ORCID Profile
0000-0002-2918-5200
Current Organisation
University of Oxford
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Publisher: SAGE Publications
Date: 21-08-2013
Abstract: Recanalization of an occluded vessel with recombinant tissue plasminogen activator is an effective strategy for treating acute ischemic stroke. Recombinant tissue plasminogen activator is administered as alteplase, a formulation containing many excipients including L-arginine, the substrate for nitric oxide production. Most studies fail to compare the effects of alteplase on brain injury to its L-arginine carrier solution. This study aimed to verify the previously reported detrimental effects of alteplase after cerebral ischemia and delineate the contribution of L-arginine. Male Wistar rats, subjected to 90 minutes of intraluminal middle cerebral artery occlusion (MCAO), were administered alteplase, the carrier solution or saline upon reperfusion. Neither alteplase nor the carrier affected cerebral blood flow (CBF) restoration throughout the first 60 minutes of reperfusion. Alteplase treatment was associated with increased mortality after MCAO. Twenty-four hours after MCAO, neurologic function and infarct volume did not differ between rats treated with alteplase, the carrier solution, or saline. Irrespective of treatment group, infarct volume was correlated with CBF during reperfusion, neuroscore, and peri-infarct depolarizations. These results suggest that alteplase treatment, independent of thrombolysis, does not cause increased ischemic injury compared with its appropriate carrier solution, supporting the continued use of alteplase in eligible ischemic stroke patients.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2011
Publisher: MDPI AG
Date: 18-09-2012
Publisher: BMJ
Date: 04-2008
Abstract: Models are used to adjust for case mix and to stratify treatment allocation in clinical trials and can, if accurate enough, be used to aid decision-making in in idual patients. We aimed to validate, in patients assessed within 6 hours of onset, a previously described six simple variable (SSV) model that was developed in stroke patients who were assessed sub-acutely. The explanatory variables in the model are age, living alone, independent pre-stroke, Glasgow Coma Scale verbal score, ability to lift arms and ability to walk. The six variables were collected at randomisation in the Third International Stroke Trial (IST3) trial of recombinant tissue plasminogen activator in ischaemic stroke. We assessed survival to 30 days and functional status at 6 months using the Oxford Handicap Scale. We constructed receiver operator characteristic (ROC) curves to establish the model's discriminatory performance and tested its calibration by charting predicted versus actual outcomes. 537 patients (mean age, 74 years) were included, of whom 422 (79%) survived 30 days and 179 (33%) were alive and independent at 6 months. The SSV model had an area under the ROC curve of 0.73 for 30-day survival and 0.82 for independent survival at 6 months. Calibration was satisfactory. This study confirms the external validity of the SSV model in an ischaemic stroke population assessed within 6 hours of symptom onset. The SSV model comprising easily collected variables can therefore be used to stratify patients in hyper-acute stroke trials, but probably is not accurate enough for decision-making in in idual patients.
Publisher: SAGE Publications
Date: 02-2009
DOI: 10.1111/J.1747-4949.2009.00241.X
Abstract: As a research community, we have failed to demonstrate that drugs that show substantial efficacy in animal models of cerebral ischemia can also improve outcome in human stroke. Accumulating evidence suggests that this may be due, at least in part, to problems in the design, conduct and reporting of animal experiments, which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: SAGE Publications
Date: 19-12-2014
DOI: 10.1111/IJS.12237
Publisher: S. Karger AG
Date: 2010
DOI: 10.1159/000315099
Publisher: SAGE Publications
Date: 06-03-2012
DOI: 10.1111/J.1747-4949.2012.00770.X
Abstract: Neuroprotection seeks to restrict injury to the brain parenchyma following an ischaemic insult by preventing salvageable neurons from dying. The concept of neuroprotection has shown promise in experimental studies, but has failed to translate into clinical success. Many reasons exist for this including the heterogeneity of human stroke and the lack of methodological agreement between preclinical and clinical studies. Even with the proposed Stroke Therapy Academic Industry Roundtable criteria for preclinical development of neuroprotective agents for stroke, we have still seen limited success in the clinic, an ex le being NXY-059, which fulfilled nearly all the Stroke Therapy Academic Industry Roundtable criteria. There are currently a number of ongoing trials for neuroprotective strategies including hypothermia and albumin, but the outcome of these approaches remains to be seen. Combination therapies with thrombolysis also need to be fully investigated, as restoration of oxygen and glucose will always be the best therapy to protect against cell death from stroke. There are also a number of promising neuroprotectants in preclinical development including haematopoietic growth factors, and inhibitors of the nicotinamide adenine dinucleotide phosphate oxidases, a source of free radical production which is a key step in the pathophysiology of acute ischaemic stroke. For these neuroprotectants to succeed, essential quality standards need to be adhered to however, these must remain realistic as the evidence that standardization of procedures improves translational success remains absent for stroke.
