Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis.

Background: Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anticyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA. Objectives: To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed. Methods: 373 patients with RA were studied. SE, padi4_94C.T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score. Results: CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C.T genotype (C/C: ORadj=0.93, padj=0.92; C/T: ORadj=2.92, padj=0.093; T/T: ORadj=15.3, padj=0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C.T with ANAs was observed, with noteworthy differences depending on SE status (SE2: ORadj=6.20, padj,0.04; SE+: ORadj=0.36, padj=0.02) and significant heterogeneity between the two SE strata (p=0.006). Conclusions: PADI4 genotype in combination with anti- CCPs and SE modulates clinical and serological characteristics of RA

Persistent clinical efficacy and safety of anti-tumour necrosis factor \textgreeka therapy with infliximab in patients with ankylosing spondylitis over 5 years: evidence for different types of response

Background: There is insufficient evidence for the long-term efficacy and safety of anti-tumour necrosis factor therapy in patients with ankylosing spondylitis (AS). This is the first report on the treatment with infliximab over 5 years.Methods: As part of a multicentre randomised trial, 69 patients with active AS at baseline (BL) have been continuously treated with infliximab (5 mg/kg i.v. every 6 weeks)---except for a short discontinuation after 3 years (FU1). The primary outcome of this extension was remission according to the ASsessment in Ankylosing Spondylitis (ASAS) criteria at the end of year 5 of the study (FU2).Results: Of the 43 patients who completed year 3, 42 agreed to continue, 38 of which (90.5%) finished year 5 (55% of 69 initially). Partial clinical remission was achieved in 13 of 38 patients (34.2%) at FU1 and FU2. At FU2, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 2.5±1.9 (BL:6.4, FU1:2.5). BASDAI values <4 were seen in 79% of patients at both, FU1 and FU2. ASAS 20% and 40% responses were seen in 32 (84%) and 24 (63%) patients at FU2, respectively. Most patients classified as non-responders at FU2 were part-time responders, as all but one patient achieved an ASAS 20% response at least once within the last 2 years. Three types of responders were identified. No major side effects occurred during years 4 and 5 of infliximab therapy.Conclusions: Infliximab is safe and efficacious in AS patients over 5 years. The majority of the patients remained on treatment and had rather persistent levels of low disease activity. Different response types could be identified

Internet Protocol (IP) Videoconferencing for Networking During a Crisis

The Alabama Cooperative Extension System (ACES) responded to clientele needs during the severe droughts in 2006 and 2007. The ACES Agronomic Crops Program Priority Team utilized interactive videoconferencing through Internet Protocol (IP), allowing real-time communication between producers, agricultural industry representatives, and state and federal officials. Travel time and costs were minimized, while information exchange was maximized. Planning through teleconferencing prior to the videoconference allowed on-site moderators to function efficiently with regard to time and topic management. Our intent is to develop procedures and infrastructure to allow faster response time and more efficient information exchange during times of crisis

Metamorphic Evidence for Tilt of the Spuzzum Pluton – Diminished Basis for the Baja British-Columbia Concept

To address the question of tilt versus translation as the mechanism responsible for discordance between paleomagnetic directions of Cretaceous plutons in the British Columbia Coast Plutonic Complex and the North American reference direction, metamorphic pressures around the margin of the Spuzzum pluton have been determined. Pressures are derived from microprobe analyses and evaluation of exchange equilibria in the assemblage garnet-biotite-plagioclase-aluminum silicate-quartz. Samples studied come from eight localities in the contact aureole around the pluton and encompass the area of a previous paleomagnetic study. The analyzed samples are coarse grained and exhibit textural features indicative of equilibrium crystallization following emplacement of the Spuzzum pluton. Results of this study indicate a complicated tilt history for the Spuzzum pluton, with tilt first to the northeast then to the southwest. The southwest tilt can fully explain the discordance of the paleomagnetic direction in the Spuzzum but does not preclude translation. However, in view of the tilt history of this pluton, the paleomagnetic dat

Quaternary structure of the European spiny lobster (Palinurus elephas) 1 x 6-mer hemocyanin from cryoEM and amino acid sequence data

Arthropod hemocyanins are large respiratory proteins that are composed of up to 48 subunits (8 x 6-mer) in the 75 kDa range. A 3D reconstruction of the 1 x 6-mer hemocyanin from the European spiny lobster Palinuris elephas has been performed from 9970 single particles using cryoelectron microscopy. An 8 Angstrom resolution of the hemocyanin 3D reconstruction has been obtained from about 600 final class averages. Visualisation of structural elements such as a-helices has been achieved. An amino acid sequence alignment shows the high sequence identity (>80%.) of the hemocyanin subunits from the European spiny lobster P. elephas and the American spiny lobster Panulirus interruptus. Comparison of the P. elephas hemocyanin electron microscopy (EM) density map with the known P. interruptus X-ray structure shows a close structural correlation, demonstrating the reliability of both methods for reconstructing proteins, By molecular modelling, we have found the putative locations for the amino acid sequence (597-605) and the C-terminal end (654-657), which are absent in the available P. interruptus X-ray data. (C) 2002 Elsevier Science Ltd. All rights reserve

Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study.

