Atorvastatin and ischemic stroke: Mechanisms and therapeutic applications.

The development of additional effective therapies for acute ischemic stroke remains a challenging but critical endeavor. Intravenous recombinant tissue plasminogen activator (rtPA) initiated within 3 hours of stroke onset remains the only approved and validated therapy for acute ischemic stroke, and regulatory approval has expanded recently. Many other therapies have been evaluated, and these trials have either been inconclusive or negative.1 These acute stroke trials do provide valuable information concerning how to implement future trials and some glimmers of hope about existing data. Some of the lessons learned from prior acute stroke trials that will help to guide future trials are outlined below. The two fundamental approaches to the development of acute stroke therapy remain reperfusion and neuroprotection. This short review will focus on the current status of both approaches and how they might be combined, hopefully in the near future. Negative acute stroke treatment trials may be explained by the following: 1. The agents evaluated in clinical trials may not have been adequately tested in preclinical studies to provide robust confirmation of efficacy in appropriate animal models. 2. Side effects precluded adequate drug assessment or did not allow use of adequate drug concentrations. 3. Because of macro-occlusions and, perhaps, micro-occlusions, the drug did not penetrate into or beyond the penumbral tissue in adequate concentrations. 4. Trials included patients not appropriate for the purported mechanism of action of the drug being tested. 5. Patients were included too late after stoke onset to allow for adequate assessment of the drug’s efficacy, and imaging studies were not done to identify patients with appropriate tissue for treatment. 6. Trials have been inadequately powered to detect modest treatment effects. 7. Trials included too many patients with mild or very severe deficits in whom treatment effects are likely difficult to assess with currently used outcome measures. 8. The single primary outcome measure …

Stroke is the third leading cause of death and a leading cause of adult disability in the United States.1 From a global perspective, stroke is also a leading cause of death and disability. The past 20 years have seen significant improvements in stroke prevention, yet each year, >700 000 people have a new or recurrent stroke.2,3 The medical and societal costs of stroke exceed $62 billion in the United States alone.4 Any intervention that could reverse or limit the effects of a stroke would have dramatic medical, societal, and public health benefits. This section will focus on treatment of acute ischemic stroke, which accounts for 80% to 85% of all strokes. Other recent publications have focused on therapies for intracerebral hemorrhage. Acute interventions to reduce the effects of an ischemic stroke can be organized into several main approaches: (1) reperfusion strategies (lytics, endovascular/mechanical); (2) neuroprotection; and (3) restoration, regeneration, and rehabilitation. ### Medical Therapies Thrombolytic therapies for acute ischemic stroke have been used or under study for 30 to 40 years, yet only recently has an agent been approved by the US Food and Drug Administration (FDA) and included in the treatment guidelines. Intravenous recombinant tissue plasminogen activator (rtPA) is the only FDA-approved medical therapy proven to reduce the effects of an ischemic stroke.5,6 Its main mechanism of action is to lyse a clot that is occluding a cerebral vessel, thereby reperfusing distal ischemic brain tissue and preventing or limiting the area of cell death and tissue necrosis. The efficacy of intravenous rtPA was proven in the pivotal National Institute of Neurological Disorders and Stroke (NINDS) rtPA study, which showed improved outcomes for patients treated within 3 hours of stroke onset.7 The NINDS tissue plasminogen activator (tPA) trial had an efficacy end point that was equivalent to the …

Ischemic stroke is one of the leading causes of brain disease, with high morbidity, disability, and mortality. MicroRNAs (miRNAs) have been identified as vital gene regulators in various types of human diseases. Accumulating evidence has suggested that aberrant expression of miRNAs play critical roles in the pathologies of ischemic stroke. Yet, the precise mechanism by which miRNAs control cerebral ischemic stroke remains unclear. In the present study, we explored whether miR-455 suppresses neuronal death by targeting TRAF3 in cerebral ischemic stroke. The expression levels of miR-455 and TRAF3 were detected by quantitative real-time polymerase chain reaction and Western blot. The role of miR-455 in cell death caused by oxygen–glucose deprivation (OGD) was assessed using Cell Counting Kit-8 (CCK-8) assay. The influence of miR-455 on infarct volume was evaluated in mouse brain after middle cerebral artery occlusion (MCAO). Bioinformatics softwares and luciferase analysis were used to find and confirm the targets of miR-455. The results showed that the expression levels of miR-455 significantly decreased in primary neuronal cells subjected to OGD and mouse brain subjected to MCAO. In addition, forced expression of miR-455 inhibited neuronal death and weakened ischemic brain infarction in focal ischemia-stroked mice. Furthermore, TRAF3 was proved to be a direct target of miR-455, and miR-455 could negatively suppress TRAF3 expression. Biological function analysis showed that TRAF3 silencing displayed the neuroprotective effect in ischemic stroke and could enhance miR-455-induced positive impact on ischemic injury both in vitro and in vivo. Taken together, miR-455 played a vital role in protecting neuronal cells from death by downregulating TRAF3 protein expression. These findings may represent a novel latent therapeutic target for cerebral ischemic stroke.

