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

Neutrophil-Related Oxidants Drive Heart and Brain Remodeling After Ischemia/Reperfusion Injury

The inflammatory response associated with myocardial and brain ischemia/reperfusion injury (IRI) is a critical determinant of tissue necrosis, functional organ recovery, and long-term clinical outcomes. In the post-ischemic period, reactive oxygen species (ROS) are involved in tissue repair through the clearance of dead cells and cellular debris. Neutrophils play a critical role in redox signaling due to their early recruitment and the large variety of released ROS. Noteworthy, ROS generated during IRI have a relevant role in both myocardial healing and activation of neuroprotective pathways. Anatomical and functional differences contribute to the responses in the myocardial and brain tissue despite a significant gene overlap. The exaggerated activation of this signaling system can result in adverse consequences, such as cell apoptosis and extracellular matrix degradation. In light of that, blocking the ROS cascade might have a therapeutic implication for cardiomyocyte and neuronal loss after acute ischemic events. The translation of these findings from preclinical models to clinical trials has so far failed because of differences between humans and animals, difficulty of agents to penetrate into specific cellular organs, and specifically unravel oxidant and antioxidant pathways. Here, we update knowledge on ROS cascade in IRI, focusing on the role of neutrophils. We discuss evidence of ROS blockade as a therapeutic approach for myocardial infarction and ischemic stroke

The Bio-Molecular Dynamics of Dental Pulp in Different Clinical Scenarios

Dental pulp (DP) is a very dynamic tissue both in health and in disease. When exposed to stressors and pathological conditions. It undergoes a complex series of biological reactions whereby alterations affect the pulp tissue at tissue cellular and molecular levels. The aim of this review is to update the reader on the various bio-molecular alterations in the dental pulp under different clinical conditions: orthodontic treatment (OT), caries, pulpitis and others. The morphological changes in the composition of the DP rang from the reversible remodeling to apoptosis and sometimes necrosis. Many apoptotic factors are involved like Bcl2, Bax and the significant increase in Caspases 9 and 3, as well as, Hsp60, its possible role and its mitochodrial localization. The inflammatory responses in dental pulp and the role of diffusible and cellular factors as well as DP stem cells were highlighted, in particular, where caries was involved in the pulpitis.Recent data report changes in tissue metabolism and homeostasis inside the DP caused by OT leading to increased levels of iNOS reactivity in the nerve fibers of the pulp. Moreover, remodeling of the extra cellular matrix(ECM) is an important feature in clinical scenarios like OT and caries whereby alterations in MMP-2 and MMP-9 expression patterns are reported leading to degradation of type IV and V collagens in the ECM. Furthermore, neurogenic factors are also modified after injuries and OT. Neuropeptides play a significant role not onlyin pain perception but also in vascular responses. Substance P increases in DP and enhances pain perception and so is the increase in CGRP which is correlated with concomitant gain in bone morphogenetic protein expression resulting in more dentin formation. The role of stem cells and the possible molecular mechanisms of dentin genesis are presented in this review. They focus on important signaling proteins and the possible role of various scaffolds in this regeneration process. In conclusion, most alterations inpulpal structure are reversible unless the pulp has a history of caries, restorations, trauma or prolonged heavy orthodontic forces. Pulpal symptoms arising from these clinical conditions should be treated appropriately and swiftly.Otherwise, exacerpation of pulpitis and the interplay of the various bio-molecular factors will lead to inhibition of repair and regeneration

Dynamic models for Large Eddy Simulation of compressible flows with a high order DG method

The impact of dynamic models for applications to LES of compressible flows is assessed in the framework of a numerical model based on high order discontinuous finite elements. The projections onto lower dimensional subspaces associated with lower degree basis functions are used as LES filter, along the lines proposed in Variational Multiscale templates. Comparisons with DNS results available in the literature for plane and constricted channel flows at Mach numbers 0.2, 0.7 and 1.5 show clearly that the dynamic models are able to improve the prediction of most key features of the flow with respect to the Smagorinsky models employed so far in a VMS-DG context

Influence of the angular scattering of electrons on the runaway threshold in air

International audienceThe runaway electron mechanism is of great importance for the understanding of the generation of x- and gamma rays in atmospheric discharges. In 1991, terrestrial gamma-ray flashes (TGFs) were discovered by the Compton Gamma-Ray Observatory. Those emissions are bremsstrahlung from high energy electrons that run away in electric fields associated with thunderstorms. In this paper, we discuss the runaway threshold definition with a particular interest in the influence of the angular scattering for electron energy close to the threshold. In order to understand the mechanism of runaway, we compare the outcome of different FokkerPlanck and Monte Carlo models with increasing complexity in the description of the scattering. The results show that the inclusion of the stochastic nature of collisions smooths the probability to run away around the threshold. Furthermore, we observe that a significant number of electrons diffuse out of the runaway regime when we take into account the diffusion in angle due to the scattering. Those results suggest using a runaway threshold energy based on the FokkerPlanck model assuming the angular equilibrium that is 1.6 to 1.8 times higher than the one proposed by [1, 2], depending on the magnitude of the ambient electric field. The threshold also is found to be 5 to 26 times higher than the one assuming forward scattering. We give a fitted formula for the threshold field valid over a large range of electric fields. Furthermore, we have shown that the assumption of forward scattering is not valid below 1 MeV where the runaway threshold usually is defined. These results are important for the thermal runaway and the runaway electron avalanche discharge mechanisms suggested to participate in the TGF generation

