Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage.

Despite the global health burden, treatment of spontaneous intracerebral haemorrhage (ICH) is largely supportive, and translation of specific medical therapies has not been successful. Zebrafish larvae offer a unique platform for drug screening to rapidly identify neuroprotective compounds following ICH. We applied the Spectrum Collection library compounds to zebrafish larvae acutely after ICH to screen for decreased brain cell death and identified 150 successful drugs. Candidates were then evaluated for possible indications with other cardiovascular diseases. Six compounds were identified, including two angiotensin-converting enzyme inhibitors (ACE-Is). Ramipril and quinapril were further assessed to confirm a significant 55% reduction in brain cell death. Proteomic analysis revealed potential mechanisms of neuroprotection. Using the INTERACT2 clinical trial dataset, we demonstrated a significant reduction in the adjusted odds of an unfavourable shift in the modified Rankin scale at 90 days for patients receiving an ACE-I after ICH (versus no ACE-I; odds ratio, 0.80; 95% confidence interval, 0.68-0.95; P=0.009). The zebrafish larval model of spontaneous ICH can be used as a reliable drug screening platform and has identified therapeutics that may offer neuroprotection. This article has an associated First Person interview with the first author of the paper.

Validation of the simplified modified Rankin scale for stroke trials: Experience from the ENCHANTED alteplase-dose arm.

BACKGROUND AND AIMS: The structured, simplified modified Rankin scale questionnaire (smRSq) may increase reliability over the interrogative approach to scoring the modified Rankin scale (mRS) in acute stroke research and practice. During the conduct of the alteplase-dose arm of the international ENhanced Control of Hypertension ANd Thrombolysis StrokE stuDy (ENCHANTED), we had an opportunity to compare each of these approaches to outcome measurement. METHODS: Baseline demographic data were recorded together with the National Institutes of Health Stroke Scale (NIHSS). Follow-up measures obtained at 90 days included mRS, smRSq, and the 5-Dimension European Quality of life scale (EQ-5D). Agreements between smRSq and mRS were assessed with the Kappa statistic. Multiple logistic regression was used to identify baseline predictors of Day 90 smRSq and mRS scores. Treatment effects, based on Day 90 smRSq/mRS scores, were tested in logistic and ordinal logistic regression models. RESULTS: SmRSq and mRS scores had good agreement (weighted Kappa 0.79, 95% confidence interval (CI) 0.78-0.81), while variables of age, atrial fibrillation, diabetes mellitus, pre-morbid mRS (1 vs. 0), baseline NIHSS scores, and imaging signs of cerebral ischemia, similarly predicted their scores. Odds ratios for death or disability, and ordinal shift, 90-day mRS scores using smRSq were 1.05 (95% CI 0.91-1.20; one-sided P = 0.23 for non-inferiority) and 0.98 (95% CI 0.87-1.11; P = 0.02 for non-inferiority), similar to those using mRS. CONCLUSIONS: This study demonstrates the utility of the smRSq in a large, ethnically diverse clinical trial population. Scoring of the smRSq shows adequate agreement with the standard mRS, thus confirming it is a reliable, valid, and useful alternative measure of functional status after acute ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Stroke in China: advances and challenges in epidemiology, prevention, and management.

With over 2 million new cases annually, stroke is associated with the highest disability-adjusted life-years lost of any disease in China. The burden is expected to increase further as a result of population ageing, an ongoing high prevalence of risk factors (eg, hypertension), and inadequate management. Despite improved access to overall health services, the availability of specialist stroke care is variable across the country, and especially uneven in rural areas. In-hospital outcomes have improved because of a greater availability of reperfusion therapies and supportive care, but adherence to secondary prevention strategies and long-term care are inadequate. Thrombolysis and stroke units are accepted as standards of care across the world, including in China, but bleeding-risk concerns and organisational challenges hamper widespread adoption of this care in China. Despite little supporting evidence, Chinese herbal products and neuroprotective drugs are widely used, and the increased availability of neuroimaging techniques also results in overdiagnosis and overtreatment of so-called silent stroke. Future efforts should focus on providing more balanced availability of specialised stroke services across the country, enhancing evidence-based practice, and encouraging greater translational research to improve outcome of patients with stroke.