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

Ischemic stroke is characterized by high morbidity, mortality and disability rate worldwide. Because of its complexity in pathogenesis and lack of effective therapeutic strategies and drugs, great breakthrough has not yet been made in the treatment of cerebral ischemic stroke. Therefore, to explore a more effective and safer therapeutic strategy for cerebral ischemic stroke has been the focus of numerous researchers. Neuroprotective effects of sonic hedgehog (Shh) signaling pathway in ischemic stroke have been reported in recent studies, but have not been fully elucidated. In our review, we elaborate the roles of Shh signaling in ischemic stroke from different aspects, including oxidative stress, excitotoxicity, neuroinflammation, apoptosis, angiogenesis, neuroplasticity, neurogenesis, astrogliosis and oligodendrogenesis. Meanwhile, Shh signaling based therapeutic approaches for cerebral ischemic stroke are also included in our review. We hope it will benefit the readers to better understand the roles of Shh signaling pathway in cerebral ischemic stroke and provide more comprehensive insights for basic research and novel strategies for the clinical treatment of cerebral ischemic stroke.

Ischemic stroke, caused by a sudden disruption of blood flow to the brain, is a leading cause of death and exerts a heavy burden on both patients and public health systems. Currently available treatments for ischemic stroke are very limited and are not feasible in many patients due to strict time windows required for their administration. Thus, novel treatment strategies are keenly required. T cells, which are part of the adaptive immune system, have gained more attention for its effects in ischemic stroke. Both preclinical and clinical studies have revealed the conflicting roles for T cells in post-stroke inflammation and as potential therapeutic targets. This review summarizes the mediators of T cell recruitment, as well as the temporal course of its infiltration through the blood-brain-barrier, choroid plexus, and meningeal pathways. Furthermore, we describe the mechanisms behind the deleterious and beneficial effects of T cells in the brain, in both antigen-dependent and antigen-independent manners, and finally we specifically focus on clinical and preclinical studies that have investigated T cells as potential therapeutic targets for ischemic stroke.

See related article, pages 1751–1758. Since the ischemic penumbra was discovered and since a therapeutic window for acute ischemic stroke has been postulated, stroke experts are looking for safe and effective drugs to treat as many acute ischemic stroke patients as possible. Maturation of ischemic damage is a complex process, triggered by hypoperfusion at critical levels and spontaneously evolving toward cell death. It is a self-perpetuating process in which some critical steps (such as ion pumps failure and iNOS production) maintain and enhance the process.1 Reperfusion may reverse the ischemic cascade but, at the same time, induces a further damage. The risk/benefit ratio of reperfusion depends on the amount of penumbral salvageable tissue, that is “individual” and only partially predictable.2,3 Spontaneous reperfusion may occur, and symptoms may reverse, partially or totally, but the percentages of spontaneous reperfusion so far reported account for approximately the 24% of all stroke cases.4 A review of published articles about cerebral angiography in stroke reported that the percentage of spontaneous reperfusion …

