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Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model. Here, we report the development of a mouse model for CADASIL via the introduction of a CADASIL-causing Notch3 point mutation into a large P1-derived artificial chromosome (PAC). In vivo expression of the mutated PAC transgene in the mouse reproduced the endogenous Notch3 expression pattern and main pathological features of CADASIL, including Notch3 extracellular domain aggregates and granular osmiophilic material (GOM) deposits in brain vessels, progressive white matter damage, and reduced cerebral blood flow. Mutant mice displayed attenuated myogenic responses and reduced caliber of brain arteries as well as impaired cerebrovascular autoregulation and functional hyperemia. Further, we identified a substantial reduction of white matter capillary density. These neuropathological changes occurred in the absence of either histologically detectable alterations in cerebral artery structure or blood-brain barrier breakdown. These studies provide in vivo evidence for cerebrovascular dysfunction and microcirculatory failure as key contributors to hypoperfusion and white matter damage in this genetic model of ischemic SVD.

The mechanisms responsible for the local increase in brain glucose utilization during functional activation remain unknown. Recent in vitro studies have identified a new signaling pathway involving an activation of glial glutamate transporters and enhancement of neuron–astrocyte metabolic interactions that suggest a putative coupling mechanism. The aim of the present study was to determine whether one of the glutamate transporters exclusively expressed in astrocytes, GLAST, is involved in the neurometabolic coupling in vivo. For this purpose, rats were microinjected into the posteromedial barrel subfield (PMBSF) of the somatosensory cortex with GLAST antisense or random phosphorothioate oligonucleotides. The physiologic activation was performed by stimulating the whisker-to-barrel pathway in anesthetized rats while measuring local cerebral glucose utilization by quantitative autoradiography in the PMBSF. Twenty-four hours after injection of two different antisense GLAST oligonucleotide sequences, and despite the presence of normal whisker-related neuronal activity in the PMBSF, the metabolic response to whisker stimulation was decreased by more than 50%. Injection of the corresponding random sequences still allowed a significant increase in glucose utilization in the activated area. The present study highlights the contribution of astrocytes to neurometabolic coupling in vivo. It provides evidence that glial glutamate transporters are key molecular components of this coupling and that neuronal glutamatergic activity is an important determinant of energy utilization. Results indicate that astrocytes should also be considered as possible sources of altered brain metabolism that could explain the distinct imaging signals observed in some pathologic situations

The aim of the study was to better understand blood-flow changes in large arteries and microvessels during the first 15 minutes of reflow in a P7 rat model of arterial occlusion. Blood-flow changes were monitored by using ultrasound imaging with sequential Doppler recordings in internal carotid arteries (ICAs) and basilar trunk. Relative cerebral blood flow (rCBF) changes were obtained by using laser speckle Doppler monitoring. Tissue perfusion was measured with [14C]-iodoantipyrine autoradiography. Cerebral energy metabolism was evaluated by mitochondrial oxygen consumption. Gradual increase in mean blood-flow velocities illustrated a gradual perfusion during early reflow in both ICAs. On ischemia, the middle cerebral artery (MCA) territory presented a residual perfusion, whereas the caudal territory remained normally perfused. On reflow, speckle images showed a caudorostral propagation of reperfusion through anastomotic connections, and a reduced perfusion in the MCA territory. Autoradiography highlighted the caudorostral gradient, and persistent perfusion in ventral and medial regions. These blood-flow changes were accompanied by mitochondrial respiration impairment in the ipsilateral cortex. Collectively, these data indicate the presence of a primary collateral pathway through the circle of Willis, providing an immediate diversion of blood flow toward ischemic regions, and secondary efficient cortical anastomoses in the immature rat brain.

The generally accepted concept that astrocytes are highly resistant to hypoxic/ischemic conditions has been challenged by an increasing amount of data. Considering the differences in functional implications of protoplasmic versus fibrous astrocytes, the authors have investigated the possibility that those discrepancies come from specific behaviors of the two cell types. The reactivity and fate of protoplasmic and fibrous astrocytes were observed after permanent occlusion of the medial cerebral artery in mice. A specific loss of glial fibrillary acidic protein (GFAP) immunolabeling in protoplasmic astrocytes occurred within minutes in the area with total depletion of regional CBF (rCBF) levels, whereas “classical” astrogliosis was observed in areas with remaining rCBF. Severe disturbance of cell function, as suggested by decreased GFAP content and increased permeability of the blood–brain barrier to macromolecules, was rapidly followed by necrotic cell death, as assessed by ultrastructure and by the lack of activation of the apoptotic protease caspase-3. In contrast to the response of protoplasmic astrocytes, fibrous astrocytes located at the brain surface and in deep cortical layers displayed a transient and limited hypertrophy, with no conspicuous cell death. These results point to a differential sensitivity of protoplasmic versus fibrous cortical astrocytes to blood deprivation, with a rapid demise of the former, adding to the suggestion that protoplasmic astrocytes play a crucial role in the pathogenesis of ischemic injury.

