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1.  Functional recovery in aging mice after experimental stroke 
Brain, behavior, and immunity  2011;25(8):1689-1700.
Aging is a non modifiable risk factor for stroke. Since not all strokes can be prevented, a major emerging area of research is the development of effective strategies to enhance functional recovery after stroke. However, in the vast majority of pre-clinical stroke studies, the behavioral tests used to assess functional recovery have only been validated for use in young animals, or are designed for rats. Mice are increasingly utilized in stroke models but well validated behavioral tests designed for rats are not necessarily reproducible in mice. We examined a battery of behavioral tests to evaluate functional recovery in an aging murine model of stroke. We found that the vertical pole, hanging wire and open field can accurately assess acute behavioral impairments after stroke in both young and aging male mice, but animals recover rapidly on these tasks. The corner test can accurately and repeatedly differentiate stroke from sham animals up to 30 days post stroke and can be performed reliably in aging mice. Aging male mice had significantly worse behavioral impairment compared to young male mice in the first two weeks after stroke but eventually recovered to the same degree as young mice. In contrast, chronic infarct size, as measured by ipsilateral cerebral atrophy, was significantly lower in aging male mice compared to young male mice. Reactive gliosis, formation of glial scar, and an enhanced innate immune response was seen in the aging brain and may contribute to the delayed behavioral recovery seen in aged animals.
PMCID: PMC3191237  PMID: 21756996
Cerebral ischemia; Aging; Functional recovery; Cerebral blood flow (CBF); Cerebral atrophy; Microglia; Glial scar; Astrocytes; GFAP (glial fibrillary acid protein); Iba1
2.  Long-term behavioral assessment of function in an experimental model for ischemic stroke 
Journal of neuroscience methods  2011;196(2):247-257.
Middle cerebral artery occlusion (MCAO) in rats is a well-studied experimental model for ischemic stroke leading to brain infarction and functional deficits. Many preclinical studies have focused on a small time window after the ischemic episode to evaluate functional outcome for screening therapeutic candidates. Short evaluation periods following injury have led to significant setbacks due to lack of information on the delayed effects of treatments, as well as short-lived and reversible neuroprotection, so called false-positive results. In this report, we evaluated long-term functional deficit for 90 days after MCAO in two rat strains with two durations of ischemic insult, in order to identify the best experimental paradigm to assess injury and subsequent recovery. Behavioral outcomes were measured pre-MCAO followed by weekly assessment post-stroke. Behavioral tests included the 18-point composite neurological score, 28-point neuroscore, rearing test, vibrissae-evoked forelimb placing test, foot fault test and the CatWalk. Brain lesions were assessed to correlate injury to behavior outcomes at the end of study. Our results indicate that infarction volume in Sprague-Dawley rats was dependent on occlusion duration. In contrast, the infarction volume in Wistar rats did not correlate with the duration of ischemic episode. Functional outcomes were not dependent on occlusion time in either strain; however, measureable deficits were detectable long-term in limb asymmetry, 18- and 28-point neuroscores, forelimb placing, paw swing speed, and gait coordination. In conclusion, these behavioral assays, in combination with an extended long-term assessment period, can be used for evaluating therapeutic candidates in preclinical models of ischemic stroke.
PMCID: PMC3539723  PMID: 21256866
Ischemic stroke; CatWalk; long-term functional recovery; middle cerebral artery occlusion; rat strain
3.  A novel approach to induction and rehabilitation of deficits in forelimb function in a rat model of ischemic stroke 
Acta Pharmacologica Sinica  2012;34(1):104-112.
Constraint-induced movement therapy (CIMT), which forces use of the impaired arm following unilateral stroke, promotes functional recovery in the clinic but animal models of CIMT have yielded mixed results. The aim of this study is to develop a refined endothelin-1 (ET-1) model of focal ischemic injury in rats that resulted in reproducible, well-defined lesions and reliable upper extremity impairments, and to determine if an appetitively motivated form of rehabilitation (voluntary forced use movement therapy; FUMT) would accelerate post-ischemic motor recovery.
Male Sprague Dawley rats (3 months old) were given multiple intracerebral microinjections of ET-1 into the sensorimotor cortex and dorsolateral striatum. Sham-operated rats received the same surgical procedure up to but not including the drill holes on the skull. Functional deficits were assessed using two tests of forelimb placing, a forelimb postural reflex test, a forelimb asymmetry test, and a horizontal ladder test. In a separate experiment ET-1 stroke rats were subjected to daily rehabilitation with FUMT or with a control therapy beginning on post-surgery d 5. Performance and post-mortem analysis of lesion volume and regional BDNF expression were measured.
Following microinjections of ET-1 animals exhibited significant deficits in contralateral forelimb function on a variety of tests compared with the sham group. These deficits persisted for up to 20 d with no mortality and were associated with consistent lesion volumes. FUMT therapy resulted in a modest but significantly accelerated recovery in the forelimb function as compared with the control therapy, but did not affect lesion size or BDNF expression in the ipsilesional hemisphere.
We conclude that refined ET-1 microinjection protocols and forcing use of the impaired forelimb in an appetitively motivated paradigm may prove useful in developing strategies to study post-ischemic rehabilitation and neuroplasticity.
PMCID: PMC4086495  PMID: 23103624
stroke; brain ischemia; endothelin-1; rehabilitation therapy; voluntary forced use movement therapy (FUMT); BDNF; neuroplasticity
4.  Remodeling of the corticospinal innervation and spontaneous behavioral recovery following ischemic stroke in adult mice 
Background and Purpose
To elucidate how the motor pathways rewire the denervated tissue after stroke, we investigated remodeling of the corticospinal tract (CST) in transgenic mice with Yellow Fluorescent Protein (YFP) CST labeling in conjunction with trans-synaptic pseudorabies virus (PRV) retrograde tracing.
Adult male CST-YFP mice were subjected to permanent right middle cerebral artery occlusion (MCAo, n=8/group). Foot-Fault test was performed to monitor functional deficit and recovery. PRV tracer was injected into the left forelimb muscles at 1 or 4 weeks after MCAo (4 days before sacrifice), respectively. A third group of CST-YFP mice without MCAo was used for normal control (n=6). The YFP labeling of CST in the cervical cord and PRV labeling of pyramidal neurons in the bilateral cortices were measured on vibratome sections using a confocal imaging system.
Compared with normal animals, axonal density in the stroke-affected side of the cervical cord was significantly decreased at 11 days (p<0.001) and significantly increased at 32 days after stroke compared to the day 11 values (p<0.05). PRV labeling was significantly decreased in the ischemic hemisphere 11 days after MCAo (p<0.001). In contrast, a significant increase was observed in PRV labeling of bilateral cortices 32 days after stroke compared to 11 days (p<0.05). The CST axonal density in the denervated spinal cord and pyramidal neuron labeling in the bilateral cortices were significantly correlated with behavioral recovery (p<0.05).