Ischemic cerebral stroke is a major cause of death and morbidity. Currently, no neuroprotective agents have been shown to impact the clinical outcomes in cerebral stroke cases. Here, we report therapeutic effects of Se nanoparticles on ischemic stroke in a murine model. Anti-transferrin receptor monoclonal antibody (OX26)-PEGylated Se nanoparticles (OX26-PEG-Se NPs) were designed and synthesized and their neuroprotective effects were measured using in vitro and in vivo approaches. We demonstrate that administration of the biodegradable nanoparticles leads to resolution of brain edema, protection of axons in hippocampus region, and myelination of hippocampal area after cerebral ischemic stroke. Our nanoparticle design ensures efficient targeting and minimal side effects. Hematological and biochemical analyses revealed no undesired NP-induced changes. To gain mechanistic insights into the therapeutic effects of these particles, we characterized the changes to the relevant inflammatory and metabolic signaling pathways. We assessed metabolic regulator mTOR and related signaling pathways such as hippo, Ubiquitin-proteasome system (ERK5), Tsc1/Tsc2 complex, FoxO1, wnt/β-catenine signaling pathway. Moreover, we examined the activity of jak2/stat3 signaling pathways and Adamts1, which are critically involved in inflammation. Together, our study provides a promising treatment strategy for cerebral stroke based on Se NP induced suppression of excessive inflammation and oxidative metabolism.

Marc Fisher MD Kennedy Lees MD Section Editors: On September 26, 2008, the New England Journal of Medicine published the results of the European Cooperative Stroke Study (ECASS) III,1 the first randomized, placebo-controlled trial to demonstrate safe and effective use of intravenous recombinant tissue plasminogen activator (rtPA) to treat patients with acute ischemic stroke (AIS) beyond 3 hours from stroke onset. The ECASS investigators studied the safety and efficacy of administering intravenous rtPA to patients with AIS 3 to 4.5 hours after AIS onset. Using the modified Rankin Scale score at 90 days after stroke occurrence as the primary end point of the study, the investigators demonstrated a modest, statistically significant increase in the likelihood of having normal or near normal recovery (modified Rankin Scale=0 or 1) in favor of rtPA treatment compared with placebo (unadjusted OR, 1.34; 95% CI, 1.02 to 1.76; P =0.04). So, what impact will the results of the study have on acute stroke management and stroke research in the United States and elsewhere? With regard to the first part of the question, the answer is complex. First, the ECASS III results will hopefully help to increase the number of thrombolysis eligible patients with AIS who receive rtPA. Twelve years after the US Food and Drug Administration approved the management of AIS within 3 hours of symptom onset as an indication for the use of intravenous rtPA, less than 5% of patients with AIS are being treated worldwide with rtPA within 3 hours of stroke onset. One of the major factors contributing to this parlous state of affairs has been disagreement among healthcare professionals about the validity of the results of the National Institutes of Neurological Disorders and Stroke (NINDS) trial of rtPA for acute stroke.2 In the late 1990s, the stroke community unexpectedly …

The Effect of Ginkgo biloba on Functional Outcome of Patients with Acute Ischemic Stroke: A Double-blind, Placebo-controlled, Randomized Clinical Trial

Vasculocentricity Versus Cerebrocentricity: What Stroke-Related Baroreceptor Reflex Sensitivity Changes Might Be Telling Us

