Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches

So who has the values?: challenges for faith-based schools in an era of values pedagogy

The chapter speaks to the emergence of values pedagogy, understood as a holistic approach to education that focusses on the values that should underpin the environment and drive the practice of education. In this sense, values becomes so all-encompassing and determinative of the educational process that it comes to constitute a comprehensive pedagogy, a way of going about the entire business of education. The past decade has seen a significant increase in emphasis on values pedagogy, in this defined sense, variously titled values education, character education and moral education, across the world, including heavily in governmental and broadly non faith-based educational contexts. The potential of such pedagogy to influence educational outcomes, ranging from socio-emotional to academic outcomes, has been demonstrated in ways that supersede most historical evidence. Granted that most of the earlier evidence about the effects of values pedagogy has come from faith-based contexts, the chapter will explore the challenges for faith-based schools in an era that sees much of its traditional distinctive pedagogy being implemented and arguably perfected more widely outside such contexts

A round robin characterisation of the thickness and composition of thin to ultra-thin AlNO films

International audienceA round robin characterisation of the thickness and composition of thin to ultra-thin AINO films was organised. Thirteen participant groups used various ion beam analysis (IBA) techniques to determine quantitatively the thickness, areal density and concentration of aluminium, nitrogen and oxygen in films with thicknesses ranging nominally from 1 to 100 nm. Most of the ratios reported are not statistically different from the reference values, and only very seldom are large deviations observed. It was not possible to identify a given technique or a group of techniques as being more reliable for analysing the ultra-thin samples. Unexpected deviations in some results reflect a need for further measurements of fundamental quantities, namely cross-sections and stopping powers in energy ranges useful for IBA. Furthermore, precise measurements of beam fluence and detector solid angle would lead to improvements in the accuracy of some of the quantities reported, particularly areal densities. (C) 2004 Elsevier B.V. All rights reserved

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood-brain barrier.

This review considers efflux of substances from brain parenchyma quantified as values of clearances (CL, stated in µL g-1 min-1). Total clearance of a substance is the sum of clearance values for all available routes including perivascular pathways and the blood-brain barrier. Perivascular efflux contributes to the clearance of all water-soluble substances. Substances leaving via the perivascular routes may enter cerebrospinal fluid (CSF) or lymph. These routes are also involved in entry to the parenchyma from CSF. However, evidence demonstrating net fluid flow inwards along arteries and then outwards along veins (the glymphatic hypothesis) is still lacking. CLperivascular, that via perivascular routes, has been measured by following the fate of exogenously applied labelled tracer amounts of sucrose, inulin or serum albumin, which are not metabolized or eliminated across the blood-brain barrier. With these substances values of total CL ≅ 1 have been measured. Substances that are eliminated at least partly by other routes, i.e. across the blood-brain barrier, have higher total CL values. Substances crossing the blood-brain barrier may do so by passive, non-specific means with CLblood-brain barrier values ranging from  1000 for water and CO2. CLblood-brain barrier values for many small solutes are predictable from their oil/water partition and molecular weight. Transporters specific for glucose, lactate and many polar substrates facilitate efflux across the blood-brain barrier producing CLblood-brain barrier values > 50. The principal route for movement of Na+ and Cl- ions across the blood-brain barrier is probably paracellular through tight junctions between the brain endothelial cells producing CLblood-brain barrier values ~ 1. There are large fluxes of amino acids into and out of the brain across the blood-brain barrier but only small net fluxes have been observed suggesting substantial reuse of essential amino acids and α-ketoacids within the brain. Amyloid-β efflux, which is measurably faster than efflux of inulin, is primarily across the blood-brain barrier. Amyloid-β also leaves the brain parenchyma via perivascular efflux and this may be important as the route by which amyloid-β reaches arterial walls resulting in cerebral amyloid angiopathy