Spontaneous functional recovery after stroke may, at least in part, be attributed to neuronal remodeling in the corticospinal system.
PMCID: PMC2704262  PMID: 19478220
functional recovery; middle cerebral artery occlusion; neuronal plasticity; mice
5.  Intracarotid administration of human bone marrow mononuclear cells in rat photothrombotic ischemia 
Increasing evidence suggests that cell therapy improves functional recovery in experimental models of stroke and myocardial infarction. So far only small pilot trials tested the effects of cell therapy in stroke patients, whereas large clinical trials were conducted in patients with ischemic heart disease. To investigate the therapeutic benefit of cell therapy to improve the recovery after stroke, we determined the efficacy of bone marrow derived mononuclear cells, which were shown to improve the recovery in experimental and clinical acute myocardial infarction studies, in a rat stroke model.
Adult male Wistar rats were randomly assigned to receive either five million human bone marrow mononuclear cells (hBMC) or placebo intraarterially 3 days after photothrombotic ischemia. For immunosuppression the animals received daily injections of cyclosporine throughout the experiment, commencing 24 hours before the cell transplantation. A battery of behavioral tests was performed before and up to 4 weeks after ischemia.
Body temperature and body weight revealed no difference between groups. Neurological deficits measured by the Rotarod test, the adhesive-removal test and the cylinder test were not improved by hBMC transplantation compared to placebo.
This study demonstrates that hBMC do not improve functional recovery when transplanted intraaterially 3 days after the onset of focal cerebral ischemia. A possible reason for the failed neurological improvement after cell therapy might be the delayed treatment initiation compared to other experimental stroke studies that showed efficacy of bone marrow mononuclear cells.
PMCID: PMC2828442  PMID: 20298535
6.  Sustained sensorimotor impairments after endothelin-1 induced focal cerebral ischemia (stroke) in aged rats 
Experimental neurology  2009;222(1):13-24.
Despite recent advances, stroke remains a leading cause of neurological disability with the vast majority of victims being the elderly, who exhibit more severe neurological deficits and a reduced capacity to recover from these disabilities in comparison to young stroke survivors. The objective of the present study was to develop a model of focal ischemic stroke in aged rats using endothelin-1 (ET-1) to produce low mortality rates as well as reliable, robust sensorimotor deficits that resemble functional impairments associated with stroke in humans. Here, we studied the functional and histological outcome following unilateral ET-1 infusions into the sensorimotor cortex of aged rats (20–23 months old). This procedure resulted in low mortality rates (13.3%) and no loss in body weight one week following surgery. Functional assessment was performed using a number of reliable behavioural tests: staircase test (fine motor function), horizontal ladder (skilled locomotion), bilateral tactile stimulation test (somatosensory function) and cylinder test (postural weight support). Following ET-1 induced stroke, all tests demonstrated large and sustained sensorimotor deficits in both forelimb and hindlimb function that failed to improve over the 28-day testing period. In addition, histological assessment revealed a substantial loss of retrogradely labelled corticospinal neurons in the ipsilesional hemisphere following stroke. Our results establish a model for the use of aged rats in future preclinical studies, which will enhance assessment of the long-term benefit of potential neural repair and regenerative strategies.
PMCID: PMC2864515  PMID: 19913535
Aged; Endothelin-1; Stroke; Behavioural deficits; Plasticity; Preclinical models
7.  Uncovering Treatment Burden as a Key Concept for Stroke Care: A Systematic Review of Qualitative Research 
PLoS Medicine  2013;10(6):e1001473.
In a systematic review of qualitative research, Katie Gallacher and colleagues examine the evidence related to treatment burden after stroke from the patient perspective.
Please see later in the article for the Editors' Summary
Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.
Methods and Findings
The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.
Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems.
Systematic Review Registration
International Prospective Register of Systematic Reviews CRD42011001123
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the blood supply of the brain is suddenly interrupted by a blood vessel in the brain being blocked by a blood clot (ischemic stroke) or bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. In the longer term, post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs that thin the blood, reduce blood pressure and reduce cholesterol (major risk factors for stroke) alongside behavioral counseling can reduce the risk of a second stroke.
Why Was This Study Done?
Treatment for, and rehabilitation from, stroke is a lengthy process that requires considerable personal investment from the patient. The term “treatment burden” describes the self-care practices that patients with stroke and other chronic diseases must perform to follow the complicated management strategies that have been developed for these conditions. Unfortunately, treatment burden can overwhelm patients. They may be unable to cope with the multiple demands placed on them by health-care providers and systems for their self-care, a situation that leads to poor adherence to therapies and poor outcomes. For example, patients may find it hard to complete all the exercises designed to help them regain full movement of their limbs after a stroke. Treatment burden has been poorly examined in relation to stroke. Here, the researchers identify and describe the treatment burden in stroke by undertaking a systematic review (a study that uses predefined criteria to identify all the literature on a given topic) of qualitative studies on the patient experience of stroke management. Qualitative studies collect non-quantitative data so, for example, a qualitative study on stroke treatment might ask people how the treatment made them feel whereas a quantitative study might compare clinical outcomes between those receiving and not receiving the treatment.
What Did the Researchers Do and Find?
The researchers identified 69 qualitative studies dealing with the experiences of stroke management of adult patients and analyzed the data in these papers using framework synthesis—an approach that divides data into thematic categories. Specifically, the researchers used a coding framework informed by normalization process theory, a sociological theory of the implementation, embedding and integration of tasks and practices; embedding is the process of making tasks and practices a routine part of everyday life and integration refers to sustaining these embedded practices. The researchers identified four main areas of treatment burden for stroke: making sense of stroke management and planning care; interacting with others, including health care professionals, family and other patients with stroke; enacting management strategies (including enduring institutional admissions, managing stroke in the community, reintegrating into society and adjusting to life after stroke); and reflecting on management to make decisions about self-care. Moreover, they identified problems in all these areas, including inadequate provision of information, poor communication with health-care providers, and unsatisfactory inpatient care.
What Do These Findings Mean?
These findings show that stroke management is extremely demanding for patients and is influenced by both the micro and macro organization of health services. At the micro organizational level, fragmented care and poor communication between patients and clinicians and between health-care providers can mean patients are ill equipped to organize their care and develop coping strategies, which makes adherence to management strategies less likely. At the macro organizational level, it can be hard for patients to obtain the practical and financial help they need to manage their stroke in the community. Overall, these findings suggest that care provision for stroke needs to be transformed so that the needs of patients rather than the needs of health-care systems are prioritized. Further work is required, however, to understand how the patient experience of treatment burden is affected by the clinical characteristics of stroke, by disability level, and by other co-existing diseases. By undertaking such work, it should be possible to generate a patient-reported outcome measure of treatment burden that, if used by policy makers and health-care providers, has the potential to improve the quality of stroke care.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation including personal stories (in English and Spanish); the US National Institutes of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices website also provides information about stroke for patients and their families, including personal stories
MedlinePlus has links to additional resources about stroke (in English and Spanish)
The UK not-for-profit website Healthtalkonline provides personal stories about stroke
Wikipedia provides information on the burden of treatment and on the normalization process theory (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC3692487  PMID: 23824703
8.  Behavioral and Histopathological Assessment of Adult Ischemic Rat Brains after Intracerebral Transplantation of NSI-566RSC Cell Lines 
PLoS ONE  2014;9(3):e91408.
