Therapeutic potential of the renin angiotensin system in ischaemic stroke

The renin angiotensin system (RAS) consists of the systemic hormone system, critically involved in regulation and homeostasis of normal physiological functions [i.e. blood pressure (BP), blood volume regulation], and an independent brain RAS, which is involved in the regulation of many functions such as memory, central control of BP and metabolic functions. In general terms, the RAS consists of two opposing axes; the ‘classical axis’ mediated primarily by Angiotensin II (Ang II), and the ‘alternative axis’ mediated mainly by Angiotensin-(1–7) (Ang-(1–7)). An imbalance of these two opposing axes is thought to exist between genders and is thought to contribute to the pathology of cardiovascular conditions such as hypertension, a stroke co-morbidity. Ischaemic stroke pathophysiology has been shown to be influenced by components of the RAS with specific RAS receptor antagonists and agonists improving outcome in experimental models of stroke. Manipulation of the two opposing axes following acute ischaemic stroke may provide an opportunity for protection of the neurovascular unit, particularly in the presence of pre-existing co-morbidities where the balance may be shifted. In the present review we will give an overview of the experimental stroke studies that have investigated pharmacological interventions of the RAS

An examination of ischaemic penumbra in the spontaneously hypertensive stroke-prone rat (SHRSP) using the MRI perfusion-diffusion mismatch model

Stroke accounts for 9% of all deaths worldwide and is a major cause of severe disability (Donnan et al, 2008). Following ischaemic stroke, the penumbra represents tissue which is hypoperfused and functionally impaired but is not yet irreversibly damaged. However, the penumbra has a finite lifespan and will proceed to infarction in the absence of swift reperfusion. Therefore, the identification and potential salvage of penumbral tissue in acute ischaemic stroke is the ultimate goal for both clinicians and experimental stroke researchers. Positron emission tomography (PET) is the ‘gold standard’ imaging modality for identifying the penumbra, but the complex logistics of PET limit its widespread use. Magnetic Resonance Imaging (MRI) is widely used for penumbra imaging in both clinical and pre-clinical research. The MRI perfusion-diffusion mismatch model provides an approximation of the penumbra, where diffusion weighted imaging (DWI) identifies the core of ischaemic injury and perfusion weighted imaging (PWI) reveals the perfusion deficit. The mismatch between the DWI and PWI provides a measure of penumbral tissue. However, there is no consensus on the perfusion and diffusion thresholds used to identify mismatch tissue in clinical and preclinical stroke research. Furthermore, in rodent stroke models differences in the evolution of ischaemic injury between strains may limit the use of a single set of threshold values. Therefore, the first aim of this thesis was to establish strain specific perfusion and diffusion thresholds to compare penumbra volume in the clinically relevant spontaneously hypertensive stroke-prone rat (SHRSP) and the normotensive control strain, Wistar-Kyoto (WKY) using 3 different methods. The SHRSP strain is characterised by the progressive development of severe hypertension which is followed by a tendency to spontaneous stroke and an increased sensitivity to experimental stroke. Experimental stroke was induced by permanent middle cerebral artery occlusion (MCAO) by the intraluminal filament method. DWI and PWI were obtained every hour from 1-4 hours post-MCAO. Strain-specific diffusion and perfusion thresholds were established from final infarct at 24 hours post-MCAO, as defined by T2 weighted imaging. The calculated ADC thresholds were comparable between the strains but the absolute perfusion threshold was significantly higher in SHRSP compared to WKY. This may be indicative of an increased sensitivity to ischaemia in the hypertensive strain. Furthermore, application of these thresholds to the acute MRI data revealed that the volume of ischaemic injury and the perfusion deficit were significantly larger in SHRSP compared to WKY and this was also reflected in the significantly larger infarct volume observed in SHRSP at 24 hours post-MCAO. Interestingly, there was evidence of a temporal increase in the volume of the perfusion deficit in SHRSP and WKY. This may indicate that there is a progressive failure of collateral blood supply in both strains following stroke. Penumbra volume was then assessed in SHRSP and WKY rats using the mismatch method and also indirectly by examining the growth of the volume of ADC derived ischaemic injury. Mismatch volume was determined by arithmetic subtraction of the volume of ischaemic injury from the volume of perfusion deficit (volumetric method) and also by manual delineation of mismatch on each of 6 coronal slices (spatial method). There was a limited volume of mismatch tissue in either strain from as early as 1 hour post-MCAO and the volumetric method generated smaller mismatch volumes than the spatial mismatch method. Mismatch volume was comparable in SHRSP and WKY from 1-4 hours post-MCAO. Penumbra was also determined retrospectively by subtracting the volume of ischaemic injury at each time point from final infarct volume. Using this method, penumbra volume was significantly larger in WKY compared to SHRSP at 30 minutes post-MCAO but penumbra volume was comparable at all later time points. This suggests that there is reduced potential for tissue salvage in SHRSP compared to WKY within the first hour following MCAO but from 1 hour onwards, there is limited potential for penumbra salvage in both strains. In addition, there was evidence of ‘negative’ mismatch tissue in SHRSP and WKY rats, where the ADC derived lesion expanded beyond the boundary of the perfusion deficit. The volume of negative mismatch tissue was comparable between the strains and was persistent over the 4 hour time course. This phenomenon may arise from the spread of toxic mediators from the ischaemic core. Oxidative stress is a major mediator of cellular injury following ischaemic stroke and reactive oxygen species, like superoxide, have multiple deleterious effects on the components of the neurovascular unit. It is well established that NADPH oxidase is the principal source of superoxide in acute ischaemic stroke and is therefore a target for potential neuroprotective strategies (Moskowitz et al, 2010). Consequently, the second aim of this thesis was to evaluate the potential neuroprotective effect of NADPH oxidase inhibition with low and high dose apocynin following permanent or transient ischaemia. Rats were administered apocynin at a dose of 5mg/kg or 30mg/kg or vehicle, at 5 minutes post-MCAO. Apocynin treatment had no significant effect on infarct volume or functional outcome at 24 hours following permanent MCAO in WKY rats. However, both low and high dose apocynin treatment significantly reduced infarct volume at 72 hours post-MCAO by 60% following 1 hour of ischaemia in Sprague-Dawley rats. Furthermore, functional outcome was improved in the low dose apocynin treated group, although this did not reach the level of statistical significance. On the basis of these results, low dose apocynin treatment was evaluated in SHRSP rats following 1 hour of ischaemia. However, apocynin treatment had no effect on the acute evolution of ischaemic injury and failed to improve stroke outcome, where the mortality rate was high in both the apocynin treated and the vehicle treated group. The conflicting effects of apocynin may be attributable to a differential expression of NADPH oxidase subunits in normotensive and hypertensive rat strains. These findings may also explain the failure of neuroprotective drugs to translate from bench to bedside, as therapies which are neuroprotective in young healthy animals may not demonstrate the same efficacy in animal models with stroke co-morbidities. Therefore, potential therapeutic strategies should be extensively evaluated in animal models with stroke risk factors before proceeding to clinical trial