Введение. В настоящее время цереброваскулярные заболевания (ЦВЗ) в России являются второй по частоте причиной смерти среди больных сахарным диабетом (СД). С гипергликемией и избыточной массой тела связывают протромботические и провоспалительные изменения, приводящие к неблагоприятным исходам инсульта и прогрессированию ЦВЗ. Цель исследования: оценить роль избыточной массы тела как дополнительного фактора риска развития нарушений гемостаза при острых и хронических формах цереброваскулярной патологии у пациентов с СД 2‑го типа (СД‑2). Материалы и методы. В исследование включено 305 пациентов с ишемическими ЦВЗ: группа 1 — 87 больных с ишемическим инсультом (ИИ) и СД‑2; группа 2 — 58 пациентов с ИИ без СД; группа 3 — 80 больных с хроническими ЦВЗ (ХЦВЗ) и СД‑2; группа 4 — 80 пациентов с ХЦВЗ без СД. Выполнены общесоматический и неврологический осмотр, магнитно-резонансная томография головного мозга, инструментальные исследования с расчетом индекса массы тела (ИМТ) и лабораторные исследования с определением гликемии и гликированного гемоглобина (HbA1c), АДФ-индуцированной (АДФ-АТ) и адреналин-индуцированной (Адр-АТ) агрегации тромбоцитов, коагулограммы, включающей содержание фибриногена и Д-димеров, международное нормализованное отношение, активированное частичное тромбопластиновое время, фибринолитическую активность (ФА), индекс фибринолиза, активность плазминогена и уровень тканевого активатора плазминогена (t-РА). Результаты. Наибольших значений глюкоза и HbA1c достигали у пациентов с ИИ и СД‑2. Во всех группах больных с цереброваскулярной патологией СД‑2 сопровождался ожирением и повышенным ИМТ. ЦВЗ (как ИИ, так и хроническая форма) в сочетании с СД‑2 протекали на фоне протромботического состояния крови, связанного с нарушением всех звеньев гемостаза, и проявлялись увеличением АДФ-АТ и Адр-АТ, повышением содержания фибриногена и Д-димеров при одновременном снижении ФА, индекса фибринолиза, активности плазминогена и уровня t-PA. Самые выраженные нарушения наблюдали у пациентов с ИИ и СД‑2, особенно со стороны фибринолиза. Выявлены значимые корреляции между ИМТ и агрегацией тромбоцитов, уровнями фибриногена и Д-димеров, ФА и t-PA. Заключение. У лиц с СД‑2 острые и хронические ЦВЗ сопровождаются ожирением и увеличенным ИМТ, который взаимосвязан с активацией тромбоцитарного и плазменного гемостаза и снижением фибринолиза. Наибольшие изменения отмечены у пациентов с острым инсультом и СД‑2, для которых характерно сочетание гиперфибриногенемии и значительное снижение фибринолиза. Повышение ИМТ у больных ЦВЗ ассоциировано с выраженностью протромботических изменений. Introduction. At present cerebrovascular diseases (CVD) in Russia is the second most common cause of death among patients with diabetes mellitus (DM). Prothrombotic and pro-inflammatory changes leading to adverse outcomes of stroke and progression of CVD are associated with hyperglycemia and obesity. Aim: to assess the role of obesity as an additional risk factor for the development of hemostasis disorders in acute and chronic forms of cerebrovascular pathology in patients with type 2 diabetes mellitus (DM‑2). Materials and methods. The study included 305 patients with ischemic CVD: group 1 — 87 patients with ischemic stroke (IS) and DM‑2; group 2 — 58 patients with IS without DM; group 3 — 80 patients with chronic CVD (CCVD) and DM‑2; group 4 — 80 patients with CCVD without DM. The following studies were completed: somatic and neurological examinations, magnetic resonance imaging of the brain, calculation of body mass index (BMI) and laboratory tests with the determination of glycemia and glycated hemoglobin (HbA1c), ADP-induced (ADP-AT) and adrenaline-induced (Adr-AT) platelet aggregation, coagulogram with fibrinogen and D-dimers content, international normalized ratio, activated partial thromboplastin time, fibrinolytic activity (FA), fibrinolysis index (FI), plasminogen activity and level of tissue plasminogen activator (t-PA). Results. The highest values of glucose and HbA1c were found in patients with IS and DM‑2. In all groups of patients with cerebrovascular pathology DM‑2 was accompanied with obesity and increased BMI. CVD (both IS and chronic form) in combination with DM‑2 were accompanied by prothrombotic blood state (associated with hemostasis disorders), and manifested by enhancement of ADP-AT and Adr-AT, increasing of fibrinogen and D-dimers content and decreasing of FA, FI, plasminogen activity and t-PA. Most expressed disturbances (especially in fibrinolysis) were observed in patients with IS and DM‑2. Significant correlations were found between BMI and platelet aggregation, levels of fibrinogen and D-dimers, FA and t-PA. Conclusion. In patients with DM‑2 acute and chronic CVD are accompanied by obesity and increased BMI and associated with activation of platelet and plasma hemostasis and decreased fibrinolysis. The largest changes were noted in patients with acute stroke and DM‑2 and characterized by a combination of hyperfibrinogenemia and a significantly decreased fibrinolysis. Increasing of BMI in patients with CVD was associated with the severity of prothrombotic changes.

