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Granulocyte colony-stimulating factor (G-CSF) is a candidate neuroprotective factor following cerebral ischemia. To determine whether G-CSF acts partly through the inhibition of nitric oxide synthase (NOS)-2 expression, we administered G-CSF to male NOS-2−/− mice after cerebral ischemia. Although male NOS-2−/− mice exhibit resistance to the gross effects of cerebral ischemia, they display neuronal loss and skilled motor deficits following cerebral ischemia. Administration of G-CSF during reperfusion reduced motor deficit and neuronal loss. Thus, G-CSF is still effective in NOS-2 gene-deficient mice, suggesting that part of the mechanism of action is independent of NOS-2. [ABSTRACT FROM AUTHOR]

Background: Dual antiplatelet therapy is usually superior to mono therapy in preventing recurrent vascular events (VEs). This systematic review assesses the safety and efficacy of triple antiplatelet therapy in comparison with dual therapy in reducing recurrent vascular events. Methods: Completed randomized controlled trials investigating the effect of triple versus dual antiplatelet therapy in patients with ischaemic heart disease (IHD), cerebrovascular disease or peripheral vascular disease were identified using electronic bibliographic searches. Data were extracted on composite VEs, myocardial infarction (MI), stroke, death and bleeding and analysed with Cochrane Review Manager software. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random effects models. Results: Twenty-five completed randomized trials (17,383 patients with IHD) were included which involving the use of intravenous (iv) GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban), aspirin, clopidogrel and/or cilostazol. In comparison with aspirin-based therapy, triple therapy using an intravenous GP IIb/IIIa inhibitor significantly reduced composite VEs and MI in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) (VE: OR 0.69, 95% CI 0.55-0.86; MI: OR 0.70, 95% CI 0.56-0.88) and ST elevation myocardial infarction (STEMI) (VE: OR 0.39, 95% CI 0.30-0.51; MI: OR 0.26, 95% CI 0.17-0.38). A significant reduction in death was also noted in STEMI patients treated with GP IIb/IIIa based triple therapy (OR 0.69, 95% CI 0.49-0.99). Increased minor bleeding was noted in STEMI and elective percutaneous coronary intervention (PCI) patients treated with GP IIb/IIIa based triple therapy. Stroke events were too infrequent for us to be able to identify meaningful trends and no data were available for patients recruited into trials on the basis of stroke or peripheral vascular disease. Conclusions: Triple antiplatelet therapy based on iv GPIIb/IIIa inhibitors was more effective than aspirin-based dual therapy in reducing VEs in patients with acute coronary syndromes (STEMI and NSTEMI). Minor bleeding was increased among STEMI and elective PCI patients treated with a GP IIb/IIIa based triple therapy. In patients undergoing elective PCI, triple therapy had no beneficial effect and was associated with an 80% increase in transfusions and an eightfold increase in thrombocytopenia. Insufficient data exist for patients with prior ischaemic stroke and peripheral vascular disease and further research is needed in these groups of patients. [ABSTRACT FROM AUTHOR]

Both low and high blood pressures (BPs) during the acute phase of stroke are associated independently with a poor outcome. Several small clinical trials have involved the alteration of BP, and this study assessed the relationship between change in BP and functional outcome. Randomized, controlled trials of interventions that would be expected, on pharmacological grounds, to alter BP in patients within 1 week of the onset of acute ischemic or hemorrhagic stroke were sought using electronic searches. Data were collected on BP and clinical outcome. The relationship between the differences in on-treatment BP and odds ratios for outcomes was assessed using meta-regression. Thirty-seven trials involving 9008 patients were included. A U- or J-shaped relationship was found among on-treatment BP difference and early death, death at the end of 90-day follow-up, and combined death or dependency at the end of follow-up. Although outcomes were not significantly reduced at any level of change in BP, the lowest odds occurred at the following times: early death (odds ratio: 0.87; 95% CI: 0.54 to 1.23), 8.1 mm Hg; death at the end of follow-up (odds-ratio: 0.96; 95% CI: 0.31 to 1.65), 14.4 mm Hg; and combined death or dependency at the end of follow-up (odds ratio: 0.95; 95% CI: 0.11 to 1.72), 14.6 mm Hg. Although large falls or increases in BP are associated with a worse outcome, modest reductions may reduce death and combine death or dependency, although the CIs are wide and compatible with an overall benefit or hazard. [ABSTRACT FROM AUTHOR]

