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

Angiopoietin2 and Tie2: Tied to Lymphangiogenesis and Lung Metastasis. New Perspectives in Antimetastatic Antiangiogenic Therapy

Invited commentar

The AHEAD Portal: A Gateway to European Historical Earthquake Data

The description of the seismicity of the European region is today fragmented into an increasing number of earthquake archives, databases, and catalogs related to individual countries or even to part of them. Therefore, the compilation of a comprehensive, European earthquake history requires dealing with a puzzle of partially overlapping, only partially public catalogs, the background of which is compiled according to varied schemes. One of the consequences is that earthquakes in the frontier areas are often interpreted in a conflicting way by the catalogs of the bordering countries. In the framework of the European Commission (EC), 2006–2010 Network of Research Infrastructures for European Seismology (NERIES) Project, the task of Networking Activity 4 (NA4) was defined precisely to conceive and develop solutions to bridge over these differences. NA4 promoted the cooperation among existing national online archives, and contributed establishing new regional online archives compiled according to common standards. As a result, a first release of the distributed European archive of historical earthquake data, for the time-window 1000–1899 and for the large earthquakes, was published in 2010. Special attention was devoted to retrieve the earthquake background information, that is, the results of historical earthquake investigation—referenced to as studies in the following -in terms of a paper, a report, a book chapter, a map, etc. As the most useful studies are those supplying a set of macroseismic data points (MDPs)- that is a list of localities (name and coordinates) with a macroseismic intensity assessment and the related macroseismic scale—a dedicated effort was addressed to make such data available. The Archive of Historical Earthquake Data (AHEAD) distributed archive was improved and updated in the frame of the 2010–2012 EC Project Seismic Hazard Harmonization in Europe (SHARE), Task 3.1 European earthquake database, with the contribution of a number of European institutions. For the time window 1000–1899, it was AHEAD (AHEAD Working Group) that supported the compilation of the SHARE European Earthquake Catalog (SHEEC; Stucchi et al., 2013). This paper describes the AHEAD portal (http://www.emidius.eu/AHEAD/; last accessed March 2014), and how it was conceived to network the local components of the distributed archive. Although local historical macroseismic databases usually supply one set of information for each earthquake, at a European scale an earthquake still might be described by several studies, available from different archives. The AHEAD portal inventories and gives access to multiple sets of information concerning each earthquake, and allows users to get comprehensive information about individual earthquakes, providing the answers to the following questions: 1. which sets of earthquake parameters (time, location, magnitude, magnitude type, maximum intensity, etc.) are available for each earthquake? 2. what is the background information, or supporting material, upon which each set of earthquake parameter determination is based

How did COVID-19 affect medical and cardiology journals? A pandemic in literature

BACKGROUND AND AIMS: The spreading speed of the COVID-19 pandemic forced the medical community to produce efforts in updating and sharing the evidence about this new disease, trying to preserve the accuracy of the data but at the same time avoiding the potentially harmful delay from discovery to implementation. The aim of our analysis was to assess the impact of the COVID-19 pandemic on medical literature in terms of proportion of COVID-19-related published papers and temporal patterns of publications within a sample of general/internal medicine and cardiology journals. METHODS: We searched through PubMed scientific papers published from 1 January 2020 to 31 January 2021 about COVID-19 in ten major medical journals, of which five were in general/internal medicine and five in the cardiology field. We analyzed the proportion of COVID-19-related papers, and we examined temporal trends in the number of published papers. RESULTS: Overall, the proportion of COVID-19-related papers was 18.5% (1986/10 756). This proportion was higher among the five selected general/internal medicine journals, compared with cardiology journals (23.8% vs 9.5%). The vast majority of papers were not original articles; in particular, in cardiology journals, there were 28% 'original articles', 17% 'review articles' and 55.1% 'miscellaneous', compared with 20.2%, 5.1% and 74.7% in general/internal medicine journals, respectively. CONCLUSIONS: Our analysis highlights the big impact of the COVID-19 pandemic on international scientific literature. General and internal medicine journals were mainly involved, with cardiology journals only at a later time

Design methodology for the development of variable stiffness devices based on layer jamming transition