Stroke is the second leading cause of death and the third leading cause of disability-adjusted life-years (DALYs) worldwide.1Lozano R Naghavi M Foreman K et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2095-2128Summary Full Text Full Text PDF PubMed Scopus (9517) Google Scholar, 2Murray CJ Vos T Lozano R Naghavi M et al.Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2197-2223Summary Full Text Full Text PDF PubMed Scopus (6098) Google Scholar Moreover, the global burden of stroke is increasing. Between 1990 and 2010, the number of stroke-related deaths increased by 26% and DALYs by 19%.1Lozano R Naghavi M Foreman K et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2095-2128Summary Full Text Full Text PDF PubMed Scopus (9517) Google Scholar, 2Murray CJ Vos T Lozano R Naghavi M et al.Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2197-2223Summary Full Text Full Text PDF PubMed Scopus (6098) Google Scholar Is this epidemic of stroke global or regional, and what is the explanation? A systematic review3Feigin VL Lawes CM Bennett DA Barker-Collo SL Parag V Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.Lancet Neurol. 2009; 8: 355-369Summary Full Text Full Text PDF PubMed Scopus (1830) Google Scholar of 56 population-based studies of the incidence and early case fatality of stroke, published from 1970 to 2008, showed that, in ten low-income and middle-income countries, the age-adjusted incidence of stroke more than doubled, from 52 per 100 000 person-years in 1970–79 to 117 per 100 000 person years in 2000–08—an increase of 5·6% per year. However, the incidence of stroke in 18 high-income countries almost halved, from 163 to 94 per 100 000 person-years—a decrease of 1% per year.3Feigin VL Lawes CM Bennett DA Barker-Collo SL Parag V Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.Lancet Neurol. 2009; 8: 355-369Summary Full Text Full Text PDF PubMed Scopus (1830) Google Scholar These data suggest divergent patterns of stroke epidemiology in different socioeconomic regions of the world, but might be subject to selection or sampling bias because of sampling of only ten of the world's low-income and middle-income countries over four decades, and diagnostic or stroke classification bias because of a failure to distinguish major pathological subtypes of stroke (ie, ischaemic vs haemorrhagic), which have different diagnostic criteria, causes, and outcomes. In The Lancet Global Health, Rita Krishnamurthi and colleagues from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and Stroke Expert Group estimate the incidence, mortality, and DALYs of first-ever ischaemic and haemorrhagic stroke (intracerebral and subarachnoid haemorrhage) in all 21 regions of the world in 1990, 2005, and 2010.4Krishnamurthi RV Feigin VL Forouzanfar MH Mensah GA et al.on behalf of the Global Burden of Diseases, Injuries, and Risk Factors Study (the GBD 2010 Study)the GBD Stroke Experts GroupGlobal and regional burden of ischaemic and haemorrhagic strokes in 1990–2010: findings from the Global Burden of Disease Study 2010.Lancet Glob Health. 2013; (published online Oct 24.)http://dx.doi.org/10.1016/S2214-109X(13)70089-5Google Scholar The investigators derived the estimates from a systematic review of all relevant studies published between 1990 and 2010. 119 studies were identified in which pathological subtypes of stroke were confirmed by brain imaging or autopsy in at least 70% of cases. Specific analytical techniques were used to calculate regional and country-specific estimates of incidence and mortality rates and DALYs lost, by age group and country income status. Surprisingly, the major finding is that, in 2010, most of the global burden of stroke was due to haemorrhagic, not ischaemic, stroke. Haemorrhagic stroke constituted a third (31·5%) of the 16·9 million incident stroke events (20% in the high-income countries and 37% in the low-income and middle- income countries), which is higher than hitherto appreciated.4Krishnamurthi RV Feigin VL Forouzanfar MH Mensah GA et al.on behalf of the Global Burden of Diseases, Injuries, and Risk Factors Study (the GBD 2010 Study)the GBD Stroke Experts GroupGlobal and regional burden of ischaemic and haemorrhagic strokes in 1990–2010: findings from the Global Burden of Disease Study 2010.Lancet Glob Health. 2013; (published online Oct 24.)http://dx.doi.org/10.1016/S2214-109X(13)70089-5Google Scholar However, despite being only half as common as ischaemic stroke, haemorrhagic stroke caused more than half (51·7%) of the 5·9 million stroke-related deaths, and three fifths (61·5%) of the 102·2 million DALYs lost throughout the world. The number of years of life lost were greater with haemorrhagic stroke because it affected people at a younger age (mean 65·1 years [SD 0·11]) than did ischaemic stroke (73·1 years [0·10]) and had a higher case fatality (57% vs 25%). The second major finding is that most of the burden of ischaemic and haemorrhagic stroke is in low-income and middle-income countries, which bear 63% of incident ischaemic strokes and 80% of haemorrhagic strokes, 57% of deaths due to ischaemic stroke and 84% due to haemorrhagic stroke, and 64% of DALYs lost due to ischaemic stroke and 86% due to haemorrhagic stroke. The average age of incident and fatal ischaemic and haemorrhagic strokes was 6 years younger in low-income and middle-income countries than in high-income countries. The third finding is that most of the burden of ischaemic and haemorrhagic stroke is in people younger than 75 years, who bear 62% of incident ischaemic strokes and 78% of haemorrhagic strokes, and 63% of