Stroke is a major cause of death and disability, with very limited treatment option. Cell-based therapies have emerged as potential treatments for stroke. Indeed, studies have shown that transplantation of neural stem cells (NSCs) exerts functional benefits in stroke models. However, graft survival and integration with the host remain pressing concerns with cell-based treatments. The current study set out to investigate those very issues using a human NSC line, NSI-566RSC, in a rat model of ischemic stroke induced by transient occlusion of the middle cerebral artery. Seven days after stroke surgery, those animals that showed significant motor and neurological impairments were randomly assigned to receive NSI-566RSC intracerebral transplants at two sites within the striatum at three different doses: group A (0 cells/µl), group B (5,000 cells/µl), group C (10,000 cells/µl), and group D (20,000 cells/µl). Weekly behavioral tests, starting at seven days and continued up to 8 weeks after transplantation, revealed dose-dependent recovery from both motor and neurological deficits in transplanted stroke animals. Eight weeks after cell transplantation, immunohistochemical investigations via hematoxylin and eosin staining revealed infarct size was similar across all groups. To identify the cell graft, and estimate volume, immunohistochemistry was performed using two human-specific antibodies: one to detect all human nuclei (HuNu), and another to detect human neuron-specific enolase (hNSE). Surviving cell grafts were confirmed in 10/10 animals of group B, 9/10 group C, and 9/10 in group D. hNSE and HuNu staining revealed similar graft volume estimates in transplanted stroke animals. hNSE-immunoreactive fibers were also present within the corpus callosum, coursing in parallel with host tracts, suggesting a propensity to follow established neuroanatomical features. Despite absence of reduction in infarct volume, NSI-566RSC transplantation produced behavioral improvements possibly via robust engraftment and neuronal differentiation, supporting the use of this NSC line for stroke therapy.
PMCID: PMC3948841  PMID: 24614895
9.  The Shh Signaling Pathway Is Upregulated in Multiple Cell Types in Cortical Ischemia and Influences the Outcome of Stroke in an Animal Model 
PLoS ONE  2015;10(4):e0124657.
Recently the sonic hedgehog (shh) signaling pathway has been shown to play an important role in regulating repair and regenerative responses after brain injury, including ischemia. However, the precise cellular components that express and upregulate the shh gene and the cellular components that respond to shh signaling remain to be identified. In this study, using a distal MCA occlusion model, our data show that the shh signal is upregulated both at the cortical area near the injury site and in the adjacent striatum. Multiple cell types upregulate shh signaling in ischemic brain, including neurons, reactive astrocytes and nestin-expressing cells. The shh signaling pathway genes are also expressed in the neural stem cells (NSCs) niche in the subventricular zone (SVZ). Conditional deletion of the shh gene in nestin-expressing cells both at the SVZ niche and at the ischemic site lead to significantly more severe behavioral deficits in these shh iKO mice after cortical stroke, measured using an automated open field locomotion apparatus (Student’s t-test, p<0.05). In contrast, animals given post-stroke treatment with the shh signaling agonist (SAG) demonstrated less deficits in behavioral function, compared to vehicle-treated mice. At 7 days after stroke, SAG-treated mice showed higher values in multiple horizontal movement parameters compared to vehicle treated mice (Student’s t-test, p<0.05) whereas there were no differences in pre-stroke measurements, (Student’s t-test, p>0.05). In summary, our data demonstrate that shh signaling plays critical and ongoing roles in response to ischemic injury and modulation of shh signaling in vivo alters the functional outcome after cortical ischemic injury.
PMCID: PMC4415811  PMID: 25927436
10.  Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms 
PLoS ONE  2015;10(6):e0127302.
Intra-arterial stem cell transplantation exerts neuroprotective effects for ischemic stroke. However, the optimal therapeutic time window and mechanisms have not been completely understood. In this study, we investigated the relationship between the timing of intra-arterial transplantation of allogeneic mesenchymal stem cells (MSCs) in ischemic stroke model in rats and its efficacy in acute phase.
Adult male Wistar rats weighing 200 to 250g received right middle cerebral artery occlusion (MCAO) for 90 minutes. MSCs (1×106cells/ 1ml PBS) were intra-arterially injected at either 1, 6, 24, or 48 hours (1, 6, 24, 48h group) after MCAO. PBS (1ml) was intra-arterially injected to control rats at 1 hour after MCAO. Behavioral test was performed immediately after reperfusion, and at 3, 7 days after MCAO using the Modified Neurological Severity Score (mNSS). Rats were euthanized at 7 days after MCAO for evaluation of infarct volumes and the migration of MSCs. In order to explore potential mechanisms of action, the upregulation of neurotrophic factor and chemotactic cytokine (bFGF, SDF-1α) induced by cell transplantation was examined in another cohort of rats that received intra-arterial transplantation at 24 hours after recanalization then euthanized at 7 days after MCAO for protein assays.
Behavioral test at 3 and 7 days after transplantation revealed that stroke rats in 24h group displayed the most robust significant improvements in mNSS compared to stroke rats in all other groups (p’s<0.05). Similarly, the infarct volumes of stroke rats in 24h group were much significantly decreased compared to those in all other groups (p’s<0.05). These observed behavioral and histological effects were accompanied by MSC survival and migration, with the highest number of integrated MSCs detected in the 24h group. Moreover, bFGF and SDF-1α levels of the infarcted cortex were highly elevated in the 24h group compared to control group (p’s<0.05).
These results suggest that intra-arterial allogeneic transplantation of MSCs provides post-stroke functional recovery and reduction of infarct volumes in ischemic stroke model of rats. The upregulation of bFGF and SDF-1α likely played a key mechanistic role in enabling MSC to afford functional effects in stroke. MSC transplantation at 24 hours after recanalization appears to be the optimal timing for ischemic stroke model, which should guide the design of clinical trials of cell transplantation for stroke patients.
PMCID: PMC4468176  PMID: 26075717
11.  Citalopram Enhances Neurovascular Regeneration and Sensorimotor Functional Recovery after Ischemic Stroke in Mice 
Neuroscience  2013;247:1-11.
