Motion perception without Nystagmus--a novel manifestation of cerebellar stroke.

PubMed

Shaikh, Aasef G

2014-01-01

The motion perception and the vestibulo-ocular reflex (VOR) each serve distinct functions. The VOR keeps the gaze steady on the target of interest, whereas vestibular perception serves a number of tasks, including awareness of self-motion and orientation in space. VOR and motion perception might abide the same neurophysiological principles, but their distinct anatomical correlates were proposed. In patients with cerebellar stroke in distribution of medial division of posterior inferior cerebellar artery, we asked whether specific location of the focal lesion in vestibulocerebellum could cause impaired perception of motion but normal eye movements. Thirteen patients were studied, 5 consistently perceived spinning of surrounding environment (vertigo), but the eye movements were normal. This group was called "disease model." Remaining 8 patients were also symptomatic for vertigo, but they had spontaneous nystagmus. The latter group was called "disease control." Magnetic resonance imaging in both groups consistently revealed focal cerebellar infarct affecting posterior cerebellar vermis (lobule IX). In the "disease model" group, only part of lobule IX was affected. In the disease control group, however, complete lobule IX was involved. This study discovered a novel presentation of cerebellar stroke where only motion perception was affected, but there was an absence of objective neurologic signs. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Decreased integration and information capacity in stroke measured by whole brain models of resting state activity.

PubMed

Adhikari, Mohit H; Hacker, Carl D; Siegel, Josh S; Griffa, Alessandra; Hagmann, Patric; Deco, Gustavo; Corbetta, Maurizio

2017-04-01

While several studies have shown that focal lesions affect the communication between structurally normal regions of the brain, and that these changes may correlate with behavioural deficits, their impact on brain's information processing capacity is currently unknown. Here we test the hypothesis that focal lesions decrease the brain's information processing capacity, of which changes in functional connectivity may be a measurable correlate. To measure processing capacity, we turned to whole brain computational modelling to estimate the integration and segregation of information in brain networks. First, we measured functional connectivity between different brain areas with resting state functional magnetic resonance imaging in healthy subjects (n = 26), and subjects who had suffered a cortical stroke (n = 36). We then used a whole-brain network model that coupled average excitatory activities of local regions via anatomical connectivity. Model parameters were optimized in each healthy or stroke participant to maximize correlation between model and empirical functional connectivity, so that the model's effective connectivity was a veridical representation of healthy or lesioned brain networks. Subsequently, we calculated two model-based measures: 'integration', a graph theoretical measure obtained from functional connectivity, which measures the connectedness of brain networks, and 'information capacity', an information theoretical measure that cannot be obtained empirically, representative of the segregative ability of brain networks to encode distinct stimuli. We found that both measures were decreased in stroke patients, as compared to healthy controls, particularly at the level of resting-state networks. Furthermore, we found that these measures, especially information capacity, correlate with measures of behavioural impairment and the segregation of resting-state networks empirically measured. This study shows that focal lesions affect the brain's ability to represent stimuli and task states, and that information capacity measured through whole brain models is a theory-driven measure of processing capacity that could be used as a biomarker of injury for outcome prediction or target for rehabilitation intervention. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Sleep Is Critical for Remote Preconditioning-Induced Neuroprotection.

PubMed

Brager, Allison J; Yang, Tao; Ehlen, J Christopher; Simon, Roger P; Meller, Robert; Paul, Ketema N

2016-11-01

Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities ( Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome. © 2016 Associated Professional Sleep Societies, LLC.

Translational MR Neuroimaging of Stroke and Recovery

PubMed Central

Mandeville, Emiri T.; Ayata, Cenk; Zheng, Yi; Mandeville, Joseph B.

2016-01-01

Multiparametric magnetic resonance imaging (MRI) has become a critical clinical tool for diagnosing focal ischemic stroke severity, staging treatment, and predicting outcome. Imaging during the acute phase focuses on tissue viability in the stroke vicinity, while imaging during recovery requires the evaluation of distributed structural and functional connectivity. Preclinical MRI of experimental stroke models provides validation of non-invasive biomarkers in terms of cellular and molecular mechanisms, while also providing a translational platform for evaluation of prospective therapies. This brief review of translational stroke imaging discusses the acute to chronic imaging transition, the principles underlying common MRI methods employed in stroke research, and experimental results obtained by clinical and preclinical imaging to determine tissue viability, vascular remodeling, structural connectivity of major white matter tracts, and functional connectivity using task-based and resting-state fMRI during the stroke recovery process. PMID:27578048

Blood-Brain Barrier Alterations Provide Evidence of Subacute Diaschisis in an Ischemic Stroke Rat Model

PubMed Central

Garbuzova-Davis, Svitlana; Rodrigues, Maria C. O.; Hernandez-Ontiveros, Diana G.; Tajiri, Naoki; Frisina-Deyo, Aric; Boffeli, Sean M.; Abraham, Jerry V.; Pabon, Mibel; Wagner, Andrew; Ishikawa, Hiroto; Shinozuka, Kazutaka; Haller, Edward; Sanberg, Paul R.; Kaneko, Yuji; Borlongan, Cesario V.

2013-01-01

Background Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB) competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas. Methodology/Principal Findings In ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO), significant BBB alterations characterized by large Evans Blue (EB) parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices. Conclusions/Significance These results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke. PMID:23675488

Optimization of a Clinically Relevant Model of White Matter Stroke in Mice: Histological and Functional Evidences

PubMed Central

Ahmad, Abdullah S.; Satriotomo, Irawan; Fazal, Jawad A.; Nadeau, Stephen E.; Doré, Sylvain

2015-01-01

Background and Purpose White matter (WM) injury during stroke increases the risk of disability and gloomy prognosis of post-stroke rehabilitation. However, modeling of WM loss in rodents has proven to be challenging. Methods We report improved WM injury models in male C57BL/6 mice. Mice were given either endothelin-1 (ET-1) or L-N5-(1-iminoethyl)ornitine (L-NIO) into the periventricular white matter (PVWM), in the corpus callosum (CC), or in the posterior limb of internal capsule (PLIC). Anatomical and functional outcomes were quantified on day 7 post injection. Results Injection of ET-1 or L-NIO caused a small focal lesion in the injection site in the PVWM. No significant motor function deficits were observed in the PVWM lesion model. We next targeted the PLIC by using single or double injections of L-NIO and found that this strategy induced small focal infarction. Interestingly, injection of L-NIO in the PLIC also resulted in gliosis, and significant motor function deficits. Conclusions By employing different agents, doses, and locations, this study shows the feasibility of inducing brain WM injury accompanied with functional deficits in mice. Selective targeting of the injury location, behavioral testing, and the agents chosen to induce WM injury are all keys to successfully develop a mouse model and subsequent testing of therapeutic interventions against WM injury. PMID:27512724

Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning

PubMed Central

Ren, Chuancheng; Gao, Xuwen; Steinberg, Gary K.; Zhao, Heng

2009-01-01

Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 minute occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 minute occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for 2 or 3 cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with 3 cycles of 15 minutes performed immediately before stroke reduced infarct size from 47.7±7.6% of control ischemia to 9.8±8.6%; at 2 cycles of 15 minutes, infarct was reduced to 24.7±7.3%; at 2 cycles of 5 minutes, infarct was not reduced. Delayed preconditioning with 3 cycles of 15 minutes conducted 2 days before stroke also reduced infarct to 23.0 ±10.9%, but with 2 cycles of 15 minutes it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with 3 cycles of 15 minutes performed 12 hours before stroke also reduced infarct to 24.7±4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia. PMID:18201834

Ischemic stroke assessment with near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Chen, Weiguo; Li, Pengcheng; Zeng, Shaoqun; Luo, Qingming; Hu, Bo

1999-09-01

Many authors have elucidated the theory about oxygenated hemoglobin, deoxygenated hemoglobin absorption in near-infrared spectrum. And the theory has opened a window to measure the hemodynamic changes caused by stroke. However, no proper animal model still has established to confirm the theory. The aim of this study was to validate near-infrared cerebral topography (NCT) as a practical tool and to try to trace the focal hemodynamic changes of ischemic stroke. In the present study, middle cerebral artery occlusion model and the photosensitizer induced intracranial infarct model had been established. NCT and functional magnetic resonance image (fMRI) were obtained during pre- and post-operation. The geometric shape and infarct area of NCT image was compared with the fMRI images and anatomical samples of each rat. The results of two occlusion models in different intervene factors showed the NCT for infarct focus matched well with fMRI and anatomic sample of each rats. The instrument might become a practical tool for short-term prediction of stroke and predicting the rehabilitation after stroke in real time.

Modeling Stroke in Mice: Permanent Coagulation of the Distal Middle Cerebral Artery

PubMed Central

Plesnila, Nikolaus; Veltkamp, Roland; Liesz, Arthur

2014-01-01

Stroke is the third most common cause of death and a main cause of acquired adult disability in developed countries. Only very limited therapeutical options are available for a small proportion of stroke patients in the acute phase. Current research is intensively searching for novel therapeutic strategies and is increasingly focusing on the sub-acute and chronic phase after stroke because more patients might be eligible for therapeutic interventions in a prolonged time window. These delayed mechanisms include important pathophysiological pathways such as post-stroke inflammation, angiogenesis, neuronal plasticity and regeneration. In order to analyze these mechanisms and to subsequently evaluate novel drug targets, experimental stroke models with clinical relevance, low mortality and high reproducibility are sought after. Moreover, mice are the smallest mammals in which a focal stroke lesion can be induced and for which a broad spectrum of transgenic models are available. Therefore, we describe here the mouse model of transcranial, permanent coagulation of the middle cerebral artery via electrocoagulation distal of the lenticulostriatal arteries, the so-called “coagulation model”. The resulting infarct in this model is located mainly in the cortex; the relative infarct volume in relation to brain size corresponds to the majority of human strokes. Moreover, the model fulfills the above-mentioned criteria of reproducibility and low mortality. In this video we demonstrate the surgical methods of stroke induction in the “coagulation model” and report histological and functional analysis tools. PMID:25145316

Identification of Isoxsuprine Hydrochloride as a Neuroprotectant in Ischemic Stroke through Cell-Based High-Throughput Screening

PubMed Central

Hill, Jeff W.; Thompson, Jeffrey F.; Carter, Mark B.; Edwards, Bruce S.; Sklar, Larry A.; Rosenberg, Gary A.

2014-01-01

Stroke is a leading cause of death and disability and treatment options are limited. A promising approach to accelerate the development of new therapeutics is the use of high-throughput screening of chemical libraries. Using a cell-based high-throughput oxygen-glucose deprivation (OGD) model, we evaluated 1,200 small molecules for repurposed application in stroke therapy. Isoxsuprine hydrochloride was identified as a potent neuroprotective compound in primary neurons exposed to OGD. Isoxsuprine, a β2-adrenergic agonist and NR2B subtype-selective N-methyl-D-aspartate (NMDA) receptor antagonist, demonstrated no loss of efficacy when administered up to an hour after reoxygenation in an in vitro stroke model. In an animal model of transient focal ischemia, isoxsuprine significantly reduced infarct volume compared to vehicle (137±18 mm3 versus 279±25 mm3, p<0.001). Isoxsuprine, a peripheral vasodilator, was FDA approved for the treatment of cerebrovascular insufficiency and peripheral vascular disease. Our demonstration of the significant and novel neuroprotective action of isoxsuprine hydrochloride in an in vivo stroke model and its history of human use suggest that isoxsuprine may be an ideal candidate for further investigation as a potential stroke therapeutic. PMID:24804769

Stroke onset time estimation from multispectral quantitative magnetic resonance imaging in a rat model of focal permanent cerebral ischemia.

PubMed

McGarry, Bryony L; Rogers, Harriet J; Knight, Michael J; Jokivarsi, Kimmo T; Sierra, Alejandra; Gröhn, Olli Hj; Kauppinen, Risto A

2016-08-01

Quantitative T2 relaxation magnetic resonance imaging allows estimation of stroke onset time. We aimed to examine the accuracy of quantitative T1 and quantitative T2 relaxation times alone and in combination to provide estimates of stroke onset time in a rat model of permanent focal cerebral ischemia and map the spatial distribution of elevated quantitative T1 and quantitative T2 to assess tissue status. Permanent middle cerebral artery occlusion was induced in Wistar rats. Animals were scanned at 9.4T for quantitative T1, quantitative T2, and Trace of Diffusion Tensor (Dav) up to 4 h post-middle cerebral artery occlusion. Time courses of differentials of quantitative T1 and quantitative T2 in ischemic and non-ischemic contralateral brain tissue (ΔT1, ΔT2) and volumes of tissue with elevated T1 and T2 relaxation times (f1, f2) were determined. TTC staining was used to highlight permanent ischemic damage. ΔT1, ΔT2, f1, f2, and the volume of tissue with both elevated quantitative T1 and quantitative T2 (V(Overlap)) increased with time post-middle cerebral artery occlusion allowing stroke onset time to be estimated. V(Overlap) provided the most accurate estimate with an uncertainty of ±25 min. At all times-points regions with elevated relaxation times were smaller than areas with Dav defined ischemia. Stroke onset time can be determined by quantitative T1 and quantitative T2 relaxation times and tissue volumes. Combining quantitative T1 and quantitative T2 provides the most accurate estimate and potentially identifies irreversibly damaged brain tissue. © 2016 World Stroke Organization.

