Timothy J. England

Granulocyte-Colony Stimulating Factor for Mobilizing Bone Marrow Stem Cells in Subacute Stroke The Stem Cell Trial of Recovery Enhancement After Stroke 2 Randomized Controlled Trial

Background and Purpose— Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34+ peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. Methods— G-CSF (10 &mgr;g/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34+ count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34+ cells reinjected on day 6. Results— Sixty patients were recruited at mean of 8 days (SD ±5) post ictus, with mean age 71 years (±12 years) and 53% men. The groups were well matched for baseline minimization/prognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3±1.3, placebo 3.0±1.3) at 90 days, or the number of injections received. G-CSF increased CD34+ and total white cell counts of 9.5- and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF–treated patients (P=0.06). In 1 participant, there was suggestion that labeled CD34+ cells had migrated to the ischemic lesion. Conclusions— This randomized, double-blind, placebo-controlled trial suggests that G-CSF is safe when administered subacutely. It is feasible to label and readminister iron-labeled CD34+ cells in patients with ischemic stroke. Clinical Trial Registration— URL: www.controlled-trials.com. Unique identifier: ISRCTN63336619.

Relationship Between Baseline Blood Pressure Parameters (Including Mean Pressure, Pulse Pressure, and Variability) and Early Outcome After Stroke Data From the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST)

Background and Purpose— High blood pressure (BP) in acute stroke is associated independently with a poor outcome. Recent evidence suggests that other hemodynamic parameters may also be associated with outcomes following stroke. Methods— The relationship between baseline BP, heart rate, and other hemodynamic parameters, and early outcomes were assessed using data from TAIST trial. Results— Death or neurological deterioration at day 10 was associated, both in unadjusted and adjusted analyses, with systolic BP (adjusted OR, 1.02; 95% CI, 1.01–1.03), mean arterial pressure (OR, 1.02; 95% CI, 1.01–1.04), pulse pressure (OR, 1.02; 95% CI, 1.01–1.03), and BP variability (OR, 1.03; 95% CI, 1.01–1.05). Similar relationships were noted for deterioration alone, and recurrent stroke. Conclusions— Early death or neurologic deterioration, deterioration, and recurrent stroke are associated independently with high systolic BP, mean arterial pressure, pulse pressure, and BP variability. These measures offer potential therapeutic targets for improving early outcome after acute ischemic stroke.

Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: A systematic review.

BACKGROUND Granulocyte-colony stimulating factor (G-CSF) shows promise as a treatment for stroke. This systematic review assesses G-CSF in experimental ischaemic stroke. METHODS Relevant studies were identified with searches of Medline, Embase and PubMed. Data were extracted on stroke lesion size, neurological outcome and quality, and analysed using Cochrane Review Manager using random effects models; results are expressed as standardised mean difference (SMD) and odds ratio (OR). RESULTS Data were included from 19 publications incorporating 666 animals. G-CSF reduced lesion size significantly in transient (SMD -1.63, p<0.00001) but not permanent (SMD -1.56, p=0.11) focal models of ischaemia. Lesion size was reduced at all doses and with treatment commenced within 4 h of transient ischaemia. Neurological deficit (SMD -1.37, p=0.0004) and limb placement (SMD -1.88, p=0.003) improved with G-CSF; however, locomotor activity (> or =4 weeks post-ischaemia) was not (SMD 0.76, p=0.35). Death (OR 0.27, p<0.0001) was reduced with G-CSF. Median study quality was 4 (range 0-7/8); Eggers test suggested significant publication bias (p<0.001). CONCLUSIONS G-CSF significantly reduced lesion size in transient but not permanent models of ischaemic stroke. Motor impairment and death were also reduced. Further studies assessing dose response, administration time, length of ischaemia and long-term functional recovery are needed.

Cannabinoids in experimental stroke: a systematic review and meta-analysis.

Cannabinoids (CBs) show promise as neuroprotectants with some agents already licensed in humans for other conditions. We systematically reviewed CBs in preclinical stroke to guide further experimental protocols. We selected controlled studies assessing acute administration of CBs for experimental stroke, identified through systematic searches. Data were extracted on lesion volume, outcome and quality, and analyzed using random effect models. Results are expressed as standardized mean difference (SMD) with 95% confidence intervals (CIs). In all, 144 experiments (34 publications) assessed CBs on infarct volume in 1,473 animals. Cannabinoids reduced infarct volume in transient (SMD −1.41 (95% CI −1.71), −1.11) P<0.00001) and permanent (−1.67 (−2.08, −1.27), P<0.00001) ischemia and in all subclasses: endocannabinoids (−1.72 (−2.62, −0.82), P=0.0002), CB1/CB2 ligands (−1.75 (−2.19, −1.31), P<0.00001), CB2 ligands (−1.65 (−2.09, −1.22), P<0.00001), cannabidiol (−1.20 (−1.63, −0.77), P<0.00001), Δ9-tetrahydrocannabinol (−1.43 (−2.01, −0.86), P<0.00001), and HU-211 (−2.90 (−4.24, −1.56), P<0.0001). Early and late neuroscores significantly improved with CB use (−1.27 (−1.58, −0.95), P<0.00001; −1.63 (−2.64, −0.62), P<0.002 respectively) and there was no effect on survival. Statistical heterogeneity and publication bias was present, median study quality was 4 (range 1 to 6/8). Overall, CBs significantly reduced infarct volume and improve functional outcome in experimental stroke. Further studies in aged, female and larger animals, with other co-morbidities are required.