Making roughness : shaping site at Granger Bay

Includes abstract.Includes bibliographical references.This project is about "roughness" at all scales . It is about Landings: land and sea and Granger Bay. It is about deposition and erosion; heaving rubble and anchored shale. It is about a working "landschaft" of multiple overlapping contested uses. It is about abstracting natural forces to create architecture

THE FORMATION OF SMALL-SCALE GLACIAL FLUTES: A CASE STUDY OF THE CASTLE CREEK FOREFIELD, CARIBOO MOUNTAINS, BC

The forefield of Castle Creek in the Caribou Mountains of B.C. contains abundant well developed small-scale glacial landforms. Detailed maps of flutes and annual moraines were produced from aerial photography and selected flutes were mapped in the field, together with sedimentological and fabric analyses. The results revealed a number of flutes with differing morphologies; long parallel-sided flutes and shorter tapering flutes, which become shorter and narrower with distance down flute, exist in different areas of the forefield. In addition there are flutes with bedrock ridges at their ice proximal ends, which appear similar to crag and tail features. Grain size and fabric patterns within flutes, were similar to those found by Benn and Evans (1996) from studies in Europe and support the sediment deformation hypothesis of Boulton (1987). These results highlight the importance of grain size and pore water pressure in creating conditions for deformation to occur

Animal models of ischaemic stroke and characterisation of the ischaemic penumbra

Over the past forty years, animal models of focal cerebral ischaemia have allowed us to identify the critical cerebral blood flow thresholds responsible for irreversible cell death, electrical failure, inhibition of protein synthesis, energy depletion and thereby the lifespan of the potentially salvageable penumbra. They have allowed us to understand the intricate biochemical and molecular mechanisms within the ‘ischaemic cascade’ that initiate cell death in the first minutes, hours and days following stroke. Models of permanent, transient middle cerebral artery occlusion and embolic stroke have been developed each with advantages and limitations when trying to model the complex heterogeneous nature of stroke in humans. Yet despite these advances in understanding the pathophysiological mechanisms of stroke-induced cell death with numerous targets identified and drugs tested, a lack of translation to the clinic has hampered pre-clinical stroke research. With recent positive clinical trials of endovascular thrombectomy in acute ischaemic stroke the stroke community has been reinvigorated, opening up the potential for future translation of adjunctive treatments that can be given alongside thrombectomy/thrombolysis. This review discusses the major animal models of focal cerebral ischaemia highlighting their advantages and limitations. Acute imaging is crucial in longitudinal pre-clinical stroke studies in order to identify the influence of acute therapies on tissue salvage over time. Therefore, the methods of identifying potentially salvageable ischaemic penumbra are discussed

A netnographic sensibility: developing the netnographic/social listening boundaries