[Predictors of epilepsy in children after ischemic stroke].

PubMed

Lvova, O A; Shalkevich, L V; Dron, A N; Lukaschuk, M Y; Orlova, E A; Gusev, V V; Suleymanova, E V; Sulimov, A V; Kudlatch, A I

To determine clinical/instrumental predictors of symptomatic epilepsy after ischemic stroke in children. One hundred and thirty-six patients, aged 0-15 years, with the diagnosis of ischemic stroke (ICD-10 I63.0-I63.9) were examined. The duration of the study was 18 months - 12 years. Patients were stratified into post-stroke (n=22) and control (n=114) groups, the latter included patients without epilepsy regardless of the presence of convulsive seizures in the acute stage of stroke. Predictors were determined based on EEG and characteristics of convulsive syndrome in the acute stage of stroke. The following prognostic criteria were found: generalized type of seizures, focal type of seizures with secondary generalization, epileptiform (peak and/or peak-wave) activity, focal character of epileptiform activity, generalized type of seizures in the combination with slow wave background activity on EEG, generalized type of seizures in the combination with slow wave activity and disorganized activity on EEG.

Defining the macroscopic and microscopic findings of experimental focal brain ischemia in rats from a forensic scientist's point of view.

PubMed

Tatlisumak, Ertugrul; Inan, Sevinc; Asirdizer, Mahmut; Apaydin, Nihal; Hayretdag, Ceyda; Kose, Can; Tekdemir, Ibrahim

2009-03-01

Approximately 10% of all deaths in the world occur as a result of stroke. Determination of the time schedule of the pathologic events in a stroke patient is invaluable for a forensic specialist. The aim of this study was to define the schedule of the macroscopic and microscopic changes that occurred in a rat model of permanent focal ischemia for providing useful clues for the evaluation of stroke patients. Male Wistar rats weighing 250 to 350 g were used in this study. Permanent focal brain ischemia was applied by the suture occlusion method. The animals were divided into 7 experimental groups (n = 6) with time schedules including 1.5, 3, 6, 12, 24, 72 hours, and the sham. Brains were harvested at the end of the determined time schedule. Lesions in the frontoparietal cortex were evaluated macroscopically first and later hematoxylin eosin stained sections from the infarct core were investigated microscopically. Macroscopically, enlargement of the ipsilateral hemisphere was mild at 6 hour, apparent at 12 and 24 hours, and mild again at 72 hours. Microscopically, ischemic changes were apparent even at 1.5 hour. Red neurons and infiltration of the parenchyma with neutrophil leukocytes were observed at 12 hours. Pannecrosis and massive leukocyte infiltration were observed at 72 hours. Macroscopic and microscopic findings obtained from a rat model may provide clues for determination of the time-dependent changes due to brain ischemia in human subjects. Finally, the benefits of determination of time course of pathologic changes in the brain for forensic scientists were discussed.

The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review

PubMed Central

Famakin, Bolanle M.

2014-01-01

It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response. Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post-stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke. A better understanding of the intricate and complex events that take place following immune response activation, to acute cerebral ischemia, is imperative for the development of effective novel immunomodulatory therapies for the treatment of acute stroke. PMID:25276490

Acute Transient Vestibular Syndrome: Prevalence of Stroke and Efficacy of Bedside Evaluation.

PubMed

Choi, Jae-Hwan; Park, Min-Gyu; Choi, Seo Young; Park, Kyung-Pil; Baik, Seung Kug; Kim, Ji-Soo; Choi, Kwang-Dong

2017-03-01

The aim of this study was to determine the prevalence of stroke and efficacy of bedside evaluation in diagnosing stroke in acute transient vestibular syndrome (ATVS). We performed a prospective, single-center, observational study that had consecutively recruited 86 patients presenting with ATVS to the emergency department of Pusan National University Yangsan Hospital from January to December 2014. All patients received a constructed evaluation, including HINTS plus (head impulse, nystagmus patterns, test of skew, and finger rubbing) and brain magnetic resonance imagings. Patients without an obvious cause further received perfusion-weighted imaging. Multivariable logistic regression was used to determine clinical parameters to identify stroke in ATVS. The prevalence of stroke was 27% in ATVS. HINTS plus could not be applied to the majority of patients because of the resolution of the vestibular symptoms, and magnetic resonance imagings were falsely negative in 43% of confirmed strokes. Ten patients (12%) showed unilateral cerebellar hypoperfusion on perfusion-weighted imaging without an infarction on diffusion-weighted imaging, and 8 of them had a focal stenosis or hypoplasia of the corresponding vertebral artery. The higher risk of stroke in ATVS was found in association with craniocervical pain (odds ratio, 9.6; 95% confidence interval, 2.0-45.2) and focal neurological symptoms/signs (odds ratio, 15.2; 95% confidence interval, 2.5-93.8). Bedside examination and routine magnetic resonance imagings have a limitation in diagnosing strokes presenting with ATVS, and perfusion imaging may help to identify strokes in ATVS of unknown cause. Associated craniocervical pain and focal neurological symptoms/signs are the useful clues for strokes in ATVS. © 2017 American Heart Association, Inc.

A systematic review and meta-analysis of the efficacy of piracetam and piracetam-like compounds in experimental stroke.

PubMed

Wheble, Philippa C R; Sena, Emily S; Macleod, Malcolm R

2008-01-01

Piracetam was a candidate neuroprotective drug for acute stroke ineffective in clinical trial. Here we use systematic review and meta-analysis to describe the evidence supporting a protective effect of piracetam and its derivatives in animal models of stroke. We present a systematic review of reports describing the use of piracetam and its derivatives in animal models of focal ischaemia, where the outcome was measured as an infarct size or neurological score (Der Simonian and Laird random effects meta-analysis). Only 2 studies, published 10 years after the first clinical trial of piracetam had been initiated, described its efficacy in animal models of stroke. A further 4 studies described the efficacy of related compounds. Piracetam and its derivatives improved the outcome by 30.2% (95% CI = 16.1-44.4). The median study quality was 4/10 (inter-quartile range = 4-6). Piracetam and its derivatives demonstrate neuroprotective efficacy in experimental stroke, but our findings raise concerns about the amount of available data, the quality of the studies and publication bias. (c) 2007 S. Karger AG, Basel.

AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke.

PubMed

Clarkson, Andrew N; Overman, Justine J; Zhong, Sheng; Mueller, Rudolf; Lynch, Gary; Carmichael, S Thomas

2011-03-09

Stroke is the leading cause of adult disability. Recovery after stroke shares similar molecular and cellular properties with learning and memory. A main component of learning-induced plasticity involves signaling through AMPA receptors (AMPARs). We systematically tested the role of AMPAR function in motor recovery in a mouse model of focal stroke. AMPAR function controls functional recovery beginning 5 d after the stroke. Positive allosteric modulators of AMPARs enhance recovery of limb control when administered after a delay from the stroke. Conversely, AMPAR antagonists impair motor recovery. The contributions of AMPARs to recovery are mediated by release of brain-derived neurotrophic factor (BDNF) in periinfarct cortex, as blocking local BDNF function in periinfarct cortex blocks AMPAR-mediated recovery and prevents the normal pattern of motor recovery. In contrast to a delayed AMPAR role in motor recovery, early administration of AMPAR agonists after stroke increases stroke damage. These findings indicate that the role of glutamate signaling through the AMPAR changes over time in stroke: early potentiation of AMPAR signaling worsens stroke damage, whereas later potentiation of the same signaling system improves functional recovery.

Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia.

PubMed

Moyanova, Slavianka Georgieva; Kortenska, Lidia Vasileva; Mitreva, Rumiana Gesheva; Pashova, Vyara Dincova; Ngomba, Richard Teke; Nicoletti, Ferdinando

2007-06-11

Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non-competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared.

Maximal potential patent foramen diameter does not correlate with the type or frequency of the neurologic event prior to closure.

PubMed

Kutty, Shelby; Brown, Kimberly; Qureshi, Athar M; Latson, Larry A

2009-01-01

We analyzed our data on patients undergoing transcatheter patent foramen ovale (PFO) closure to determine if the maximal potential PFO diameter (MPPD) by balloon sizing correlates with important clinical characteristics in this population. We defined stroke as a focal neurologic deficit lasting >24 h, or focal deficit of shorter duration associated with permanent MRI/CT changes consistent with a focal infarction. Parameters analyzed included age, gender, anticoagulation, hypertension, smoking, MRI/CT findings and MPPD at catheterization. We specifically analyzed the type of neurologic event (stroke/transient ischemic attack, TIA), and number of recorded preceding clinical neurologic events. In 216 consecutive patients, 167 suffered a stroke. MRI/CT changes consistent with one or more embolic events were seen in 156 patients; 49 had a clinical TIA. There was no significant difference in MPPD between stroke (11.0 +/- 3.6 mm) and TIA groups (10.9 +/- 3.9 mm; 95% confidence interval for difference: -1.33 to 1.00). MPPD did not differ between MRI/CT-positive vs. -negative strokes, and had no correlation with the number of identified pre-closure clinical neurologic events. Continued investigation is needed to determine whether other PFO characteristics, or other anatomic/physiologic parameters, may be useful to identify patients at high risk for cryptogenic stroke/TIA, even before they have their first neurologic event. Copyright 2008 S. Karger AG, Basel.

Fluoxetine maintains a state of heightened responsiveness to motor training early after stroke in a mouse model

PubMed Central

Ng, Kwan; Gibson, Ellen M.; Hubbard, Robert; Yang, Juemin; Caffo, Brian; O’Brien, Richard; Krakauer, John W.; Zeiler, Steven R.

2016-01-01

Background and purpose Data from both humans and animal models suggest that most recovery from motor impairment occurs in a sensitive period that lasts only weeks after stroke and is mediated in part by an increased responsiveness to training. Here we used a mouse model of focal cortical stroke to test two hypotheses. First we investigated if responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Methods Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area (CFA). The mice were then retrained after a 1-day or 7-day delay with and without fluoxetine. Results Recovery of prehension after a CFA stroke was complete if training was initiated one day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine appeared to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. Conclusions There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke. PMID:26294676

Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model.

PubMed

Ng, Kwan L; Gibson, Ellen M; Hubbard, Robert; Yang, Juemin; Caffo, Brian; O'Brien, Richard J; Krakauer, John W; Zeiler, Steven R

2015-10-01

Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke. © 2015 American Heart Association, Inc.

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

PubMed Central

2011-01-01

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions. PMID:21266064

Reversible Disruption of Neuronal Mitochondria by Ischemic and Traumatic Injury Revealed by Quantitative Two-Photon Imaging in the Neocortex of Anesthetized Mice

PubMed Central

Kislin, Mikhail; Sword, Jeremy; Fomitcheva, Ioulia V.; Croom, Deborah; Pryazhnikov, Evgeny; Lihavainen, Eero; Toptunov, Dmytro; Rauvala, Heikki; Ribeiro, Andre S.

2017-01-01

Mitochondria play a variety of functional roles in cortical neurons, from metabolic support and neuroprotection to the release of cytokines that trigger apoptosis. In dendrites, mitochondrial structure is closely linked to their function, and fragmentation (fission) of the normally elongated mitochondria indicates loss of their function under pathological conditions, such as stroke and brain trauma. Using in vivo two-photon microscopy in mouse brain, we quantified mitochondrial fragmentation in a full spectrum of cortical injuries, ranging from severe to mild. Severe global ischemic injury was induced by bilateral common carotid artery occlusion, whereas severe focal stroke injury was induced by Rose Bengal photosensitization. The moderate and mild traumatic injury was inflicted by focal laser lesion and by mild photo-damage, respectively. Dendritic and mitochondrial structural changes were tracked longitudinally using transgenic mice expressing fluorescent proteins localized either in cytosol or in mitochondrial matrix. In response to severe injury, mitochondrial fragmentation developed in parallel with dendritic damage signified by dendritic beading. Reconstruction from serial section electron microscopy confirmed mitochondrial fragmentation. Unlike dendritic beading, fragmentation spread beyond the injury core in focal stroke and focal laser lesion models. In moderate and mild injury, mitochondrial fragmentation was reversible with full recovery of structural integrity after 1–2 weeks. The transient fragmentation observed in the mild photo-damage model was associated with changes in dendritic spine density without any signs of dendritic damage. Our findings indicate that alterations in neuronal mitochondria structure are very sensitive to the tissue damage and can be reversible in ischemic and traumatic injuries. SIGNIFICANCE STATEMENT During ischemic stroke or brain trauma, mitochondria can either protect neurons by supplying ATP and adsorbing excessive Ca2+, or kill neurons by releasing proapoptotic factors. Mitochondrial function is tightly linked to their morphology: healthy mitochondria are thin and long; dysfunctional mitochondria are thick (swollen) and short (fragmented). To date, fragmentation of mitochondria was studied either in dissociated cultured neurons or in brain slices, but not in the intact living brain. Using real-time in vivo two-photon microscopy, we quantified mitochondrial fragmentation during acute pathological conditions that mimic severe, moderate, and mild brain injury. We demonstrated that alterations in neuronal mitochondria structural integrity can be reversible in traumatic and ischemic injuries, highlighting mitochondria as a potential target for therapeutic interventions. PMID:28077713

Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I

PubMed Central

2014-01-01

Background Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. Results Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood–brain barrier breakdown was associated with displacement of tight-junction protein Occludin. Conclusion Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke. PMID:24468193

Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I.