Recent clinical trials have demonstrated that treatment with selective serotonin reuptake inhibitors (SSRIs) after stroke enhances motor functional recovery; however, the underlying mechanisms remain to be further elucidated. We hypothesized that daily administration of the clinical drug citalopram would produce these functional benefits via enhancing neurovascular repair in the ischemic peri-infarct region. To test this hypothesis, focal ischemic stroke was induced in male C57/B6 mice by permanent ligation of distal branches of the middle cerebral artery to the barrel cortex and 7-min occlusion of the bilateral common carotid arteries. Citalopram (10 mg/kg, i.p.) was injected 24 hrs after stroke and daily thereafter. To label proliferating cells, bromo-deoxyuridine was injected daily beginning 3 days after stroke. Immunohistochemical and functional assays were performed to elucidate citalopram-mediated cellular and sensorimotor changes after stroke. Citalopram treatment had no significant effect on infarct formation or edema 3 days after stroke; however, citalopram-treated mice had better functional recovery than saline-treated controls 3 and 14 days after stroke in the adhesive removal test. Increased expression of brain derived neurotrophic factor was detected in the peri-infarct region 7 days after stroke in citalopram-treated animals. The number of proliferating neural progenitor cells and the distance of neuroblast migration from the sub-ventricular zone towards the ischemic cortex were significantly greater in citalopram-treated mice at 7 days after stroke. Immunohistochemical staining and co-localization analysis showed that citalopram-treated animals generated more new neurons and microvessels in the peri-infarct region 21 and 28 days after stroke. Taken together, these results suggest that citalopram promotes post-stroke sensorimotor recovery likely via enhancing neurogenesis, neural cell migration and the microvessel support in the peri-infarct region of the ischemic brain.
PMCID: PMC3916088  PMID: 23590907
Ischemic stroke; SSRI; Citalopram; Neurogenesis; Angiogenesis
12.  Associations between Stroke Mortality and Weekend Working by Stroke Specialist Physicians and Registered Nurses: Prospective Multicentre Cohort Study 
PLoS Medicine  2014;11(8):e1001705.
In a multicenter observational study, Benjamin Bray and colleagues evaluate whether weekend rounds by stroke specialist physicians, or the ratio of registered nurses to beds on weekends, is associated with patient mortality after stroke.
Please see later in the article for the Editors' Summary
Observational studies have reported higher mortality for patients admitted on weekends. It is not known whether this “weekend effect” is modified by clinical staffing levels on weekends. We aimed to test the hypotheses that rounds by stroke specialist physicians 7 d per week and the ratio of registered nurses to beds on weekends are associated with mortality after stroke.
Methods and Findings
We conducted a prospective cohort study of 103 stroke units (SUs) in England. Data of 56,666 patients with stroke admitted between 1 June 2011 and 1 December 2012 were extracted from a national register of stroke care in England. SU characteristics and staffing levels were derived from cross-sectional survey. Cox proportional hazards models were used to estimate hazard ratios (HRs) of 30-d post-admission mortality, adjusting for case mix, organisational, staffing, and care quality variables. After adjusting for confounders, there was no significant difference in mortality risk for patients admitted to a stroke service with stroke specialist physician rounds fewer than 7 d per week (adjusted HR [aHR] 1.04, 95% CI 0.91–1.18) compared to patients admitted to a service with rounds 7 d per week. There was a dose–response relationship between weekend nurse/bed ratios and mortality risk, with the highest risk of death observed in stroke services with the lowest nurse/bed ratios. In multivariable analysis, patients admitted on a weekend to a SU with 1.5 nurses/ten beds had an estimated adjusted 30-d mortality risk of 15.2% (aHR 1.18, 95% CI 1.07–1.29) compared to 11.2% for patients admitted to a unit with 3.0 nurses/ten beds (aHR 0.85, 95% CI 0.77–0.93), equivalent to one excess death per 25 admissions. The main limitation is the risk of confounding from unmeasured characteristics of stroke services.
Mortality outcomes after stroke are associated with the intensity of weekend staffing by registered nurses but not 7-d/wk ward rounds by stroke specialist physicians. The findings have implications for quality improvement and resource allocation in stroke care.
Please see later in the article for the Editors' Summary
Editors' Summary
In a perfect world, a patient admitted to hospital on a weekend or during the night should have as good an outcome as a patient admitted during regular working hours. But several observational studies (investigations that record patient outcomes without intervening in any way; clinical trials, by contrast, test potential healthcare interventions by comparing the outcomes of patients who are deliberately given different treatments) have reported that admission on weekends is associated with a higher mortality (death) rate than admission on weekdays. This “weekend effect” has led to calls for increased medical and nursing staff to be available in hospitals during the weekend and overnight to ensure that the healthcare provided at these times is of equal quality to that provided during regular working hours. In the UK, for example, “seven-day working” has been identified as a policy and service improvement priority for the National Health Service.
Why Was This Study Done?
Few studies have actually tested the relationship between patient outcomes and weekend physician or nurse staffing levels. It could be that patients who are admitted to hospital on the weekend have poor outcomes because they are generally more ill than those admitted on weekdays. Before any health system introduces potentially expensive increases in weekend staffing levels, better evidence that this intervention will improve patient outcomes is needed. In this prospective cohort study (a study that compares the outcomes of groups of people with different baseline characteristics), the researchers ask whether mortality after stroke is associated with weekend working by stroke specialist physicians and registered nurses. Stroke occurs when the brain's blood supply is interrupted by a blood vessel in the brain bursting (hemorrhagic stroke) or being blocked by a blood clot (ischemic stroke). Swift treatment can limit the damage to the brain caused by stroke, but of the 15 million people who have a stroke every year, about 6 million die within a few hours and another 5 million are left disabled.
What Did the Researchers Do and Find?
The researchers extracted clinical data on 56,666 patients who were admitted to stroke units in England over an 18-month period from a national stroke register. They obtained information on the characteristics and staffing levels of the stroke units from a biennial survey of hospitals admitting patients with stroke, and information on deaths among patients with stroke from the national register of deaths. A quarter of the patients were admitted on a weekend, almost half the stroke units provided stroke specialist physician rounds seven days per week, and the remainder provided rounds five days per week. After adjustment for factors that might have affected outcomes (“confounders”) such as stroke severity and the level of acute stroke care available in each stroke unit, there was no significant difference in mortality risk between patients admitted to a stroke unit with rounds seven days/week and patients admitted to a unit with rounds fewer than seven days/week. However, patients admitted on a weekend to a stroke unit with 1.5 nurses/ten beds had a 30-day mortality risk of 15.2%, whereas patients admitted to a unit with 3.0 nurses/ten beds had a mortality risk of 11.2%, a mortality risk difference equivalent to one excess death per 25 admissions.
What Do These Findings Mean?