Dietary intake of key nutrients and subarachnoid hemorrhage: a population-based case-control study in Australasia.

BACKGROUND: A healthy, balanced diet can prevent stroke, but little is known about dietary risk factors for subarachnoid hemorrhage (SAH). We aimed to determine the relationship between common dietary habits and risk of SAH. METHODS: In a population-based, case-control study of SAH undertaken across 4 Australasian cities, a standardized questionnaire was used to obtain information on the frequency of consumption of 15 common food items and alcohol in incident cases (n = 383) and frequency-matched community controls (n = 473). Logistic regression models were used to estimate the independent effects of these dietary factors, after adjusting for conventional risk factors for SAH. Data are reported with odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The risk of SAH rose with increasing consumption of fat or skin on meat (p trend = 0.04), being highest in those with consumption >4 times weekly compared with no fat or skin on meat (adjusted OR 1.70, 95% CI 1.09-2.66), while use of skim or reduced-fat milk (p trend = 0.01) and fruit (p trend = 0.04) was associated with a reduced risk of SAH compared with rare use. Among people with a history of hypertension, frequently adding salt to food was associated with an increased risk of SAH, irrespective of whether they were (OR 2.58, 95% CI 1.29-5.13) or were not (OR 2.88, 95% CI 1.46-5.70) currently taking antihypertensive treatment. CONCLUSIONS: Frequent intake of fat appears to be associated with an increased risk of SAH, particularly in people with hypertension, while frequent use of skim or reduced-fat milk and fruit appears protective for SAH.

Current management of intracerebral haemorrhage in China: a national, multi-centre, hospital register study.

BACKGROUND: We aimed to examine current practice of the management and secondary prevention of intracerebral haemorrhage (ICH) in China where the disease is more common than in Western populations. METHODS: Data on baseline characteristics, management in-hospital and post-stroke, and outcome of ICH patients are from the ChinaQUEST (QUality Evaluation of Stroke Care and Treatment) study, a multi-centre, prospective, 62 hospital registry in China during 2006-07. RESULTS: Nearly all ICH patients (n = 1572) received an intravenous haemodiluting agent such as mannitol (96%) or a neuroprotectant (72%), and there was high use of intravenous traditional Chinese medicine (TCM) (42%). Neurosurgery was undertaken in 137 (9%) patients; being overweight, having a low Glasgow Coma Scale (GCS) score on admission, and Total Anterior Circulation Syndrome (TACS) clinical pattern on admission, were the only baseline factors associated with this intervention in multivariate analyses. Neurosurgery was associated with nearly three times higher risk of death/disability at 3 months post-stroke (odd ratio [OR] 2.60, p < 0.001). Continuation of antihypertensives in-hospital and at 3 and 12 months post-stroke was reported in 732/935 (78%), 775/935 (83%), and 752/935 (80%) living patients with hypertension, respectively. CONCLUSIONS: The management of ICH in China is characterised by high rates of use of intravenous haemodiluting agents, neuroprotectants, and TCM, and of antihypertensives for secondary prevention. The controversial efficacy of these therapies, coupled with the current lack of treatments of proven benefit, is a call for action for more outcomes based research in ICH.

Age and gender variations in the management of ischaemic stroke in China.