PubMed

Zinnanti, William J; Lazovic, Jelena; Housman, Cathy; Antonetti, David A; Koeller, David M; Connor, James R; Steinman, Lawrence

2014-01-27

Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood-brain barrier breakdown was associated with displacement of tight-junction protein Occludin. Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

Human Data Supporting Glyburide in Ischemic Stroke

PubMed Central

Sheth, Kevin N.; Simard, J. Marc; Elm, Jordan; Kronenberg, Golo; Kunte, Hagen; Kimberly, W. Taylor

2016-01-01

The SUR1-TRPM4 channel is a critical determinant of edema and hemorrhagic transformation after focal ischemia. Blockade of this channel by the small molecule glyburide results in improved survival and neurological outcome in multiple preclinical models of ischemic stroke. A robust, compelling body of evidence suggests that an intravenous (IV) formulation of glyburide, RP-1127, can prevent swelling and improve outcome in patients with stroke. Retrospective studies of diabetic stroke patients show improved outcomes in patients who are continued on sulfonylureas after stroke onset. Early phase II study of MRI and plasma biomarkers support the conclusion that RP-1127 may decrease swelling and hemorrhagic transformation. Finally, the ongoing phase II RP-1127 development program has demonstrated continued safety as well as feasibility of enrollment and tolerability of the intervention. Continued efforts to complete the ongoing phase IIb study and definitive efficacy studies are urgently needed to bring a candidate pharmacotherapy to a population of severe stroke patients that currently have no alternative. PMID:26463916

Human Data Supporting Glyburide in Ischemic Stroke.

PubMed

Sheth, Kevin N; Simard, J Marc; Elm, Jordan; Kronenberg, Golo; Kunte, Hagen; Kimberly, W Taylor

2016-01-01

The SUR1-TRPM4 channel is a critical determinant of edema and hemorrhagic transformation after focal ischemia. Blockade of this channel by the small molecule glyburide results in improved survival and neurological outcome in multiple preclinical models of ischemic stroke. A robust, compelling body of evidence suggests that an intravenous formulation of glyburide, RP-1127, can prevent swelling and improve outcome in patients with stroke. Retrospective studies of diabetic stroke patients show improved outcomes in patients who are continued on sulfonylureas after stroke onset. An early phase II study using magnetic resonance imaging and plasma biomarkers supports the conclusion that RP-1127 may decrease swelling and hemorrhagic transformation. Finally, the ongoing phase II RP-1127 development program has demonstrated continued safety as well as feasibility of enrollment and tolerability of the intervention. Continued efforts to complete the ongoing phase II study and definitive efficacy studies are needed to bring a candidate pharmacotherapy to a population of severe stroke patients that currently have no alternative.

EEG patterns from acute to chronic stroke phases in focal cerebral ischemic rats: correlations with functional recovery.

PubMed

Zhang, Shao-jie; Ke, Zheng; Li, Le; Yip, Shea-ping; Tong, Kai-yu

2013-04-01

Monitoring the neural activities from the ischemic penumbra provides critical information on neurological recovery after stroke. The purpose of this study is to evaluate the temporal alterations of neural activities using electroencephalography (EEG) from the acute phase to the chronic phase, and to compare EEG with the degree of post-stroke motor function recovery in a rat model of focal ischemic stroke. Male Sprague-Dawley rats were subjected to 90 min transient middle cerebral artery occlusion surgery followed by reperfusion for seven days (n = 58). The EEG signals were recorded at the pre-stroke phase (0 h), acute phase (3, 6 h), subacute phase (12, 24, 48, 72 h) and chronic phase (96, 120, 144, 168 h) (n = 8). This study analyzed post-stroke seizures and polymorphic delta activities (PDAs) and calculated quantitative EEG parameters such as the alpha-to-delta ratio (ADR). The ADR represented the ratio between alpha power and delta power, which indicated how fast the EEG activities were. Forelimb and hindlimb motor functions were measured by De Ryck's test and the beam walking test, respectively. In the acute phase, delta power increased fourfold with the occurrence of PDAs, and the histological staining showed that the infarct was limited to the striatum and secondary sensory cortex. In the subacute phase, the alpha power reduced to 50% of the baseline, and the infarct progressed to the forelimb cortical region. ADRs reduced from 0.23 ± 0.09 to 0.04 ± 0.01 at 3 h in the acute phase and gradually recovered to 0.22 ± 0.08 at 168 h in the chronic phase. In the comparison of correlations between the EEG parameters and the limb motor function from the acute phase to the chronic phase, ADRs were found to have the highest correlation coefficients with the beam walking test (r = 0.9524, p < 0.05) and De Ryck's test (r = 0.8077, p < 0.05). This study measured EEG activities after focal cerebral ischemia and showed that functional recovery was closely correlated with the neural activities in the penumbra. Longitudinal EEG monitoring at different phases after a stroke can provide information on the neural activities, which are well correlated with the motor function recovery.

Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice

PubMed Central

Chaparro, Rafael E; Izutsu, Miwa; Sasaki, Toshihiro; Sheng, Huaxin; Zheng, Yi; Sadeghian, Homa; Qin, Tao; von Bornstadt, Daniel; Herisson, Fanny; Duan, Bin; Li, Jing-Song; Jiang, Kai; Pearlstein, Molly; Pearlstein, Robert D; Smith, David E; Goldberg, Itzhak D; Ayata, Cenk; Warner, David S

2015-01-01

Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood–brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke. PMID:25712497

Purinergic 2X7 receptor/NLRP3 pathway triggers neuronal apoptosis after ischemic stroke in the mouse.

PubMed

Ye, Xinchun; Shen, Tong; Hu, Jinxia; Zhang, Liang; Zhang, Yunshan; Bao, Lei; Cui, Chengcheng; Jin, Guoliang; Zan, Kun; Zhang, Zuohui; Yang, Xinxin; Shi, Hongjuan; Zu, Jie; Yu, Ming; Song, Chengjie; Wang, Yulan; Qi, Suhua; Cui, Guiyun

2017-06-01

Previous research has shown that Purinergic 2X7 receptor (P2X7R) and NLRP3 inflammasome contribute to the inflammatory activation. In this study, we investigated whether P2X7R/NLRP3 pathway is involved in the caspase-3 dependent neuronal apoptosis after ischemic stroke by using a focal cortex ischemic stroke model. The expressions of P2X7R, NLRP3 inflammsome components, and cleaved caspase-3 were significantly enhanced in the ischemic brain tissue after stroke. However, the expression of cleaved caspase-3 was significantly attenuated after treatment of stroke with P2X7R antagonist (BBG) or NLRP3 inhibitor (MCC950). The treatment also significantly reduced the infarction volume, neuronal apoptosis, and neurological impairment. In addition, in vitro data also support the hypothesis that P2X7R/NLRP3 pathway plays a vital role in caspase-3 dependent neuronal apoptosis after ischemic stroke. Further investigation of effective regulation of P2X7R and NLRP3 in stroke is warranted. Copyright © 2017. Published by Elsevier Inc.

Chromium supplementation improved post-stroke brain infarction and hyperglycemia.

PubMed

Chen, Wen-Ying; Mao, Frank Chiahung; Liu, Chia-Hsin; Kuan, Yu-Hsiang; Lai, Nai-Wei; Wu, Chih-Cheng; Chen, Chun-Jung

2016-04-01

Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia.

The neurovascular unit, matrix proteases, and innate inflammation.

PubMed

del Zoppo, Gregory J

2010-10-01

In the central nervous system, microvessel-neuron interactions appear highly coordinated. The rapid simultaneous responses of the microvasculature, neurons, and glia to focal ischemia in experimental ischemic stroke suggest that these responses could be viewed in a unitary fashion, rather than as individual components. The "neurovascular unit" consists of microvessels (endothelial cells-basal lamina matrix-astrocyte end-feet [and pericytes]), astrocytes, neurons and their axons, and other supporting cells that are likely to modulate the function of the "unit." Each cell component generates an inflammatory response to ischemia. Matrix metalloproteinase (MMP)-9 was first associated with hemorrhagic transformation following focal ischemia in an experimental model. A series of studies of ischemic stroke patients also suggests a relationship between MMP-9 levels and several consequences of ischemic injury, including hemorrhagic transformation. Recent experimental work suggests specific cell sources for MMP-9 generation and for matrix proteases from four distinct families that could impact neurovascular unit integrity. © 2010 New York Academy of Sciences.

Contribution of EEG in transient neurological deficits.

PubMed

Lozeron, Pierre; Tcheumeni, Nadine Carole; Turki, Sahar; Amiel, Hélène; Meppiel, Elodie; Masmoudi, Sana; Roos, Caroline; Crassard, Isabelle; Plaisance, Patrick; Benbetka, Houria; Guichard, Jean-Pierre; Houdart, Emmanuel; Baudoin, Hélène; Kubis, Nathalie

2018-01-01

Identification of stroke mimics and 'chameleons' among transient neurological deficits (TND) is critical. Diagnostic workup consists of a brain imaging study, for a vascular disease or a brain tumour and EEG, for epileptiform discharges. The precise role of EEG in this diagnostic workup has, however, never been clearly delineated. However, this could be crucial in cases of atypical or incomplete presentation with consequences on disease management and treatment. We analysed the EEG patterns on 95 consecutive patients referred for an EEG within 7 days of a TND with diagnostic uncertainty. Patients were classified at the discharge or the 3-month follow-up visit as: 'ischemic origin', 'migraine aura', 'focal seizure', and 'other'. All patients had a brain imaging study. EEG characteristics were correlated to the TND symptoms, imaging study, and final diagnosis. Sixty four (67%) were of acute onset. Median symptom duration was 45 min. Thirty two % were 'ischemic', 14% 'migraine aura', 19% 'focal seizure', and 36% 'other' cause. EEGs were recorded with a median delay of 1.6 day after symptoms onset. Forty EEGs (42%) were abnormal. Focal slow waves were the most common finding (43%), also in the ischemic group (43%), whether patients had a typical presentation or not. Epileptiform discharges were found in three patients, one with focal seizure and two with migraine aura. Non-specific EEG focal slowing is commonly found in TND, and may last several days. We found no difference in EEG presentation between stroke mimics and stroke chameleons, and between other diagnoses.

Risk of bias reporting in the recent animal focal cerebral ischaemia literature.

PubMed

Bahor, Zsanett; Liao, Jing; Macleod, Malcolm R; Bannach-Brown, Alexandra; McCann, Sarah K; Wever, Kimberley E; Thomas, James; Ottavi, Thomas; Howells, David W; Rice, Andrew; Ananiadou, Sophia; Sena, Emily

2017-10-15

Findings from in vivo research may be less reliable where studies do not report measures to reduce risks of bias. The experimental stroke community has been at the forefront of implementing changes to improve reporting, but it is not known whether these efforts are associated with continuous improvements. Our aims here were firstly to validate an automated tool to assess risks of bias in published works, and secondly to assess the reporting of measures taken to reduce the risk of bias within recent literature for two experimental models of stroke. We developed and used text analytic approaches to automatically ascertain reporting of measures to reduce risk of bias from full-text articles describing animal experiments inducing middle cerebral artery occlusion (MCAO) or modelling lacunar stroke. Compared with previous assessments, there were improvements in the reporting of measures taken to reduce risks of bias in the MCAO literature but not in the lacunar stroke literature. Accuracy of automated annotation of risk of bias in the MCAO literature was 86% (randomization), 94% (blinding) and 100% (sample size calculation); and in the lacunar stroke literature accuracy was 67% (randomization), 91% (blinding) and 96% (sample size calculation). There remains substantial opportunity for improvement in the reporting of animal research modelling stroke, particularly in the lacunar stroke literature. Further, automated tools perform sufficiently well to identify whether studies report blinded assessment of outcome, but improvements are required in the tools to ascertain whether randomization and a sample size calculation were reported. © 2017 The Author(s).