These findings show that the provision of stroke specialist physician rounds seven days/week in stroke units in England did not influence the (weak) association between weekend admission for stroke and death recorded in this study, but mortality outcomes after stroke were associated with the intensity of weekend staffing by registered nurses. The accuracy of these findings may be affected by the measure used to judge the level of acute care available in each stroke unit and by residual confounding. For example, patients admitted to units with lower nursing levels may have shared other unknown characteristics that increased their risk of dying after stroke. Moreover, this study considered the impact of staffing levels on mortality only and did not consider other relevant outcomes such as long-term disability. Despite these limitations, these findings support the provision of higher weekend ratios of registered nurses to beds in stroke units, but given the high costs of increasing weekend staffing levels, it is important that controlled trials of different models of physician and nursing staffing are undertaken as soon as possible.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Meeta Kerlin
Information about plans to introduce seven-day working into the National Health Service in England is available; the 2013 publication “NHS Services—Open Seven Days a Week: Every Day Counts” provides examples of how hospitals across England are working together to provide routine healthcare services seven days a week; a “Behind the Headlines” article on the UK National Health Service Choices website describes a recent observational study that investigated the association between admission to hospital on the weekend and death, and newspaper coverage of the study's results; the Choices website also provides information about stroke for patients and their families, including personal stories
A US nurses' site includes information on the association of nurse staffing with patient safety
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation, including personal stories (in English and Spanish); the US National Institute of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
PMCID: PMC4138029  PMID: 25137386
13.  Estimates of Outcomes Up to Ten Years after Stroke: Analysis from the Prospective South London Stroke Register 
PLoS Medicine  2011;8(5):e1001033.
Charles Wolfe and colleagues collected data from the South London Stroke Register on 3,373 first strokes registered between 1995 and 2006 and showed that between 20% and 30% of survivors have poor outcomes up to 10 years after stroke.
Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population.
Methods and Findings
Data were collected from the population-based South London Stroke Register, a prospective population-based register documenting all first in a lifetime strokes since 1 January 1995 in a multi-ethnic inner city population. The outcomes assessed are reported as estimates of need and included disability (Barthel Index <15), inactivity (Frenchay Activities Index <15), cognitive impairment (Abbreviated Mental Test < 8 or Mini-Mental State Exam <24), anxiety and depression (Hospital Anxiety and Depression Scale >10), and mental and physical domain scores of the Medical Outcomes Study 12-item short form (SF-12) health survey. Estimates were stratified by age, gender, and ethnicity, and age-adjusted using the standard European population. Plots of outcome estimates over time were constructed to examine temporal trends and sociodemographic differences. Between 1995 and 2006, 3,373 first-ever strokes were registered: 20%–30% of survivors had a poor outcome over 10 y of follow-up. The highest rate of disability was observed 7 d after stroke and remained at around 110 per 1,000 stroke survivors from 3 mo to 10 y. Rates of inactivity and cognitive impairment both declined up to 1 y (280/1,000 and 180/1,000 survivors, respectively); thereafter rates of inactivity remained stable till year eight, then increased, whereas rates of cognitive impairment fluctuated till year eight, then increased. Anxiety and depression showed some fluctuation over time, with a rate of 350 and 310 per 1,000 stroke survivors, respectively. SF-12 scores showed little variation from 3 mo to 10 y after stroke. Inactivity was higher in males at all time points, and in white compared to black stroke survivors, although black survivors reported better outcomes in the SF-12 physical domain. No other major differences were observed by gender or ethnicity. Increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
Between 20% and 30% of stroke survivors have a poor range of outcomes up to 10 y after stroke. Such epidemiological data demonstrate the sociodemographic groups that are most affected longer term and should be used to develop longer term management strategies that reduce the significant poor outcomes of this group, for whom effective interventions are currently elusive.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the brain's blood supply is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs and behavioral counseling can reduce the risk of a second stroke. However, people can also have problems with cognition (thinking, awareness, attention, learning, judgment, and memory) after a stroke, and they can become depressed or anxious. These “outcomes” can persist for many years, but although stroke is acknowledged as a long-term condition, most existing data on stroke outcomes are limited to a year after the stroke and often focus on disability alone. Longer term, more extensive information is needed to help plan services and to help develop research to improve outcomes. In this burden of disease analysis, the researchers use follow-up data collected by the prospective South London Stroke Register (SLSR) to provide long-term population-based estimates of disability, cognition, and psychological outcomes after a first stroke. The SLSR has recorded and followed all patients of all ages in an inner area of South London after their first-ever stroke since 1995.
What Did the Researchers Do and Find?
Between 1995 and 2006, the SLSR recorded 3,373 first-ever strokes. Patients were examined within 48 hours of referral to SLSR, their stroke diagnosis was verified, and their sociodemographic characteristics (including age, gender, and ethnic origin) were recorded. Study nurses and fieldworkers then assessed the patients at three months and annually after the stroke for disability (using the Barthel Index, which measures the ability to, for example, eat unaided), inactivity (using the Frenchay Activities Index, which measures participation in social activities), and cognitive impairment (using the Abbreviated Mental Test or the Mini-Mental State Exam). Anxiety and depression and the patients' perceptions of their mental and physical capabilities were also assessed. Using preset cut-offs for each outcome, 20%–30% of stroke survivors had a poor outcome over ten years of follow-up. So, for example, 110 individuals per 1,000 population were judged disabled from three months to ten years, rates of inactivity remained constant from year one to year eight, at 280 affected individuals per 1,000 survivors, and rates of anxiety and depression fluctuated over time but affected about a third of the population. Notably, levels of inactivity were higher among men than women at all time points and were higher in white than in black stroke survivors. Finally, increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
What Do These Findings Mean?
Although the accuracy of these findings may be affected by the loss of some patients to follow-up, these population-based estimates of outcome measures for survivors of a first-ever stroke for up to ten years after the event provide concrete evidence that stroke is a lifelong condition with ongoing poor outcomes. They also identify the sociodemographic groups of patients that are most affected in the longer term. Importantly, most of the measured outcomes remain relatively constant (and worse than outcomes in an age-matched non-stroke-affected population) after 3–12 months, a result that needs to be considered when planning services for stroke survivors. In other words, these findings highlight the need for health and social services to provide long-term, ongoing assessment and rehabilitation for patients for many years after a stroke.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the US National Institute of Health SeniorHealth Web site has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices Web site also provides information about stroke for patients and their families
MedlinePlus has links to additional resources about stroke (in English and Spanish)
More information about the South London Stroke Register is available
PMCID: PMC3096613  PMID: 21610863
14.  Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice 
Glial scarring is traditionally thought to be detrimental after stroke. But emerging studies now suggest that reactive astrocytes may also contribute to neurovascular remodeling. Here, we assessed the effects and mechanisms of metabolic inhibition of reactive astrocytes in a mouse model of stroke recovery. Five days after stroke onset, astrocytes were metabolically inhibited with fluorocitrate (FC, 1 nmol). Markers of reactive astrocytes (glial fibrillary acidic protein (GFAP), HMGB1), markers of neurovascular remodeling (CD31, synaptophysin, PSD95), and behavioral outcomes (neuroscore, rotarod latency) were quantified from 1 to 14 days. As expected, focal cerebral ischemia induced significant neurological deficits in mice. But over the course of 14 days after stroke onset, a steady improvement in neuroscore and rotarod latencies were observed as the mice spontaneously recovered. Reactive astrocytes coexpressing GFAP and HMGB1 increased in peri-infarct cortex from 1 to 14 days after cerebral ischemia in parallel with an increase in the neurovascular remodeling markers CD31, synaptophysin, and PSD95. Compared with stroke-only controls, FC-treated mice demonstrated a significant decrease in HMGB1-positive reactive astrocytes and neurovascular remodeling, as well as a corresponding worsening of behavioral recovery. Our results suggest that reactive astrocytes in peri-infarct cortex may promote neurovascular remodeling, and these glial responses may aid functional recovery after stroke.
