Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease in which anti-ADAMTS13 autoantibodies cause severe enzyme deficiency. ADAMTS13 deficiency causes the loss of regulation of von Willebrand factor multimeric size and platelet-tethering function, which results in the formation of disseminated microvascular platelet microthrombi. Precisely how anti-ADAMTS13 autoantibodies, or antibody subsets, cause ADAMTS13 deficiency (ADAMTS13 activity generally < 10%) has not been formally investigated. METHODS: We analysed 92 acquired TTP episodes at presentation, through treatment and remission/relapse using epitope mapping and functional analyses to understand the pathogenic mechanisms of anti-ADAMTS13 IgG. RESULTS: 89/92 of TTP episodes had IgG recognising the ADAMTS13 N-terminal domains. The central spacer domain was the only N-terminal antigenic target detected. 38/92 TTP episodes had autoantibodies recognising the N-terminal domains alone; 54/92 TTP episodes also had antibodies against the ADAMTS13 C-terminal domains (TSP2-8 and/or CUB domains). Changes in autoantibody specificity were detected in 9/16 patients at relapse, suggesting a continued development of the disease. Functional analyses on IgG from 43 patients revealed inhibitory IgG were limited to anti-spacer domain antibodies. However, 15/43 patients had autoantibodies with no detectable inhibitory action and as many as 32/43 patients had autoantibodies with inhibitory function that was insufficient to account for the severe deficiency state, suggesting that in many patients there is an alternative pathogenic mechanism. We therefore analysed plasma ADAMTS13 antigen levels in 91 acquired TTP presentation samples. We demonstrated markedly reduced ADAMTS13 antigen levels in all presentation samples, median 6% normal (range 0-47%), with 84/91 patients having < 25% ADAMTS13 antigen. ADAMTS13 antigen in the lowest quartile at first presentation was associated with increased mortality (odds ratio 5.7). CONCLUSIONS: Anti-spacer domain autoantibodies are the major inhibitory antibodies in acquired TTP. However, depletion of ADAMTS13 antigen (rather than enzyme inhibition) is a dominant pathogenic mechanism. ADAMTS13 antigen levels at presentation have prognostic significance. Taken together, our results provide new insights into the pathophysiology of acquired TTP

The eclipsing Cataclysmic Variable GS Pavonis: Evidence for disk radius changes

We have obtained differential time series photometry of the cataclysmic variable GS Pavonis over a timespan of 2 years. These show that this system is deeply eclipsing (~2-3.5 mag) with an orbital period of 3.72 hr. The eclipse depth and out-of-eclipse light levels are correlated. From this correlation we deduce that the disk radius is changing and that the eclipses in the low state are total. The derived distance to GS Pav is 790+/-90 pc, with a height above the galactic plane of 420+/-60 pc. We classify GS Pav as a novalike system.Comment: 4 pages, including 2 figures, accepted for publication in A&A Letter

Production of single-domain magnetite throughout life by sockeye salmon, Oncorhynchus nerka

Although single-domain particles of biogenic magnetite have been found in different species of pelagic fishes, nothing is known about when it is synthesized, or about whether the time during life when it is produced is correlated with the development of responses to magnetic field stimuli. We have investigated production of biogenic magnetite suitable for use in magnetoreception in different life stages of the sockeye salmon, Oncorhynchus nerka (Walbaum). Sockeye salmon were chosen because responses in orientation arenas to magnetic field stimuli have been demonstrated in both fry and smolt stages of this species. We found significant quantities of single-domain magnetite in connective tissue from the ethmoid region of the skull of adult (4-year-old) sockeye salmon. The ontogenetic study revealed an orderly increase in the amount of magnetic material in the same region of the skull but not in other tissues of sockeye salmon fry, yearlings and smolts. The physical properties of this material closely matched those of magnetite particles extracted from the ethmoid tissue of the adult fish. We suggest that single-domain magnetite particles suitable for use in magnetoreception are produced throughout life in the ethmoid region of the skull in sockeye salmon. Based on theoretical calculations, we conclude that there are enough particles present in the skulls of the fry to mediate their responses to magnetic field direction. By the smolt stage, the amount of magnetite present in the front of the skull is sufficient to provide the fish with a magnetoreceptor capable of detecting small changes in the intensity of the geomagnetic field. Other tissues of the salmon, such as the eye and skin, often contained ferromagnetic material, although the magnetizations of these tissues were usually more variable than in the ethmoid tissue. These deposits of unidentified magnetic material, some of which may be magnetite, appear almost exclusively in adults and so would not be useful in magnetoreception by young fish. We suggest that tissue from within the ethmoid region of the skull in pelagic fishes is the only site yet identified where magnetite suitable for use in magnetoreception is concentrated

AGENT: Awareness Game Environment for Natural Training

We propose AGENT, the Awareness Game Environment for Natural Training, as a virtual environment in which serious games can be enacted. AGENT combines research on interactive storytelling, game design, turn-taking and social signal processing with a multi-modal UI in a modular fashion. Current work in progress will deliver a rst demonstrable prototype within 2013

A new approach to (quasi) periodic boundary conditions in micromagnetics: the macrogeometry

We present a new method to simulate repetitive ferromagnetic structures. This macro geometry approach combines treatment of short-range interactions (i.e. the exchange field) as for periodic boundary conditions with a specification of the arrangement of copies of the primary simulation cell in order to correctly include effects of the demagnetizing field. This method (i) solves a consistency problem that prevents the naive application of 3d periodic boundary conditions in micromagnetism and (ii) is well suited for the efficient simulation of repetitive systems of any size

Spin-polarized currents in exchange spring systems

We present a computational study of the magnetization dynamics of a trilayer exchange spring system in the form of a cylindrical nanopillar in the presence of an electric current. A three-dimensional micromagnetic model is used, where the interaction between the current and the local magnetization is taken into account following a recent model by Zhang and Li [Phys. Rev. Lett. 93, 127204 (2004)] We obtain a stationary rotation of the magnetization of the system around its axis, accompanied by a compression of the artificial domain wall in the direction of the electron flow