Effects of the Oral Ingestion of Probiotics on Brain Damage in a Transient Model of Focal Cerebral Ischemia in Mice

PubMed Central

Akhoundzadeh, Kobra; Vakili, Abedin; Shadnoush, Mahdi; Sadeghzadeh, Jafar

2018-01-01

Background: Probiotics are microorganisms that may influence brain function via altering brain neurochemistry. New research evidence suggests that probiotic bacteria might protect tissue damage through diminishing the production of free radicals and/or inflammatory cytokines. Therefore, this study was designed to evaluate the effects of probiotic bacteria on the prevention or reduction of brain damage in an experimental model of stroke in mice. Methods: In this study, 30 male BLC57 mice were randomly divided into 6 equal groups. Focal cerebral ischemia was induced via middle cerebral artery occlusion for 45 minutes, followed by 24 hours of reperfusion, in the mice. Probiotics at a concentration of 107 CFU/mL were administered by oral gavage daily for 14 days before ischemia. Infarct size, neurological outcome, and biochemical markers were measured 24 hours after brain ischemia. Statistical analysis were performed using the one-way ANOVA and/or Kruskal–Wallis ANOVA on rank by Sigma Stat (2.0; Jandel Scientific) software. Results: Our results indicated that pretreatment with probiotics significantly reduced infarct size by 52% (P=0.001) but could not improve neurological function (P=0.26). Moreover, the administration of probiotics significantly decreased the malondialdehyde content (P=0.001) and the tumor necrosis factor-alpha level (P=0.004) in the ischemic brain tissue. Conclusion: The findings of the present study showed that probiotic supplements might be useful in the prevention or attenuation of brain ischemic injury in patients at risk of stroke. Probiotics may open new therapeutic alternatives for the prevention of stroke. More preclinical and clinical studies are, however, needed to clarify their efficacy in cerebral stroke. PMID:29398750

Inhibition of Cathepsin B Alleviates Secondary Degeneration in Ipsilateral Thalamus After Focal Cerebral Infarction in Adult Rats.

PubMed

Zuo, Xialin; Hou, Qinghua; Jin, Jizi; Zhan, Lixuan; Li, Xinyu; Sun, Weiwen; Lin, Kunqin; Xu, En

2016-09-01

Secondary degeneration in areas beyond ischemic foci can inhibit poststroke recovery. The cysteine protease Cathepsin B (CathB) regulates cell death and intracellular protein catabolism. To investigate the roles of CathB in the development of secondary degeneration in the ventroposterior nucleus (VPN) of the ipsilateral thalamus after focal cerebral infarction, infarct volumes, immunohistochemistry and immunofluorescence, and Western blotting analyses were conducted in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. We observed marked neuron loss and gliosis in the ipsilateral thalamus after dMCAO, and the expression of CathB and cleaved caspase-3 in the VPN was significantly upregulated; glial cells were the major source of CathB. Although it had no effect on infarct volume, delayed intracerebroventricular treatment with the membrane-permeable CathB inhibitor CA-074Me suppressed the expression of CathB and cleaved caspase-3 in ipsilateral VPN and accordingly alleviated the secondary degeneration. These data indicate that CathB mediates a novel mechanism of secondary degeneration in the VPN of the ipsilateral thalamus after focal cortical infarction and suggest that CathB might be a therapeutic target for the prevention of secondary degeneration in patients after stroke. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Incidence of seizures following initial ischemic stroke in a community-based cohort: The Framingham Heart Study.

PubMed

Stefanidou, Maria; Das, Rohit R; Beiser, Alexa S; Sundar, Banu; Kelly-Hayes, Margaret; Kase, Carlos S; Devinsky, Orrin; Seshadri, Sudha; Friedman, Daniel

2017-04-01

We examined the incidence of seizures following ischemic stroke in a community-based sample. All subjects with incident ischemic strokes in the Framingham Original and Offspring cohorts between 1982 and 2003 were identified and followed for up to 20 years to determine incidence of seizures. Seizure-type was based on the 2010 International League Against Epilepsy (ILAE) classification. Disability was stratified into mild/none, moderate and severe, based on post-stroke neurological deficit documentation according to the Framingham Heart Study (FHS) protocol and functional status was determined using the Barthel Index. An initial ischemic stroke occurred in 469 subjects in the cohort and seizures occurred in 25 (5.3%) of these subjects. Seizure incidence was similar in both large artery atherosclerosis (LAA) (6.8%) and cardio-embolic (CE) (6.2%) strokes. No seizures occurred following lacunar strokes. The predominant seizure type was focal seizure with or without evolution to bilateral convulsive seizure. One third of participants had seizures within the first 24h from stroke onset and half of all seizures occurred within the first 30days. On multivariate analysis, moderate and severe disability following stroke was associated with increased risk of incident seizure. Seizures occurred in approximately 5% of subjects after an ischemic stroke. One third of these seizures occurred in the first 24h after stroke and none followed lacunar strokes. Focal seizures with or without evolution in bilateral convulsive seizures were the most common seizure type. Moderate and severe disability was predictive of incident seizures. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Nasal temperatures in dairy cows are influenced by positive emotional state.

PubMed

Proctor, Helen S; Carder, Gemma

2015-01-01

Understanding how animals express positive emotions is an important area of focus for animal welfare science, yet it is widely neglected. Emotions can be either positive or negative in valence, depending on the rewarding or punishing nature of the stimulus, and they can vary in the degree of arousal or excitement. Previous literature has shown a strong connection between peripheral temperatures and high arousal, negative experiences. Stress, fear and frustration have all been found to cause a drop in peripheral temperature. Little is known however, about whether the experience of positive emotions affects peripheral temperatures. In this study we sought to identify whether the nasal temperature of cows was affected by emotions, and if nasal temperature could be reliably used as a measure of emotional state in cows. We induced a positive, low arousal emotional state by stroking cows in preferred regions, in a similar manner to allogrooming. We performed 350 full focal observations, each comprising three conditions; pre-stroking, stroking, and post-stroking. During each 15minute focal observation we remotely took the focal cow's nasal temperature six times, twice during each condition. We analysed the data using the one-way ANOVA repeated measures test and found a significant difference overall (F (2, 1.935)=9.372, p<0.01). Post-hoc pairwise comparisons indicated that the total mean nasal temperature decreased significantly during the stroking condition (25.91°C, SD=1.21), compared with both the pre-stroking (26.27°C, SD=1.01, p<0.01) and post-stroking conditions (26.44°C, SD=1.12, p<0.01). There was no significant difference between the pre-stroking and post-stroking conditions (p=0.14). We suggest that the cows were in a low state of arousal during the entire focal observation, as no other changes to the cows' environment had been made, and the cows were habituated to both the procedure and the researchers. Furthermore, the stroking stimulus is known to induce a state of relaxation and lower the heart rate of cows. This leads us to conclude that the drop in nasal temperature was indicative of the change in valence, rather than a change in arousal. These findings show that positive emotional state may have the same effect on the peripheral temperatures of mammals as a negative state does. This raises questions regarding the triggers for emotional fever, which is often considered to be associated only with negative states and high arousal. Our results indicate that nasal temperature in cows may prove to be a useful measure of a change in emotional state, but further research is required to validate these findings and to explore the effect of arousal on peripheral temperatures. Copyright © 2014 Elsevier Inc. All rights reserved.

Evaluation of cerebral blood flow changes in focal cerebral ischemia rats by using transcranial Doppler ultrasonography.

PubMed

Li, Le; Ke, Zheng; Tong, Kai Yu; Ying, Michael

2010-04-01

Ischemic stroke is typically characterized by the disruption of cerebral blood flow. This study aimed to consecutively evaluate the cerebral blood flow changes in a focal ischemia rat model during the occlusion-reperfusion procedure and along the recovery stage after stroke. In 12 Sprague Dawley (SD) rats, a middle cerebral artery occlusion/reperfusion (MCAo/r) surgery was conducted, which combines a permanent occlusion of the right common carotid artery (CCA), external carotid artery (ECA) and a transient occlusion of the right internal carotid artery (ICA) and middle cerebral artery (MCA) with a monofilament introduced from the proximal ICA towards the distal right ICA then removed after 90 min. Blood flow velocity (BFV) from the concerned arteries were measured using ultrasonography (13-4 MHz) at the basal stage before the surgery, after the reperfusion stage and during the post-stroke status. At reperfusion stage and after, BFV increased significantly in the left ICA and in the basilar artery (BA) (starting from post-24 h, p < 0.05 vs. basal). Moreover, BFV were reversed in the distal right ICA and reflow was recorded in the right MCA. Time-average maximum BFV in the right MCA at reperfusion and post-stroke 24-96 h was decreased significantly (p < 0.05 vs. basal). The reversed flow in the right ICA was enabled by the settlement of the collateral supply through the circle of Willis which consisted in higher BFV in the opposite ICA and in the BA still 24 h, although the proximal right ICA remain occluded. Ultrasound measurement of BFV helps to provide information on the redistribution of the blood flow supply after the onset of stroke. Copyright 2010 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Combining robotic training and inactivation of the healthy hemisphere restores pre-stroke motor patterns in mice

PubMed Central

Spalletti, Cristina; Alia, Claudia; Lai, Stefano; Panarese, Alessandro; Conti, Sara

2017-01-01

Focal cortical stroke often leads to persistent motor deficits, prompting the need for more effective interventions. The efficacy of rehabilitation can be increased by ‘plasticity-stimulating’ treatments that enhance experience-dependent modifications in spared areas. Transcallosal pathways represent a promising therapeutic target, but their role in post-stroke recovery remains controversial. Here, we demonstrate that the contralesional cortex exerts an enhanced interhemispheric inhibition over the perilesional tissue after focal cortical stroke in mouse forelimb motor cortex. Accordingly, we designed a rehabilitation protocol combining intensive, repeatable exercises on a robotic platform with reversible inactivation of the contralesional cortex. This treatment promoted recovery in general motor tests and in manual dexterity with remarkable restoration of pre-lesion movement patterns, evaluated by kinematic analysis. Recovery was accompanied by a reduction of transcallosal inhibition and ‘plasticity brakes’ over the perilesional tissue. Our data support the use of combinatorial clinical therapies exploiting robotic devices and modulation of interhemispheric connectivity. PMID:29280732

Perinatal ischemic stroke: a five-year retrospective study in a level-III maternity

PubMed Central

Machado, Virgínia; Pimentel, Sónia; Pinto, Filomena; Nona, José

2015-01-01

Objective To study the incidence, clinical presentation, risk factors, imaging diagnosis, and clinical outcome of perinatal stroke. Methods Data was retrospectively collected from full-term newborns admitted to the neonatal unit of a level III maternity in Lisbon with cerebral stroke, from January 2007 to December 2011. Results There were 11 cases of stroke: nine were arterial ischemic stroke and two were cerebral venous sinus thrombosis. We estimated an incidence of arterial ischemic stroke of 1.6/5,000 births and of cerebral venous sinus thrombosis of 7.2/100,000 births. There were two cases of recurrent stroke. Eight patients presented with symptoms while the remaining three were asymptomatic and incidentally diagnosed. The most frequently registered symptoms (8/11) were seizures; in that, generalized clonic (3/8) and focal clonic (5/8). Strokes were more commonly left-sided (9/11), and the most affected artery was the left middle cerebral artery (8/11). Transfontanelle ultrasound was positive in most of the patients (10/11), and stroke was confirmed by cerebral magnetic resonance in all patients. Electroencephalographic recordings were carried out in five patients and were abnormal in three (focal abnormalities n=2, burst-suppression pattern n=1). Eight patients had previously identified risk factors for neonatal stroke which included obstetric and neonatal causes. Ten patients were followed up at outpatients setting; four patients developed motor deficits and one presented with epilepsy. Conclusions Although a modest and heterogeneous sample, this study emphasizes the need for a high level of suspicion when it comes to neonatal stroke, primarily in the presence of risk factors. The prevalence of neurological sequelae in our series supports the need of long-term follow-up and early intervention strategies. PMID:25993071

Dynamic imaging of cerebral blood flow in rat reperfused mini-stroke model using laser speckle temporal contrast analysis

NASA Astrophysics Data System (ADS)

Wang, Zhen; Luo, Weihua; Li, Pengcheng; Zeng, Shaoqun; Luo, Qingming

2007-05-01

Laser speckle temporal contrast analysis (LSTCA) was used to image the cerebral blood flow (CBF) of ischemic area in reperfused mini-stroke model in rats. Focal cortical ischemia in male Sprague-Dawley rats (n=20) was induced by deliberate ligation of multiple branches of the middle cerebral artery (MCA) together with a nylon ring and the dura. LSTCA was used to monitor the spatio-temporal characteristics of cerebral blood flow dynamics in the rat somatosensory cortex in the ischemic and reperfused stages. The infarction volume was measured by 2, 3, 5- triphenyltetrazolium chloride (TTC) staining 24 hours after reperfusion. The distribution of changes in cerebral blood flow which outlined by the laser speckle imaging represented the relative CBF gradient (21.98+/-1.96%, 67.2+/-1.67 %, 107.24+/-4.71 % of the baseline) from ischemic core, penumbra zone to normal tissue immediately after cortical ischemia, in which a central ischemic core had little or no perfusion surrounded by a penumbral region with reduced perfusion, in addition, we had shown the existence of a surrounding region of hyperemic tissue; Thereafter a postrecanalization hyperperfusion occurred in the same infarct core since 24 hours after reperfusion (242.62+/-18.52% of the baseline). Histology of the ischemic regions at 24 hours after reperfusion revealed small focal infarcts that were typically 3~4 mm in diameter, approximately equal to the nylon ring in size and position and essentially accordant with the spatial distribution of the ischemic cortex with below 30% residual CBF of the pre-ischemic baseline. It was demonstrated that this technique of LSTCA was easy to implement and availably used to image the spatial and temporal evolution of CBF changes with high resolution in rat reperfused mini-stroke model.

