No description available.

No description available.

No description available.

Cerebral ischaemia is characterised by an interruption in cerebral blood flow (CBF) leading to neuronal dysfunction and death. Pre-existing systemic inflammation is strongly associated with exaggerated brain injury following cerebral ischaemia with experimental studies showing that increased damage is mediated by interleukin (IL)-1 dependent pathways. The mechanisms through which systemic inflammation worsens stroke have yet to be elucidated, therefore in this thesis we sought to further determine how systemic inflammation affects outcome after acute cerebral ischaemia. The effects of acute pre-existing inflammation on cerebral perfusion and infarct volume after transient middle cerebral artery occlusion (MCAo) in rats were measured using magnetic resonance imaging (MRI). Systemic IL-1 caused a severe reduction in CBF and increase in infarct volume compared to vehicle. CBF changes were accompanied by upregulation of the vasoconstricting peptide endothelin (ET)-1. Blockade of ET-1 receptors reversed hypoperfusion, reduced ischaemic damage and improved functional outcome when assessed at 48h. Streptoccocus pneumoniae is the most common infection in patients at risk of stroke and is associated with an elevated inflammatory profile. The effect of an acute S. pneumoniae challenge on stroke outcome was assessed in mice and rats following transient MCAo. S. pneumoniae induced a systemic IL-1 response, exacerbated brain injury and increased platelet adhesion to the endothelium. Blockade of IL-1 with IL-1 receptor antagonist (IL-1Ra) and administration of glycoprotein (Gp) Ibα (to reduce platelet-endothelial interactions) reversed infection-mediated exacerbation of ischaemic injury and improved functional impairments after MCAo. Presence of chronic inflammation in the form of advanced age and obesity are associated with poorer outcomes following ischaemic stroke. The neuroprotective effects of delayed IL-1Ra on stroke outcome were assessed in aged lean and corpulent rats versus young rats at 7 days post-stroke. IL-1Ra reduced ischaemic damage, blood brain barrier (BBB) breakdown, improved functional outcomes and preserved neurogenesis in young and aged co-morbid rats at 24 hours and 7 days. Overall, these findings suggest systemic IL-1 is a common point of convergence in both acute and chronic pre-existing inflammatory disorders that are risk factors for stroke. Systemic IL-1 leads to excessive ischaemic damage through effects on the endothelium and the coagulation cascade. These results lend further support to the hypothesis that IL-1 is a potential therapeutic target in ischaemic stroke.

No description available.

No description available.

Inflammation in the absence of infection (sterile inflammation) is a crucial host defence response to tissue injury, but is also considered to contribute to the pathogenesis of many diverse disease states, including stroke. Sterile inflammation is initiated by damage associated molecular patterns (DAMPs) which are endogenous molecules released from necrotic cells or that are modified during disease. The pro-inflammatory cytokines IL-1α and IL-1β are key mediators of inflammation. IL-1β release is controlled by caspase-1 which, in turn, is regulated by the inflammasome. The NOD-, LRR-, pyrin domain-containing 3 (NLRP3) inflammasome is most typically associated with sterile inflammation and the recognition of DAMPs. Thus, understanding the mechanisms of NLRP3-activating DAMP-induced inflammation may lead to the identification of novel therapeutic targets with which to treat inflammatory diseases. This thesis sought to determine how NLRP3-activating DAMPs affect the pro-inflammatory response of glia, the immune cells of the brain. Experimental models in vitro typically use a pathogen associated molecular pattern (PAMP) such as LPS to prime cells before observing their response to NLRP3-activating DAMPs. As the brain is protected by the blood brain barrier (BBB), it is unlikely glia would be exposed to PAMP priming. However it remains unclear as to how glia respond to NLRP3-activating DAMPs in the absence of priming, or what the source of endogenous priming is. Therefore, the initial hypothesis was to investigate the pro-inflammatory response of mixed glia in vitro to NLRP3-activating DAMPs in the absence of PAMP priming. It is shown here for the first time that NLRP3-activating DAMPs can initiate an IL-1-NLRP3-independent inflammatory response in mixed glia in the absence of PAMP priming. Moreover, it is shown that the acute phase protein serum amyloid A is elevated in plasma after stroke and may act as an endogenous priming signal to allow IL-1β-dependent inflammation to contribute to the damage after breakdown of the BBB.Inflammation following acute sterile injury such as stroke is augmented by persisting cell death. It was therefore hypothesised that NLRP3-activating DAMPs released after the initial injury, may initiate a form of programmed cell death that continues to drive inflammation. Using inhibitors of specific types of cell death, it was identified that NLRP3-activating DAMP induced cell death is likely to be necrosis and not programmed cell death. Further investigation into the biological importance of DAMP-induced IL-1-independent inflammation and the specific contribution of acute phase proteins to brain pathology may aid the identification of new therapeutic targets.

<p>Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion. </p><p>The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group. </p><p>Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication. </p><p>In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated. </p><p>In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.</p>

Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion. The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group. Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication. In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated. In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.

Intra-dialytic haemodynamic instability is a common and disabling problem which may lead to morbidity and mortality though repeated organ ischaemia, but it has proven difficult to link any particular blood pressure threshold with hard patient outcomes. The relationship between blood pressure and downstream organ ischaemia during haemodialysis has not been well characterised. Previous attempts to predict and prevent intra-dialytic hypotension have had mixed results, partly due to patient and event heterogeneity. Using the brain as the indicator organ, we aimed to model the dynamic relationship between blood pressure, real-time symptoms, downstream organ ischaemia during haemodialysis, in order to identify the most physiologically grounded, prognostic definition of intra-dialytic decompensation. Following on from this, we aimed to predict the onset of intra-dialytic decompensation using personalised, probabilistic models of multivariate, continuous physiological data, ultimately working towards an early warning system for intra-dialytic adverse events. This was a prospective study of 60 prevalent haemodialysis patients who underwent extensive, continuous physiological monitoring of haemodynamic, cardiorespiratory, tissue oxygenation and dialysis machine parameters for 3-4 weeks. In addition, longitudinal cognitive function testing was performed at baseline and at 12 months. Despite their use in clinical practice, we found that blood pressure thresholds alone have a poor trade off between sensitivity and specificity for predicting downstream tissue ischaemia during haemodialysis. However, the performance of blood pressure thresholds could be improved by stratification for the presence or absence of cerebral autoregulation, and personalising thresholds according to the individual lower limit of autoregulation. For patients without autoregulation, the optimal blood pressure target was a mean arterial pressure (MAP) of 70mmHg. A key finding was that cumulative intra-dialytic exposure to cerebral ischaemia, but not to hypotension per se, corresponded to change in executive cognitive function over 12 months. Therefore we chose cerebral ischaemia as the definition of intra-dialytic decompensation for predictive modelling. We were able to demonstrate that the development of cerebral desaturation could be anticipated from earlier deviations of univariate physiological data from the expected trajectory for a given patient, but sensitivity was limited by the heterogeneity of events even within one individual. The most useful phys- iological data streams included peripheral saturation variance, cerebral saturation variance, heart rate and mean arterial pressure. Multivariate data fusion techniques using these variables created promising personalised models capable of giving an early warning of decompensation. Future work will involve the refinement and prospective testing of these models. In addition, we envisage a prospective study assessing the benefit of autoregulation-guided blood pressure targets on short term outcomes such as patient symptoms and wellbeing, as well as longer term outcomes such as cognitive function.