INTRODUCTION: Patients with active rheumatoid arthritis who had failed at least one disease-modifying anti-rheumatic drug (DMARD) were treated with adalimumab (ADA) in the ReAct study with the option to continue treatment for 5 years in ReAlise. The purpose of this study was to evaluate the long-term safety and effectiveness of ADA as prescribed from the first injection in ReAct to the last observation in ReAlise. METHODS: Patients received ADA alone or in combination with DMARDs according to usual clinical care practices. Adverse events (AEs) were tabulated by five time windows after the first ADA injection. Effectiveness measures included achievement of low disease activity (LDA), defined as Simplified Disease Activity Index (SDAI) ≤11, or remission, (REM), defined as SDAI ≤3.3. RESULTS: Of the 6,610 ReAct patients, 3,435 (52%) continued in ReAlise. At baseline in ReAct, mean age was 54 years, mean DAS28 was 6.0 and mean HAQ DI was 1.64. The mean treatment duration was 1,016 days, representing 18,272 patient-years (PYs) of ADA exposure. Overall incidence rates of serious AEs and serious infections were 13.8 and 2.8 events (E)/100 PYs, respectively. Serious AEs occurred most frequently in the first 6 months and deceased thereafter. Standardised mortality ratio was 0.71 (95% CI 0.57 to 0.87) and standardised incidence ratio for malignancies was 0.64 (95% CI 0.53 to 0.76). LDA was achieved by 50% and REM by 21% of patients at last observation. CONCLUSIONS: Results of this large observational study of ADA in routine clinical practice were consistent with controlled trials, with no new safety concerns during a follow-up of more than 5 years. Effectiveness of ADA was maintained during long-term observation. TRIAL REGISTRATION: NCT00448383, NCT0023488

Immunomics in inflammatory rheumatic diseases

Autoimmune diseases such as rheumatoid arthritis (RA) are characterized by autoantibodies to different autoantigenic proteins. Using proteomic 2D immunoblots, we identified a new 40 kDa autoantigen – hnRNP A3 – from HeLa nuclear extracts, which is frequently (30%) detected by RA. Moreover, we used a set of protein arrays of about 50 000 proteins derived from a human foetal brain cDNA expression library for screening with patient sera. Additionally, we utilized a human foetal brain cDNA library in a robot-based T7 phage display screening system with RA patient sera. To determine the diversity of the enriched library, we amplified the cDNA inserts and hybridized them onto the custom-made human ENSEMBL cDNA array. By these methods, over 80 clones were identified to bind patient immunoglobulins. Moreover, nine clones show only IgA-specific reactivity. We have now evaluated two different clones thoroughly: the carboxyl-terminal half of the nucleolar phosphoprotein p130 (NOPP 130) and a clone representing a 41-amino-acid mimetic peptide showing homology to calreticulin, a previously reported autoantigen. The remaining proteins are still undergoing thorough investigation. Applying state-of-the-art proteomic techniques, such as protein array and phage display, we have succeeded in identifying more than 80 potentially autoantigenic marker molecules, of which we have characterized a subset for RA specificity by screening with large numbers of patient and control sera. However, none of the molecules characterized thus far is exclusively discriminatory for RA and they all exhibit overlap with other autoimmune diseases

Password-based group key exchange in a constant number of rounds

Abstract. With the development of grids, distributed applications are spread across multiple computing resources and require efficient security mechanisms among the processes. Although protocols for authenticated group Diffie-Hellman key exchange protocols seem to be the natural mechanisms for supporting these applications, current solutions are either limited by the use of public key infrastructures or by their scalability, requiring a number of rounds linear in the number of group members. To overcome these shortcomings, we propose in this paper the first provably-secure password-based constant-round group key exchange protocol. It is based on the protocol of Burmester and Desmedt and is provably-secure in the random-oracle and ideal-cipher models, under the Decisional Diffie-Hellman assumption. The new protocol is very efficient and fully scalable since it only requires four rounds of communication and four multi-exponentiations per user. Moreover, the new protocol avoids intricate authentication infrastructures by relying on passwords for authentication.