Disruptions of network connectivity predict impairment in multiple behavioral domains after stroke

PubMed Central

Ramsey, Lenny E.; Metcalf, Nicholas V.; Chacko, Ravi V.; Weinberger, Kilian; Baldassarre, Antonello; Hacker, Carl D.; Shulman, Gordon L.; Corbetta, Maurizio

2016-01-01

Deficits following stroke are classically attributed to focal damage, but recent evidence suggests a key role of distributed brain network disruption. We measured resting functional connectivity (FC), lesion topography, and behavior in multiple domains (attention, visual memory, verbal memory, language, motor, and visual) in a cohort of 132 stroke patients, and used machine-learning models to predict neurological impairment in individual subjects. We found that visual memory and verbal memory were better predicted by FC, whereas visual and motor impairments were better predicted by lesion topography. Attention and language deficits were well predicted by both. Next, we identified a general pattern of physiological network dysfunction consisting of decrease of interhemispheric integration and intrahemispheric segregation, which strongly related to behavioral impairment in multiple domains. Network-specific patterns of dysfunction predicted specific behavioral deficits, and loss of interhemispheric communication across a set of regions was associated with impairment across multiple behavioral domains. These results link key organizational features of brain networks to brain–behavior relationships in stroke. PMID:27402738

Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.

PubMed

Choi, Sang-Ho; Arai, Allison L; Mou, Yongshan; Kang, Byeongteck; Yen, Cecil Chern-Chyi; Hallenbeck, John; Silva, Afonso C

2018-03-01

MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia. SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests. Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors. Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke. © 2018 American Heart Association, Inc.

Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice

PubMed Central

Ghosh, Somnath; Canugovi, Chandrika; Yoon, Jeong Seon; Wilson, David M.; Croteau, Deborah L.; Mattson, Mark P.; Bohr, Vilhelm A.

2017-01-01

Oxidative DNA damage is mainly repaired by base excision repair (BER). Previously, our lab showed that mice lacking the BER glycosylases Ogg1 or Neil1 recover more poorly from focal ischemic stroke than wild-type mice. Here, a mouse model was used to investigate whether loss of one of the two alleles of Xrcc1, which encodes a non-enzymatic scaffold protein required for BER, alters recovery from stroke. Ischemia and reperfusion caused higher brain damage and lower functional recovery in Xrcc1+/− mice than in wild-type mice. Additionally, a greater percentage of Xrcc1+/− mice died as a result of the stroke. Brain samples from human individuals who died of stroke and individuals who died of non-neurological causes were assayed for various steps of BER. Significant losses of thymine glycol incision, abasic endonuclease incision and single nucleotide incorporation activities were identified, as well as lower expression of XRCC1 and NEIL1 proteins in stroke brains compared to controls. Together, these results suggest that impaired BER is a risk factor in ischemic brain injury and contributes to its recovery. PMID:25971543

The pathophysiology of post-stroke aphasia: A network approach.

PubMed

Thiel, Alexander; Zumbansen, Anna

2016-06-13

Post-stroke aphasia syndromes as a clinical entity arise from the disruption of brain networks specialized in language production and comprehension due to permanent focal ischemia. This approach to post-stroke aphasia is based on two pathophysiological concepts: 1) Understanding language processing in terms of distributed networks rather than language centers and 2) understanding the molecular pathophysiology of ischemic brain injury as a dynamic process beyond the direct destruction of network centers and their connections. While considerable progress has been made in the past 10 years to develop such models on a systems as well as a molecular level, the influence of these approaches on understanding and treating clinical aphasia syndromes has been limited. In this article, we review current pathophysiological concepts of ischemic brain injury, their relationship to altered information processing in language networks after ischemic stroke and how these mechanisms may be influenced therapeutically to improve treatment of post-stroke aphasia. Understanding the pathophysiological mechanism of post-stroke aphasia on a neurophysiological systems level as well as on the molecular level becomes more and more important for aphasia treatment, as the field moves from standardized therapies towards more targeted individualized treatment strategies comprising behavioural therapies as well as non-invasive brain stimulation (NIBS).

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke: Reopening a Postischemic Sensitive Period.

PubMed

Zeiler, Steven R; Hubbard, Robert; Gibson, Ellen M; Zheng, Tony; Ng, Kwan; O'Brien, Richard; Krakauer, John W

2016-09-01

Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity-a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke. To test this prediction, we induced a second stroke in the AGm of mice with incomplete recovery after a first stroke in CFA. Mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in CFA. After a 7-day poststroke delay, the mice were then retrained to asymptote. We then induced a second stroke in the AGm, and after only a 1-day delay, retrained the mice. Recovery of prehension was incomplete when training was started after a 7-day poststroke delay and continued for 19 days. However, a second focal stroke in the AGm led to a dramatic response to 9 days of training, with full recovery to normal levels of performance. New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke. © The Author(s) 2015.

T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

PubMed Central

Clarkson, Benjamin D.S.; Ling, Changying; Shi, Yejie; Harris, Melissa G.; Rayasam, Aditya; Sun, Dandan; Salamat, M. Shahriar; Kuchroo, Vijay; Lambris, John D.; Sandor, Matyas

2014-01-01

T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, but the relevant T cell–derived mediators of tissue injury remain unknown. Using a mouse model of transient focal brain ischemia, we report that IL-21 is highly up-regulated in the injured mouse brain after cerebral ischemia. IL-21–deficient mice have smaller infarcts, improved neurological function, and reduced lymphocyte accumulation in the brain within 24 h of reperfusion. Intracellular cytokine staining and adoptive transfer experiments revealed that brain-infiltrating CD4+ T cells are the predominant IL-21 source. Mice treated with decoy IL-21 receptor Fc fusion protein are protected from reperfusion injury. In postmortem human brain tissue, IL-21 localized to perivascular CD4+ T cells in the area surrounding acute stroke lesions, suggesting that IL-21–mediated brain injury may be relevant to human stroke. PMID:24616379

Dynamic Modulation of Microglia/Macrophage Polarization by miR-124 after Focal Cerebral Ischemia.

PubMed

Hamzei Taj, Somayyeh; Kho, Widuri; Aswendt, Markus; Collmann, Franziska M; Green, Claudia; Adamczak, Joanna; Tennstaedt, Annette; Hoehn, Mathias

2016-12-01

Mononuclear phagocytes respond to ischemic stroke dynamically, undergoing an early anti-inflammatory and protective phenotype followed by the pro-inflammatory and detrimental type. These dual roles of microglia/macrophages suggest the need of subtle adjustment of their polarization state instead of broad suppression. The most abundant brain-specific miRNA, miR-124, promotes neuronal differentiation but can also modulate microglia activation and keeps them in a quiescent state. We addressed whether the intracerebral injection of miR-124 in a mouse model of ischemic stroke before or after the peak phase of the pro-inflammatory polarization modifies the pro-/anti- inflammatory balance. In the sub-acute phase, 48 h after stroke, liposomated miR-124 shifted the predominantly pro-inflammatory polarized microglia/macrophages toward the anti-inflammatory phenotype. The altered immune response improved neurological deficit at day 6 after stroke. When miR-124 was injected 10 days after stroke, the pro-/anti- inflammatory ratio was still significantly reduced although to a lower degree and had no effect on recovery at day 14. This study indicates that miR-124 administration before the peak of the pro-inflammatory process of stroke is most effective in support of increasing the rehabilitation opportunity in the sub-acute phases of stroke. Our findings highlight the important role of immune cells after stroke and the therapeutic relevance of their polarization balance.

The relationship between aortic stiffness and changes in retinal microvessels among Asian ischemic stroke patients.

PubMed

De Silva, D A; Woon, F-P; Manzano, J J F; Liu, E Y; Chang, H-M; Chen, C; Wang, J J; Mitchell, P; Kingwell, B A; Cameron, J D; Lindley, R I; Wong, T Y; Wong, M-C

2012-12-01

Large-artery stiffness is a risk factor for stroke, including cerebral small-vessel disease. Retinal microvascular changes are thought to mirror those in cerebral microvessels. We investigated the relationship between aortic stiffness and retinal microvascular changes in Asian ischemic stroke patients. We studied 145 acute ischemic stroke patients in Singapore who had aortic stiffness measurements using carotid-femoral pulse wave velocity (cPWV). Retinal photographs were assessed for retinal microvessel caliber and qualitative signs of focal arteriolar narrowing, arteriovenous nicking and enhanced arteriolar light reflex. Aortic stiffening was associated with retinal arteriolar changes. Retinal arteriolar caliber decreased with increasing cPWV (r=-0.207, P=0.014). After adjusting for age, gender, hypertension, diabetes, mean arterial pressure and small-vessel stroke subtype, patients within the highest cPWV quartile were more likely to have generalized retinal arteriolar narrowing defined as lowest caliber tertile (odds ratio (OR) 6.84, 95% confidence interval (CI) 1.45-32.30), focal arteriolar narrowing (OR 13.85, CI 1.82-105.67), arteriovenous nicking (OR 5.08, CI 1.12-23.00) and enhanced arteriolar light reflex (OR 3.83, CI 0.89-16.48), compared with those within the lowest quartile. In ischemic stroke patients, aortic stiffening is associated with retinal arteriolar luminal narrowing as well as features of retinal arteriolosclerosis.

Nonhuman primate models of focal cerebral ischemia

PubMed Central

Fan, Jingjing; Li, Yi; Fu, Xinyu; Li, Lijuan; Hao, Xiaoting; Li, Shasha

2017-01-01

Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model. PMID:28400817

Focal Stroke in the Developing Rat Motor Cortex Induces Age- and Experience-Dependent Maladaptive Plasticity of Corticospinal System

PubMed Central

Gennaro, Mariangela; Mattiello, Alessandro; Mazziotti, Raffaele; Antonelli, Camilla; Gherardini, Lisa; Guzzetta, Andrea; Berardi, Nicoletta; Cioni, Giovanni; Pizzorusso, Tommaso

2017-01-01

Motor system development is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal tracts (CST). Clinical evidence suggests that age is crucial for developmental stroke outcome, with early lesions inducing a “maladaptive” strengthening of ipsilateral projections from the healthy hemisphere and worse motor impairment. Here, we investigated in developing rats the relation between lesion timing, motor outcome and CST remodeling pattern. We induced a focal ischemia into forelimb motor cortex (fM1) at two distinct pre-weaning ages: P14 and P21. We compared long-term motor outcome with changes in axonal sprouting of contralesional CST at red nucleus and spinal cord level using anterograde tracing. We found that P14 stroke caused a more severe long-term motor impairment than at P21, and induced a strong and aberrant contralesional CST sprouting onto denervated spinal cord and red nucleus. The mistargeted sprouting of CST, and the worse motor outcome of the P14 stroke rats were reversed by an early skilled motor training, underscoring the potential of early activity-dependent plasticity in modulating lesion outcome. Thus, changes in the mechanisms controlling CST plasticity occurring during the third postnatal week are associated with age-dependent regulation of the motor outcome after stroke. PMID:28706475

Focal Stroke in the Developing Rat Motor Cortex Induces Age- and Experience-Dependent Maladaptive Plasticity of Corticospinal System.

PubMed

Gennaro, Mariangela; Mattiello, Alessandro; Mazziotti, Raffaele; Antonelli, Camilla; Gherardini, Lisa; Guzzetta, Andrea; Berardi, Nicoletta; Cioni, Giovanni; Pizzorusso, Tommaso

2017-01-01

Motor system development is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal tracts (CST). Clinical evidence suggests that age is crucial for developmental stroke outcome, with early lesions inducing a "maladaptive" strengthening of ipsilateral projections from the healthy hemisphere and worse motor impairment. Here, we investigated in developing rats the relation between lesion timing, motor outcome and CST remodeling pattern. We induced a focal ischemia into forelimb motor cortex (fM1) at two distinct pre-weaning ages: P14 and P21. We compared long-term motor outcome with changes in axonal sprouting of contralesional CST at red nucleus and spinal cord level using anterograde tracing. We found that P14 stroke caused a more severe long-term motor impairment than at P21, and induced a strong and aberrant contralesional CST sprouting onto denervated spinal cord and red nucleus. The mistargeted sprouting of CST, and the worse motor outcome of the P14 stroke rats were reversed by an early skilled motor training, underscoring the potential of early activity-dependent plasticity in modulating lesion outcome. Thus, changes in the mechanisms controlling CST plasticity occurring during the third postnatal week are associated with age-dependent regulation of the motor outcome after stroke.

