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

Шляхи підвищення ефективності фінансово-господарської діяльності підприємства

Мета даної статті полягає в необхідності виробити заходи з підвищення ефективності фінансово-господарської діяльності підприємства (на прикладі Кримського республіканського підприємства «Виробниче підприємство водопровідно-каналізаційної галузі» м. Сімферополя)

Vibrational spectrum of solid picene (C_22H_14)

Recently, Mitsuhashi et al., have observed superconductivity with transition temperature up to 18 K in potassium doped picene (C22H14), a polycyclic aromatic hydrocarbon compound [Nature 464 (2010) 76]. Theoretical analysis indicate the importance of electron-phonon coupling in the superconducting mechanisms of these systems, with different emphasis on inter- and intra-molecular vibrations, depending on the approximations used. Here we present a combined experimental and ab-initio study of the Raman and infrared spectrum of undoped solid picene, which allows us to unanbiguously assign the vibrational modes. This combined study enables the identification of the modes which couple strongly to electrons and hence can play an important role in the superconducting properties of the doped samples

Quantum tomography, phase space observables, and generalized Markov kernels

We construct a generalized Markov kernel which transforms the observable associated with the homodyne tomography into a covariant phase space observable with a regular kernel state. Illustrative examples are given in the cases of a 'Schrodinger cat' kernel state and the Cahill-Glauber s-parametrized distributions. Also we consider an example of a kernel state when the generalized Markov kernel cannot be constructed.Comment: 20 pages, 3 figure

Systematic Study of the Kaon to Pion Multiplicity Ratios in Heavy-Ion Collisions

We present a systematic study of the kaon to pion multiplicity ratios (K+/pi+ and K-/pi-) in heavy-ion collisions from AGS to RHIC energy using the Relativistic Quantum Molecular Dynamics (RQMD) model. The model satisfactorily describes the available experimental data on K+/pi+ and K-/pi-. Within the model, we find that the strong increase of the ratios with the number of participants is mainly due to hadronic rescattering of produced mesons with ingoing baryons and their resonances. The enhancement of K/pi in heavy-ion collisions with respect to elementary p+p interactions is larger at AGS energy than SPS energy, and decreases smoothly with bombarding energy. The total multiplicity ratios at RHIC energy are predicted by RQMD to be K+/pi+ = 0.19 and K-/pi- = 0.15.Comment: 10 pages, 8 figures, RevTeX style. A section is added to discuss effects of rope formatio

A wildland fire model with data assimilation

A wildfire model is formulated based on balance equations for energy and fuel, where the fuel loss due to combustion corresponds to the fuel reaction rate. The resulting coupled partial differential equations have coefficients that can be approximated from prior measurements of wildfires. An ensemble Kalman filter technique with regularization is then used to assimilate temperatures measured at selected points into running wildfire simulations. The assimilation technique is able to modify the simulations to track the measurements correctly even if the simulations were started with an erroneous ignition location that is quite far away from the correct one.Comment: 35 pages, 12 figures; minor revision January 2008. Original version available from http://www-math.cudenver.edu/ccm/report

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

On the complementarity of the quadrature observables

In this paper we investigate the coupling properties of pairs of quadrature observables, showing that, apart from the Weyl relation, they share the same coupling properties as the position-momentum pair. In particular, they are complementary. We determine the marginal observables of a covariant phase space observable with respect to an arbitrary rotated reference frame, and observe that these marginal observables are unsharp quadrature observables. The related distributions constitute the Radon tranform of a phase space distribution of the covariant phase space observable. Since the quadrature distributions are the Radon transform of the Wigner function of a state, we also exhibit the relation between the quadrature observables and the tomography observable, and show how to construct the phase space observable from the quadrature observables. Finally, we give a method to measure together with a single measurement scheme any complementary pair of quadrature observables.Comment: Dedicated to Peter Mittelstaedt in honour of his eightieth birthda