ORCID Profile
0000-0003-4278-8302
Current Organisation
University of Adelaide
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Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.JOCN.2011.12.019
Abstract: Non-accidental head injury (NAHI), also termed the "shaken baby syndrome", is a major cause of death and severe neurological dysfunction in children under three years of age, but it is debated whether shaking alone is sufficient to produce brain injury and mortality or whether an additional head impact is required. In an attempt to resolve this question, we used a lamb model of NAHI since these animals have a relatively large gyrencephalic brain and weak neck muscles resembling those of a human infant. Three anaesthetised lambs of lower body weight than others in the experimental group died unexpectedly after being shaken, proving that shaking alone can be lethal. In these lambs, axonal injury, neuronal reaction and albumin extravasation were widely distributed in the hemispheric white matter, brainstem and at the craniocervical junction, and of much greater magnitude than in higher body weight lambs which did not die. Moreover, in the eyes of these shaken lambs, there was damage to retinal inner nuclear layer neurons, mild, patchy ganglion cell axonal injury, widespread Muller glial reaction, and uveal albumin extravasation. This study proved that shaking of a subset of lambs can result in death, without an additional head impact being required.
Publisher: Informa Healthcare
Date: 25-04-2012
DOI: 10.1517/13543784.2012.683113
Abstract: Subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality, even for patients who receive early neurointerventionist management. Early mechanisms of secondary brain injury precede the delayed vasospasm phase and contribute to the poor outcome. These mechanisms and their intervention are discussed, including high intracranial pressure (ICP), low cerebral perfusion pressure (CPP), acute vasospasm, disturbed cerebral autoregulation, cerebral edema, oxidative stress, seizures, microvascular damage and hyperglycemia. Erythropoietin, statins and magnesium have been particularly promising in experimental studies. Multiple mechanisms, including delayed vasospasm, may contribute to cerebral ischemia and poor outcome following SAH. Treatments that simultaneously target multiple secondary injury pathways show significant potential as therapeutic agents, particularly those that attenuate vasospasm in addition to having other neuroprotective properties.
Publisher: SAGE Publications
Date: 26-05-2021
DOI: 10.1177/0271678X211018901
Abstract: Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required.
Publisher: SAGE Publications
Date: 02-09-2009
Abstract: MicroRNAs (miRNAs) regulate gene expression and have a critical role in many biologic and pathologic processes. We hypothesized that miRNA expression profiles in injured brain (hippoc us) would show common as well as unique profiles when compared with those of blood. Adult, untouched, control rats were compared with rats with sham surgeries, ischemic strokes, brain hemorrhage (lysed blood, fresh blood, or thrombin), and kainate-induced seizures. Brain and whole-blood miRNA expression profiles were assessed 24 h later using TaqMan rodent miRNA arrays. MicroRNA response profiles were different for each condition. Many miRNAs changed more than 1.5-fold in brain and blood after each experimental manipulation, and several miRNAs were upregulated or downregulated in both brain and blood after a given injury. A few miRNAs (e.g., miR-298, miR-155, and miR-362-3p) were upregulated or downregulated more than twofold in both brain and blood after several different injuries. The results show the possible use of blood miRNAs as biomarkers for brain injury that selected blood miRNAs may correlate with miRNA changes in the brain and that many of the mRNAs, previously shown to be regulated in brain and blood after brain injury, are likely accounted for by changes in miRNA expression.