High blood pressure (BP) is present in 80% of patients with acute ischaemic stroke and is independently associated with poor outcome. Although this epidemiology suggests that BP should be lowered acutely, concerns about dysfunctional cerebral autoregulation suggest otherwise. Several small randomised trials have assessed cerebral blood flow with various antihypertensive classes and agents in acute ischaemic stroke. Overall, these studies showed no change in cerebral perfusion, although the numbers of studies and patients are limited and there are methodological problems with some trials. There are no large published randomised trials assessing outcome with BP lowering in acute stroke. Calcium channel blockers did not alter outcome after ischaemic stroke (29 trials, 7,665 patients). However, some trials, especially those testing intravenous calcium channel blockers (INWEST) or oral β-receptor antagonists (BEST) reported real or potential hazard. In contrast, oral candesartan reduced combined vascular events in 339 patients with ischaemic stroke (ACCESS) although it had no effect on disability. The CHHIPS trial found that death was reduced in patients randomised to active treatment (labetalol, lisinopril) as compared with placebo. Two larger trials reported that glucose-potassium-insulin therapy (GIST) or magnesium (IMAGES) lowered BP but had no effect on functional outcome. The INTERACT pilot trial studied patients with intracerebral haemorrhage and found that an intensive BP-lowering regime non-significantly reduced haematoma expansion. There are four large ongoing trials examining whether to continue or stop pre-stroke antihypertensive therapy (COSSACS, ENOS) or lower BP in acute stroke (ENOS, SCAST) or haemorrhage (INTERACT 2). Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Estrogens are believed to provide females with endogenous protection against cerebrovascular events although clinical trials studying long-term hormone replacement have yielded disappointing results. In contrast, estrogens might be neuroprotective after experimental ischemia. We performed a systematic review of controlled experimental studies that administered estrogens before, or after, cerebral ischemia and measured lesion volume. Relevant studies were found from searching PubMed, Embase and Web of Science. From 161 identified publications, 27 studies using 1304 experimental subjects were analyzed using the Cochrane Review Manager software. Estrogens reduced lesion volume in a dose-dependent manner, after either transient (P<0.001) or permanent (P<0.001) ischemia and whether administered before or up to 4 h after ischemia onset; no studies assessed efficacy for later time periods. The effect size for estrogens decreased with increasing quality scores for studies of transient ischemia. Estrogens reduced lesion volume when administered to ovariectomized females and young adult males, but had no effect in intact females. Limited data were present for aged animals and the full dose–response relationship was not available in all experimental groups. On the basis of these data, estrogens are a candidate treatment for ischemic stroke, although further preclinical studies are also warranted.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 1103–1113. doi:10.1038/sj.jcbfm.9600270; published online 25 January 2006 [ABSTRACT FROM AUTHOR]

Growth factors possess neuroprotective and neurotrophic properties in vitro, but few have been extensively studied in vivo after stroke. In the present study, we investigated the potential functional benefits of granulocyte colony-stimulating factor (G-CSF) administration after focal cerebral ischemia. Male mice underwent 60-minute middle cerebral artery occlusion (MCAO) and received G-CSF (50 μg/kg, subcutaneously) or vehicle (saline) at the onset of reperfusion. Granulocyte colony-stimulating factor-treated mice killed at 48 hours after MCAO revealed a >45% reduction (P<0.05) in lesion volume. In terms of body weight recovery, and in tests of motor (grid test and rotarod) and cognitive ability (water maze), MCAO significantly worsened the outcome in vehicle-treated mice as compared with shams (P<0.05). However, G-CSF treatment was beneficial as, compared with vehicle, this significantly improved weight recovery and motor ability. This effect was most apparent on the water maze where G-CSF-treated mice were indistinguishable from shams in terms of acquiring the task. These results indicate long-term beneficial effects of a single dose of G-CSF administered on reperfusion, and illustrate the need to further investigate the mechanisms of G-CSF action.Journal of Cerebral Blood Flow & Metabolism (2005) 25, 431–439. doi:10.1038/sj.jcbfm.9600033 Published online 19 January 2005 [ABSTRACT FROM AUTHOR]

