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

Targeting interleukin-1β protects from aortic aneurysms induced by disrupted transforming growth factor β signaling

Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor β (TGF-β) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-β. The results revealed that Smad4 inhibition activated interleukin-1β (IL-1β) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1β antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-β signaling, such as those driven by SMAD4 mutations

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

Free volume, molecular grains, self-organisation, and anisotropic entropy : machining materials

In this article, the relationship between molecular architecture and the formation of twist-bend phases is reviewed under the context of shape dependency. We conclude that the twist-bend phase is a universal phenomenon, which occurs in a wide variety of materials, for dimers through to main chain polymers. In the process, the chemical information on molecular design is effectively lost or irrelevant, and molecular topology takes precedence over electrostatic interactions in mesophase formation. As a consequence of this macro-scale material, engineering by shape alone becomes a possibility, potentially more phases may be realised, and entropy is anisotropic

Geologic map, volcanic stratigraphy and structure of the Cabo de Gata volcanic zone, Betic-Rif orogen, SE Spain

The geologic map of the Neogene Cabo de Gata volcanic zone is presented together with a comprehensive volcanic stratigraphy and structure based on logging, correlation and mapping. Volcanic rocks are interbedded with sedimentary rocks throughout the Cabo de Gata volcanic zone. The volcano-sedimentary succession of Cabo de Gata has been divided into formations according to lithology, age, composition and stratigraphic position. The contacts between sedimentary units and volcanic units and between formations are unconformities. Sedimentary units were deposited during periods of volcanic repose. The depositional environment of volcanism in Cabo de Gata is characterized as shallow-water submarine to emergent based on lithofacies of volcanic rocks and on fossil content and sedimentary structures of sedimentary rocks. The eruptive style in Cabo de Gata is dominantly effusive, although small-volume explosive eruptions due to magma-water interaction processes and to explosions of lava flow and domes complexes occurred.Peer Reviewe