BACKGROUND: Stroke is a major health issue in China. AIMS: We aimed to describe the management of patients admitted to hospitals in China with acute ischaemic stroke, and to determine whether there were any differences by age and gender. METHODS: Using a multicentre prospective hospital register across all eight major economic (geographic) regions in China, data on the socioeconomic characteristics, medical history, clinical features, and in-hospital investigations, management, and outcomes were collected on consecutive patients with acute stroke due to cerebral ischaemia during a 5-month period in 2006. RESULTS: Overall, traditional Chinese medicine and neuroprotectant use were remarkably high, with nearly 80% of patients receiving the former and >70% receiving the latter in hospital. Length of hospital stay was also long (median duration 16-days). Multivariate analyses revealed no clinically important differences in management between the genders. For the age-specific analyses, there were significant trends of decreasing use of thrombolysis (P=0·04), warfarin (P=0·01), corticosteroids (P=0·03), and lipid-lowering therapy (P=0·001); however, more assisted feeding (P=0·004) and rising rates of disability and in-hospital complications occurred with increasing age. CONCLUSIONS: New information is provided regarding the current state of ischaemic stroke management in China. Notably, there is high use of traditional Chinese medicine and neuroprotectants and long lengths of hospital stay. Similar to many other countries, differences in stroke care and management by age and gender also exist to a small extent in China.

Pharmaceutical interventions for emotionalism after stroke.

BACKGROUND: Antidepressants may be useful in the treatment of abnormal crying associated with stroke. This is an update of a Cochrane Review first published in 2004. OBJECTIVES: To determine whether pharmaceutical treatment reduces the frequency of emotional displays in people with emotionalism after stroke. SEARCH STRATEGY: We searched the trials registers of the Cochrane Stroke Group and the Cochrane Depression Anxiety and Neurosis Group (last searched August 2009). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2009), MEDLINE (1966 to May 2008), EMBASE (1980 to May 2008), CINAHL (1982 to May 2008), PsycINFO (1967 to May 2008), Arts and Humanities Index (1991 to May 2008), BIOSIS Previews (2002 to May 2008), Science Citation Index (1992 to May 2008), Social Sciences Citation Index (1991 to May 2008), Sociological Abstract/Sociofile (1974 to May 2008), ISI Web of Science (2002 to May 2008), reference lists, clinical trials registers, conference proceedings and dissertation abstracts. We also contacted authors, researchers and pharmaceutical companies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing psychotropic medication to placebo in people with stroke and emotionalism (also known as emotional lability or pathological crying and laughing). DATA COLLECTION AND ANALYSIS: We obtained data for people who no longer met the criteria for emotionalism, and on reduction in frequency of crying. Primary analyses were the proportion of patients who met the criteria for emotionalism at the end of treatment. Secondary outcomes included emotionalism and depression scores, cognitive function, death, activities of daily living and adverse effects. MAIN RESULTS: We included seven trials involving 239 participants. Data were available for five trials with 213 participants. Five trials showed large effects of treatment: 50% reduction in emotionalism, diminished tearfulness, improvements (reduction) in lability, tearfulness and scores on the Pathological Laughter and Crying Scale. However, confidence intervals were wide indicating that treatment may have had only a small positive effect, or even a small negative effect (in one trial). Only two studies systematically reported adverse events; no discernible differences were seen between groups. AUTHORS' CONCLUSIONS: Antidepressants can reduce the frequency and severity of crying or laughing episodes. The effect does not seem specific to one drug or class of drugs. Our conclusions must be qualified by several methodological deficiencies in the studies. More reliable data are required before recommendations can be made about the treatment of post-stroke emotionalism.

Effects of moderate-dose omega-3 fish oil on cardiovascular risk factors and mood after ischemic stroke: a randomized, controlled trial.