Netnography is constantly evolving as technologies and access to online data develop. Our paper outlines how large data sets of social media can be analysed through bridging the divide between the small, rich and contextually nuanced data that is the hallmark of netnography and the scope and scale of data made possible through social media listening conventions. We define this approach as netnographic sensibility and with the use of a short case study discuss the process through which social media data could be gathered, triangulated and analysed. We orientate the paper around two interrelated questions: investigating how netnographic insights can be extended using social media monitoring tools, and asking how this can be used to add richness and depth to understanding mass consumer realities. Our contribution complements the widely established methodological approach of netnography as we argue that netnography has the capacity and capability to embrace technological advances within the domain of social listening to add value for academic researchers

The performativity of sustainability: making a conduit a marketing device

This paper examines how a conduit, as a ‘working infrastructure’ with material and social qualities, shapes and connects the business and practices of sustainable waste management. Conduits have had a prominent but passive role in explanations of food leftovers within households. We show that a conduit, as an assemblage of investments and practices among interested actors, requires and allows for the further economisation and calculation of waste management. Conduits shape business-to-business exchanges and relationships, deriving demand across domains of exchange and managing risks to the continuation of industrial processes. They resist singular stewardship, instead allowing multiple actors to recognise their interdependence and contest the development of facilities and services. Marketing communications form an important dimension of the conduit, albeit distributed across different parts of the conduit, in aligning actors’ practices of sorting and ‘moving things along’ at and between locations

Understanding Interaction Through the Lens of Materiality and the Processual Nature of Artifacts

The elements and processes to understand organisational business-to-business interactions have been extensively explored. The context and forms these interactions takeunderpinmajor threads of research in the Markets-as-Networks tradition of understanding business networks. Standard operating procedures (SOPs), job specs, contracts andbriefs as physical objects play material roles within these business-to-business interactions, guiding and managing how these relationships play out. This paper primarily builds on the rich Markets-as-Networks tradition by refocusing attention on the role artifacts play in the interaction process. In addition there appears to be non-material artifacts, without physical forms, that also aid in guiding and managing interactions. This paper incorporates the construct of materiality into considering non-material artifacts,broadening the scope of our analysis and allowing us to gain a more comprehensive understanding of the role various artifacts play in business-to-business interactions. Two cases considering inter-organisational routines through the lens of an artifactual unit of analysis are outlined.These two cases raise issues of focus in relation to the context of interaction core to the Markets-as-Networks tradition. As a consequence this paper takes a closer look at: the processual characteristics within long term, close and complex relationships; the roles that artifacts play in these interactions represented by organisational and inter-organisational routines; how the artifactual characteristics in themselves either aid, alter or hinder the context of interaction.By drawing distinctions,relating to the materiality of artifacts, we illustrate how mangers’ understanding of the role artifacts, and unseen artifacts can play in impacting on guiding and managing business-to-business relationships. The conclusion of this paper discusses the managerial relevance of the processual characteristics of artifacts and their form of materiality. By comparing and contrasting two inter-organisational cases through the lens of materiality and the processual characteristics embodied in artifacts managers can gain a better understanding how various artifacts can guide and manage processes of interaction

Validation of an observational instrument for measuring role behavior in social work groups as one aspect of maturity

Thesis (M.S.)--Boston Universit

I am still bed six :a collection of poetry, and, Poetry as therapy and poetry beyond therapy

PhD ThesisThis collection of lyrical poetry is significantly inspired by personal experiences, particularly a diagnosis of Ankylosing Spondylitis, a chronic inflammatory arthritis and autoimmune condition. Issues such as hospitalisation, the power dynamics between doctors and patients, and managing both physical and emotional pain inform the writing. Highly specified form in the poetry serves to contain and organise powerful emotions using simple, epigrammatic language. The layout of the research mirrors the layout of the poetry. The researcher’s own experiences of finding therapeutic value in her own poetry writing led to the research element which explores how and why poetry writing works therapeutically and whether poetry is more effective than other forms of therapeutic writing. The specific benefits of poetry writing as therapy for those who have experienced emotional distress are explored in depth. The difference between poetry as therapy and poetry as art is also considered. A small scale research study was undertaken with service users at a local charity, who have experienced emotional distress. A qualitative, semi-structured interview design was used, which was then analysed using Interpretational Phenomenological Analysis. The findings suggest that poetry is a particularly useful form of therapeutic writing as poetry promotes successful processing of a traumatic event through the use of image and metaphor. The participants retained the distinction between their priority of expressing themselves honestly and a preoccupation with artistic endeavour. Stevie Smith and Julia Darling provide examples of poets who found therapeutic elements in the writing process. Some of their poems are analysed in depth and their views on poetry’s therapeutic effects are considered. Alongside this, the difference between poetry as therapy and poetry as art is explored. Research reveals that poetry as therapy prioritises self-expression and poetry as art prioritises artfulness, but the two are not completely distinct; rather, they lie on a spectrum.the John McKie Elliot Trust who kindly supported me with a generous donation towards my studies