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

The role of working memory and verbal fluency in autobiographical memory in early Alzheimer’s disease and matched controls

Retrieval of autobiographical memories (AMs) is important for “sense of self”. Previous research and theoretical accounts suggest that working memory (WM) and semantic and phonemic fluency abilities facilitate the hierarchical search for, and reliving of past, personal events in the mind’s eye. However, there remains a lack of consensus as to the nature of the relationships between these cognitive functions and the truly episodic aspects of AM. The present study therefore aimed to explore the associations between these variables in a sample with a wide range of cognitive abilities. The study incorporated a between-groups component, and a correlational component with multiple regression. Participants with Alzheimer’s disease (n = 10) and matched healthy controls (n = 10) were assessed on measures of semantic and episodic AM search and retrieval, auditory and spatial WM, and semantic and phonemic fluency. The AD group produced less episodic AM content compared to controls. Semantic fluency predicted episodic AM retrieval independent of age effects but there were no significant relationships between measures of phonemic fluency, WM and episodic AM. The results suggest that the ability to maintain hierarchical search of the semantic knowledge-base is important for truly episodic reliving, and interventions for people with AM impairment might therefore benefit from incorporating structured, individualised external memory-aids to facilitate AM search and retrieval

Tectono-stratigraphic evolution of the intermontane Tarom Basin (NW sectors of the Arabia-Eurasia collision zone): insights into the vertical growth of the Iranian Plateau margin

The intermontane Tarom Basin of NW Iran (Arabia-Eurasia collision zone) is located at the transition between the Iranian Plateau (IP) to the SW and the Alborz Mountains to the NE. This basin was filled by Late Cenozoic synorogenic red beds that retain first-order information on the erosional history of adjacent topography, the vertical growth of the plateau margin and its lateral (orogen perpendicular) expansion. Here, we perform a multidisciplinary study including magnetostratigraphy, sedimentology, geochronology and sandstone petrography on these red beds. Our data show that widespread Eocene arc volcanism in NW Iran terminated at ~ 38-36 Ma, while intrabasinal synorogenic sedimentation occurred between ~ 16.5 and < 7.6 Ma, implying that the red beds are stratigraphically equivalent to the Upper Red Formation. After 7.6 Ma, the basin experienced intrabasinal deformation, uplift and erosion in association with the establishment of external drainage. Fluvial connectivity with the Caspian Sea, however, was interrupted by at least four episodes of basin aggradation. During endorheic conditions the basin fill did not reach the elevation of the plateau interior and hence the Tarom Basin was never integrated into the plateau realm. Furthermore, our provenance data indicate that the northern margin of the basin experienced a greater magnitude of deformation and exhumation than the southern one (IP margin). This agrees with recent Moho depth estimates, suggesting that crustal shortening and thickening cannot be responsible for the vertical growth of the northern margin of the IP, and hence surface uplift must have been driven by deep-seated processes

Tectono-stratigraphic evolution of the intermontane Tarom Basin (NW sectors of the Arabia-Eurasia collision zone): insights into the vertical growth of the Iranian Plateau margin

The intermontane Tarom Basin of NW Iran (Arabia-Eurasia collision zone) is located at the transition between the Iranian Plateau (IP) to the SW and the Alborz Mountains to the NE. This basin was filled by Late Cenozoic synorogenic red beds that retain first-order information on the erosional history of adjacent topography, the vertical growth of the plateau margin and its lateral (orogen perpendicular) expansion. Here, we perform a multidisciplinary study including magnetostratigraphy, sedimentology, geochronology and sandstone petrography on these red beds. Our data show that widespread Eocene arc volcanism in NW Iran terminated at ~ 38-36 Ma, while intrabasinal synorogenic sedimentation occurred between ~ 16.5 and < 7.6 Ma, implying that the red beds are stratigraphically equivalent to the Upper Red Formation. After 7.6 Ma, the basin experienced intrabasinal deformation, uplift and erosion in association with the establishment of external drainage. Fluvial connectivity with the Caspian Sea, however, was interrupted by at least four episodes of basin aggradation. During endorheic conditions the basin fill did not reach the elevation of the plateau interior and hence the Tarom Basin was never integrated into the plateau realm. Furthermore, our provenance data indicate that the northern margin of the basin experienced a greater magnitude of deformation and exhumation than the southern one (IP margin). This agrees with recent Moho depth estimates, suggesting that crustal shortening and thickening cannot be responsible for the vertical growth of the northern margin of the IP, and hence surface uplift must have been driven by deep-seated processes

Numerical Analysis Using WRF-SBM for the Cloud Microphysical Structures in the C3VP Field Campaign: Impacts of Supercooled Droplets and Resultant Riming on Snow Microphysics

Two distinct snowfall events are observed over the region near the Great Lakes during 19-23 January 2007 under the intensive measurement campaign of the Canadian CloudSat/CALIPSO validation project (C3VP). These events are numerically investigated using the Weather Research and Forecasting model coupled with a spectral bin microphysics (WRF-SBM) scheme that allows a smooth calculation of riming process by predicting the rimed mass fraction on snow aggregates. The fundamental structures of the observed two snowfall systems are distinctly characterized by a localized intense lake-effect snowstorm in one case and a widely distributed moderate snowfall by the synoptic-scale system in another case. Furthermore, the observed microphysical structures are distinguished by differences in bulk density of solid-phase particles, which are probably linked to the presence or absence of supercooled droplets. The WRF-SBM coupled with Goddard Satellite Data Simulator Unit (G-SDSU) has successfully simulated these distinctive structures in the three-dimensional weather prediction run with a horizontal resolution of 1 km. In particular, riming on snow aggregates by supercooled droplets is considered to be of importance in reproducing the specialized microphysical structures in the case studies. Additional sensitivity tests for the lake-effect snowstorm case are conducted utilizing different planetary boundary layer (PBL) models or the same SBM but without the riming process. The PBL process has a large impact on determining the cloud microphysical structure of the lake-effect snowstorm as well as the surface precipitation pattern, whereas the riming process has little influence on the surface precipitation because of the small height of the system