Publisher: SAGE Publications
Date: 25-08-2010
Abstract: Alteplase is the only drug licensed for acute ischemic stroke, and in this formulation, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is stabilized in a solution of L-arginine. Improved functional outcomes after alteplase administration have been shown in clinical trials, along with improved histological and behavioral measures in experimental models of embolic stroke. However, in animal models of mechanically induced ischemia, alteplase can exacerbate ischemic damage. We have systematically reviewed the literature of both rtPA and L-arginine administration in mechanical focal ischemia. The rtPA worsens ischemic damage under certain conditions, whereas L-arginine can have both beneficial and deleterious effects dependent on the time of administration. The interaction between rtPA and L-arginine may be leading to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular unit. We suggest that alternative formulations of rtPA, in the absence of L-arginine, would provide new insight into rtPA neurotoxicity, and have the potential to offer more efficacious thrombolytic therapy for ischemic stroke patients.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1111/J.1538-7836.2011.04486.X
Abstract: Deep vein thrombosis (DVT) is an important complication of stroke, but the evidence to support commonly used prophylactic strategies is conflicting. To describe the incidence, extent, associated clinical features and evolution of DVT after stroke. The CLOTS trials 1 and 2 together randomized 5632 immobile stroke patients in 135 hospitals in nine countries. We screened patients for asymptomatic DVT with compression duplex ultrasound (CDU) at about 7-10 days and again at about 25-30 days after enrollment. Six hundred and forty-one (11.4%) of 5632 patients had DVT detected on the first CDU scan at a median of 8 days (interquartile range [IQR] 7-10 days) after enrollment, and an additional 176 (3.1%) had a DVT on the second CDU scan at a median of 28 days (IQR 26-30 days). Of the 817 with DVTs, 289 (35%) were symptomatic and 39 (5%) had pulmonary embolism (PE) confirmed by imaging. Six hundred and seventy-six (83%) were unilateral, 141 (17%) were bilateral, 322 (39%) were limited to calf veins, 172 (21%) were popliteal, and 323 (40%) were femoral. Among the 542 patients with DVT and a weak leg, the DVT affected the weaker leg in 396 (73%), the stronger leg in 59 (11%), and was bilateral in 87 (16%). Among the 318 patients with a DVT detected on the first CDU scan who had a second scan, the DVT regressed in 148 (47%), stayed the same in 140 (44%), and progressed in only 30 (9%). Although most DVTs develop within the first week, some develop later, and some early DVTs progress. Any prophylaxis needs to be started early but ideally continued for at least 4 weeks.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2021
DOI: 10.1161/STROKEAHA.120.031742
Abstract: Circadian biology modulates almost all aspects of mammalian physiology, disease, and response to therapies. Emerging data suggest that circadian biology may significantly affect the mechanisms of susceptibility, injury, recovery, and the response to therapy in stroke. In this review erspective, we survey the accumulating literature and attempt to connect molecular, cellular, and physiological pathways in circadian biology to clinical consequences in stroke. Accounting for the complex and multifactorial effects of circadian rhythm may improve translational opportunities for stroke diagnostics and therapeutics.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.NEULET.2019.05.023