DALYs lost due to ischaemic stroke and 83% due to haemorrhagic stroke. The fourth finding is that, over the past two decades (1990–2010) the absolute number of people with incident ischaemic stroke has increased significantly by 37% and incident haemorrhagic stroke by 47%, the number of deaths due to ischaemic stroke by 21% and haemorrhagic stroke by 20%, and the number of DALYs lost due to ischaemic stroke by 18% and haemorrhagic stroke by 14%. The increase in absolute numbers has arisen despite a reduction in the age-standardised incidence of ischaemic stroke by 13% and haemorrhagic stroke by 19%, a reduction in the mortality rates of ischaemic stroke by 37% and haemorrhagic stroke by 38%, and a reduction in DALYs rates of ischaemic stroke by 34% and haemorrhagic stroke by 39%. The reduction in rates probably shows improved education, prevention, diagnosis, treatment, and rehabilitation of stroke. The increase in absolute numbers, despite a reduction in rates, is presumably because global population growth and increasing life expectancy have increased the denominator by a greater proportion than the increasing number of stroke events has increased the numerator. The fifth finding is that the incidence of haemorrhagic stroke in low-income and middle-income countries is one rate that has increased over the past two decades (22% increase, 95% CI 5–30), particularly in people younger than 75 years (19%, 5–30). Indeed, low-income and middle-income countries had a 40% higher incidence, 77% higher mortality, and 65% higher DALY rates of haemorrhagic stroke than did high-income countries. Krishnamurthi and colleagues' results suggest that key priorities in the quest to reduce the global and regional burden of stroke are prevention of haemorrhagic stroke, particularly in low-income and middle-income countries, and in people younger than 75 years. Most haemorrhagic strokes can be attributed to hypertension and an unhealthy lifestyle (eg, physical inactivity, obesity, unhealthy diet, alcohol excess, and smoking; table).5Lawes CM Vander Hoorn S Rodgers A for the International Society of HypertensionGlobal burden of blood-pressure-related disease, 2001.Lancet. 2008; 371: 1513-1518Summary Full Text Full Text PDF PubMed Scopus (1708) Google Scholar, 6O'Donnell MJ Xavier D Liu L et al.on behalf of the INTERSTROKE investigatorsRisk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.Lancet. 2010; 376: 112-123Summary Full Text Full Text PDF PubMed Scopus (2049) Google ScholarTableRisk factors for haemorrhagic stroke in 663 cases of acute first haemorrhagic stroke (within 5 days of symptom onset) compared with 3000 controls with no history of stroke who were matched with cases for age and sex, assessed in 22 countries between 2007 and 20106O'Donnell MJ Xavier D Liu L et al.on behalf of the INTERSTROKE investigatorsRisk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.Lancet. 2010; 376: 112-123Summary Full Text Full Text PDF PubMed Scopus (2049) Google ScholarPrevalenceOdds ratio (99% CI)Population-attributable riskControlsCasesHistory of hypertension954/2996 (32%)399/662 (60%)3·8 (3·0–4·8)44% (37–52%)Regular physical activity362/2994 (12%)45/662 (7%)0·7 (0·4–1·1)28% (7–67%)Waist-to-hip ratio (T3 vs T1)984/2960 (33%)231/655 (35%)1·4 (1·02–1·9)26% (14–43%)Diet risk score (T3 vs T1)904/2982 (30%)221/658 (34%)1·4 (1·01–2·0)24% (12–43%)Alcohol intake*More than 30 drinks per month or binge drinker. T3=tertile 3. T1=tertile 1.324/2989 (11%)108/660 (16%)2·0 (1·3–3·0)15% (8–24%)Current smokers732/2994 (24%)207/662 (31%)1·4 (1·1–2·0)9% (4–20%)Psychosocial stress440/2987 (15%)124/654 (19%)1·2 (0·9–1·7)3% (1–16%)Data are n/N (%), unless otherwise indicated. Multivariable model adjusted for age, sex and region.* More than 30 drinks per month or binge drinker. T3=tertile 3. T1=tertile 1. Open table in a new tab Data are n/N (%), unless otherwise indicated. Multivariable model adjusted for age, sex and region. Population-based mass strategies to reduce consumption of salt, calories, alcohol, and tobacco by improving education and the environment will complement high-risk strategies of identifying those at risk of haemorrhagic (and ischaemic) stroke, thus empowering these individuals to improve their lifestyle behaviours and, if necessary, lower their mean blood pressure and blood pressure variability with appropriate doses of antihypertensive drugs.7Rose G Strategy of prevention: lessons from cardiovascular disease.Br Med J. 1981; 282: 1847-1851Crossref PubMed Scopus (800) Google Scholar, 8Hankey GJ Nutrition and the risk of stroke.Lancet Neurol. 2012; 11: 66-81Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 9Law MR Morris JK Wald NJ Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies.BMJ. 2009; 338: b1665Crossref PubMed Scopus (2008) Google Scholar, 10Webb AJS Fischer U Mehta Z Rothwell PM Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis.Lancet. 2010; 375: 906-915Summary Full Text Full Text PDF PubMed Scopus (563) Google Scholar I declare that I have no conflicts of interest. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010Although age-standardised mortality rates for ischaemic and haemorrhagic stroke have decreased in the past two decades, the absolute number of people who have these stroke types annually, and the number with related deaths and DALYs lost, is increasing, with most of the burden in low-income and middle-income countries. Further study is needed in these countries to identify which subgroups of the population are at greatest risk and who could be targeted for preventive efforts. Full-Text PDF Open Access

