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Introduction Ischemic cerebral small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Most ischemic cerebral SVDs involve a diffuse arteriopathy [...], 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.

Abstract Background The over-expression of transforming growth factor β-1(TGF-β1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidβ (Aβ) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-β1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-β1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Aβ-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-β1-induced pathology. Methods Two-month-old TGF-β1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Aβ precursor protein (APP) by western blot analysis; Aβ deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means ± SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. Results Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Aβ or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Aβ42- with no change in APP contents – while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. Conclusions i) TGF-β1 over-expressing mice may not be an appropriate model of Aβ-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-β1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-β1 actions in brain.

Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC) and that Notch3 is required for arterial specification of vSMC but not of endothelial cells. The data from observation on Notch3 mice reveal Notch3 to be first cell-autonomous regulator of arterial differentiation and maturation of vSMC.

Abstract: A mass balance is formulated to evaluate the mobilization of chlorinated ethene compounds (CE) from the rock matrix of a fractured mudstone aquifer under pre‐ and postbioremediation conditions. The analysis relies on a sparse number of monitoring locations and is constrained by a detailed description of the groundwater flow regime. Groundwater flow modeling developed under the site characterization identified groundwater fluxes to formulate the CE mass balance in the rock volume exposed to the injected remediation amendments. Differences in the CE fluxes into and out of the rock volume identify the total CE mobilized from diffusion, desorption, and nonaqueous phase liquid dissolution under pre‐ and postinjection conditions. The initial CE mass in the rock matrix prior to remediation is estimated using analyses of CE in rock core. The CE mass mobilized per year under preinjection conditions is small relative to the total CE mass in the rock, indicating that current pump‐and‐treat and natural attenuation conditions are likely to require hundreds of years to achieve groundwater concentrations that meet regulatory guidelines. The postinjection CE mobilization rate increased by approximately an order of magnitude over the 5 years of monitoring after the amendment injection. This rate is likely to decrease and additional remediation applications over several decades would still be needed to reduce CE mass in the rock matrix to levels where groundwater concentrations in fractures achieve regulatory standards. [ABSTRACT FROM AUTHOR]

Abstract: Field characterization of a trichloroethene (TCE) source area in fractured mudstones produced a detailed understanding of the geology, contaminant distribution in fractures and the rock matrix, and hydraulic and transport properties. Groundwater flow and chemical transport modeling that synthesized the field characterization information proved critical for designing bioremediation of the source area. The planned bioremediation involved injecting emulsified vegetable oil and bacteria to enhance the naturally occurring biodegradation of TCE. The flow and transport modeling showed that injection will spread amendments widely over a zone of lower‐permeability fractures, with long residence times expected because of small velocities after injection and sorption of emulsified vegetable oil onto solids. Amendments transported out of this zone will be diluted by groundwater flux from other areas, limiting bioremediation effectiveness downgradient. At nearby pumping wells, further dilution is expected to make bioremediation effects undetectable in the pumped water. The results emphasize that in fracture‐dominated flow regimes, the extent of injected amendments cannot be conceptualized using simple homogeneous models of groundwater flow commonly adopted to design injections in unconsolidated porous media (e.g., radial diverging or dipole flow regimes). Instead, it is important to synthesize site characterization information using a groundwater flow model that includes discrete features representing high‐ and low‐permeability fractures. This type of model accounts for the highly heterogeneous hydraulic conductivity and groundwater fluxes in fractured‐rock aquifers, and facilitates designing injection strategies that target specific volumes of the aquifer and maximize the distribution of amendments over these volumes. [ABSTRACT FROM AUTHOR]