A low mortality, high morbidity reduced intensity status epilepticus (RISE) model of epilepsy and epileptogenesis in the rat

Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles.

Evaluation of moisture sources for the Central European summer flood of May/June 2013 based on regional climate model simulations

Heavy precipitation affected Central Europe in May/June 2013, triggering damaging floods both on the Danube and the Elbe rivers. Based on a modelling approach with COSMO-CLM, moisture fluxes, backward trajectories, cyclone tracks and precipitation fields are evaluated for the relevant time period 30 May–2 June 2013. We identify potential moisture sources and quantify their contribution to the flood event focusing on the Danube basin through sensitivity experiments: Control simulations are performed with undisturbed ERA-Interim boundary conditions, while multiple sensitivity experiments are driven with modified evaporation characteristics over selected marine and land areas. Two relevant cyclones are identified both in reanalysis and in our simulations, which moved counter-clockwise in a retrograde path from Southeastern Europe over Eastern Europe towards the northern slopes of the Alps. The control simulations represent the synoptic evolution of the event reasonably well. The evolution of the precipitation event in the control simulations shows some differences in terms of its spatial and temporal characteristics compared to observations. The main precipitation event can be separated into two phases concerning the moisture sources. Our modelling results provide evidence that the two main sources contributing to the event were the continental evapotranspiration (moisture recycling; both phases) and the North Atlantic Ocean (first phase only). The Mediterranean Sea played only a minor role as a moisture source. This study confirms the importance of continental moisture recycling for heavy precipitation events over Central Europe during the summer half year.

Rossby wave propagation on potential vorticity fronts with finite width

The horizontal gradient of potential vorticity (PV) across the tropopause typically declines with lead time in global numerical weather forecasts and tends towards a steady value dependent on model resolution. This paper examines how spreading the tropopause PV contrast over a broader frontal zone affects the propagation of Rossby waves. The approach taken is to analyse Rossby waves on a PV front of finite width in a simple single-layer model. The dispersion relation for linear Rossby waves on a PV front of infinitesimal width is well known; here an approximate correction is derived for the case of a finite width front, valid in the limit that the front is narrow compared to the zonal wavelength. Broadening the front causes a decrease in both the jet speed and the ability of waves to propagate upstream. The contribution of these changes to Rossby wave phase speeds cancel at leading order. At second order the decrease in jet speed dominates, meaning phase speeds are slower on broader PV fronts. This asymptotic phase speed result is shown to hold for a wide class of single-layer dynamics with a varying range of PV inversion operators. The phase speed dependence on frontal width is verified by numerical simulations and also shown to be robust at finite wave amplitude, and estimates are made for the error in Rossby wave propagation speeds due to the PV gradient error present in numerical weather forecast models.

Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and are typically associated with deficient in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1R antagonists. Of further interest are various findings that CB1R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky2J’ model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.

1,8-cineol potentiates IRF3-mediated antiviral response in human stem cells and an ex vivo model of rhinosinusitis

Common cold is one of the most frequent human inflammatory diseases caused by viruses and can facilitate bacterial super-infections resulting in sinusitis or pneumonia. The active ingredient of the drug Soledum, 1,8-cineole, is commonly applied for treating inflammatory diseases of the respiratory tract. However, the potential of 1,8-cineole for treating primary viral infections of the respiratory tract remains unclear. In the present study, we demonstrate for the first time that 1,8-cineole potentiates Poly(I:C)-induced activity of the anti-viral transcription factor Interferon Regulatory Factor 3, while simultaneously reducing pro-inflammatory NF-κB-activity in human cell lines, inferior turbinate stem cells (ITSCs) and ex vivo cultivated human nasal mucosa. Co-treatment of cell lines with Poly(I:C) and 1,8-cineole resulted in significantly increased IRF3 reporter gene activity compared to Poly(I:C) alone, whereas NF-κB-activity was reduced. Accordingly, 1,8-cineole- and Poly(I:C)-treatment led to increased nuclear translocation of IRF3 in ITSCs and a human ex vivo model of rhinosinusitis compared to the Poly(I:C)-treated approach. Nuclear translocation of IRF3 was significantly increased in ITSCs and slice cultures treated with LPS and 1,8-cineole compared to the LPS-treated cells mimicking bacterial infection. Our findings strongly suggest that 1,8-cineole potentiates the antiviral activity of IRF3 in addition to its inhibitory effect on pro-inflammatory NF-κB-signalling and may thus broaden its field of application.

Uncertainties in tidally adjusted estimates of sea level rise flooding (bathtub model) for the Greater London

Sea-level rise (SLR) from global warming may have severe consequences for coastal cities, particularly when combined with predicted increases in the strength of tidal surges. Predicting the regional impact of SLR flooding is strongly dependent on the modelling approach and accuracy of topographic data. Here, the areas under risk of sea water flooding for London boroughs were quantified based on the projected SLR scenarios reported in Intergovernmental Panel on Climate Change (IPCC) fifth assessment report (AR5) and UK climatic projections 2009 (UKCP09) using a tidally-adjusted bathtub modelling approach. Medium- to very high-resolution digital elevation models (DEMs) are used to evaluate inundation extents as well as uncertainties. Depending on the SLR scenario and DEMs used, it is estimated that 3%–8% of the area of Greater London could be inundated by 2100. The boroughs with the largest areas at risk of flooding are Newham, Southwark, and Greenwich. The differences in inundation areas estimated from a digital terrain model and a digital surface model are much greater than the root mean square error differences observed between the two data types, which may be attributed to processing levels. Flood models from SRTM data underestimate the inundation extent, so their results may not be reliable for constructing flood risk maps. This analysis provides a broad-scale estimate of the potential consequences of SLR and uncertainties in the DEM-based bathtub type flood inundation modelling for London boroughs.