Publisher: SAGE Publications
Date: 09-09-2009
Abstract: Blood gene expression profiles of very brief (5 and 10 mins) focal ischemia that simulates transient ischemic attacks in humans were compared with ischemic stroke (120 mins focal ischemia), sham, and naïve controls. The number of significantly regulated genes after 5 and 10 mins of cerebral ischemia was 39 and 160, respectively (fold change ⩾∣1.5∣ and P .05). There were 103 genes common to brief focal ischemia and ischemic stroke. Ingenuity pathway analysis showed that genes regulated in the 5 mins group were mainly involved in small molecule biochemistry. Genes regulated in the 10 mins group were involved in cell death, development, growth, and proliferation. Such genes were also regulated in the ischemic stroke group. Genes common to ischemia were involved in the inflammatory response, immune response, and cell death—indicating that these pathways are a feature of focal ischemia, regardless of the duration. These results provide evidence that brief focal ischemia differentially regulates gene expression in the peripheral blood in a manner that could distinguish brief focal ischemia from ischemic stroke and controls in rats. We postulate that this will also occur in humans.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2010
DOI: 10.1161/STROKEAHA.110.591875
Abstract: Background and Purpose— White matter hyperintensities (WMH) are areas of high signal detected by T2 and fluid-attenuated inversion recovery sequences on brain MRI. Although associated with aging, cerebrovascular risk factors, and cognitive impairment, the pathogenesis of WMH remains unclear. Thus, RNA expression was assessed in the blood of in iduals with and without extensive WMH to search for evidence of oxidative stress, inflammation, and other abnormalities described in WMH lesions in brain. Methods— Subjects included 20 with extensive WMH (WMH+), 45% of whom had Alzheimer disease, and 18 with minimal WMH (WMH−), 44% of whom had Alzheimer disease. All subjects were clinically evaluated and underwent quantitative MRI. Total RNA from whole blood was processed on human whole genome Affymetrix HU133 Plus 2.0 microarrays. RNA expression was analyzed using an analysis of covariance. Results— Two hundred forty-one genes were differentially regulated at ±1.2-fold difference ( P .005) in subjects with WMH+ as compared to WMH−, regardless of cognitive status and 50 genes were differentially regulated with ±1.5-fold difference ( P .005). Cluster and principal components analyses showed that the expression profiles for these genes distinguished WMH+ from WMH− subjects. Function analyses suggested that WMH-specific genes were associated with oxidative stress, inflammation, detoxification, and hormone signaling, and included genes associated with oligodendrocyte proliferation, axon repair, long-term potentiation, and neurotransmission. Conclusions— The unique RNA expression profile in blood associated with WMH is consistent with roles of systemic oxidative stress and inflammation, as well as other potential processes in the pathogenesis or consequences of WMH.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2009
Publisher: Elsevier
Date: 2007
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/578480
Abstract: Classical inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of neurogenic inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of neurogenic inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and neurogenic inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.NEUROSCIENCE.2012.06.047
Abstract: We have recently reported on the efficacy of an NK1 tachykinin receptor antagonist in improving outcome following stroke, including reduced blood-brain barrier (BBB) disruption, reduced cerebral edema and improved functional outcome. The clinically approved stroke treatment, tissue plasminogen activator (tPA), has been associated with an increased risk of hemorrhage and death, if given at later time points. Accordingly, adjunctive therapies have been investigated to reduce the adverse effects of tPA and improve outcome. The aim of the present study was to characterize the effects of a combination of an NK1 tachykinin receptor antagonist with tPA, on BBB permeability and functional outcome following transient ischemic stroke in rats. Stroke was induced in male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion where occlusion was maintained for 2h, followed by reperfusion. Animals received either 25mg/kg of N-acetyl-l-tryptophan or 1mg/kg of tPA, either alone or in combination, or equal volume saline vehicle, intravenously at the time of reperfusion. Functional outcome was assessed by the rotarod, bilateral asymmetry test, modified neuroscore and open field tests. BBB permeability was assessed by Evans Blue extravasation. Combination therapy of an NK1 tachykinin receptor antagonist with tPA significantly reduced BBB permeability, functional deficits and the incidence of intracerebral hemorrhage and death. As such, combined tPA-NK1 tachykinin receptor antagonist treatment may represent a novel therapeutic intervention for the treatment of reperfusion injury in acute ischemic stroke.
Publisher: Elsevier BV
Date: 04-2012
Publisher: Informa UK Limited
Date: 12-2019
DOI: 10.2147/MDER.S235804
Publisher: SAGE Publications
Date: 28-03-2021
DOI: 10.1177/0271678X211005877
Abstract: There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippoc al dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippoc al regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippoc us, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippoc us, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.