Left Hemisphere Regions Are Critical for Language in the Face of Early Left Focal Brain Injury

ERIC Educational Resources Information Center

Beharelle, Anjali Raja; Dick, Anthony Steven; Josse, Goulven; Solodkin, Ana; Huttenlocher, Peter R.; Levine, Susan C.; Small, Steven L.

2010-01-01

A predominant theory regarding early stroke and its effect on language development, is that early left hemisphere lesions trigger compensatory processes that allow the right hemisphere to assume dominant language functions, and this is thought to underlie the near normal language development observed after early stroke. To test this theory, we…

The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9.

PubMed

Sánchez-Blázquez, Pilar; Pozo-Rodrigálvarez, Andrea; Merlos, Manuel; Garzón, Javier

2018-06-01

The glutamate N-methyl-D-aspartate receptor (NMDAR) plays an essential role in the excitotoxic neural damage that follows ischaemic stroke. Because the sigma-1 receptor (σ1R) can regulate NMDAR transmission, exogenous and putative endogenous regulators of σ1R have been investigated using animal models of ischaemic stroke. As both agonists and antagonists provide some neural protection, the selective involvement of σ1Rs in these effects has been questioned. The availability of S1RA (E-52862/MR309), a highly selective σ1R antagonist, prompted us to explore its therapeutic potential in an animal model of focal cerebral ischaemia. Mice were subjected to right middle cerebral artery occlusion (MCAO), and post-ischaemic infarct volume and neurological deficits were determined across a range of intervals after the stroke-inducing surgery. Intracerebroventricular or intravenous treatment with S1RA significantly reduced the cerebral infarct size and neurological deficits caused by permanent MCAO (pMCAO). Compared with the control/sham-operated mice, the neuroprotective effects of S1RA were observed when delivered up to 5 h prior to surgery and 3 h after ischaemic onset. Interestingly, neither mice with the genetic deletion of σ1R nor wild-type mice that were pre-treated with the σ1R agonist PRE084 showed beneficial effects after S1RA administration with regard to stroke infarction. S1RA-treated mice showed faster behavioural recovery from stroke; this finding complements the significant decreases in matrix metalloproteinase-9 (MMP-9) expression and reactive astrogliosis surrounding the infarcted cortex. Our data indicate that S1RA, via σ1R, holds promising potential for clinical application as a therapeutic agent for ischaemic stroke.

Quantitative characterization of the progression of focal brain ischemia in a rat photochemical stroke model using in-vivo MRI

NASA Astrophysics Data System (ADS)

Van der Linden, Anne-Marie; Verhoye, Marleen; De Ryck, M.

2000-04-01

Stroke models, if used in drug evaluation studies, should have a predictable and reproducible course and outcome. While most drug trials focus on the lesion outcome, our study shows the importance of studying lesion growth instead of lesion outcome. In the study reported here, the time course of a photochemically induced neocortical infarct is studied in rats, using diffusion-weighted magnetic resonance imaging, while the rats were submitted to a rigorous control of physiological parameters, ensuring constant body temperature, blood gases (pO2 and pCO2), arterial pressure, heart rate and plasma glucose levels. Under such a stable physiological condition, rats were imaged as soon as possible after lesion up to 6 hours, which is the most important period to determine the slope of further lesion growth and final outcome. The data show that the initial size of the lesion is important for the further outcome of the stroke, both in lesion size and severity of the ischemic damage, as reflected by changes in the Apparent Diffusion Coefficient.

Athletics, minor trauma, and pediatric arterial ischemic stroke.

PubMed

Sepelyak, Kathryn; Gailloud, Philippe; Jordan, Lori C

2010-05-01

Pediatric arterial ischemic stroke may occur as the result of trivial head or neck trauma sustained during a sports activity. We describe three cases of sports-related stroke in previously healthy school-age children and discuss acute and long-term stroke care. Possible mechanisms of sports-related stroke are addressed, as is evaluation for cause of stroke in children. In one of the reported cases, the child was found to have a vertebral artery dissection as the cause of his stroke, but no definitive cause of stroke was identified in the other two cases despite extensive evaluation. The advisability and timing of returning to athletic activities after stroke is also discussed. Many children with sports-related stroke are initially seen by a sports trainer, a pediatrician, or an ER physician. Thus, it is particularly important that these professionals are aware of the possibility of ischemic stroke occurring after even mild athletic injury. Childhood stroke may result from injuries sustained during athletic activities and should be considered when a child has acute focal neurologic signs.

Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

PubMed

Paliwal, Pankaj; Dash, Debabrata; Krishnamurthy, Sairam

2018-04-01

Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. All the pharmacokinetic parameters of piracetam including area under curve (AUC 0-24 ), maximum plasma concentration (C max ), time to reach the maximum plasma concentration (t max ), elimination half-life (t 1/2 ), volume of distribution (V z ), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC 0-2 ) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for brain penetration. This indicates that variables influencing brain penetration may not be limiting factors for use of piracetam in ischemic stroke.

Identifying Key Words in 9-1-1 Calls for Stroke: A Mixed Methods Approach.

PubMed

Richards, Christopher T; Wang, Baiyang; Markul, Eddie; Albarran, Frank; Rottman, Doreen; Aggarwal, Neelum T; Lindeman, Patricia; Stein-Spencer, Leslee; Weber, Joseph M; Pearlman, Kenneth S; Tataris, Katie L; Holl, Jane L; Klabjan, Diego; Prabhakaran, Shyam

2017-01-01

Identifying stroke during a 9-1-1 call is critical to timely prehospital care. However, emergency medical dispatchers (EMDs) recognize stroke in less than half of 9-1-1 calls, potentially due to the words used by callers to communicate stroke signs and symptoms. We hypothesized that callers do not typically use words and phrases considered to be classical descriptors of stroke, such as focal neurologic deficits, but that a mixed-methods approach can identify words and phrases commonly used by 9-1-1 callers to describe acute stroke victims. We performed a mixed-method, retrospective study of 9-1-1 call audio recordings for adult patients with confirmed stroke who were transported by ambulance in a large urban city. Content analysis, a qualitative methodology, and computational linguistics, a quantitative methodology, were used to identify key words and phrases used by 9-1-1 callers to describe acute stroke victims. Because a caller's level of emotional distress contributes to the communication during a 9-1-1 call, the Emotional Content and Cooperation Score was scored by a multidisciplinary team. A total of 110 9-1-1 calls, received between June and September 2013, were analyzed. EMDs recognized stroke in 48% of calls, and the emotional state of most callers (95%) was calm. In 77% of calls in which EMDs recognized stroke, callers specifically used the word "stroke"; however, the word "stroke" was used in only 38% of calls. Vague, non-specific words and phrases were used to describe stroke victims' symptoms in 55% of calls, and 45% of callers used distractor words and phrases suggestive of non-stroke emergencies. Focal neurologic symptoms were described in 39% of calls. Computational linguistics identified 9 key words that were more commonly used in calls where the EMD identified stroke. These words were concordant with terms identified through qualitative content analysis. Most 9-1-1 callers used vague, non-specific, or distractor words and phrases and infrequently provide classic stroke descriptions during 9-1-1 calls for stroke. Both qualitative and quantitative methodologies identified similar key words and phrases associated with accurate EMD stroke recognition. This study suggests that tools incorporating commonly used words and phrases could potentially improve EMD stroke recognition.

Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase

PubMed Central

Moroni, F; Cozzi, A; Chiarugi, A; Formentini, L; Camaioni, E; Pellegrini-Giampietro, DE; Chen, Y; Liang, S; Zaleska, MM; Gonzales, C; Wood, A; Pellicciari, R

2012-01-01

BACKGROUND AND PURPOSES Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2. EXPERIMENTAL APPROACH Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia). KEY RESULTS In male rats with tMCAO, HYDAMTIQ (0.1–10 mg·kg−1) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO. CONCLUSION AND IMPLICATIONS Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits. PMID:21913897

Deficiency in Serine Protease Inhibitor Neuroserpin Exacerbates Ischemic Brain Injury by Increased Postischemic Inflammation

PubMed Central

Ludewig, Peter; Bernreuther, Christian; Krasemann, Susanne; Arunachalam, Priyadharshini; Gerloff, Christian; Glatzel, Markus; Magnus, Tim

2013-01-01

The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns−/−) mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns−/− mice. Our results show excessive microglial activation in Ns−/− mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA. PMID:23658802

CDP-choline liposomes provide significant reduction in infarction over free CDP-choline in stroke

PubMed Central

Adibhatla, Rao Muralikrishna; Hatcher, J.F.; Tureyen, K.

2007-01-01

Cytidine-5′-diphosphocholine (CDP-choline, Citicoline, Somazina) is in clinical use (intravenous administration) for stroke treatment in Europe and Japan, while USA phase III stroke clinical trials (oral administration) were disappointing. Others showed that CDP-choline liposomes significantly increased brain uptake over the free drug in cerebral ischemia models. Liposomes were formulated as DPPC, DPPS, cholesterol, GM1 ganglioside; 7/4/7/1.57 molar ratio or 35.8/20.4/35.8/8.0 mol%. GM1 ganglioside confers long-circulating properties to the liposomes by suppressing phagocytosis. CDP-choline liposomes deliver the agent intact to the brain, circumventing the rate-limiting, cytidine triphosphate:phosphocholine cytidylyltransferase in phosphatidylcholine synthesis. Our data show that CDP-choline liposomes significantly ( P < 0.01) decreased cerebral infarction (by 62%) compared to the equivalent dose of free CDP-choline (by 26%) after 1 h focal cerebral ischemia and 24 h reperfusion in spontaneously hypertensive rats. Beneficial effects of CDP-choline liposomes in stroke may derive from a synergistic effect between the phospholipid components of the liposomes and the encapsulated CDP-choline. PMID:16153613

PSD-93 deletion inhibits Fyn-mediated phosphorylation of NR2B and protects against focal cerebral ischemia.

PubMed

Zhang, Meijuan; Li, Qingjie; Chen, Ling; Li, Jie; Zhang, Xin; Chen, Xiang; Zhang, Qingxiu; Shao, Yuan; Xu, Yun

2014-08-01

Modification of N-methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity appears to be a potential target in the treatment of ischemic stroke. Postsynaptic density protein-93 (PSD-93) specifically binds the C-terminal tails of the NMDAR, which is critical to couple NMDAR activity to specific intracellular signaling. This study is to investigate whether PSD-93 disruption displays neuroprotection in a focal ischemic stroke model of adult mice and, if it does, to explore possible mechanisms. It was found that, following middle cerebral artery occlusion (MCAO), PSD-93 knockout (KO) mice manifested significant reductions in infarcted volume, neurological deficits and number of degenerated neurons. PSD-93 deletion also reduced cultured cortical neuronal death caused by glucose and oxygen deprivation (OGD). Ischemic long term potentiation (i-LTP) could not be induced in the PSD-93 KO group and wild type (WT) groups pretreated with either AP-5 (NMDAR inhibitor) or PP2 (Src family inhibitor). PSD-93 KO decreased the phosphorylation of the NR2B at Tyr1472 and the interaction between NR2B and Fyn after MCAO. Together, our study demonstrated that PSD-93 KO confers profound neuroprotection against ischemic brain injury, which probably links to the inhibitory effect on Fyn-mediated phosphorylation of NR2B caused by PSD-93 deletion. These findings may provide a novel avenue for the treatment of ischemic stroke. Copyright © 2014 Elsevier Inc. All rights reserved.

Neuroprotective effect of cathodal transcranial direct current stimulation in a rat stroke model.

PubMed

Notturno, Francesca; Pace, Marta; Zappasodi, Filippo; Cam, Etrugul; Bassetti, Claudio L; Uncini, Antonino

2014-07-15

Experimental focal brain ischemia generates in the penumbra recurrent depolarizations which spread across the injured cortex inducing infarct growth. Transcranial direct current stimulation can induce a lasting, polarity-specific, modulation of cortical excitability. To verify whether cathodal transcranial direct current stimulation could reduce the infarct size and the number of depolarizations, focal ischemia was induced in the rat by the 3 vessels occlusion technique. In the first experiment 12 ischemic rats received cathodal stimulation (alternating 15 min on and 15 min off) starting 45 min after middle cerebral artery occlusion and lasting 4 h. In the second experiment 12 ischemic rats received cathodal transcranial direct current stimulation with the same protocol but starting soon after middle cerebral artery occlusion and lasting 6 h. In both experiments controls were 12 ischemic rats not receiving stimulation. Cathodal stimulation reduced the infarct volume in the first experiment by 20% (p=0.002) and in the second by 30% (p=0.003). The area of cerebral infarction was smaller in animals receiving cathodal stimulation in both experiments (p=0.005). Cathodal stimulation reduced the number of depolarizations (p=0.023) and infarct volume correlated with the number of depolarizations (p=0.048). Our findings indicate that cathodal transcranial direct current stimulation exert a neuroprotective effect in the acute phase of stroke possibly decreasing the number of spreading depolarizations. These findings may have translational relevance and open a new avenue in neuroprotection of stroke in humans. Copyright © 2014. Published by Elsevier B.V.