PMCID: PMC2949171  PMID: 19997116
angiogenesis; astrocytes; cerebral ischemia; high-mobility group box 1; neuroplasticity; neuroprotection
15.  Plasminogen Deficiency Causes Reduced Corticospinal Axonal Plasticity and Functional Recovery after Stroke in Mice 
PLoS ONE  2014;9(4):e94505.
Tissue plasminogen activator (tPA) has been implicated in neurite outgrowth and neurological recovery post stroke. tPA converts the zymogen plasminogen (Plg) into plasmin. In this study, using plasminogen knockout (Plg-/-) mice and their Plg-native littermates (Plg+/+), we investigated the role of Plg in axonal remodeling and neurological recovery after stroke. Plg+/+ and Plg-/- mice (n = 10/group) were subjected to permanent intraluminal monofilament middle cerebral artery occlusion (MCAo). A foot-fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the corticospinal tract (CST). Animals were euthanized 4 weeks after stroke. Neurite outgrowth was also measured in primary cultured cortical neurons harvested from Plg+/+ and Plg-/- embryos. In Plg+/+ mice, the motor functional deficiency after stroke progressively recovered with time. In contrast, recovery in Plg-/- mice was significantly impaired compared to Plg+/+ mice (p<0.01). BDA-positive axonal density of the CST originating from the contralesional cortex in the denervated side of the cervical gray matter was significantly reduced in Plg-/- mice compared with Plg+/+ mice (p<0.05). The behavioral outcome was highly correlated with the midline-crossing CST axonal density (R2>0.82, p<0.01). Plg-/- neurons exhibited significantly reduced neurite outgrowth. Our data suggest that plasminogen-dependent proteolysis has a beneficial effect during neurological recovery after stroke, at least in part, by promoting axonal remodeling in the denervated spinal cord.
PMCID: PMC3986098  PMID: 24732409
16.  An activated protein C analog protects from ischemic stroke and extends the therapeutic window of tPA in aged female mice and hypertensive rats 
Background and purpose
3K3A-activated protein C (APC) protects young, healthy male rodents after ischemic stroke. 3K3A-APC is currently under development as a neuroprotectant for acute ischemic stroke in humans. Stroke Therapy Academic Industry Roundtable (STAIR) recommends that after initial studies in young, healthy male animals, further studies should be performed in females, aged animals and animals with comorbid conditions. Here, we studied the effects of delayed 3KA-APC therapy alone and with tissue plasminogen activator (tPA) in aged female mice and spontaneously hypertensive rats (SHR).
We used STAIR recommendations for ensuring good scientific inquiry. Murine recombinant 3K3A-APC (0.2 mg/kg) alone or with recombinant tPA (10 mg/kg) was given intravenously 4 hours after transient middle cerebral artery occlusion (MCAo) in aged female mice and rats, and after embolic stroke in SHR. 3K3A-APC was additionally administered within 3–7 days after stroke. The neuropathological analysis and neurological scores, foot-fault, forelimb asymmetry and/or adhesive removal tests were performed within 7 and 28 days of stroke.
In all models, tPA alone had no effects on the infarct volume or behavior. 3K3A-APC alone or with tPA reduced the infarct volume 7 days after the MCAo in aged female mice and embolic stroke in SHR by 62–66% and 50–53%, respectively, improved significantly (p<0.05) behavior, and eliminated tPA-induced intracerebral microhemorrhages. In aged female mice, 3K3A-APC was protective within 4 weeks of stroke.
3K3A-APC protects from ischemic stroke and extends the therapeutic window of tPA in aged female mice and in SHR with a comorbid condition.
PMCID: PMC3912991  PMID: 24159062
ischemic stroke; proteases; neuroprotection; old female mice; hypertensive rats
17.  Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke 
The European journal of neuroscience  2014;39(12):2129-2138.
Metformin is currently the first-line treatment drug for type 2 diabetes. Metformin is a well-known activator of AMP-activated protein kinase (AMPK). In experimental studies, metformin has been shown to exert direct vascular effects by increasing vascular endothelial growth factor expression and improving microvascular density. As stroke is the leading cause of long-term disability and angiogenesis is implicated as an important mechanism in functional recovery, we hypothesized that chronic metformin treatment would improve post-stroke functional recovery by enhancing functional microvascular density. For this study, C57BL/6N male mice were subjected to a 60-min middle cerebral artery occlusion, and were given 50 mg/kg/day metformin beginning 24 h post-stroke for 3 weeks. Behavioral recovery was assessed using adhesive-tape removal and the apomorphine-induced turning test. The role of angiogenesis was assessed by counting vessel branch points from fluorescein-conjugated lectin-perfused brain sections. Importantly even if metformin treatment was initiated 24 h after injury it enhanced recovery and significantly improved stroke-induced behavioral deficits. This recovery occurred in parallel with enhanced angiogenesis and with restoration of endogenous cerebral dopaminergic tone and revascularization of ischemic tissue. We assessed if the effects on recovery and angiogenesis were mediated by AMPK. When tested in AMPK α-2 knockout mice, we found that metformin treatment did not have the same beneficial effects on recovery and angiogenesis, suggesting that metformin-induced angiogenic effects are mediated by AMPK. The results from this study suggest that metformin mediates post-stroke recovery by enhancing angiogenesis, and these effects are mediated by AMPK signaling.
PMCID: PMC4061245  PMID: 24649970
AMPK; apomorphine; cerebral ischemia; metformin
18.  Targeted Over-Expression of Glutamate Transporter 1 (GLT-1) Reduces Ischemic Brain Injury in a Rat Model of Stroke 
PLoS ONE  2011;6(8):e22135.
Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke. We generated an adeno-associated viral (AAV) vector expressing the rat GLT-1 cDNA (AAV-GLT1). Functional expression of AAV-GLT1 was confirmed by increased glutamate clearance rate in non-stroke rat brain as measured by in vivo amperometry. AAV-GLT1 was injected into future cortical region of infarction 3 weeks prior to 60 min middle cerebral artery occlusion (MCAo). Tissue damage was assessed at one and two days after MCAo using TUNEL and TTC staining, respectively. Behavioral testing was performed at 2, 8 and 14 days post-stroke. Animals receiving AAV-GLT1, compared to AAV-GFP, showed significant decreases in the duration and magnitude of extracellular glutamate, measured by microdialysis, during the 60 minute MCAo. A significant reduction in brain infarction and DNA fragmentation was observed in the region of AAV-GLT1 injection. Animals that received AAV-GLT1 showed significant improvement in behavioral recovery following stroke compared to the AAV-GFP group. We demonstrate that focal overexpression of the glutamate transporter, GLT-1, significantly reduces ischemia-induced glutamate overflow, decreases cell death and improves behavioral recovery. These data further support the role of glutamate in the pathogenesis of ischemic damage in brain and demonstrate that targeted gene delivery to decrease the ischemia-induced glutamate overflow reduces the cellular and behavioral deficits caused by stroke.
