T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor

Essential tremor is a common disorder that lacks molecular targets for therapeutic development. T-type calcium channel activation has been postulated to underlie rhythmicity in the olivo-cerebellar system that is implicated in essential tremor. We therefore tested whether compounds that antagonize T-type calcium channel currents suppress tremor in two mouse models that possess an essential tremor-like pharmacological response profile. Tremor was measured using digitized spectral motion power analysis with harmaline-induced tremor and in the GABA_A receptor α1 subunit-null model. Mice were given ethosuximide, zonisamide, the neuroactive steroid (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile (ECN), the 3,4-dihydroquinazoline derivative KYS05064, the mibefradil derivative NNC 55-0396, or vehicle. In non-sedating doses, each compound reduced harmaline-induced tremor by at least 50% (range of maximal suppression: 53-81%), and in the GABA_A α1-null model by at least 70% (range 70-93%). Because the T-type calcium channel Cav3.1 is the dominant subtype expressed in the inferior olive, we assessed the tremor response of Cav3.1-deficient mice to harmaline, and found that null and heterozygote mice exhibit as much tremor as wild-type mice. In addition, ECN and NNC 55-0396 suppressed harmaline tremor as well in Cav3.1-null mice as in wild-type mice. The finding that five T-type calcium antagonists suppress tremor in two animal tremor models suggests that T-type calcium channels may be an appropriate target for essential tremor therapy development. It is uncertain whether medications developed to block only the Cav3.1 subtype would exhibit efficacy.     

Sedimentation Patterns of Toxin-Producing Microcystis Morphospecies in Freshwater Reservoirs

Understanding the annual cycle of Microcystis is essential for managing the blooms of this toxic cyanobacterium. The current work investigated the sedimentation of microcystin-producing Microcystis spp. in three reservoirs from Central Spain during the summer and autumn of 2006 and 2007. We confirmed remarkable settling fluxes during and after blooms ranging 10⁶–10⁹ cells m⁻² d⁻¹, which might represent 0.1%–7.6% of the organic matter settled. A comprehensive analysis of the Valmayor reservoir showed average Microcystis settling rates (0.04 d⁻¹) and velocities (0.7 m d⁻¹) that resembled toxin settling in the same reservoir and were above most reported elsewhere. M. aeruginosa settling rate was significantly higher than that of M. novacekii and M. flos-aquae. Despite the fact that colony sizes did not differ significantly in their average settling rates, we observed extremely high and low rates in large colonies (>5000 cells) and a greater influence of a drop in temperature on small colonies (<1000 cells). We found a 4–14 fold decrease in microcystin cell quota in settling Microcystis of the Cogotas and Valmayor reservoirs compared with pelagic populations, and the hypothetical causes of this are discussed. Our study provides novel data on Microcystis settling patterns in Mediterranean Europe and highlights the need for including morphological, chemotypical and physiological criteria to address the sedimentation of complex Microcystis populations.     

Infarto cerebeloso: pronóstico y complicaciones de sus territorios vasculares

Introduction

Cerebellar infarction (CI) is uncommon, but may result in severe complications. The aim of our study was to determine the characteristics of patients with CI, as well as their outcomes as regards the territories affected.

Patients and methods

Data were collected from 124 patients admitted to our department during a five-year period, with a radiological diagnosis of CI, and with or without involvement of other brain territories.

Results

The mean age in our series was 65.2 years, with most being male (68.5%). The posterior inferior cerebellar artery (PICA) was the most commonly affected territory at 49.2%, followed by superior cerebellar artery (SCA) at 17.7%, and anterior inferior cerebellar artery (AICA) at 10.5%. There was simultaneous supratentorial involvement in 13.7%, and two or three cerebellar arteries involved in 8.9%. The main aetiology in PICA was atherothrombosis (P = .02). On the other hand, cardio-embolism was the main origin in cases with more than one affected territory (P = .04). No particular aetiology could be found in SCA and AICA. There was haemorrhagic transformation in 29 patients (23.4%), particularly in the PICA and when other territories were involved. There was hydrocephalus in 15 patients (12.1%, 12 of them PICA; P = .02) in 2.9 ± 1.5 days from stroke onset. At discharge, the degree of disability was worse if more than one arterial territory was involved (Rankin ≥ 3, 64% versus 31-36%; P = .05). Four (3.2%) patients died.

Conclusions

CI is very heterogeneous. Nevertheless, it is noteworthy that PICA infarction is the most frequent type and its aetiology is usually atherothrombotic. Moreover, it is the territory most frequently associated with severe complications, which take place during the first week of the stroke.