Rationale Antiplatelet agents such as aspirin, clopidogrel and dipyridamole are effective in reducing the risk of recurrence after a stroke. Importantly, the risk of recurrence is highest immediately after the index event while antiplatelets cause bleeding. Aims and/or hypothesis The 'Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke' (TARDIS) trial is testing whether short-term intensive antiplatelet therapy is safe and effective in reducing the early risk of recurrence as compared with standard guideline-based therapy. Design TARDIS is an international multi-center prospective randomized open-label blinded-end-point trial, with funding from the UK Health Technology Assessment program. Patients with acute ischemic stroke or transient ischemic attack are randomized within 48 h to intensive/triple antiplatelet therapy or guideline antiplatelets taken for one-month. Patients or relatives give written informed (proxy) consent and all sites have research ethics approval. Analyses will be done by intention-to-treat. Study Outcome The primary outcome is shift in stroke recurrent events and their severity, assessed using the modified Rankin Scale, at three-months. Discussion This paper and attachment describe the trial's statistical analysis plan, as developed from the protocol during recruitment and prior to unblinding of data. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the primary and baseline publications. The data from the trial will provide the first large-scale randomized evidence for the use of intensive antiplatelet therapy for preventing recurrence after acute stroke and transient ischemic attack. [ABSTRACT FROM AUTHOR]

Objective: Increased megakaryocyte size and megakaryocyte ploidy have been observed in man following myocardial infarction and sudden cardiac death. The aim of this study was to compare megakaryocyte ploidy in patients with and without coronary artery atherosclerosis. Methods: Sternal megakaryocytes were obtained immediately prior to cardiac surgery in 26 patients with significant coronary artery atherosclerosis requiring surgical bypass grafting and in 14 age matched control patients requiring cardiac valve replacement or repair with minimal or no coronary atherosclerosis on arteriography. Megakaryocytes were identified using a monoclonal antibody to the CD41 (GPIIb/IIIa) surface antigen and ploidy was studied using flow cytometry. Results: Megakaryocyte modal ploidy was significantly higher in the coronary atherosclerosis patients (modal ploidy 8N, n = 0 subjects; 16N, n = 16; 32N, n = 10) as compared with the control group (modal ploidy 8N, n = 5 subjects; 16N, n = 7; 32N, n = 2), p = 0.008. Ploidy correlated with the degree of coronary atherosclerosis defined as the number of atherosclerotic vessels observed on angiography (r = 0.51, p< 0.001, 95% confidence limits 0.25 to 0.70) and the serum total cholesterol concentration (r = 0.50, p = 0.006, 95% confidence limits 0.18 to 0.72). Bleeding time was not different [315(semiquartile range 45) s v 315(75) s] between the two groups in spite of the fact that 20 of 26 coronary atherosclerosis patients were taking aspirin versus one of 14 valve patients. Conclusions: Megakaryocyte ploidy is increased in human coronary atherosclerosis and correlates with serum lipids. Hypercholesterolaemia may induce increases in megakaryocyte ploidy, and hence the production of hyperfunctional platelets, which will contribute to atherogenesis.Cardiovascular Research 1994;28:1348-1352 [ABSTRACT FROM PUBLISHER]