Pica as a pe rsistent eating disorder associated with iron deficiency anae mia: two case reports

Introduction: Pica is a mysterious condition characterised by patients developing cravings for non- nutritive substances that may escalate into serious medical complications. We present two case reports with a somewhat unusual nature of presentation attributed to iron deficiency. The first is a 25-year old African woman with abnormal uterine bleeding presenting with a fondness for eating clay, cold drinks, and icepacks. The second is 15- year old African girl who presented with bleeding from the nose, habitual smelling of soil, consuming ice packs and chewing rubber bands. Both presented with haematological parameters diagnostic of iron deficiency anaemia.Conclusion: Despite being practised for centuries, the clinical significance of pica symptoms is often not recognised particularly among the younger physicians. Both our patients responded well to managing the primary cause of blood loss and iron supplementation. We are convinced that pica is an important pointer to iron deficiency and clinicians should suspect occult blood loss in a patient presenting with pica symptoms.Keywords: pica, eating disorder, iron deficiency anaemia, case repor

A semi-implicit, second-order-accurate numerical model for multiphase underexpanded volcanic jets

Abstract. An improved version of the PDAC (Pyroclastic Dispersal Analysis Code, Esposti Ongaro et al., 2007) numerical model for the simulation of multiphase volcanic flows is presented and validated for the simulation of multiphase volcanic jets in supersonic regimes. The present version of PDAC includes second-order time- and space discretizations and fully multidimensional advection discretizations in order to reduce numerical diffusion and enhance the accuracy of the original model. The model is tested on the problem of jet decompression in both two and three dimensions. For homogeneous jets, numerical results are consistent with experimental results at the laboratory scale (Lewis and Carlson, 1964). For nonequilibrium gas–particle jets, we consider monodisperse and bidisperse mixtures, and we quantify nonequilibrium effects in terms of the ratio between the particle relaxation time and a characteristic jet timescale. For coarse particles and low particle load, numerical simulations well reproduce laboratory experiments and numerical simulations carried out with an Eulerian–Lagrangian model (Sommerfeld, 1993). At the volcanic scale, we consider steady-state conditions associated with the development of Vulcanian and sub-Plinian eruptions. For the finest particles produced in these regimes, we demonstrate that the solid phase is in mechanical and thermal equilibrium with the gas phase and that the jet decompression structure is well described by a pseudogas model (Ogden et al., 2008). Coarse particles, on the other hand, display significant nonequilibrium effects, which associated with their larger relaxation time. Deviations from the equilibrium regime, with maximum velocity and temperature differences on the order of 150 m s−1 and 80 K across shock waves, occur especially during the rapid acceleration phases, and are able to modify substantially the jet dynamics with respect to the homogeneous case

Automated Mapping of Vulnerability Advisories onto their Fix Commits in Open Source Repositories

The lack of comprehensive sources of accurate vulnerability data represents a critical obstacle to studying and understanding software vulnerabilities (and their corrections). In this paper, we present an approach that combines heuristics stemming from practical experience and machine-learning (ML) - specifically, natural language processing (NLP) - to address this problem. Our method consists of three phases. First, an advisory record containing key information about a vulnerability is extracted from an advisory (expressed in natural language). Second, using heuristics, a subset of candidate fix commits is obtained from the source code repository of the affected project by filtering out commits that are known to be irrelevant for the task at hand. Finally, for each such candidate commit, our method builds a numerical feature vector reflecting the characteristics of the commit that are relevant to predicting its match with the advisory at hand. The feature vectors are then exploited for building a final ranked list of candidate fixing commits. The score attributed by the ML model to each feature is kept visible to the users, allowing them to interpret of the predictions. We evaluated our approach using a prototype implementation named Prospector on a manually curated data set that comprises 2,391 known fix commits corresponding to 1,248 public vulnerability advisories. When considering the top-10 commits in the ranked results, our implementation could successfully identify at least one fix commit for up to 84.03% of the vulnerabilities (with a fix commit on the first position for 65.06% of the vulnerabilities). In conclusion, our method reduces considerably the effort needed to search OSS repositories for the commits that fix known vulnerabilities