PMCID: PMC3154194  PMID: 21853027
19.  The CCR2/CCL2 Interaction Mediates the Transendothelial Recruitment of Intravascularly Delivered Neural Stem Cells to the Ischemic Brain 
Background and Purpose
The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia.
Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2+/+ and CCR2−/− reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test.
Using NSC isolated from CCR2+/+ and CCR2−/− mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2−/− mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2+/+ cells within 6 hours after transplantation in contrast to CCR2−/− cells. Mice receiving CCR2+/+ grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2−/− NSC.
The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.
PMCID: PMC3371396  PMID: 21836091
chemokines; intravascular transplantation; neural stem cells; regenerative medicine; stroke; transendothelial recruitment
20.  Erythropoietin therapy for acute stroke is both safe and beneficial. 
Molecular Medicine  2002;8(8):495-505.
BACKGROUND: Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man. MATERIALS AND METHODS: The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 X 10(4) IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age <80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset <8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of infarct size (sequential MRI evaluation using diffusion-weighted [DWI] and fluid-attenuated inversion recovery sequences [FLAIR]) and the damage marker S100ss. RESULTS: No safety concerns were identified. Cerebrospinal fluid EPO increased to 60-100 times that of nontreated patients, proving that intravenously administered rhEPO reaches the brain. In the efficacy trial, patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40-7:55). Admission neurologic scores and serum S100beta concentrations were strong predictors ofoutcome. Analysis of covariance controlled for these two variables indicated that rhEPO treatment was associated with an improvement in follow-up and outcome scales. A strong trend for reduction in infarct size in rhEPO patients as compared to controls was observed by MRI. CONCLUSION: Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month. A larger scale clinical trial is warranted.
PMCID: PMC2040012  PMID: 12435860
21.  Delayed administration of a PTEN inhibitor bpv improves functional recovery after experimental stroke 
Neuroscience  2012;231:272-281.
PTEN inhibitors administered prior to or immediately after experimental stroke confer acute neuroprotection. However, it remains unclear if delayed treatment with a PTEN inhibitord improves long-term functional recovery after stroke. We addressed the issue in this study. Adult male mice were subjected to 1 hour of middle cerebral artery occlusion (MCAO) followed by treatment with a well-established PTEN inhibitor bpv or saline daily for 14 days, starting at 24 hours after MCAO. Functional recovery was assessed with behavioral tests and acute infarct volumes were analyzed histologically. Delayed bpv treatment did not reduce infarction during the acute phase, but significantly improved long-term functional recovery after MCAO. Since PTEN is a critical intrinsic inhibitory factor in axonal regeneration, we further examined bpv effects on axonal densities following MCAO using bielschowsky silver staining and immunohistochemistry with antibodies against myelin basic protein. Delayed bpv treatment significantly increased axon densities in the ischemic brain at 14 days after MCAO. Moreover, PTEN expression persistently remained high in the ischemic brain over 14 days after MCAO, and bpv treatment increased post-ischemic activation of Akt and mTOR in the ischemic brain. Akt and mTOR activation are the well-established cascades downstream to PTEN inhibition and have been shown to contribute to post-injury axonal regrowth in response to PTEN inhibition. Consistently, in an in vitro neuronal ischemia model, bpv enhanced axonal outgrowth of primary cortical neurons after oxygen-glucose deprivation and the enhancing effects were abolished by Akt/mTOR inhibition. In conclusion, delayed bpv treatment improved functional recovery from experimental stroke possibly via enhancing axonal growth and Akt/mTOR activation contributed to bpv-enhanced post-stroke axon growth.
PMCID: PMC3691271  PMID: 23219909
PTEN inhibitor; bpv; functional recovery; axonal densities; stroke
22.  Social interaction plays a critical role in neurogenesis and recovery after stroke 
Translational Psychiatry  2014;4(1):e351-.
Stroke survivors often experience social isolation. Social interaction improves quality of life and decreases mortality after stroke. Male mice (20–25 g; C57BL/6N), all initially pair housed, were subjected to middle cerebral artery occlusion (MCAO). Mice were subsequently assigned into one of three housing conditions: (1) Isolated (SI); (2) Paired with their original cage mate who was also subjected to stroke (stroke partner (PH-SP)); or (3) Paired with their original cage mate who underwent sham surgery (healthy partner (PH-HP)). Infarct analysis was performed 72 h after stroke and chronic survival was assessed at day 30. Immediate post-stroke isolation led to a significant increase in infarct size and mortality. Interestingly, mice paired with a healthy partner had significantly lower mortality than mice paired with a stroke partner, despite equivalent infarct damage. To control for changes in infarct size induced by immediate post-stroke isolation, additional cohorts were assessed that remained pair housed for three days after stroke prior to randomization. Levels of brain-derived neurotrophic factor (BDNF) were assessed at 90 days and cell proliferation (in cohorts injected with 5-bromo-2′-deoxyuridine, BrdU) was evaluated at 8 and 90 days after stroke. All mice in the delayed housing protocol had equivalent infarct volumes (SI, PH-HP and PH-SP). Mice paired with a healthy partner showed enhanced behavioral recovery compared with either isolated mice or mice paired with a stroke partner. Behavioral improvements paralleled changes in BDNF levels and neurogenesis. These findings suggest that the social environment has an important role in recovery after ischemic brain injury.
PMCID: PMC3905235  PMID: 24473442
brain-derived neurotrophic factor; infarct; middle cerebral artery occlusion; neurogenesis; post-stroke recovery; social isolation
23.  Constraint-Induced Movement Therapy for Rehabilitation of Arm Dysfunction After Stroke in Adults 
Executive Summary
The purpose of this evidence-based analysis is to determine the effectiveness and cost of CIMT for persons with arm dysfunction after a stroke.
Clinical Need: Condition and Target Population
A stroke is a sudden loss of brain function caused by the interruption of blood flow to the brain (ischemic stroke) or the rupture of blood vessels in the brain (hemorrhagic stroke). A stroke can affect any number of areas including the ability to move, see, remember, speak, reason, and read and write. Stroke is the leading cause of adult neurological disability in Canada; 300,000 people or 1% of the population live with its effects. Up to 85% of persons experiencing a complete stroke have residual arm dysfunction which will interfere with their ability to live independently. Rehabilitation interventions are the cornerstone of care and recovery after a stroke.
