Cannabinoids in the treatment of epilepsy: current status and future prospects

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fatcontaining meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebocontrolled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures

Towards the QFT on Curved Spacetime Limit of QGR. I: A General Scheme

In this article and a companion paper we address the question of how one might obtain the semiclassical limit of ordinary matter quantum fields (QFT) propagating on curved spacetimes (CST) from full fledged Quantum General Relativity (QGR), starting from first principles. We stress that we do not claim to have a satisfactory answer to this question, rather our intention is to ignite a discussion by displaying the problems that have to be solved when carrying out such a program. In the present paper we propose a scheme that one might follow in order to arrive at such a limit. We discuss the technical and conceptual problems that arise in doing so and how they can be solved in principle. As to be expected, completely new issues arise due to the fact that QGR is a background independent theory. For instance, fundamentally the notion of a photon involves not only the Maxwell quantum field but also the metric operator - in a sense, there is no photon vacuum state but a "photon vacuum operator"! While in this first paper we focus on conceptual and abstract aspects, for instance the definition of (fundamental) n-particle states (e.g. photons), in the second paper we perform detailed calculations including, among other things, coherent state expectation values and propagation on random lattices. These calculations serve as an illustration of how far one can get with present mathematical techniques. Although they result in detailed predictions for the size of first quantum corrections such as the gamma-ray burst effect, these predictions should not be taken too seriously because a) the calculations are carried out at the kinematical level only and b) while we can classify the amount of freedom in our constructions, the analysis of the physical significance of possible choices has just begun.Comment: LaTeX, 47 p., 3 figure

An update of the evolving epidemic of blaKPC carrying Klebsiella pneumoniae in Sicily, Italy, 2014: Emergence of multiple Non-ST258 Clones

Background: In Italy, Klebsiella pneumoniae carbapenemase producing K. pneumoniae (KPC-Kp) strains are highly endemic and KPC producing CC258 is reported as the widely predominating clone. In Palermo, Italy, previous reports have confirmed this pattern. However, recent preliminary findings suggest that an epidemiological change is likely ongoing towards a polyclonal KPC-Kp spread. Here we present the results of molecular typing of 94 carbapenem non susceptible K. pneumoniae isolates detected during 2014 in the three different hospitals in Palermo, Italy. Methods and Results: Ninety-four consecutive, non replicate carbapenem non susceptible isolates were identified in the three largest acute general hospitals in Palermo, Italy, in the six-month period March-August 2014. They were characterized by PCR for β-lactam, aminoglycoside and plasmid mediated fluoroquinolone resistance genetic determinants. The mgrB gene of the colistin resistant isolates was amplified and sequenced. Clonality was assessed by pulsed field gel electrophoresis and multilocus sequence typing. Eight non-CC258 sequence types (STs) were identified accounting for 60% of isolates. In particular, ST307 and ST273 accounted for 29% and 18% of isolates. CC258 isolates were more frequently susceptible to gentamicin and non-CC258 isolates to amikacin. Colistin non susceptibility was found in 42% of isolates. Modifications of mgrB were found in 32 isolates. Conclusions: Concurrent clonal expansion of some STs and lateral transmission of genetic resistance determinants are likely producing a thorough change of the KPC-Kp epidemiology in Palermo, Italy. In our setting mgrB inactivation proved to substantially contribute to colistin resistance. Our findings suggest the need to continuously monitor the KPC-Kp epidemiology and to assess by a nationwide survey the possible shifting towards a polyclonal epidemic

INFN Camera demonstrator for the Cherenkov Telescope Array

The Cherenkov Telescope Array is a world-wide project for a new generation of ground-based Cherenkov telescopes of the Imaging class with the aim of exploring the highest energy region of the electromagnetic spectrum. With two planned arrays, one for each hemisphere, it will guarantee a good sky coverage in the energy range from a few tens of GeV to hundreds of TeV, with improved angular resolution and a sensitivity in the TeV energy region better by one order of magnitude than the currently operating arrays. In order to cover this wide energy range, three different telescope types are envisaged, with different mirror sizes and focal plane features. In particular, for the highest energies a possible design is a dual-mirror Schwarzschild-Couder optical scheme, with a compact focal plane. A silicon photomultiplier (SiPM) based camera is being proposed as a solution to match the dimensions of the pixel (angular size of ~ 0.17 degrees). INFN is developing a camera demonstrator made by 9 Photo Sensor Modules (PSMs, 64 pixels each, with total coverage 1/4 of the focal plane) equipped with FBK (Fondazione Bruno Kessler, Italy) Near UltraViolet High Fill factor SiPMs and Front-End Electronics (FEE) based on a Target 7 ASIC, a 16 channels fast sampler (up to 2GS/s) with deep buffer, self-trigger and on-demand digitization capabilities specifically developed for this purpose. The pixel dimensions of $6\times6$ mm$^2$ lead to a very compact design with challenging problems of thermal dissipation. A modular structure, made by copper frames hosting one PSM and the corresponding FEE, has been conceived, with a water cooling system to keep the required working temperature. The actual design, the adopted technical solutions and the achieved results for this demonstrator are presented and discussed.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589

Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291

Searches for Cosmic-Ray Electron Anisotropies with the Fermi Large Area Telescope

The Large Area Telescope on board the \textit{Fermi} satellite (\textit{Fermi}-LAT) detected more than 1.6 million cosmic-ray electrons/positrons with energies above 60 GeV during its first year of operation. The arrival directions of these events were searched for anisotropies of angular scale extending from $\sim$ 10 $^\circ$ up to 90$^\circ$, and of minimum energy extending from 60 GeV up to 480 GeV. Two independent techniques were used to search for anisotropies, both resulting in null results. Upper limits on the degree of the anisotropy were set that depended on the analyzed energy range and on the anisotropy's angular scale. The upper limits for a dipole anisotropy ranged from $\sim0.5$ to $\sim10$.Comment: 16 pages, 10 figures, accepted for publication in Physical Review D - contact authors: M.N. Mazziotta and V. Vasileio

Search for Early Gamma-ray Production in Supernovae Located in a Dense Circumstellar Medium with the Fermi LAT

Supernovae (SNe) exploding in a dense circumstellar medium (CSM) are hypothesized to accelerate cosmic rays in collisionless shocks and emit GeV gamma rays and TeV neutrinos on a time scale of several months. We perform the first systematic search for gamma-ray emission in Fermi LAT data in the energy range from 100 MeV to 300 GeV from the ensemble of 147 SNe Type IIn exploding in dense CSM. We search for a gamma-ray excess at each SNe location in a one year time window. In order to enhance a possible weak signal, we simultaneously study the closest and optically brightest sources of our sample in a joint-likelihood analysis in three different time windows (1 year, 6 months and 3 months). For the most promising source of the sample, SN 2010jl (PTF10aaxf), we repeat the analysis with an extended time window lasting 4.5 years. We do not find a significant excess in gamma rays for any individual source nor for the combined sources and provide model-independent flux upper limits for both cases. In addition, we derive limits on the gamma-ray luminosity and the ratio of gamma-ray-to-optical luminosity ratio as a function of the index of the proton injection spectrum assuming a generic gamma-ray production model. Furthermore, we present detailed flux predictions based on multi-wavelength observations and the corresponding flux upper limit at 95% confidence level (CL) for the source SN 2010jl (PTF10aaxf).Comment: Accepted for publication in ApJ. Corresponding author: A. Franckowiak ([email protected]), updated author list and acknowledgement

Search for anisotropies in cosmic-ray positrons detected by the PAMELA experiment

The PAMELA detector was launched on board of the Russian Resurs-DK1 satellite on June 15, 2006. Data collected during the first four years have been used to search for large-scale anisotropies in the arrival directions of cosmic-ray positrons. The PAMELA experiment allows for a full sky investigation, with sensitivity to global anisotropies in any angular window of the celestial sphere. Data samples of positrons in the rigidity range 10 GV $\leq$ R $\leq$ 200 GV were analyzed. This article discusses the method and the results of the search for possible local sources through analysis of anisotropy in positron data compared to the proton background. The resulting distributions of arrival directions are found to be isotropic. Starting from the angular power spectrum, a dipole anisotropy upper limit \delta = 0.166 at 95% C.L. is determined. Additional search is carried out around the Sun. No evidence of an excess correlated with that direction was found.Comment: The value of the dipole anisotropy upper limit has been changed. The method is correct but there was a miscalculation in the relative formul

The ANTARES Collaboration: Contributions to ICRC 2017 Part I: Neutrino astronomy (diffuse fluxes and point sources)

Papers on neutrino astronomy (diffuse fluxes and point sources, prepared for the 35th International Cosmic Ray Conference (ICRC 2017, Busan, South Korea) by the ANTARES Collaboratio

Fermi LAT observations of cosmic-ray electrons from 7 GeV to 1 TeV

We present the results of our analysis of cosmic-ray electrons using about 8 million electron candidates detected in the first 12 months on-orbit by the Fermi Large Area Telescope. This work extends our previously-published cosmic-ray electron spectrum down to 7 GeV, giving a spectral range of approximately 2.5 decades up to 1 TeV. We describe in detail the analysis and its validation using beam-test and on-orbit data. In addition, we describe the spectrum measured via a subset of events selected for the best energy resolution as a cross-check on the measurement using the full event sample. Our electron spectrum can be described with a power law $\propto {\rm E}^{-3.08 \pm 0.05}$ with no prominent spectral features within systematic uncertainties. Within the limits of our uncertainties, we can accommodate a slight spectral hardening at around 100 GeV and a slight softening above 500 GeV.Comment: 20 pages, 23 figures, 2 tables, published in Physical Review D 82, 092004 (2010) - contact authors: C. Sgro', A. Moisee