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Background and Purpose-Functional stimulation is accompanied by increases in regional cerebral blood flow which exceed metabolic demands under normal circumstances, but it is unknown whether functional stimulation is beneficial or detrimental in the setting of acute ischemia. The aim of this study was to determine the effect of forepaw stimulation during temporary focal ischemia on neurological and tissue outcome in a rat model of reversible focal forebrain ischemia. Methods-Sprague-Dawley rats were prepared for temporary occlusion of the right middle cerebral artery (MCA) using the filament model. Cerebral blood flow in the MCA territory was continuously monitored with a laser-Doppler flowmeter. Subdermal electrodes were inserted into the dorsal forepaw to stimulate either the forepaw ipsilateral or contralateral to the occlusion starting 1 minute into ischemia and continuing throughout the ischemic period. A neurological evaluation was undertaken after 24 hours of reperfusion, and animals were then euthanized and brain slices stained with 2,3,5-triphenyltetrazolium chloride. Cortical and striatal damage was measured separately. Results-The cortical and striatal infarct volumes were both significantly reduced in the contralateral stimulated group compared with the ipsilateral stimulated group (48% total reduction). There were no statistically significant differences in the neurobehavioral scores between the 2 groups, or in the laser-Doppler flow measurements from the MCA core. Conclusions-Functional stimulation of ischemic tissue may decrease tissue damage and improve outcome from stroke.Although the precise mechanism of this effect remains to be determined, functional stimulation could readily be translated to clinical practice. Key Words: cerebral ischemia, focal Ⅲ electrical stimulation therapy Ⅲ middle cerebral artery occlusion T here remains intense interest in discovering novel neuroprotective therapies for use in acute cerebral ischemia. Most recent research efforts have focused on compounds designed to interfere with the cascade of deleterious events that occur in tissue during and in the minutes and hours after cerebral ischemia. 1 Although many compounds have been investigated, to-date none have proven clinically useful in humans. 2,3 Nonpharmacological treatment techniques, such as hypothermia and hyperoxemia, have also been proposed, 4 but it remains to be seen how they transfer from laboratory to bedside. There are even studies suggesting that electrical stimulation of the cerebellar fastigial nucleus 5,6 before ischemia, or the spinal cord 7-9 weeks and months after the ischemic insult can reduce damage.Functional stimulation is accompanied by an increase in regional cerebral blood flow (CBF) in activated brain regions. We have shown previously in a rat model of graded cerebral ischemia that when CBF is reduced by as much as 90%, forepaw stimulation is still able to elicit an increase in blood flow in the somatosensory cortex, 10 and studies in stroke patients demonstrate that CBF can be activated...

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The fractional Brownian motion is a generalization of ordinary Brownian motion, used particularly when long-range dependence is required. Its explicit introduction is due to B.B. Mandelbrot and J.W. van Ness (1968) as a self-similar Gaussian process W (H) (t) with stationary increments. Here self-similarity means that (a −H W (H) (at) : t ≥ 0) d = (W (H) (t) : t ≥ 0), where H ∈ (0, 1) is the Hurst parameter of fractional Brownian motion.F.B. Knight gave a construction of ordinary Brownian motion as a limit of simple random walks in 1961. Later his method was simplified by P. Révész (1990) and then by the present author (1996). This approach is quite natural and elementary, and as such, can be extended to more general situations. Based on this, here we use moving averages of a suitable nested sequence of simple random walks that almost surely uniformly converge to fractional Brownian motion on compacts when H ∈ ( 1 4 , 1). The rate of convergence proved in this case is O(N − min(H− 1 4 , 1 4 ) log N ), where N is the number of steps used for the approximation.If the more accurate (but also more intricate) Komlós, Major, Tusnády (1975, 1976 approximation is used instead to embed random walks into ordinary Brownian motion, then the same type of moving averages almost surely uniformly converge to fractional Brownian motion on compacts for any H ∈ (0, 1). Moreover, the convergence rate is conjectured to be the best possible O(N −H log N ), though only O(N − min(H, 1 2 ) log N ) is proved here.

Spreading depolarizations are accompanied by transient changes in cerebral blood flow (CBF). In a post-hoc analysis of previously studied control rats we analysed CBF time courses after middle cerebral artery occlusion in the rat in order to test whether intra-ischemic flow, reperfusion, and different parameters of peri-infarct flow transients (PIFTs) (amplitude, number) can predict outcome. Sprague-Dawley rats anesthetized with either halothane (n=23) or isoflurane (n=32) underwent 90-minute filament occlusion of the middle cerebral artery followed by 72 hours of reperfusion. The infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Relative CBF changes were monitored by laser Doppler flowmetry at 4–5 mm lateral, and 1–2 mm posterior to Bregma. An additional filament occlusion study (n=12) was performed to validate that PIFTs were coupled to direct current shifts of spreading depolarization. The PIFT-direct current shift study revealed that every PIFT was associated with a negative direct current shift typical of spreading depolarization. Post-hoc analysis showed that the number of PIFTs, especially with the combination of intra-ischemic level of flow, can predict the development of cortical infarcts. These findings show that PIFTs can serve as an early biomarker in predicting outcome in preclinical animal studies.

In the lifetime of an individual, every single gene will have undergone mutation on about 10¹⁰ separate occasions. Nevertheless, cancer occurs mainly with advancing age. Here, we hypothesize that the evolutionary pressure driving the creation of the T cell receptor (TCR) repertoire was primarily the homeostatic surveillance of the genome. The subtly variable T cells may in fact constitute an evolutionary link between the invariable innate and hypervariable B cell systems. The new model is based on the homeostatic role of T cells, suggesting that molecular complementarity between the positively selected TCR and the self peptide-presenting major histocompatibility complex molecules establishes and regulates homeostasis, strictly limiting variations of its components. Notwithstanding, the ‘homeostatic role of T cells’ model offers a more realistic explanation as to how a naïve clonal immune system can cope with the much faster replicating pathogens, despite a limited repertoire that is capable of facing only a small fraction of the vast antigenic universe at a time.

In this paper we define Brownian local time as the almost sure limit of the local times of a nested sequence of simple, symmetric random walks. The limit is jointly continuous in (t, x). The rate of convergence is n 1 4 (log n) 3 4 that is close to the best possible. The tools we apply are almost exclusively from elementary probability theory.