The ethical and legal implications of deactivating an implantable cardioverter-defibrillator in a patient with terminal cancer

In this paper, the ethical and legal issues raised by the deactivation of implantable cardioverter-defibrillators (ICDs) in patients with terminal cancer is considered. It is argued that the ICD cannot be well described either as a treatment or as a non-treatment option, and thus raises complex questions regarding how rules governing deactivation should be framed. A new category called “integral devices” is proposed. Integral devices require their own special rules, reflecting their position as a “halfway house” between a form of treatment and a part of the body. The practical problems faced by doctors working in palliative medicine with regard to the deactivation of ICDs are also considered.

Endocannabinoids modulate human blood–brain barrier permeability in vitro

Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood–brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model.

Carbon fibre micro-electrodes for concomitant in vivo electrophysiological and voltammetric measurements: no reciprocal influences

Differential pulse voltammetry and more recently cyclic voltammetry have been successfully used to monitor basal levels of endogenous chemicals by means of treated carbon fibre microbiosensors inserted in specific brain regions. In this study, feasibility of concomitant in vivo recordings of stable electrophysiological signals and basal ascorbate, catecholaminergic and indolaminergic voltammetric peaks at the same cerebral site by means of a single electrically treated carbon fibre micro electrode (microbiosensor) is presented. The results indicate that these two independent techniques can be combined in vivo at a single electrode, and that voltammetric measurements of unstimulated levels of extracellular compounds do not alter concomitant basal cell firing for a period long enough (more than 6 h) to allow pharmacological manipulations.

Asymptomatic Hemorrhagic Transformation of Infarction and Its Relationship With Functional Outcome and Stroke Subtype Assessment From the Tinzaparin in Acute Ischaemic Stroke Trial

Background and Purpose— Asymptomatic hemorrhagic transformation of infarction (AHTI) is common, but its risk factors and relationship with functional outcome are poorly defined. Methods— The analyses used data from the Tinzapararin in Acute Ischaemic Stroke Trial, a randomized controlled trial assessing tinzaparin (low molecular weight heparin) versus aspirin in 1484 patients with acute ischemic stroke. CT head scans (baseline, day 10) were adjudicated for the presence of hemorrhagic transformation. Stroke subtype was classified according to modified Trial of Org 10172 in Acute Stroke Treatment (small vessel, large vessel, cardioembolic) and the Oxfordshire Community Stroke Project (total anterior, partial anterior, lacunar, and posterior circulatory syndromes). Modified Rankin scale and Barthel Index were measured at 3 and 6 months. Analyses were adjusted for age, sex, severity, blood pressure, infarct volume, and treatment. Symptomatic hemorrhage was excluded. Results— At day 10, AHTI did not differ between aspirin (300 mg; 32.8%) and medium-dose (100 IU/kg; 36.0%) and high-dose (175 IU/kg; 31.4%) tinzaparin groups (P=0.44). Relative to lacunar stroke, AHTI on follow-up CT was significantly increased in total anterior circulation syndrome (odds ratio, 11.5; 95% CI, 7.1 to 18.7) and partial anterior circulation syndrome (odds ratio, 7.2; 95% CI, 4.5 to 11.4) stroke. Similarly, relative to small vessel disease, AHTI was increased in large vessel (odds ratio, 15.1; 95% CI, 9.4 to 24.3) and cardioembolic (odds ratio, 14.1; 95% CI, 8.5 to 23.5) stroke. After adjustment for infarct volume, the presence of AHTI was not associated with outcome at 3 or 6 months as measured by the modified Rankin Scale and Barthel Index. Conclusions— AHTI is increased in ischemic stroke with cortical syndromes and of large vessel or cardioembolic etiology. Heparin does not increase AHTI. AHTI is not associated with functional outcome.

Stem cells for enhancing recovery after stroke: a review

The potential application for stem cell therapy is vast, and development for use in ischaemic stroke is still in its infancy. Access to stem cells for research is contentious; however, stem cells are obtainable from both animal and human. Despite a limited understanding of their mechanisms of action, clinical trials assessing stem cells in human stroke have been performed. Trials are also underway evaluating haematopoietic precursors mobilised with granulocyte-colony stimulating factor, an approach offering an autologous means of administrating stem cells for therapeutic purposes. This review summarises current knowledge in regard to stem cells and their potential for helping improve recovery after stroke.

A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility

Background Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke. Methodology/Principal Findings A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01). Conclusions/Significance Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy. Trial Registration Controlled-Trials.com ISRCTN83673558