Kitasato Symposium 2009: New Prospects for Cytokine Inhibition

The Kitasato Symposium 2009: New Prospects for Cytokine Inhibition was held in Berlin, Germany from 7 to 9 May 2009. The key aims of this meeting were to bring together a group of front-line researchers and rheumatologists to evaluate the use of cytokine blockade and to examine the role of certain cytokines in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. A keynote lecture delivered by Professor Jean-Michel Dayer provided an up-to-date overview of the interactions occurring between the immune system and acute phase proteins. Other speakers discussed the role of cytokines in rheumatoid arthritis, including their role in joint destruction, as well as their regulatory role upon T cells and B cells. The involvement of cytokines in other autoimmune diseases was also addressed

Design of a Phase 4 Randomized, Double-Blind, Placebo-Controlled Trial Assessing the ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels, and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Patients (PREDICTRA)

Introduction: The current American College of Rheumatology and European League Against Rheumatism treatment recommendations advise tapering biological disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) who achieve stable clinical remission while receiving bDMARDs. However, not all patients maintain remission or low disease activity after tapering or discontinuation of bDMARDs. The aim of the ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) study, or PREDICTRA, is to generate data on patient and disease characteristics that may predict the clinical course of a fixed dose-tapering regimen with the bDMARD adalimumab. Methods and analysis: PREDICTRA is an ongoing, multicentre, phase IV, randomised, double-blind, parallel-group study of adalimumab dose tapering controlled by withdrawal in participants with RA who achieved stable clinical remission while receiving adalimumab. The study includes a screening period, a 4-week lead-in period with open-label adalimumab 40 mg every other week and a subsequent 36-week double-blind period during which participants are randomised 5:1 to adalimumab 40 mg every 3 weeks (taper arm) or placebo (withdrawal arm). The primary explanatory efficacy variables are lead-in baseline hand and wrist MRI-detected synovitis and bone marrow oedema scores, as well as a composite of both scores; the dependent variable is the occurrence of flare up to week 40. Additional efficacy variables, safety, pharmacokinetics, biomarkers and immunogenicity will also be assessed, and an ultrasound substudy will be conducted. Ethics and dissemination: The study is conducted in accordance with the International Conference on Harmonisation guidelines, local laws and the ethical principles of the Declaration of Helsinki. All participants are required to sign a written informed consent statement before the start of any study procedures

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.

Paleomagnetic Evidence of Vertical Axis Block Rotations from the Mesozoic of Northern Chile

We present paleomagnetic results for three Mesozoic formations from northern Chile: La Ternera Formation (Upper Triassic), Quebrada Monardes Formation (Upper Jurassic); Cerrillos Formation (Upper Cretaceous). Results from the Cerrillos are divided into eastern (Cuesta El Gao (CEG)) and western (Elisa De Bordo (EBD)) localities. Most specimens from La Ternera volcanic and sedimentary rocks are mag­netically stable, as shown by alternating field and thermal demagnetization. More complicated but still reliable results were obtained from Quebrada Monardes red beds. Normal and reverse polarities are present in both units; means of both populations are antiparallel at 95% confi­dence. The Quebrada Monardes Formation also yields positive conglomerate and fold tests. Paleomagnetic poles for La Ternera and Quebrada- Monardes are 60.9S, 218.3E (A95, 7.8°), and 66.9S, 191.6E (A95, 12.7°), respectively. Com­parison with appropriate reference poles shows that this region of Chile has undergone about 25° of clockwise rotation, with negligible lati­tudinal transport. Cerrillos CEG results are less reliable and possibly complicated by remag- netization during emplacement of early Tertiary intrusives. Most Cerrillos EDB specimens are stable, but marked increase in scatter upon un­folding suggests remagnetization. Results for the Cerrillos CEG locality, which is contiguous to the sampling area of the La Ternera and Que­brada Monardes formations, show only about half the rotation of those two units, suggesting that rotation commenced after deposition of the Que­brada Monardes rocks in the Late Jurassic and was approximately half complete by the time Cer­rillos CEG rocks acquired their magnetization. Cerrillos EDB results come from an area approxi­mately 40 km to the west; these show roughly 45° of clockwise rotation. Dispersion is very low between EDB sites, suggesting that secular vari­ation may not be completely averaged. Neverthe­less, the great difference in direct:ion between the two Cerrillos localities suggests that they lie in different structural blocks

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

Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study

Objective: To investigate the association between baseline disease activity and the occurrence of flares after adalimumab tapering or withdrawal in patients with rheumatoid arthritis (RA) in sustained remission. Methods: The PREDICTRA phase IV, randomised, double-blind (DB) study (ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels, and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Patients) enrolled patients with RA receiving adalimumab 40 mg every other week who were in sustained remission ≥6 months. After a 4-week, open-label lead-in (OL-LI) period, patients were randomised 5:1 to DB adalimumab taper (every 3 weeks) or withdrawal (placebo) for 36 weeks. The primary endpoint was the association between DB baseline hand and wrist MRI-detected inflammation with flare occurrence. Results: Of 146 patients treated during the OL-LI period, 122 were randomised to taper (n=102) or withdrawal (n=20) arms. Patients had a mean 12.9 years of active disease and had received adalimumab for a mean of 5.4 years (mean 2.2 years in sustained remission). Overall, 37 (36%) and 9 (45%) patients experienced a flare in the taper and withdrawal arms, respectively (time to flare, 18.0 and 13.3 weeks). None of the DB baseline disease characteristics or adalimumab concentration was associated with flare occurrence after adalimumab tapering. Approximately half of the patients who flared regained clinical remission after 16 weeks of open-label rescue adalimumab. The safety profile was consistent with previous studies. Conclusions: Approximately one-third of patients who tapered adalimumab versus half who withdrew adalimumab experienced a flare within 36 weeks. Time to flare was numerically longer in the taper versus withdrawal arm. Baseline MRI inflammation was not associated with flare occurrence. Trial registration number: NCT02198651, EudraCT 2014-001114-26

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

Proteasome alpha-type subunit C9 is a primary target of autoantibodies in sera of patients with myositis and systemic lupus erythematosus

Autoantibodies occur in low frequencies among patients with myositis characterizing only distinct subsets of this disease. Most of these known antibodies are directed to enzymatically active complexes. The 20S proteasome represents an essential cytoplasmatic protein complex for intracellular nonlysosomal protein degradation, and is involved in major histocompatibility complex class I restricted antigen processing. In this study we investigated whether the 20S proteasome complex is an antibody target in myositis and in other autoimmune diseases. 34 sera of poly/dermatomyositis patients were assayed for antiproteasomal antibodies using enzyme-linked immunosorbent assay, immunoblot, and two-dimensional non-equilibrium pH gradient electrophoresis (NEPHGE). Sera was from patients with systemic lupus erythematosus (SLE), mixed connective tissue disease, and rheumatoid arthritis; healthy volunteers served as controls. In 62% (21/34) of the cases sera from patients with myositis and in 58% (30/52) of the cases sera from patients with SLE reacted with the 20S proteasome. These frequencies exceeded those of sera from patients with mixed connective tissue disease, rheumatoid arthritis, and healthy controls. The alpha-type subunit C9 of the 20S proteasome was determined to be the predominant target of the autoimmune sera in myositis and SLE. Lacking other frequent autoantibodies in myositis, the antiproteasome antibodies are the most common humoral immune response so far detected in this disease entity