Publisher: Public Library of Science (PLoS)
Date: 27-07-2012
Publisher: Springer Science and Business Media LLC
Date: 2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-10-2011
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.BRAINRES.2011.03.066
Abstract: Previous studies have suggested that substance P (SP) plays a critical role in the development of brain oedema and functional deficits following traumatic brain injury and that SP receptor antagonism may improve outcome. No studies have described such a role in ischemic stroke. The present study characterized the effects of the NK1 tachykinin receptor antagonist, n-acetyl-L-tryptophan (NAT), on blood-brain barrier (BBB) breakdown, oedema formation, infarct volume and functional outcome following reversible ischemic stroke in rats. Ischemia was induced using a reversible thread model of middle cerebral artery occlusion where occlusion was maintained for 2 h before reperfusion. Animals received either NAT or equal volume saline vehicle intravenously at 2 h post-reperfusion. Ischaemic stroke resulted in increased perivascular SP immunoreactivity at 24 h. Administration of NAT significantly reduced oedema formation and BBB permeability at 24 h post-ischemia and significantly improved functional outcome as assessed over 7 days. There was no effect on infarct volume. We conclude that inhibition of SP activity with a NK1 tachykinin receptor antagonist is effective in reducing cerebral oedema, BBB permeability and functional deficits following reversible ischemia and may therefore represent a novel therapeutic approach to the treatment of ischaemic stroke.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
DOI: 10.1161/STROKEAHA.110.588335
Abstract: Background and Purpose— A blood-based biomarker of acute ischemic stroke would be of significant value in clinical practice. This study aimed to (1) replicate in a larger cohort our previous study using gene expression profiling to predict ischemic stroke and (2) refine prediction of ischemic stroke by including control groups relevant to ischemic stroke. Methods— Patients with ischemic stroke (n=70, 199 s les) were compared with control subjects who were healthy (n=38), had vascular risk factors (n=52), and who had myocardial infarction (n=17). Whole blood was drawn ≤3 hours, 5 hours, and 24 hours after stroke onset and from control subjects. RNA was processed on whole genome microarrays. Genes differentially expressed in ischemic stroke were identified and analyzed for predictive ability to discriminate stroke from control subjects. Results— The 29 probe sets previously reported predicted a new set of ischemic strokes with 93.5% sensitivity and 89.5% specificity. Sixty- and 46-probe sets differentiated control groups from 3-hour and 24-hour ischemic stroke s les, respectively. A 97-probe set correctly classified 86% of ischemic strokes (3 hour+24 hour), 84% of healthy subjects, 96% of vascular risk factor subjects, and 75% with myocardial infarction. Conclusions— This study replicated our previously reported gene expression profile in a larger cohort and identified additional genes that discriminate ischemic stroke from relevant control groups. This multigene approach shows potential for a point-of-care test in acute ischemic stroke.
Publisher: Wiley
Date: 29-10-2010
DOI: 10.1002/ANA.22187
Publisher: Springer Science and Business Media LLC
Date: 12-02-2011
Publisher: Springer Science and Business Media LLC
Date: 02-2011
Publisher: Portico
Date: 2007
DOI: 10.1358/DNP.2007.20.4.1103527
Abstract: Each year, 15 million people suffer a stroke, of which 5 million die and 5 million are left permanently disabled. Cerebral swelling is of particular concern following stroke as it accounts for much of the death and disability. However, the mechanisms leading to cerebral swelling are not yet fully understood. Recent studies from our laboratory suggest that neuropeptides, and specifically substance P, may be involved in the injury processes that occur following acute insults to the brain such as stroke and trauma, and may be responsible, in part, for edema formation. Levels of substance P are increased following CNS injury, indicative of neurogenic inflammation, and this is associated with injury to the blood-brain barrier, the development of cerebral edema, cell death and functional deficits. Subsequent studies inhibiting neuropeptide release have consistently shown decreased cerebral edema and improved neurological outcome, while substance P antagonists administered after the insult are efficacious in reducing post-stroke cerebral edema and neurological deficits. The current review summarizes the evidence supporting the benefits of inhibiting neurogenic inflammation to treat ischemic stroke.
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2023
DOI: 10.1101/2023.04.24.538047
Abstract: We have previously demonstrated that a cortical stroke causes persistent impairment of hippoc al-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-β accumulation in the hippoc us, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-β around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippoc al cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the colocalization of amyloid-β with vasculature and blood-brain-barrier integrity were assessed in the cortex and hippoc al regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippoc us and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that was exacerbated in vessels with amyloid-β deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippoc us, indicative of a compromised blood-brain-barrier. Our findings indicate that hippoc al vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.
No related grants have been discovered for Renee Turner.