Abstract: Hamartin, a component of the tuberous sclerosis complex (TSC) that actively inhibits the mammalian target of rapamycin (mTOR), may mediate the endogenous resistance of Cornu Ammonis 3 (CA3) hippoc al neurons following global cerebral ischemia. Pharmacological compounds that selectively inhibit mTOR may afford neuroprotection following ischemic stroke. We hypothesize that AZD2014, a novel mTORC1/2 inhibitor, may protect neurons following oxygen and glucose deprivation (OGD). Primary neuronal cultures from E18 Wistar rat embryos were exposed to 2 h OGD or normoxia. AZD2014 was administered either during OGD, 24 h prior to OGD or for 24 h following OGD. Cell death was quantified by lactate dehydrogenase assay. We characterized the expression of mTOR pathway proteins following exposure to AZD2014 using western blotting. Following 2 h OGD +24 h recovery, AZD2014 increased neuronal death when present during OGD. Rapamycin, the archetypal mTOR inhibitor, had no effect on cell death. Treatment with AZD2014 24 h prior to OGD and 24 h after OGD also enhanced cell death. While Western blotting showed a trend towards decreased expression levels of phospho-Akt relative to total Akt with increasing AZD2014 concentration, hamartin expression was also significantly decreased leading to activation of mTOR. AZD2014 was detrimental to neurons that underwent ischemia. AZD2014 appeared to reduce hamartin, a known neuroprotective mediator, thereby preventing any beneficial effects of mTOR inhibition. Further characterization of the role of in idual mTOR complexes (mTORC1 and mTORC2) and their upstream and downstream regulators are necessary to reveal whether these pathways are neuroprotective targets for stroke.
Publisher: Wiley
Date: 30-08-2011
Publisher: SAGE Publications
Date: 17-09-2008
Abstract: As a research community, we have failed to show that drugs, which show substantial efficacy in animal models of cerebral ischemia, can also improve outcome in human stroke. Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct, and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: SAGE Publications
Date: 06-2009
Abstract: Correction to: Journal of Cerebral Blood Flow & Metabolism (2009) 29, 221–223 doi:10.1038/jcbfm.2008.101 Following the publication of this article, the authors noted that Dr Buchan's first name was misspelled. The correct and complete author name is above.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
DOI: 10.1161/STROKEAHA.108.525386
Abstract: Background and Purpose— As a research community, we have failed to demonstrate that drugs which show substantial efficacy in animal models of cerebral ischemia can also improve outcome in human stroke. Summary of Review— Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Conclusions— Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: SAGE Publications
Date: 29-11-2019
Abstract: Amplifying endogenous neuroprotective mechanisms is a promising avenue for stroke therapy. One target is mammalian target of rapamycin (mTOR), a serine/threonine kinase regulating cell proliferation, cell survival, protein synthesis, and autophagy. Animal studies investigating the effect of rapamycin on mTOR inhibition following cerebral ischemia have shown conflicting results. To conduct a systematic review and meta-analysis evaluating the effectiveness of rapamycin in reducing infarct volume in animal models of ischemic stroke. Our search identified 328 publications. Seventeen publications met inclusion criteria (52 comparisons: 30 reported infarct size and 22 reported neurobehavioral score). Study quality was modest (median 4 of 9) with no evidence of publication bias. The point estimate for the effect of rapamycin was a 21.6% (95% CI, 7.6%–35.7% p 0.01) improvement in infarct volume and 30.5% (95% CI 17.2%–43.8%, p 0.0001) improvement in neuroscores. Effect sizes were greatest in studies using lower doses of rapamycin. Low-dose rapamycin treatment may be an effective therapeutic option for stroke. Modest study quality means there is a potential risk of bias. We recommend further high-quality preclinical studies on rapamycin in stroke before progressing to clinical trials.
