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Biomedical subjects

A M Buchan

Publications and source records attributed to A M Buchan.

At least 19 recordsLinked to original sources
PubMed2006

Kir6.2-containing ATP-sensitive potassium channels protect cortical neurons from ischemic/anoxic injury in vitro and in vivo.

ATP-sensitive potassium (K(ATP)) channels are weak inward rectifiers that appear to play an important role in protecting neurons against ischemic damage. Cerebral stroke is a major health issue, and vulnerability to stroke damage is regional within the brain. Thus, we set out to determine whether K(ATP) channels protect cortical neurons against ischemic insults. Experiments were performed using Kir6.2(-/-) K(ATP) channel knockout and Kir6.2(+/+) wildtype mice. We compared results obtained in Kir6.2(-/-) and wildtype mice to evaluate the protective role of K(ATP) channels against focal ischemia in vivo, and, using cortical slices, against anoxic stress in vitro. Immunohistochemistry confirmed the presence of K(ATP) channels in the cortex of wildtype, but not Kir6.2(-/-), mice. Results from in vivo and in vitro experimental models indicate that Kir6.2-containing K(ATP) channels in the cortex provide protection from neuronal death. Briefly, in vivo focal ischemia (15 min) induced severe neurological deficits and large cortical infarcts in Kir6.2(-/-) mice, but not in wildtype mice. Imaging analyses of cortical slices exposed briefly to oxygen and glucose deprivation (OGD) revealed a substantial number of damaged cells (propidium iodide-labeled) in the Kir6.2(-/-) OGD group, but few degenerating neurons in the wildtype OGD group, or in the wildtype and Kir6.2(-/-) control groups. Slices from the three control groups had far more surviving cells (anti-NeuN antibody-labeled) than slices from the Kir6.2(-/-) OGD group. These findings suggest that stimulation of endogenous cortical K(ATP) channels may provide a useful strategy for limiting the damage that results from cerebral ischemic stroke.

Animals↗
PubMed2006

Neuroprotection and neurogenesis: modulation of cornus ammonis 1 neuronal survival after transient forebrain ischemia by prior fimbria-fornix deafferentation.

Severe transient forebrain ischemia causes selective neuronal death in the hippocampal cornus ammonis 1 region. We tested the hypothesis that fimbria-fornix deafferentation can provide long-term protection to cornus ammonis 1 neurons and modulate neurogenesis following ischemia. Fimbria-fornix lesion or sham-fimbria-fornix lesion was performed on Wistar rats 13 days prior to 10 min forebrain ischemia or sham ischemia. Temperature was regulated and rats survived for 7, 14 or 28 days. Immunofluorescent bromodeoxyuridine and neuron specific nuclear protein staining and immunochemistry terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining were performed. At 7 days after ischemia, 73%+/-14% of cornus ammonis 1 neurons were damaged, while deafferentation reduced the injury to 36%+/-17% of cornus ammonis 1 neurons. This protection persisted for at least 28 days. Ischemia significantly increased the number of bromodeoxyuridine-positive cells (85-90 cells/section in stroke group vs. 6 to 11 cells/section in normal or sham stroke group), with very few terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-stained cells adjacent to the hippocampal cornus ammonis 1. Fimbria-fornix lesioning followed by ischemia increased the percentage of new neurons 13-fold over ischemia alone and 6.5-fold over sham lesion plus ischemia. The results indicate that fimbria-fornix deafferentation provides long-term neuroprotection in cornus ammonis 1 following forebrain ischemia and promotes neurogenesis after ischemic insults.

Analysis of Variance↗
PubMed2006

Translational vehicles for neuroprotection.

This review will analyse particular criteria in the analysis of stroke diagnosis and treatment, which are pivotal for the successful translation of experimental data from the laboratory to humans.

Animals↗
PubMed2006

Insular cortical ischaemia does not independently predict acute hypertension or hyperglycaemia within 3 h of onset.

OBJECTIVES: To test the hypothesis that insular cortical ischaemia is associated with acute hypertension and hyperglycaemia. METHODS: From the Canadian Activase for Stroke Effectiveness Study, which included only patients treated with thrombolysis hyperacutely (ie, within 3 h of onset of stroke), 966 patients were identified with ischaemia affecting (n = 685), or sparing (n = 281), the insular cortex. Demographic and clinical data, pretreatment indices of blood pressure, blood glucose, atrial fibrillation, and clinical imaging and outcome measures were compared between the two groups. Multivariable linear regression was used to assess predictors of systolic blood pressure and glucose levels before thrombolysis. RESULTS: Pretreatment hypertension (p = 0.009), but not hyperglycaemia (p = 0.32), was predicted by insular ischaemia in univariable linear regression analyses. After adjusting for other factors, however, insular cortical ischaemia was not found to be an independent predictor for acute hypertension or hyperglycaemia. CONCLUSIONS: Raised blood pressure or serum glucose levels in hyperacute (<3 h) cerebral ischaemia is not independently predicted by insular involvement. Several hours are required for sympathetic manifestations of insular ischaemia to evolve.

