammatory arthritis

Purpose: Comparative evidence regarding the responsiveness of the EQ-5D and SF-6D in arthritis patients is conflicting and insufficient across the range of disease severity. We examined the comparative responsiveness of the EQ-5D and SF-6D in cohorts of patients with early inflammatory disease through to severe rheumatoid arthritis (RA). Methods: Responsiveness was tested using the effect size (ES) and standardised response mean (SRM). Correlation of change in EQ-5D and SF-6D with disease specific measures was tested using Pearson correlations and the Steiger's Z test. Treatment response and self-reported change were used as anchors of important change. Results: The EQ-5D was more responsive to deterioration (ES ratio (EQ-5D/SF-6D): 1.6-3.0) and the SF-6D more responsive to improvement (ES ratio (SF-6D/EQ-5D): 1.1-1.8) in health. The SF-6D did not respond well to deterioration in patients with established severe RA (ES and SRM 0.08). The EQ-5D provided larger absolute mean change estimates but with greater variance compared to the SF-6D. Conclusions: The comparative responsiveness of the EQ-5D and SF-6D differs according to the direction of change. The level of mean change of the EQ-5D relative to the SF-6D has implications for cost-effectiveness analysis. Use of the SF-6D in patients with severe progressive disease may be inappropriate. © 2009 The Author(s)

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

A model for improving microbial biofuel production using a synthetic feedback loop

Cells use feedback to implement a diverse range of regulatory functions. Building synthetic feedback control systems may yield insight into the roles that feedback can play in regulation since it can be introduced independently of native regulation, and alternative control architectures can be compared. We propose a model for microbial biofuel production where a synthetic control system is used to increase cell viability and biofuel yields. Although microbes can be engineered to produce biofuels, the fuels are often toxic to cell growth, creating a negative feedback loop that limits biofuel production. These toxic effects may be mitigated by expressing efflux pumps that export biofuel from the cell. We developed a model for cell growth and biofuel production and used it to compare several genetic control strategies for their ability to improve biofuel yields. We show that controlling efflux pump expression directly with a biofuel-responsive promoter is a straightforward way of improving biofuel production. In addition, a feed forward loop controller is shown to be versatile at dealing with uncertainty in biofuel production rates

AcrB Trimer Stability and Efflux Activity, Insight from Mutagenesis Studies

The multidrug transporter AcrB in Escherichia coli exists and functions as a homo-trimer. The assembly process of obligate membrane protein oligomers, including AcrB, remains poorly understood. In a previous study, we have shown that individual AcrB subunit is capable of folding independently, suggesting that trimerization of AcrB follows a three-stage pathway in which monomers first fold, and then assemble. Here we destabilized the AcrB trimer through mutating a single Pro (P223) in the protruding loop of AcrB, which drastically reduced the protein activity. We replaced P223 separately with five residues, including Ala, Val, Tyr, Asn, and Gly, and found that AcrBP223G was the least active. Detailed characterization of AcrBP223G revealed that the protein existed as a well-folded monomer after purification, but formed a trimer in vivo. The function of the mutant could be partly restored through strengthening the stability of the trimer using an inter-subunit disulfide bond. Our results also suggested that the protruding loop is well structured during AcrB assembly with P223 served as a “wedge” close to the tip to stabilize the AcrB trimer structure. When this wedge is disrupted, the stability of the trimer is reduced, accompanied by a decrease of drug efflux activity

Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations

Multidrug resistance is a serious problem in current chemotherapy. The efflux system largely responsible for resistance in Escherichia coli contains the drug transporter, AcrB. The structures of AcrB were solved in 2002 as the symmetric homo-trimer, and then in 2006 as the asymmetric homo-trimer. The latter suggested a functionally rotating mechanism. Here, by molecular simulations of the AcrB porter domain, we uncovered allosteric coupling and the drug export mechanism in the AcrB trimer. Allosteric coupling stabilized the asymmetric structure with one drug molecule bound, which validated the modelling. Drug dissociation caused a conformational change and stabilized the symmetric structure, providing a unified view of the structures reported in 2002 and 2006. A dynamic study suggested that, among the three potential driving processes, only protonation of the drug-bound protomer can drive the functional rotation and simultaneously export the drug

Novel methodology to discern predictors of remission and patterns of disease activity over time using rheumatoid arthritis clinical trials data

Objectives To identify predictors of remission and disease activity patterns in patients with rheumatoid arthritis (RA) using individual participant data (IPD) from clinical trials. Methods Phases II and III clinical trials completed between 2002 and 2012 were identified by systematic literature review and contact with UK market authorisation holders. Anonymised baseline and follow-up IPD from non-biological arms were amalgamated. Multiple imputation was used to handle missing outcome and covariate information. Random effects logistic regression was used to identify predictors of remission, measured by the DAS28 score at 6 months. Novel latent class mixed models characterised DAS28 over time.Results IPD of 3290 participants from 18 trials were included. Of these participants, 92% received methotrexate (MTX). Remission rates were estimated at 8.4% (95%CI: 7.4%-9.5%) overall, 17% (95%CI: 14.8%-19.4%) for MTX-naïve early RA patients, and 3.2% (95%CI: 2.4%-4.3%) for those with prior MTX exposure at entry. In prior MTX-exposed patients, lower baseline DAS28 and MTX-re-initiation were associated with remission. In MTX-naïve patients, being young, white, male, with better functional and mental health, lower baseline DAS28 and receiving concomitant glucocorticoids were associated with remission. Three DAS28 trajectory sub-populations were identified in MTX-naïve and MTX-exposed patients. A number of variables were associated with sub-population membership and DAS28 levels within sub-populations. Conclusions Predictors of remission differed between MTX-naïve and prior MTX-exposed patients at entry. Latent class mixed models supported differential non-biologic therapy response, with three distinct trajectories observed in both MTX-naïve and MTX-exposed patients. Findings should be useful when designing future RA trials and interpreting results of biomarker studies. <br/

Vitamin D in health and disease: Current perspectives

Despite the numerous reports of the association of vitamin D with a spectrum of development, disease treatment and health maintenance, vitamin D deficiency is common. Originating in part from the diet but with a key source resulting from transformation by exposure to sunshine, a great deal of the population suffers from vitamin D deficiency especially during winter months. It is linked to the treatment and pathogenesis and/or progression of several disorders including cancer, hypertension, multiple sclerosis, rheumatoid arthritis, osteoporosis, muscle weakness and diabetes. This widespread deficiency of Vitamin D merits consideration of widespread policies including increasing awareness among the public and healthcare professionals