Analgesic treatment of ciguatoxin-induced cold allodynia

Ciguatera, the most common form of nonbacterial ichthyosarcotoxism, is caused by consumption of fish that have bioaccumulated the polyether sodium channel activator ciguatoxin. The neurological symptoms of ciguatera include distressing, often persistent sensory disturbances such as paraesthesias and the pathognomonic symptom of cold allodynia. We show that intracutaneous administration of ciguatoxin in humans elicits a pronounced axon-reflex flare and replicates cold allodynia. To identify compounds able to inhibit ciguatoxin-induced Na-v responses, we developed a novel in vitro ciguatoxin assay using the human neuroblastoma cell line SH-SY5Y. Pharmacological characterisation of this assay demonstrated a major contribution of Na(v)1.2 and Na(v)1.3, but not Na(v)1.7, to ciguatoxin-induced Ca2+ responses. Clinically available Nav inhibitors, as well as the K(v)7 agonist flupirtine, inhibited tetrodotoxin-sensitive ciguatoxin-evoked responses. To establish their in vivo efficacy, we used a novel animal model of ciguatoxin-induced cold allodynia. However, differences in the efficacy of these compounds to reverse ciguatoxin-induced cold allodynia did not correlate with their potency to inhibit ciguatoxin-induced responses in SH-SY5Y cells or at heterologously expressed Nav1.3, Na(v)1.6, Na(v)1.7, or Na(v)1.8, indicating cold allodynia might be more complex than simple activation of Na-v channels. These findings highlight the need for suitable animal models to guide the empiric choice of analgesics, and suggest that lamotrigine and flupirtine could be potentially useful for the treatment of ciguatera. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved

Spectrum and Variability of Mrk501 as observed by the CAT Imaging Telescope

The CAT Imaging Telescope has observed the BL Lac object Markarian 501 between March and August 1997. We report here on the variability over this time including several large flares. We present also preliminary spectra for all these data, for the low emission state, and for the largest flare.Comment: 4 pages, 4 figures, Late

Observation of the Crab Nebula Gamma-Ray Emission Above 220 Gev by the Cat Cherenkov Imaging Telescope

The CAT imaging telescope, recently built on the site of the former solar plant Themis (French Pyrenees), observed gamma-rays from the Crab nebula from October 1996 to March 1997. This steady source, often considered as the standard candle of very-high-energy gamma-ray astronomy, is used as a test-beam to probe the performances of the new telescope, particularly its energy threshold (220 GeV at 20 degrees zenith angle) and the stability of its response. Due to the fine-grain camera, an accurate analysis of the longitudinal profiles of shower images is performed, yielding the source position in two dimensions for each individual shower.Comment: 5 pages, 3 figures, Tex, contribution to 25th ICRC Durba

Extending the Langevin model to variable-density pressure-gradient-driven turbulence

We extend the generalized Langevin model, originally developed for the Lagrangian fluid particle velocity in constant-density shear-driven turbulence, to variable-density (VD) pressure-gradient-driven flows. VD effects due to non-uniform mass concentrations (e.g. mixing of different species) are considered. In the extended model large density fluctuations leading to large differential fluid accelerations are accounted for. This is an essential ingredient to represent the strong coupling between the density and velocity fields in VD hydrodynamics driven by active scalar mixing. The small scale anisotropy, a fundamentally "non-Kolmogorovian" feature of pressure-gradient-driven flows, is captured by a tensorial stochastic diffusion term. The extension is so constructed that it reduces to the original Langevin model in the limit of constant density. We show that coupling a Lagrangian mass-density particle model to the proposed extended velocity equation results in a statistical representation of VD turbulence that has important benefits. Namely, the effects of the mass flux and the specific volume, both essential in the prediction of VD flows, are retained in closed form and require no explicit closure assumptions. The paper seeks to describe a theoretical framework necessary for subsequent applications. We derive the rigorous mathematical consequences of assuming a particular functional form of the stochastic momentum equation coupled to the stochastic density field in VD flows. A previous article discussed VD mixing and developed a stochastic Lagrangian model equation for the mass-density. Second in the series, this article develops the momentum equation for VD hydrodynamics. A third, forthcoming paper will combine these ideas on mixing and hydrodynamics into a comprehensive framework: it will specify a model for the coupled problem and validate it by computing a Rayleigh-Taylor flow.Comment: Accepted in Journal of Turbulence, Jan 7, 201

Detection of Vhe Gamma-Rays from MRK 501 with the Cat Imaging Telescope

The CAT imaging telescope on the site on the former solar plant Themis has been observing gamma-rays from Mrk501 above 220 GeV in March and April 1997. This source is shown to be highly variable and the light curve is presented. The detected gamma-ray rate for the most intense flare is in excess of 10 per minute.Comment: 5 pages, 4 figures, Tex, contribution to 25th ICRC Durba

Very High Energy Gamma-ray spectral properties of Mrk 501 from CAT Cerenkov telescope observations in 1997