Constraint-Induced Movement Therapy
Constraint-Induced Movement (CIMT) is a behavioural approach to neurorehabilitation based on the principle of ‘learned non-use’. The term is derived from studies in nonhuman primates in which somatosensory deafferentation of a single forelimb was performed and after which the animal then failed to use that limb. This failure to use the limb was deemed ‘learned non-use’. The major components of CIMT include: i) intense repetitive task-oriented training of the impaired limb ii) immobilization of the unimpaired arm, and iii) shaping. With regard to the first component, persons may train the affected arm for several hours a day for up to 10-15 consecutive days. With immobilization, the unaffected arm may be restrained for up to 90% of waking hours. And finally, with shaping, the difficulty of the training tasks is progressively increased as performance improves and encouraging feedback is provided immediately when small gains are achieved.
Research Question
What is the effectiveness and cost of CIMT compared with physiotherapy and/or occupational therapy rehabilitative care for the treatment of arm dysfunction after stroke in persons 18 years of age and older?
Research Methods
Literature Search
Search Strategy
A literature search was performed on January 21, 2011 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Library, Centre for Reviews and Dissemination. (Appendix 1) A preliminary search completed in August 2010 found a Cochrane Systematic review published in 2009. As a result, the literature search for this evidence-based analysis was designed to include studies published from January 1, 2008 to January 21, 2011.
Inclusion Criteria
Systematic reviews of randomized controlled trials with or without meta-analysis.
Study participants 18 years of age and older with arm dysfunction after stroke.
Studies comparing the use of CIMT with occupational therapy and/or physiotherapy rehabilitative care (usual care) to improve arm function.
Studies which described CIMT as having the following three components: i) restraining unimpaired arm and/or wrist with a sling, hand splint or cast; ii) intensive training with functional task practice of the affected arm; iii) application of shaping methodology during training. No restriction was placed on intensity or duration of treatment otherwise.
Duration and intensity of therapy is equal in treatment and control groups.
Therapy beginning a minimum of one month after stroke.
Published between 2008 and 2011.
Exclusion Criteria
Narrative reviews, case series, case reports, controlled clinical trials.
Letters to the editor
Grey literature.
Non-English language publications.
Outcomes of Interest
Primary Outcome
Arm motor function: Action Research Arm Test (ARAT)
Secondary Outcome
Arm motor impairment: Fugl-Meyer Motor Assessment (FMA)
Activities of daily living (ADL): Functional Independence Measure (FIM), Chedoke Arm and Hand Inventory
Perceived motor function: Motor Activity Log (MAL) Amount of Use (AOU) and Quality of Movement (QOM) scales
Quality of Life: Stroke Impact Scale (SIS)
Summary of Findings
A significant difference was found in our primary outcome of arm motor function measured with the Action Research Arm Test in favour of CIMT compared with usual care delivered with the same intensity and duration. Significant differences were also found in three of the five secondary outcome measures including Arm Motor Impairment and Perceived Motor Function Amount of Use and Quality of Use. There was a nonsignificant effect found with the FIM score and the quality of life Stroke Impact Scale outcome measure. The nonsignificant effect found with the scale score and the quality of life score may be a factor of a nonresponsive outcome measure (FIM scale) and/or a type II statistical error from an inadequate sample size. The quality of evidence was moderate for arm motor function and low for all other outcome measures except quality of life, which was very low.
Summary of Results*
CI, Confidence Intervals; n, Sample Size
PMCID: PMC3377570  PMID: 23074418
24.  A new look at glutamate and ischemia: NMDA agonist improves long-term functional outcome in a rat model of stroke 
Future neurology  2011;6(6):823-834.
Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists failed to improve, or even worsened, stroke outcome. Recent findings of a persistent post-stroke decline in NMDAR density, which plays a pivotal role in plasticity and memory formation, suggest that NMDAR stimulation, rather than inhibition, may prove beneficial in the subacute period after stroke.
This study aims to examine the effect of the NMDAR partial agonist d-cycloserine (DCS) on long-term structural, functional and behavioral outcomes in rats subjected to transient middle cerebral artery occlusion, an animal model of ischemic stroke.
Materials & methods
Rats (n = 36) that were subjected to 90 min of middle cerebral artery occlusion were given a single injection of DCS (10 mg/kg) or vehicle (phosphate-buffered saline) 24 h after occlusion and followed up for 30 days. MRI (structural and functional) was used to measure infarction, atrophy and cortical activation due to electrical forepaw stimulation. Memory function was assessed on days 7, 21 and 30 postocclusion using the novel object recognition test. A total of 20 nonischemic controls were included for comparison.
DCS treatment resulted in significant improvement of somatosensory and cognitive function relative to vehicle treatment. By day 30, cognitive performance of the DCS-treated animals was indistinguishable from nonischemic controls, while vehicle-treated animals demonstrated a stable memory deficit. DCS had no significant effect on infarction or atrophy.
These results support a beneficial role for NMDAR stimulation during the recovery period after stroke, most likely due to enhanced neuroplasticity rather than neuroprotection.
PMCID: PMC3229223  PMID: 22140354
cognition; d-cycloserine; fMRI; infarction; NMDA receptor; stroke
25.  Simvastatin attenuates stroke-induced splenic atrophy and lung susceptibility to spontaneous bacterial infection in mice 
Background and Purpose
Statins are widely used in the primary and secondary prevention of ischemic stroke, but their effects on stroke-induced immunodeppression and post-stroke infections are elusive. We investigated effects of simvastatin treatment on stroke-induced splenic atrophy and lung susceptibility to bacterial infection in acute experimental stroke in mice.
Ischemic stroke was induced by transient occlusion of middle cerebral artery (MCAO) followed by reperfusion. In some experiments, splenectomies were performed 2 weeks prior to MCAO. Animals were randomly assigned to sham and MCAO groups treated subcutaneously with vehicle or simvastatin (20 mg/kg/day). Brain infarction, neurological function, brain interferon-γ expression, splenic atrophy and apoptosis, and lung infection were examined.
Simvastatin reduced stroke-induced spleen atrophy and splenic apoptosis via increased mitochrondrial anti-apoptotic Bcl-2 expression and decreased pro-apoptotic Bax translocation from cytosol into mitochondria. Splenectomy reduced brain interferon-γ (3d) and infarct size (5d) after stroke and these effects were reversed by adoptive transfer of splenocytes. Simvastatin inhibited brain interferon-γ (3d) and reduced infarct volume and neurological deficits (5d) after stroke, and these protective effects were observed not only in naïve stroke mice but also in splenectomied stroke mice adoptively transferred with splenocytes. Simvastatin also decreased the stroke-associated lung susceptibility to spontaneous bacterial infection.
Results provide the first direct experimental evidence that simvastatin ameliorates stroke-induced peripheral immunodepression by attenuating spleen atrophy and lung bacterial infection. These findings contribute to a better understanding of beneficial effects of statins in the treatment of stroke.
PMCID: PMC3609888  PMID: 23391769
Brain ischemia; bacterial infection; immune response; statin; spleen

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