Study objective – The objective was to measure platelet function in vivo (as cutaneous bleeding time), the role of catecholamines, and the effect of inhibiting thromboxane synthesis on bleeding time, in patients with myocardial infarction, unstable angina, and non-cardiac chest pain.Design – Haemotological variables and plasma catecholamines were compared between patient diagnostic groups using the Kruskal-Wallis test, Conover's multiple comparison test, and Wilcoxon paired rank sum test.Patients – 49 patients entered the study and 45 were assigned to three groups: myocardial infarction (n=26), unstable angina (n=9), and non-coronary chest pain (control) (n=10). There were no significant differences between groups for age or sex. Patients with myocardial infarction smoked more than the others.Measurements and results – Compared to the controls, bleeding time in patients with myocardial infarction was shortened, while in unstable angina it was normal. Plasma adrenaline and noradrenaline concentrations were higher in the myocardial infarction group than in the unstable angina and control groups, but were not correlated with bleeding time. Bleeding time was remeasured 2 h after ingestion of 300 mg aspirin and increased in all subjects, especially in those with myocardial infarction, but it remained significantly shorter in the infarct group than in the comparison groups. Plasma adrenaline was inversely correlated with the bleeding time after aspirin in the infarct group.Conclusions – The shortened bleeding time may be an indicator of an increased prethrombotic tendency present in patients with myocardial infarction but not in those with unstable angina. The effect appears to be mediated by both thromboxane A2 and adrenaline. [ABSTRACT FROM PUBLISHER]

The article reflects on the role of pulse pressure in predicting acute stroke. The authors discuss findings of several studies indicating that pulse pressure, which refers to the difference between systolic and diastolic pressure, is also a strong predictor of cardiovascular risk in middle aged and older people, people with high blood pressure and left ventricular dysfunction as well as those who survived myocardial infarction.

Objectives To review completed trials assessing effect of hormone replacement therapy on subsequent risk of stroke, assessing stroke by pathological type, severity, and outcome. Design Systematic review of randomized controlled trials identified from the Cochrane Library, Embase, and Medline; reviews; and reference lists of relevant papers. Studies reviewed 28 trials, with 39 769 subjects, were identified. Review measures Rates for cerebrovascular events analysed with a random effects model. Sensitivity analyses for heterogeneity included phase of prevention (primary or secondary), type of hormone replacement therapy (oestrogen alone or combined with progesterone), type of oestrogen (estradiol or conjugated equine oestrogen), size of trial (< 5000 or > 5000 patients), length of follow up (£3 years or > 3 years), sex (women only or men only), and trial quality (high or low). Results Hormone replacement therapy was associated with significant increases in total stroke (odds ratio 1.29 (95% confidence interval 1.13 to 1.47), n = 28), non-fatal stroke (1.23 (1.06 to 1.44), n = 21), stroke leading to death or disability (1.56 (1.11 to 2.20), n = 14), ischaemic stroke (1.29 (1.06 to 1.56), n = 16), and a trend to more fatal stroke (1.28 (0.87 to 1.88), n = 22). It was not associated with haemorrhagic stroke (1.07 (0.65 to 1.75), n = 17) or transient ischaemic attack (1.02 (0.78 to 1.34), n = 22). Statistical heterogeneity was not present in any analysis. Conclusions Hormone replacement therapy was associated with an increased risk of stroke, particularly of ischaemic type. Among subjects who had a stroke, those taking hormone replacement therapy seemed to have a worse outcome. Hormone replacement therapy cannot be recommended for the primary or secondary prevention of stroke.. [ABSTRACT FROM AUTHOR]

The article comments on the findings of a study by Martin Dennis and colleagues in "The Lancet" on the safety and efficacy of thigh-length graduated compression stockings (GCS) to prevent deep vein thrombosis (DVT) in patients who have suffered a stroke. It discusses the use of compression Doppler ultrasound to detect (DVT). The results indicated that the stockings do not reduce DVT in patients following stroke, though they do work following surgery. It explores why the CLOTS 1 trial may have obtained an incorrect conclusion and suggests that the role of GCS needs to be assessed in other settings.

An abstract of the article "Efficiency gains resulting from the ordinal analysis of a functional outcome scale: a case study of a major phase III stroke trial," by Gordon D. Murray and colleagues, is presented.