Plasminogen Activators and Ischemic Stroke: Conditions for Acute Delivery

PubMed Central

del Zoppo, Gregory J

2013-01-01

Appropriate acute treatment with plasminogen activators (PAs) can significantly increase the probability of minimal or no disability in selected ischemic stroke patients. There is a great deal of evidence showing that intravenous recombinant tissue PAs (rt-PA) infusion accomplishes this goal, recanalization with other PAs has also been demonstrated in the development of this treatment. Recanalization of symptomatic, documented carotid or vertebrobasilar arterial territory occlusions have also been achieved by local intra-arterial PA delivery, although only a single prospective double-blinded randomized placebo-controlled study has been reported. The increase in intracerebral hemorrhage with these agents by either delivery approach underscores the need for careful patient selection, dose-appropriate safety and efficacy, proper clinical trial design, and an understanding of the evolution of cerebral tissue injury due to focal ischemia. Principles underlying the evolution of focal ischemia have been expanded by experience with acute PA intervention. Several questions remain open that concern the manner in which PAs can be applied acutely in ischemic stroke and how injury development can be limited. PMID:23539414

Neuroinflammation in Ischemic Pediatric Stroke.

PubMed

Steinlin, Maja

2017-08-01

Over the last decades, the importance of inflammatory processes in pediatric stroke have become increasingly evident. Ischemia launches a cascade of events: activation and inhibition of inflammation by a large network of cytokines, adhesion and small molecules, protease, and chemokines. There are major differences in the neonatal brain compared to adult brain, but developmental trajectories of the process during childhood are not yet well known. In neonatal stroke ischemia is the leading pathophysiology, but infectious and inflammatory processes have a significant input into the course and degree of tissue damage. In childhood, beside inflammation lanced by ischemia itself, the event of ischemia might be provoked by an underlying inflammatory pathophysiology: transient focal arteriopathy, dissection, sickle cell anemia, Moyamoya and more generalized in meningitides, generalized vasculitis or genetic arteriopathies (as in ADA2). Focal inflammatory reactions tend to be located in the distal part of the carotid artery or the proximal medial arteries, but generalized processes rather tend to affect the small arteries. Copyright © 2017. Published by Elsevier Inc.

Optical microangiography reveals collateral blood perfusion dynamics in mouse cerebral cortex after focal stroke

NASA Astrophysics Data System (ADS)

Baran, Utku; Li, Yuandong; Wang, Ruikang K.

2015-03-01

Arteriolo-arteriolar anastomosis's role in regulating blood perfusion through penetrating arterioles during stroke is yet to be discovered. We apply ultra-high sensitive optical microangiography (UHS-OMAG) and Doppler optical microangiography (DOMAG) techniques to evaluate vessel diameter and red blood cell velocity changes in large number of pial and penetrating arterioles in relation with arteriolo-arteriolar anastomosis (AAA) during and after focal stroke. Thanks to the high sensitivity of UHS-OMAG, we were able to image pial microvasculature up to capillary level through a cranial window (9 mm2), and DOMAG provided clear image of penetrating arterioles up to 500μm depth. Results showed that penetrating arterioles close to a strong AAA connection dilate whereas penetrating arterioles constrict significantly in weaker AAA regions. These results suggest that AAA plays a major role in active regulation of the pial arterioles, and weaker AAA connections lead to poor blood perfusion to penumbra through penetrating arterioles.

Depletion of CD11c+ Cells Does Not Influence Outcomes in Mice Subjected to Transient Middle Cerebral Artery Occlusion.

PubMed

Kraft, Peter; Scholtyschik, Karolina; Schuhmann, Michael K; Kleinschnitz, Christoph

2017-01-01

While it has been shown that different T-cell subsets have a detrimental role in the acute phase of ischemic stroke, data on the impact of dendritic cells (DC) are missing. Classic DC can be characterized by the cluster of differentiation (CD)11c surface antigen. In this study, we depleted CD11c+ cells by using a CD11c-diphtheria toxin (DTX) receptor mouse strain that allows selective depletion of CD11c+ cells by DTX injection. For stroke induction, we used the model of transient middle cerebral artery occlusion (tMCAO) and analyzed stroke volume and functional outcome on days 1 and 3 as well as expression of prototypical pro- and anti-inflammatory cytokines on day 1 after tMCAO. Three different protocols for CD11c+ cell depletion, tMCAO duration, and readout time point were applied. Injection of DTX (5 or 100 ng/g) reliably depleted CD11c+ cells without influencing the fractions of other immune cell subsets. CD11c+ cell depletion had no impact on stroke volume, but mice with a longer DTX pretreatment performed worse than those with vehicle treatment. CD11c+ cell depletion led to a decrease in cortical interleukin (IL)-1β and IL-6 messenger ribonucleic acid levels. We show, for the first time, that CD11c+ cell depletion does not influence stroke volume in a mouse model of focal cerebral ischemia. Nevertheless, given the unspecificity of the CD11c surface antigen for DC, mouse models that allow a more selective depletion of DC are needed to investigate the role of DC in stroke pathophysiology. © 2017 S. Karger AG, Basel.

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice

PubMed Central

Sozmen, Elif G.; Rosenzweig, Shira; Llorente, Irene L.; DiTullio, David J.; Machnicki, Michal; Vinters, Harry V.; Havton, Lief A.; Giger, Roman J.; Hinman, Jason D.

2016-01-01

White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis. In these areas of only partial damage, local white matter progenitors respond to injury, as oligodendrocyte progenitors (OPCs) proliferate. However, OPCs fail to mature into oligodendrocytes (OLs) even in regions of demyelination with intact axons and instead divert into an astrocytic fate. Local axonal sprouting occurs, producing an increase in unmyelinated fibers in the corpus callosum. The OPC maturation block after white matter stroke is in part mediated via Nogo receptor 1 (NgR1) signaling. In both aged and young adult mice, stroke induces NgR1 ligands and down-regulates NgR1 inhibitors during the peak OPC maturation block. Nogo ligands are also induced adjacent to human white matter stroke in humans. A Nogo signaling blockade with an NgR1 antagonist administered after stroke reduces the OPC astrocytic transformation and improves poststroke oligodendrogenesis in mice. Notably, increased white matter repair in aged mice is translated into significant poststroke motor recovery, even when NgR1 blockade is provided during the chronic time points of injury. These data provide a perspective on the role of NgR1 ligand function in OPC fate in the context of a specific and common type of stroke and show that it is amenable to systemic intervention to promote recovery. PMID:27956620

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice.

PubMed

Sozmen, Elif G; Rosenzweig, Shira; Llorente, Irene L; DiTullio, David J; Machnicki, Michal; Vinters, Harry V; Havton, Lief A; Giger, Roman J; Hinman, Jason D; Carmichael, S Thomas

2016-12-27

White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis. In these areas of only partial damage, local white matter progenitors respond to injury, as oligodendrocyte progenitors (OPCs) proliferate. However, OPCs fail to mature into oligodendrocytes (OLs) even in regions of demyelination with intact axons and instead divert into an astrocytic fate. Local axonal sprouting occurs, producing an increase in unmyelinated fibers in the corpus callosum. The OPC maturation block after white matter stroke is in part mediated via Nogo receptor 1 (NgR1) signaling. In both aged and young adult mice, stroke induces NgR1 ligands and down-regulates NgR1 inhibitors during the peak OPC maturation block. Nogo ligands are also induced adjacent to human white matter stroke in humans. A Nogo signaling blockade with an NgR1 antagonist administered after stroke reduces the OPC astrocytic transformation and improves poststroke oligodendrogenesis in mice. Notably, increased white matter repair in aged mice is translated into significant poststroke motor recovery, even when NgR1 blockade is provided during the chronic time points of injury. These data provide a perspective on the role of NgR1 ligand function in OPC fate in the context of a specific and common type of stroke and show that it is amenable to systemic intervention to promote recovery.

MORIN MITIGATES OXIDATIVE STRESS, APOPTOSIS AND INFLAMMATION IN CEREBRAL ISCHEMIC RATS

PubMed Central

Chen, Yanrong; Li, Yanke; Xu, Huali; Li, Gang; Ma, Yunxia; Pang, Yu Jun

2017-01-01

Background: Morin is a flavanoid which exhibits potent antioxidant activity in various oxidative stress related diseases. The current study was attempted to scrutinize the preclinical bio-efficacy of morin on focal ischemia. Methods: The animal model of focal cerebral ischemic injury was done by midbrain carotid artery occlusion (MCAO) method, followed by Morin (30mg/kg) administration for seven days. Results: The outcome of the study showed that treatment with morin displayed positive effects in reducing the focal cerebral ischemia. This effect was evident with the improvements in neurological deficits, reduction in MDA content and elevation of antioxidant levels (SOD, GSH and Gpx). Furthermore, protein expression of Bax and caspase-3 were effectively down-regulated, whilst the expression of Bcl-2 was significantly elevated. On the other hand, the mRNA expression of proinflammatory cytokines was significantly reduced in focal cerebral ischemic rats upon morin intervention. Conclusion: Thus, the beneficial effects of morin on cerebral ischemia assault may result from the reduction of oxidative stress, inhibition of apoptosis and inflammation. The neuroprotective effects of morin supplement may serve as potent adjuvant in the amelioration of ischemic stroke. PMID:28573251

Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke

PubMed Central

Frankowski, Jan C.; DeMars, Kelly M.; Ahmad, Abdullah S.; Hawkins, Kimberly E.; Yang, Changjun; Leclerc, Jenna L.; Doré, Sylvain; Candelario-Jalil, Eduardo

2015-01-01

Cyclooxygenase-2 (COX-2) is activated in response to ischemia and significantly contributes to the neuroinflammatory process. Accumulation of COX-2-derived prostaglandin E2 (PGE2) parallels the substantial increase in stroke-mediated blood-brain barrier (BBB) breakdown. Disruption of the BBB is a serious consequence of ischemic stroke, and is mainly mediated by matrix metalloproteinases (MMPs). This study aimed to investigate the role of PGE2 EP1 receptor in neurovascular injury in stroke. We hypothesized that pharmacological blockade or genetic deletion of EP1 protects against BBB damage and hemorrhagic transformation by decreasing the levels and activity of MMP-3 and MMP-9. We found that post-ischemic treatment with the EP1 antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation in an experimental model of transient focal cerebral ischemia. These neurovascular protective effects of EP1 inactivation are associated with a significant reduction in MMP-9/-3, less peripheral neutrophil infiltration, and a preservation of tight junction proteins (ZO-1 and occludin) composing the BBB. Our study identifies the EP1 signaling pathway as an important link between neuroinflammation and MMP-mediated BBB breakdown in ischemic stroke. Targeting the EP1 receptor could represent a novel approach to diminish the devastating consequences of stroke-induced neurovascular damage. PMID:26648273

Rose Bengal Photothrombosis by Confocal Optical Imaging In Vivo: A Model of Single Vessel Stroke.

PubMed

Talley Watts, Lora; Zheng, Wei; Garling, R Justin; Frohlich, Victoria C; Lechleiter, James Donald

2015-06-23

In vivo imaging techniques have increased in utilization due to recent advances in imaging dyes and optical technologies, allowing for the ability to image cellular events in an intact animal. Additionally, the ability to induce physiological disease states such as stroke in vivo increases its utility. The technique described herein allows for physiological assessment of cellular responses within the CNS following a stroke and can be adapted for other pathological conditions being studied. The technique presented uses laser excitation of the photosensitive dye Rose Bengal in vivo to induce a focal ischemic event in a single blood vessel. The video protocol demonstrates the preparation of a thin-skulled cranial window over the somatosensory cortex in a mouse for the induction of a Rose Bengal photothrombotic event keeping injury to the underlying dura matter and brain at a minimum. Surgical preparation is initially performed under a dissecting microscope with a custom-made surgical/imaging platform, which is then transferred to a confocal microscope equipped with an inverted objective adaptor. Representative images acquired utilizing this protocol are presented as well as time-lapse sequences of stroke induction. This technique is powerful in that the same area can be imaged repeatedly on subsequent days facilitating longitudinal in vivo studies of pathological processes following stroke.