Acute Disease↗
PubMed2005

A study of the workload and effectiveness of a comprehensive acute stroke service.

OBJECTIVE: To study the workload of and use of acute intervention within an established acute stroke service, the Calgary Stroke Programme (CSP). METHODS: Prospective record of all acute referrals, diagnoses, and management decisions over a 4 month period. RESULTS: The CSP received 572 referrals (median: 32 per week), 88% of which were made between 7 am and midnight. Of the 427 patients seen in person, 29% had not had an acute stroke or transient ischaemic attack (TIA). Fifty percent of patients with suspected acute stroke were referred within 3 h of symptom onset and 11% with acute ischaemic stroke (equating to 35% of those referred within 3 h of onset and seen in person) were treated with thrombolysis. CONCLUSION: Centralisation of services facilitates the rapid referral of, and use of acute interventions in, patients with acute stroke and TIA. Centralised services are likely to be busy (although less so at night), to attract large numbers of patients with disorders that mimic stroke and TIA, and yet still likely to treat only the minority of acute strokes using thrombolysis. These observations may help those planning similar services and underline the need to develop more widely applicable treatments for acute stroke.

Acute Disease↗
PubMed2005

Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging.

BACKGROUND AND OBJECTIVES: Controversy exists about the optimal imaging technique in acute stroke. It was hypothesised that CT is comparable with DWI, when both are read systematically using quantitative scoring. METHODS: Ischaemic stroke patients who had CT within six hours and DWI within seven hours of onset were included. Five readers used a quantitative scoring system (ASPECTS) to read the baseline (b) and follow up CT and DWI. Use of MRI in acute stroke was also assessed in patients treated with tissue plasminogen activator (tPA) by prospectively recording reasons for exclusion. Patients were followed clinically at three months. RESULTS: bDWI and bCT were available for 100 consecutive patients (admission median NIHSS = 9). The mean bDWI and bCT ASPECTS were positively related (p<0.001). The level of interrater agreement ranged from good to excellent across all modalities and time periods. Bland-Altman plots showed more variability between bCT and bDWI than at 24 hours. The difference between bCT and bDWI was < or =2 ASPECTS points. Of bCT scans with ASPECTS 8-10, 81% had DWI ASPECTS 8-10. Patients with bCT ASPECTS of 8-10 were 1.9 times more likely to have a favourable outcome at 90 days than those with a score of 0-7 (95% CI 1.1 to 3.1, p = 0.002). The relative likelihood of favourable outcome with a bDWI ASPECTS 8-10 was 1.4 (95% CI 1.0 to 1.9, p = 0.10). Of patients receiving tPA 45% had contraindications to urgent MRI. CONCLUSION: The differences between CT and DWI in visualising early infarction are small when using ASPECTS. CT is faster and more accessible than MRI, and therefore is the better neuroimaging modality for the treatment of acute stroke.

Aged↗
PubMed2005

Intra-arterial thrombolysis for retinal artery occlusion: the Calgary experience.

INTRODUCTION: Retinal artery occlusion represents a medical emergency with poor prognosis for visual recovery. Spontaneous improvement is estimated to occur in less than 15% of central retinal artery occlusion (CRAO) cases and conventional treatments have provided only limited benefit. Intra-arterial thrombolysis has been reported as a potentially efficacious and safe treatment. METHODS: We performed a retrospective chart review of all retinal artery occlusion cases treated with intra-arterial recombinant tissue-type plasminogen activator (rtPA) from January 1998 to May 2004. Patients received Goldmann perimetry visual field testing at a variable interval following the procedure (2 days-2.5 years). Visual acuity (VA) was re-assessed in May 2004. RESULTS: Eight cases (59-77 years) were treated for CRAO, 6-18 hours post-onset with intra-arterial rtPA (10-20 mg over 15-60 minutes); one case of branch occlusion (BRAO) was treated with 30 mg rtPA over 75 minutes, 12 hours post-onset. Among the six patients with CRAO assessed in clinic, three experienced improvement in VA by two or more gradations (Snellen lines); three improved by one gradation. However, none achieved a final VA better than 20/300. The case of branch occlusion improved to a VA of 20/20. All patients had residual monocular field defects. CONCLUSIONS: Our findings reveal a limited benefit for intra-arterial tPA compared to the rate of spontaneous improvement and conventional forms of therapy for retinal artery occlusion.

Adult↗
PubMed2004

Lost in translation: taking neuroprotection from animal models to clinical trials.

