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Spreading depolarizations (SDs) occur spontaneously in the cerebral cortex of subarachnoid hemorrhage, stroke or traumatic brain injury patients. Accumulating evidence prove that SDs exacerbate focal ischemic injury by converting zones of the viable but non-functional ischemic penumbra to the core region beyond rescue. Yet the SD-related mechanisms to mediate neurodegeneration remain poorly understood. Here we show in the cerebral cortex of isoflurane-anesthetized, young and old laboratory rats, that SDs propagating under ischemic penumbra-like conditions decrease intra and- extracellular tissue pH transiently to levels, which have been recognized to cause tissue damage. Further, tissue pH after the passage of each spontaneous SD event remains acidic for over 10 minutes. Finally, the recovery from SD-related tissue acidosis is hampered further by age. We propose that accumulating acid load is an effective mechanism for SD to cause delayed cell death in the ischemic nervous tissue, particularly in the aged brain.

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Spreading depolarizations of long cumulative duration have been implicated in lesion development and progression in patients with stroke and traumatic brain injury. Spreading depolarizations evolve less likely in the aged brain, but it remains to be determined at what age the susceptibility to spreading depolarizations starts to decline, especially in ischemia. Spreading depolarizations were triggered by epidural electric stimulation prior and after ischemia induction in the cortex of 7-30 weeks old anesthetized rats (n ¼ 38). Cerebral ischemia was achieved by occlusion of both common carotid arteries. Spreading depolarization occurrence was confirmed by the acquisition of DC potential and electrocorticogram. Cerebral blood flow variations were recorded by laser-Doppler flowmetry. Dendritic spine density in the cortex was determined in Golgi-COX stained sections. Spreading depolarization initiation required increasingly greater electric charge with older age, a potential outcome of consolidation of cortical connections, indicated by altered dendritic spine distribution. The threshold of spreading depolarization elicitation increased with ischemia in all age groups, which may be caused by tissue acidosis and increased K þ conductance, among other factors. In conclusion, the brain appears to be the most susceptible to spreading depolarizations at adolescent age; therefore, spreading depolarizations may occur in young patients of ischemic or traumatic brain injury at the highest probability.

We demonstrate that signal-to-noise ratio (SNR) can be significantly improved by stochastic resonance in a double well potential. The overdamped dynamical system was studied using mixed signal simulation techniques. The system was driven by wideband Gaussian white noise and a periodic pulse train with variable amplitude and duty cycle. Operating the system in the non-linear response range, we obtained SNR gains much greater than unity. In addition to the classical SNR definition, the ratio of the total power of the signal to the power of the noise part was also measured and it showed better signal improvement.

Poly(3-octylthiophene)/silver nanocomposites (P3OT/Ag) were prepared by impregnating the polymer powder in silver perchlorate salt solutions. The total silver content, up to 6 wt %, was determined by inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The electric conductivities of the composites were measured and correlated with the silver content. Conductivity increased by more than 5 orders of magnitude with silver doping. The incorporated silver was speciated by X-ray diffraction (XRD). Silver was found in the form of both Ag and AgCl, predominantly in metallic nanocrystallites. The size distribution of the nanoparticles, determined from transmission electron microscopy (TEM), was found to be bimodal with two maxima around 3 and 17 nm, correlating with the two forms of silver in the composite. Increased conductivity was interpreted by results obtained by photoacoustic Fourier transform infrared spectroscopy (PAS-FTIR). The observed large Seebeck coefficient of P3OT is promising from the point of view of thermoelectric application.

Background and purpose:The Na + /Ca 2+ exchanger (NCX) may contribute to triggered activity and transmural dispersion of repolarization, which are substrates of torsades de pointes (TdP) type arrhythmias. This study examined the effects of selective inhibition of the NCX by SEA0400 on the occurrence of dofetilide-induced TdP. Experimental approach: Effects of SEA0400 (1 mmol·L ) were also tested against dofetilide-induced TdP. Key results: Acute AV block caused a chaotic idioventricular rhythm and strikingly increased beat-to-beat variability of the RR and QT intervals. SEA0400 exaggerated the dofetilide-induced increase in the heart rate-corrected QT interval (QTc) and did not reduce the incidence of dofetilide-induced TdP [100% in the SEA0400 + dofetilide group vs. 75% in the dofetilide (100 nmol·L -1) control]. In the second set of experiments, verapamil further increased the dofetilide-induced QTc prolongation and neither verapamil nor lidocaine reduced the dofetilide-induced increase in the beat-to-beat variability of the QT interval. However, lidocaine decreased and verapamil prevented the development of dofetilide-induced TdP as compared with the dofetilide control (TdP incidence: 13%, 0% and 88% respectively). Conclusions and implications: Na + /Ca 2+ exchanger does not contribute to dofetilide-induced TdP, whereas Na + and Ca 2+ channel activity is involved in TdP genesis in isolated, AV-blocked rabbit hearts. Neither QTc prolongation nor an increase in the beat-to-beat variability of the QT interval is a sufficient prerequisite of TdP genesis in rabbit hearts.

Background and purpose: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or a-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in a 1 -adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or a-chloralose were infused simultaneously with the a 1 -adrenoceptor agonist phenylephrine (15 mg kg À1 min À1 , i.v.) and dofetilide (0.04 mg kg À1 min À1 , i.v.). The electrocardiographic QT interval, the T peak -T end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilideinduced torsades de pointes (TdP) as compared with the results with a-chloralose (40% (P ¼ 0.011) and 70% (P ¼ 0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with a-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the a-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared. (2008) 153, 75-89; doi:10.1038/sj.bjp.0707536; published online 29 October 2007 Keywords: intravenous anaesthesia; pentobarbital; propofol; a-chloralose; torsades de pointes; pro-arrhythmia; dofetilide; a 1 -adrenoceptor stimulation; phenylephrine; rabbit Abbreviations: ECG, electrocardiogram; PNN8, percentage of successive QT intervals that differ by more than 8 ms; RMSSD, root mean square of the successive differences in the RR or QT intervals; SAP MF, spectral power of the systolic arterial pressure in the mid-frequency range British Journal of Pharmacology