Safranal is an active ingredient of saffron (Crocus sativus L.). Its neuroprotective role in ischemic stroke (IS) through reducing oxidative stress damage has been widely reported. However, the neurorestorative mechanisms of safranal are still in the preliminary stage of exploration. the present study is aimed to discuss the effects of safranal on the recovery of neural function after IS. A middle cerebral artery occlusion/reperfusion (MCAO/R) rat model and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in rat brain microvascular endothelial cells (RBMEC) were established to explore the effects of safranal on IS in vivo and in vitro. It was found that safranal dramatically reduced infarct size and Nissl's body loss in rats subjected to MCAO/R. Safranal also promoted neuron survival, stimulated neurogenesis, induced angiogenesis and increased SIRT1 expression in vivo and in vitro. Silencing of SIRT1 reversed the above effects of safranal on OGD/R-induced RBMEC. The present study indicated that safranal was a promising compound to exert neurorestorative effect in IS via upregulating SIRT1 expression. These results offer insight into developing new mechanisms in the recovery of neural function after safranal treatment of IS.

Uric acid is an end product of purine metabolism. Hyperuricemia is defined as serum uric acid level 〉420 μmol/L in man, and 360 μmol/L in woman. Several mechanisms can cause elevated serum uric acid levels. Systematic reviews and Meta-analyses have shown that hyperuricemia is significantly correlated with the increased morbidity and mortality in patients with ischemic stroke. However, as a powerful antioxidant and a radical scavenger, uric acid seems to have a neuroprotective effect in ischemic stroke. Uric acid administered early can enhance the effect of recombinant tissue plasminogen activator （rtPA） thrombolytic therapy in rats with thromboembolic stroke. Therefore, it is necessary to conduct a randomized controlled trial for the clinical effects of rtPA thrombolysis in combination with uric acid in patients with acute ischemic stroke. A phase 3 clinical trial is ongoing, and its results are worth waiting for. Key words: Stroke; Brain Ischemia; Uric Acid; Hyperuricemia