Caffeinol has been proposed as a neuroprotectant for human trials. This review covers a variety of animal models used and various attempts to take animal protocols to human trials. The accompanying paper discusses the rabbit model that was used to identify the efficacy of tissue plasminogen activator (tPA) treatment. To date, this is the only model that was able to achieve laboratory to clinical translational success. Use of caffeinol as a cytoprotective agent in rat models yielded exciting results, which led to clinical trials. However, caffeinol given with tPA in rabbits leads to increased hemorrhage. Caffeinol alone does not prove to be neuroprotective, as vasodilation by itself is not efficacious. However, vasodilation combined with thrombolysis (caffeinol with tPA) poses an increased risk of hemorrhage. For a more translational approach to study neuroprotection and neuroprotective agents in human trials, it is necessary to demonstrate the efficacy of the procedure and purported agents in several animal models.

Animals↗
PubMed2004

The probability of middle cerebral artery MRA flow signal abnormality with quantified CT ischaemic change: targets for future therapeutic studies.

OBJECTIVES: In this study we define the probability of vascular abnormality in the middle cerebral artery (MCA) territory according to the extent of ischaemic change seen using computed tomography (CT). We assessed the sensitivity and specificity of the hyperdense middle cerebral artery (HMCA) and the "dot" sign using magnetic resonance angiography (MRA). METHODS: Patients presenting with ischaemic stroke had a CT scan (<6 h) prior to MRI (<7 h). A quantitative CT scoring system (ASPECTS) was applied to CT and diffusion weighted images (DWI) at baseline and follow up (24 h) by five independent observers. The presence of HMCA and the MCA "dot" sign was also evaluated. An expert reader assessed the 3D time of flight (TOF) MRA in the anterior circulation for areas of decreased vascular signal in the MCA territory, with an absent signal taken to represent severely reduced or absent flow. RESULTS: A total of 100 consecutive patients had baseline CT and MR scans. The median NIHSS was 9. The median CT ASPECTS was 8 and equalled the median DWI ASPECTS. There were a total of 10 HMCA and 19 MCA "dot" signs, with four patients having both HMCA and "dot" signs. A total of 47 MRA flow signal abnormalities were observed in the anterior circulation. CONCLUSIONS: In the absence of accessible neurovascular imaging, the extent of CT ischaemia (ASPECTS) is a strong predictor of vascular occlusion. The CT hyperdense artery signs have a high positive predictive value but low negative predictive value.

Aged↗
PubMed2004

The rise and fall of NMDA antagonists for ischemic stroke.

It has long been accepted that high concentrations of glutamate can destroy neurons, and this is the basis of the theory of excitotoxicity during brain injury such as stroke. Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists such as Selfotel, Aptiganel, Gavestinel and others failed to show neuroprotective efficacy in human clinical trials or produced intolerable central nervous system adverse effects. The failure of these agents has been attributed to poor studies in animal models and to poorly designed clinical trials. We also speculate that NMDA receptor antagonism may have hindered endogenous mechanisms for neuronal survival and neuroregeneration. It remains to be proven in human stroke whether NMDA receptor antagonism can be neuroprotective.

Animals↗
PubMed2003

Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke.

One hundred seventy-six consecutive patients treated with IV tissue plasminogen activator (tPA) for acute ischemic stroke were examined prospectively, and orolingual angioedema was found in nine (5.1%; 95% CI 2.3 to 9.5). The reaction was typically mild, transient, and contralateral to the ischemic hemisphere. Risk of angioedema was associated with angiotensin-converting enzyme inhibitors (relative risk [RR] 13.6; 95% CI 3.0 to 62.7) and signs on initial CT of ischemia in the insular and frontal cortex (RR 9.1; 95% CI 1.4 to 30.0).

Aged↗
PubMed2003

CT assessment of conjugate eye deviation in acute stroke.

Conjugate eye deviation seen on clinical examination helps to localize pathology in acute ischemic stroke. Eye deviation can also be assessed on a CT head scan. The authors found that CT eye deviation reliably lateralizes to the ischemic hemisphere (positive predictive value 93%) without reference to clinical examination. In an era of thrombolysis and rapid decision making in acute ischemic stroke, eye deviation on CT can help quickly direct attention to the affected hemisphere.

Acute Disease↗
PubMed2001

Symptomatic hemorrhage after alteplase therapy not due to silent ischemia.

BACKGROUND: Stroke thrombolysis-related intracerebral hemorrhage may occur remotely from the anatomical site of ischemia. One postulated mechanism for this is simultaneous multiple embolization with hemorrhage into a "silent" area of ischemia. RESULTS: A patient suffered a disabling stroke affecting the right cerebral hemisphere. He was treated with intravenous alteplase and underwent extensive early imaging with multimodal MRI. Several hours after treatment he developed a brainstem hemorrhage despite having no evidence of ischemia on DWI MRI in the brainstem. CONCLUSION: Not all occurrences of remote ICH after stroke thrombolysis are secondary to multiple emboli with silent ischemia.

Aged↗