The BL Lac object Mrk 501 went into a very high state of activity during 1997, both in VHE gamma-rays and X-rays. We present here results from observations at energies above 250 GeV carried out between March and October 1997 with the CAT Cerenkov imaging Telescope. The average differential spectrum between 30 GeV and 13 TeV shows significant curvature and is well represented by phi_0 * E_TeV^{-(alpha + beta*log10(E_TeV))}, with: phi_0 = 5.19 +/- 0.13 {stat} +/- 0.12 {sys-MC} +1.66/-1.04 {sys-atm} * 10^-11 /cm^2/s/TeV alpha = 2.24 +/- 0.04 {stat} +/- 0.05 {sys} beta = 0.50 +/- 0.07 {stat} (negligible systematics). The TeV spectral energy distribution of Mrk 501 clearly peaks in the range 500 GeV-1 TeV. Investigation of spectral variations shows a significant hardness-intensity correlation with no measurable effect on the curvature. This can be described as an increase of the peak TeV emission energy with intensity. Simultaneous and quasi-simultaneous CAT VHE gamma-ray and BeppoSAX hard X-ray detections for the highest recorded flare on 16th April and for lower-activity states of the same period show correlated variability with a higher luminosity in X-rays than in gamma-rays. The observed spectral energy distribution and the correlated variability between X-rays and gamma-rays, both in amplitude and in hardening of spectra, favour a two-component emission scheme where the low and high energy components are attributed to synchrotron and inverse Compton (IC) radiation, respectively.Comment: Submitted to Astronomy and Astrophysics, 8 pages including 6 figures. Published with minor change

The CAT Imaging Telescope for Very-High-Energy Gamma-Ray Astronomy

The CAT (Cherenkov Array at Themis) imaging telescope, equipped with a very-high-definition camera (546 fast phototubes with 0.12 degrees spacing surrounded by 54 larger tubes in two guard rings) started operation in Autumn 1996 on the site of the former solar plant Themis (France). Using the atmospheric Cherenkov technique, it detects and identifies very high energy gamma-rays in the range 250 GeV to a few tens of TeV. The instrument, which has detected three sources (Crab nebula, Mrk 421 and Mrk 501), is described in detail.Comment: 24 pages, 15 figures. submitted to Elsevier Preprin

Efficient and reliable nonlocal damage models

We present an efficient and reliable approach for the numerical modelling of failure with nonlocal damage models. The two major numerical challenges––the strongly nonlinear, highly localized and parameter-dependent structural response of quasi-brittle materials, and the interaction between nonadjacent finite elements associated to nonlocality––are addressed in detail. Reliability of the numerical results is ensured by an h-adaptive strategy based on error estimation. We use a residual-type error estimator for nonlinear FE analysis based on local computations, which, at the same time, accounts for the nonlocality of the damage model. Efficiency is achieved by a proper combination of load-stepping control technique and iterative solver for the nonlinear equilibrium equations. A major issue is the computation of the consistent tangent matrix, which is nontrivial due to nonlocal interaction between Gauss points. With computational efficiency in mind, we also present a new nonlocal damage model based on the nonlocal average of displacements. For this new model, the consistent tangent matrix is considerably simpler to compute than for current models. The various ideas discussed in the paper are illustrated by means of three application examples: the uniaxial tension test, the three-point bending test and the single-edge notched beam test.Peer ReviewedPostprint (author’s final draft

EXPRES. II. Searching for Planets Around Active Stars: A Case Study of HD 101501

By controlling instrumental errors to below 10 cm/s, the EXtreme PREcision Spectrograph (EXPRES) allows for a more insightful study of photospheric velocities that can mask weak Keplerian signals. Gaussian Processes (GP) have become a standard tool for modeling correlated noise in radial velocity datasets. While GPs are constrained and motivated by physical properties of the star, in some cases they are still flexible enough to absorb unresolved Keplerian signals. We apply GP regression to EXPRES radial velocity measurements of the 3.5 Gyr old chromospherically active Sun-like star, HD 101501. We obtain tight constraints on the stellar rotation period and the evolution of spot distributions using 28 seasons of ground-based photometry, as well as recent $TESS$ data. Light curve inversion was carried out on both photometry datasets to reveal the spot distribution and spot evolution timescales on the star. We find that the $> 5$ m/s rms radial velocity variations in HD 101501 are well-modeled with a GP stellar activity model without planets, yielding a residual rms scatter of 45 cm/s. We carry out simulations, injecting and recovering signals with the GP framework, to demonstrate that high-cadence observations are required to use GPs most efficiently to detect low-mass planets around active stars like HD 101501. Sparse sampling prevents GPs from learning the correlated noise structure and can allow it to absorb prospective Keplerian signals. We quantify the moderate to high-cadence monitoring that provides the necessary information to disentangle photospheric features using GPs and to detect planets around active stars.Comment: 25 pages, 16 figures, accepted to A