Variable stiffness mechanisms as Jamming Transition draw huge attention recently in Soft Robotics. This paper proposes a comprehensive design methodology for developing variable stiffness devices based on layer jamming. Starting from pre-existing modelling, we highlight the design parameters that should be considered, extracting them from literature and our direct experience with the phenomenon. Then we validated the methodology applying the design process to previous layer jamming cases presented in literature. The comparison between the results obtained from our methodology and those presented in the analyzed previous works highlights a good predictive capability, demonstrating that this methodology can be used as a valid tool to design variable stiffness devices based on layer jamming transition. Finally, in order to provide the scientific community with an easily usable tool to design variable stiffness structures based on layer jamming transition, we have elaborated a Matlab script that guides the user through the main design parameters implementing the proposed methodology in an interactive process

Quantum Homodyne Tomography as an Informationally Complete Positive Operator Valued Measure

We define a positive operator valued measure $E$ on $[0,2\pi]\times R$ describing the measurement of randomly sampled quadratures in quantum homodyne tomography, and we study its probabilistic properties. Moreover, we give a mathematical analysis of the relation between the description of a state in terms of $E$ and the description provided by its Wigner transform.Comment: 9 page

Relations between convergence rates in Schatten p-norms

In quantum estimation theory and quantum tomography, the quantum state obtained by sampling converges to the `true' unknown density matrix under topologies that are different from the natural notion of distance in the space of quantum states, i.e. the trace class norm. In this paper, we address such problem, finding relations between the rates of convergence in the Schatten $p$-norms and in the trace class norm

Towards a seismogenic source model of the Dinarides

Geology-based seismogenic source models are becoming the fundamental input for seismic hazard assessment at the scale of an entire country. In this work, we will illustrate in simple steps the complex process that leads from basic data to a fully-fledged seismogenic source model of the Dinaride thrust belt, running along coastal Croatia, Montenegro and part of Albania. We started from a layer of basic geological and structural data and explored a wide range of indicators of recent tectonic activity, such as drainage anomalies/diversions and displaced or warped geological markers. We then analyzed the interplay of these indicators with known or prospective tectonic structures. To the picture thus obtained, we added a layer with a revised historical seismic catalog and selected a few earthquakes for which we re-estimate epicenter and magnitude. At the end of our analyses we combined all these data in a structured GIS database. With these data at hand, we also compared the longer-term indicators with present-day stress/strain data such as GPS velocities and earthquake focal solutions. Following the approach already developed for the construction of the Database of Individual Seismogenic Sources for Italy, we developed a seismogenic source model for the Dinarides in which the better constrained seismogenic faults have been mapped and parameterized and made ready for use in seismic hazard practice. We believe that our experience in the Dinarides will become useful in unifying and formalizing the process of constructing seismic source models in other countries

Surface activated chemical ionization - Electrospray mass spectrometry in the analysis of urinary thiodiglycolic acid

RATIONALE Thiodiglycolic acid (TDGA) is a urinary metabolite of the oxazaphosphorine class of chemotherapeutics, in particular of ifosfamide. Ifosfamide metabolism generates chloroacetaldehyde (CAA), a toxic compound associated with neurotoxicity, nephrotoxicity, urotoxicity and cardiotoxicity. CAA, in turn, interacts with cellular thiol groups leading to GSH depletion, cell death and generation of thiodiglycolic acid (TDGA), as a final product. TDGA is mainly excreted in the urine. The ability to accurately measure TDGA in urine, therefore, will be a useful way of monitoring the ifosfamide exposure during chemotherapy. METHODS TDGA in urine samples was measured with liquid chromatograpy coupled to mass spectrometry (LC-MS) by means of a novel Surface Activated Chemical Ionization - Electrospray (SACI-ESI) or a classical ESI ion source alone. RESULTS The SACI - ESI and ESI alone based methods for analysis of urinary TDGA were optimized and compared. A strong reduction in matrix effect together with enhanced quantification performances was obtained with the SACI \u2013 ESI when compared with the ESI. In particular, an increase in quantification precision (from 85 to 95%) and accuracy (from 59 to 90%) were observed, which allowed for optimal detection of TDGA. CONCLUSIONS The LC-SACI-ESI-MS approach provides a very sensitive and quantitative method for the analysis of TDGA. Thanks to sensitivity enhancement and matrix effect reduction, the SACI \u2013 ESI enables the use of a relatively low cost ion-trap mass spectrometer in the analysis of this toxicity biomarker in urine. Due to these characteristics, this approach would constitutes an invaluable tool in the clinical laboratory, for measuring TDGA and other toxicity related biomarkers of chemotherapy with proper sensitivity and accuracy