BACKGROUND AND PURPOSE: Fish-derived omega-3 fatty acids have long been associated with cardiovascular protection. In this trial, we assessed whether treatment with a guideline-recommended moderate-dose fish oil supplement could improve cardiovascular biomarkers, mood- and health-related quality of life in patients with ischemic stroke. METHODS: Patients with CT-confirmed stroke were randomized to 3 g/day encapsulated fish oil containing approximately 1.2 g total omega-3 (0.7 g docosahexaenoic acid; 0.3 g eicosapentaenoic acid) or placebo oil (combination palm and soy) taken daily over 12 weeks. Serum triglycerides, total cholesterol and associated lipoproteins, selected inflammatory and hemostatic markers, mood, and health-related quality of life were assessed at baseline and follow-up. The primary outcome was change in triglycerides. Compliance was assessed by capsule count and serum phospholipid omega-3 levels (Australian Clinical Trials Registration: ACTRN12605000207617). RESULTS: One hundred two patients were randomized to fish oil or placebo. Intention-to-treat and per-protocol (>85% compliance) analyses showed no significant effect of fish oil treatment on any lipid, inflammatory, hemostatic, or composite mood parameters measured. Adherence to treatment based on pill count was good (89%) reflected by increased serum docosahexanoic acid (P<0.001) and eicosapentaenoic acid (P=0.0006) in the fish oil group. Analysis of oil composition, however, showed some degradation and potentially adverse oxidation products at the end of the study. CONCLUSIONS: There was no effect of 12 weeks of treatment with moderate-dose fish oil supplements on cardiovascular biomarkers or mood in patients with ischemic stroke. It is possible that insufficient dose, short duration of treatment, and/or oxidation of the fish oils may have influenced these outcomes.

Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: a systematic review.

OBJECTIVES: identify, appraise, and synthesize data from randomized, controlled trials of vitamin D supplementation in older people. DESIGN: A systematic review of trials identified from searches of databases, reference lists, review articles, and recent conference proceedings. SETTING: Most studies performed in ambulatory setting. PARTICIPANTS: Older people (mean age=60). INTERVENTIONS: Vitamin D or vitamin D metabolites. MEASUREMENTS: Strength, physical performance, or falls. RESULTS: Thirteen trials involving 2,496 patients met this study's inclusion criteria. Most of the trials were small and had methodological problems. In 10 trials, there was no evidence that vitamin D or vitamin D metabolites had an effect on falls or physical function, but three trials showed a positive effect of vitamin D in combination with calcium. When available data from the four highest quality trials were pooled (n=1,317), there continued to be no evidence that vitamin D reduced the risk of falling (relative risk= 0.99, 95% confidence interval=0.89-1.11), although a single trial of vitamin D and calcium showed a positive effect. CONCLUSION: Although there is insufficient evidence that vitamin D supplementation alone improves physical performance in older people, some data suggest a benefit from vitamin D combined with calcium supplementation, but this requires confirmation in large, well-designed trials.

A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS).

OBJECTIVES: To determine the effectiveness of vitamin D and home-based quadriceps resistance exercise on reducing falls and improving the physical health of frail older people after hospital discharge. DESIGN: Multicenter, randomized, controlled trial with a factorial design. SETTING: Five hospitals in Auckland, New Zealand, and Sydney, Australia. PARTICIPANTS: Two hundred forty-three frail older people. INTERVENTIONS: Patients were randomized to receive a single dose of vitamin D (calciferol, 300,000 IU) or placebo tablets and 10 weeks of high-intensity home-based quadriceps resistance exercise or frequency-matched visits. MEASUREMENTS: The primary endpoints were physical health according to the short-form health survey at 3 months and falls over 6 months. Physical performance and self-rated function were secondary endpoints. Assessments took place in the participants' homes at 3 and 6 months after randomization and were performed by blinded assessors. RESULTS: There was no effect of either intervention on physical health or falls, but patients in the exercise group were at increased risk of musculoskeletal injury (risk ratio = 3.6, 95% confidence interval = 1.5-8.0). Vitamin D supplementation did not improve physical performance, even in those who were vitamin D deficient (<12 ng/mL) at baseline. CONCLUSION: Neither vitamin D supplementation nor a home-based program of high-intensity quadriceps resistance exercise improved rehabilitation outcomes in frail older people after hospitalization. There was no effect of vitamin D on physical performance, and the exercises increased the risk of musculoskeletal injury. These findings do not support the routine use of these interventions at these dosages in the rehabilitation of frail older people.