Publisher: SAGE Publications
Date: 06-07-2010
DOI: 10.1111/J.1747-4949.2010.00442.X
Abstract: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Recommendations of the Synergium are: : There is a need to develop: ( 1 ) New systems of working together to break down the prevalent ‘silo’ mentality ( 2 ) New models of vertically integrated basic, clinical, and epidemiological disciplines and ( 3 ) Efficient methods of identifying other relevant areas of science. : ( 1 ) Establish a global chronic disease prevention initiative with stroke as a major focus. ( 2 ) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. ( 3 ) Develop, implement and evaluate a population approach for stroke prevention. ( 4 ) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. : Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. : ( 1 ) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. ( 2 ) Standardize poststroke rehabilitation based on best evidence. ( 3 ) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. ( 4 ) Carry out rigorous clinical research to advance stroke recovery. :( 1 ) Work toward global unrestricted access to stroke-related information. ( 2 ) Build centralized electronic archives and registries. (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. by using a ***‘Brain Health’ concept that enables promotion of preventive measures. To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
Publisher: Oxford University Press (OUP)
Date: 14-09-2013
DOI: 10.1093/BRAIN/AWT201
Abstract: The science of metric-based patient stratification for intravenous thrombolysis, revolutionized by the landmark National Institute of Neurological Disorders and Stroke trial, has transformed acute ischaemic stroke therapy. Recanalization of an occluded artery produces tissue reperfusion that unequivocally improves outcome and function in patients with acute ischaemic stroke. Recanalization can be achieved mainly through intravenous thrombolysis, but other methods such as intra-arterial thrombolysis or mechanical thrombectomy can also be employed. Strict guidelines preclude many patients from being treated by intravenous thrombolysis due to the associated risks. The quiet art of informed patient selection by careful assessment of patient baseline factors and brain imaging could increase the number of eligible patients receiving intravenous thrombolysis. Outside of the existing eligibility criteria, patients may fall into therapeutic 'grey areas' and should be evaluated on a case by case basis. Important factors to consider include time of onset, age, and baseline blood glucose, blood pressure, stroke severity (as measured by National Institutes of Health Stroke Scale) and computer tomography changes (as measured by Alberta Stroke Programme Early Computed Tomography Score). Patients with traditional contraindications such as wake-up stroke, malignancy or dementia may have the potential to receive benefit from intravenous thrombolysis if they have favourable predictors of outcome from both clinical and imaging criteria. A proportion of patients experience complications or do not respond to intravenous thrombolysis. In these patients, other endovascular therapies or a combination of both may be used to provide benefit. Although an evidence-based approach to intravenous thrombolysis for acute ischaemic stroke is pivotal, it is imperative to examine those who might benefit outside of protocol-driven practice.
Publisher: Society for Neuroscience
Date: 30-01-2017
DOI: 10.1523/JNEUROSCI.0005-16.2016
Abstract: Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO 2 , arterial O 2 , and brain activity and is largely constant in the awake state. Although small changes in arterial CO 2 are particularly potent to change CBF (1 mmHg variation in arterial CO 2 changes CBF by 3%–4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E 2 (PgE 2 ) plays a key role for cerebrovascular CO 2 reactivity, and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with in vivo work in rats and C57BL/6J mice to examine the hemodynamic responses to CO 2 and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE 2 synthesis. We demonstrate that hypercapnia (increased CO 2 ) evokes an increase in astrocyte [Ca 2+ ] i and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE 2 (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE 2 is decreased and vasodilation triggered by increased astrocyte [Ca 2+ ] i in vitro and by hypercapnia in vivo is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO 2 . Reductions in glutathione levels in aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage. SIGNIFICANCE STATEMENT Neuronal activity leads to the generation of CO 2 , which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE 2 . We demonstrate that hypercapnia (increased CO 2 ) evokes increases in astrocyte calcium signaling, which in turn stimulates COX-1 activity and generates downstream PgE 2 production. We demonstrate that astrocyte calcium-evoked production of the vasodilator PgE 2 is critically dependent on brain levels of the antioxidant glutathione. These data suggest a novel role for astrocytes in the regulation of CO 2 -evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in aging and stroke, will give rise to dysfunctional CBF regulation and may result in subsequent neuronal damage.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alastair Buchan.