This paper presents the most recent developments in shotcrete technology obtained in the last 5 years through the \"Industrial Chair on Shotcrete and Concrete Repair\" hosted at Laval University. The main goal of this paper is to inform those involved in the construction and repair of civil engineering concrete structures of the various possibilities of \"shotcrete.\" The two first sections present the basic principles in pneumatic application of concrete along with the two processes in shotcrete technology, the dry-mix and wet-mix. The advantages of both processes as well as the general rules to follow in a shotcrete application are also presented and explained. The third and last section, the most important, highlights the latest developments in shotcrete technology. These developments concern the use of set accelerating admixtures in dry process shotcrete and their effects on the durability of materials, the use of liquid and powdered air-entraining admixtures in dry-mix shotcrete as well as the concept of \"high initial air content\" in wet mix shotcrete.Key words: shotcrete, set accelerator, air-entraining admixture, durability, setting time.

The development of a flow forecasting system for public dam management in southern Quebec is presented. The system is based on distributed hydrological models using 3-h time steps to correctly perform short-term forecasts on small watersheds, located upstream of these dams, with quick hydrological responses. The contribution of models in the complete process of forecast evaluation is also studied. A numerical application, using the flood of the Chaudière river in July 2001, illustrated that distributed models with short time steps are needed despite the added complexity in the installation, calibration, and operation of the forecasting system. Also, the analysis of flow forecasted for the Spring 2003 flood shows that interpretation of model runs can lead the operational forecaster to better forecasting of results and can be improved by the use of distributed models.Key words: hydrology, flow forecast, distributed hydrological model, flood.

Real-time assessments of stream flows under ice cover, using two distinct objective approaches, were compared over a 5-year period. Approaches based on artificial neural networks, defining mathematical relationships between stream flow, water level, and air temperature, and on a deterministic hydrological model were applied at eight gauged sites located in southern Quebec. Good results were obtained using both approaches, when no snowmelt contributes to the rise of the inflows. In the other hydrological situations, the neural network results were the best, but results of both approaches were sensibly poorer. Nevertheless, the potential for increasing the skills of the deterministic model seems high. Otherwise, a preliminary analysis showed that both approaches lead to stream-flow estimations that are not radically worse than the ones performed by the team of experts.

Real-time assessments of stream flows under ice cover, using two distinct objective approaches, were compared over a 5-year period. Approaches based on artificial neural networks, defining mathematical relationships between stream flow, water level, and air temperature, and on a deterministic hydrological model were applied at eight gauged sites located in southern Quebec. Good results were obtained using both approaches, when no snowmelt contributes to the rise of the inflows. In the other hydrological situations, the neural network results were the best, but results of both approaches were sensibly poorer. Nevertheless, the potential for increasing the skills of the deterministic model seems high. Otherwise, a preliminary analysis showed that both approaches lead to stream-flow estimations that are not radically worse than the ones performed by the team of experts.Key words: discharge measurement, hydrology, ice-affected stream flow, hydrological modeling, neural network.

The development of a flow forecasting system for public dam management in southern Quebec is presented. The system is based on distributed hydrological models using 3-h time steps to correctly perform short-term forecasts on small watersheds, located upstream of these dams, with quick hydrological responses. The contribution of models in the complete process of forecast evaluation is also studied. A numerical application, using the flood of the Chaudière river in July 2001, illustrated that distributed models with short time steps are needed despite the added complexity in the installation, calibration, and operation of the forecasting system. Also, the analysis of flow forecasted for the Spring 2003 flood shows that interpretation of model runs can lead the operational forecaster to better forecasting of results and can be improved by the use of distributed models.Key words: hydrology, flow forecast, distributed hydrological model, flood.