The dichotomy of memantine treatment for ischemic stroke: dose-dependent protective and detrimental effects

PubMed Central

Trotman, Melissa; Vermehren, Philipp; Gibson, Claire L; Fern, Robert

2015-01-01

Excitotoxicity is a major contributor to cell death during the acute phase of ischemic stroke but aggressive pharmacological targeting of excitotoxicity has failed clinically. Here we investigated whether pretreatment with low doses of memantine, within the range currently used and well tolerated for the treatment of Alzheimer's disease, produce a protective effect in stroke. A coculture preparation exposed to modeled ischemia showed cell death associated with rapid glutamate rises and cytotoxic Ca2+ influx. Cell death was significantly enhanced in the presence of high memantine concentrations. However, low memantine concentrations significantly protected neurons and glia via excitotoxic cascade interruption. Mice were systemically administered a range of memantine doses (0.02, 0.2, 2, 10, and 20 mg/kg/day) starting 24 hours before 60 minutes reversible focal cerebral ischemia and continuing for a 48-hour recovery period. Low dose (0.2 mg/kg/day) memantine treatment significantly reduced lesion volume (by 30% to 50%) and improved behavioral outcomes in stroke lesions that had been separated into either small/striatal or large/striatocortical infarcts. However, higher doses of memantine (20 mg/kg/day) significantly increased injury. These results show that clinically established low doses of memantine should be considered for patients ‘at risk' of stroke, while higher doses are contraindicated. PMID:25407270

The impact of Magnetic Resonance Imaging (MRI) on ischemic stroke detection and incidence: minimal impact within a population-based study.

PubMed

Kleindorfer, Dawn; Khoury, Jane; Alwell, Kathleen; Moomaw, Charles J; Woo, Daniel; Flaherty, Matthew L; Adeoye, Opeolu; Ferioli, Simona; Khatri, Pooja; Kissela, Brett M

2015-09-25

There are several situations in which magnetic resonance imaging (MRI) might impact whether an cerebrovascular event is considered a new stroke. These include clinically non-focal events with positive imaging for acute cerebral infarction, and worsening of older symptoms without evidence of new infarction on MRI. We sought to investigate the impact of MRI on stroke detection and stroke incidence, by describing agreement between a strictly clinical definition of stroke and a definition based on physician opinion, including MRI imaging findings. All hospitalized strokes that occurred in five Ohio and Northern Kentucky counties (population 1.3 million) in the calendar year of 2005 were identified using ICD-9 discharge codes 430-436. The two definitions used were: "clinical case definition" which included sudden onset focal neurologic symptoms referable to a vascular territory for >24 h, compared to the "best clinical judgment of the physician definition", which considers all relevant information, including neuroimaging findings. The 95% confidence intervals (CI) for the incidence rates were calculated assuming a Poisson distribution. Rates were standardized to the 2000 U.S. population, adjusting for age, race, and sex, and included all age groups. There were 2403 ischemic stroke events in 2269 patients; 1556 (64%) had MRI performed. Of the events, 2049 (83%) were cases by both definitions, 185 (7.7%) met the clinical case definition but were non-cases in the physician's opinion and 169 (7.0%) were non-cases by clinical definition but were cases in the physician's opinion. There was no significant difference in the incidence rates of first-ever or total ischemic strokes generated by the two different definitions, or when only those with MRI imaging were included. We found that MRI findings do not appear to substantially change stroke incidence estimates, as the strictly clinical definition of stroke did not significantly differ from a definition that included imaging findings. Including MRI in the case definition "rules out" almost the same number of strokes as it "rules in".

Neuroprotective effect of mesenchymal stem cell through complement component 3 downregulation after transient focal cerebral ischemia in mice.

PubMed

Jung, Hye-Seon; Jeong, Si-Yeon; Yang, Jiwon; Kim, So-Dam; Zhang, Baojin; Yoo, Hyun Seung; Song, Sun U; Jeon, Myung-Shin; Song, Yun Seon

2016-10-28

Bone marrow-derived mesenchymal stem cells (MSCs) are used in stroke treatment despite the poor understanding of its mode of action. The immune suppressive and anti-inflammatory properties of MSCs possibly play important roles in regulating neuroinflammation after stroke. We investigated whether MSCs reduce the inflammatory complement component 3 (C3) levels, thus, providing neuroprotection during stroke. Mice were subjected to transient focal cerebral ischemia (tFCI), after which MSCs were intravenously injected. The infarct volume of the brain was reduced in MSC-injected tFCI mice, and C3 expression was significantly reduced in both the brain and the blood. Additionally, the profiles of other inflammatory mediators demonstrated neuroprotective changes in the MSCs-treated group. In order to analyze the effect of MSCs on neurons during cerebral ischemia, primary cortical neurons were co-cultured with MSCs under oxygen-glucose deprivation (OGD). Primary neurons co-cultured with MSCs exhibited reduced levels of C3 expression and increased protection against OGD, indicating that treatment with MSCs reduces excessive C3 expression and rescues ischemia-induced neuronal damage. Our finding suggests that reduction of C3 expression by MSCs can help to ameliorate ischemic brain damage, offering a new neuroprotective strategy in stroke therapy. Copyright © 2016. Published by Elsevier Ireland Ltd.

2-(2-Benzofuranyl)-2-Imidazoline Mediates Neuroprotection by Regulating the Neurovascular Unit Integrity in a Rat Model of Focal Cerebral Ischemia.

PubMed

Zhang, Zheng; Zhang, Linlei; Chen, Jiaou; Cao, Yungang; Qu, Man; Lin, Xinda; Han, Zhao; Ji, Xunming

2018-06-01

We showed previously that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor (I2R) exerts neuroprotective effects in ischemia stroke via an unknown mechanism. The present study was to investigate whether 2-BFI can protect the neurovascular unit (NVU) using a rat model of 90 min focal cerebral ischemia. Rats were randomly divided into three groups: thesham-operated group; the vehicle control group and the 2-BFI group which received 2-BFI (3 mg/kg) immediately after the start of middle cerebralartery occlusion (MCAO). Neurological deficit score, infarct size, apoptosis level, brain water content and Evans Blue extravasation were assessed at 24 h after stroke. Expressions of occludin and zonula occludens 1 (ZO-1), collagen IV, aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9) and MMP-2 were assessed by Western blotting. 2-BFI treatment was associated with significant improvement of neurological performance and decreased infarct volume at 24 h after stroke. Apoptosis level reduced significantly by 2-BFI compared to the vehicle group (34.3 ± 5.4% vs 56.1 ± 7.9%, p < 0.05). Significant decreased of brain water content (79.5 ± 2.6% vs 84.62 ± 2%, p < 0.05) and Evans Blue extravasation (1.2 ± 0.5 vs 2.5 ± 0.41 µg/g, p < 0.05) of ipsilateral hemisphere was observed in 2-BFI group compared to vehicle group. Expressions of occludin, ZO-1 and collagen IV were significantly higher while MMP-9 level significantly lower in 2-BFI group. AQP-4 and MMP-2 showed no difference between 2-BFI and the vehicle groups. These results suggest that the neuroprotective effects of 2-BFI in acute ischemic brain damage are at least partly due to the drug's ability to improve the functions of NVU. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Intraluminal Middle Cerebral Artery Occlusion (MCAO) Model for Ischemic Stroke with Laser Doppler Flowmetry Guidance in Mice

PubMed Central

McConnell, Douglas J.; Afzal, Aqeela; Mocco, J

2011-01-01

Stroke is the third leading cause of death and the leading cause of disability in the world, with an estimated cost of near $70 billion in the United States in 20091,2. The intraluminal middle cerebral artery occlusion (MCAO) model was developed by Koizumi4 in 1986 to simulate this impactful human pathology in the rat. A modification of the MCAO method was later presented by Longa3. Both techniques have been widely used to identify molecular mechanisms of brain injury resulting from ischemic stroke and potential therapeutic modalities5. This relatively noninvasive method in rats has been extended to use in mice to take advantage of transgenic and knockout strains6,7. To model focal cerebral ischemia, an intraluminal suture is advanced via the internal carotid artery to occlude the base of the MCA. Retracting the suture after a specified period of time mimics spontaneous reperfusion, but the suture can also be permanently retained. This video will be demonstrating the two major approaches for performing intraluminal MCAO procedure in mice in a stepwise fashion, as well as providing insights for potential drawbacks and pitfalls. The ischemic brain tissue will subsequently be stained by 2,3,5-triphenyltetrazolium chloride (TTC) to evaluate the extent of cerebral infarction8. PMID:21587164

Caffeinol at the receptor level; Anti-ischemic effect of NMDA receptor blockade is potentiated by caffeine

PubMed Central

Zhao, Xiurong; Strong, Roger; Piriyawat, Paisith; Palusinski, Robert; Grotta, James C.; Aronowski, Jaroslaw

2010-01-01

Background and Purpose Although caffeinol (combination of low dose of caffeine and ethanol) was shown to robustly reduce stroke damage in experimental models and is now in clinical evaluation for treatment of ischemic stroke, little is known about the potential mechanism of its action. Methods We have used an in vivo excitotoxicity model based on intracortical infusion of NMDA and model of reversible focal ischemia to demonstrate NMDA receptor inhibition as one potential mechanism of Caffeinol anti-ischemic activity. Results Caffeinol reduced the size of excitotoxic lesion and substitution of ethanol in Caffeinol with CNS-1102 and MK-801, but not with MgSO4, produced treatment with strong synergistic effect that was at least as robust in reducing ischemic damage as Caffeinol. This NMDA receptor antagonist and caffeine combination showed long window of opportunity, activity in spontaneously hypertensive rats, and unlike Caffeinol was fully effective in animals chronically pre-treated with ethanol. Conclusions Our study suggests that anti-excitotoxic properties may underlie some of the anti-ischemic effect of Caffeinol. This study provides strong evidence that the anti-ischemic effect of NMDA receptor blockers in general can be dramatically augmented by caffeine, thus opening a possibility for new utilization of NMDA-based pharmacology in the treatment of stroke. PMID:20044532

Biochemical and inflammatory biomarkers in ischemic stroke: translational study between humans and two experimental rat models

PubMed Central

2014-01-01

Background our objective was to examine the plasma levels of three biological markers involved in cerebral ischemia (IL-6, glutamate and TNF-alpha) in stroke patients and compare them with two different rat models of focal ischemia (embolic stroke model- ES and permanent middle cerebral artery occlusion ligation model-pMCAO) to evaluate which model is most similar to humans. Secondary objectives: 1) to analyze the relationship of these biological markers with the severity, volume and outcome of the brain infarction in humans and the two stroke models; and 2) to study whether the three biomarkers are also increased in response to damage in organs other than the central nervous system, both in humans and in rats. Methods Multi-center, prospective, case-control study including acute stroke patients (n = 58) and controls (n = 19) with acute non-neurological diseases Main variables: plasma biomarker levels on admission and at 72 h; stroke severity (NIHSS scale) and clinical severity (APACHE II scale); stroke volume; functional status at 3 months (modified Rankin Scale [mRS] and Barthel index [BI]). Experimental groups: ES (n = 10), pMCAO (n = 6) and controls (tissue stress by leg compression) (n = 6). Main variables: plasma biomarker levels at 3 and 72 h; volume of ischemic lesion (H&E) and cell death (TUNEL). Results in stroke patients, IL-6 correlated significantly with clinical severity (APACHE II scale), stroke severity (NIHSS scale), infarct volume (cm3) and clinical outcome (mRS) (r = 0.326, 0.497, 0.290 and 0.444 respectively; P < 0.05). Glutamate correlated with stroke severity, but not with outcome, and TNF-alpha levels with infarct volume. In animals, The ES model showed larger infarct volumes (median 58.6% vs. 29%, P < 0.001) and higher inflammatory biomarkers levels than pMCAO, except for serum glutamate levels which were higher in pMCAO. The ES showed correlations between the biomarkers and cell death (r = 0.928 for IL-6; P < 0.001; r = 0.765 for TNF-alpha, P < 0.1; r = 0.783 for Glutamate, P < 0.1) and infarct volume (r = 0.943 for IL-6, P < 0.0001) more similar to humans than pMCAO. IL-6, glutamate and TNF-α levels were not higher in cerebral ischemia than in controls. Conclusions Both models, ES and pMCAO, show differences that should be considered when conducting translational studies. IL-6, Glutamate and TNF-α are not specific for cerebral ischemia either in humans or in rats. PMID:25086655

Improving neurovascular outcomes with bilateral forepaw stimulation in a rat photothrombotic ischemic stroke model

PubMed Central

Liao, Lun-De; Bandla, Aishwarya; Ling, Ji Min; Liu, Yu-Hang; Kuo, Li-Wei; Chen, You-Yin; King, Nicolas KK; Lai, Hsin-Yi; Lin, Yan-Ren; Thakor, Nitish V.

2014-01-01

Abstract. Restoring perfusion to the penumbra during the hyperacute phase of ischemic stroke is a key goal of neuroprotection. Thrombolysis is currently the only approved treatment for ischemic stroke. However, its use is limited by the narrow therapeutic window and side effect of bleeding. Therefore, other interventions are desired that could potentially increase the perfusion of the penumbra. Here, we hypothesized that bilateral peripheral electrical stimulation will improve cerebral perfusion and restore cortical neurovascular response. We assess the outcomes of bilateral forepaw electrical stimulation at intensities of 2 and 4 mA, administered either unilaterally or bilaterally. We developed a combined electrocorticogram (ECoG)-functional photoacoustic microscopy (fPAM) system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to acute, focal stroke. The fPAM system is used for cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) and the ECoG for neural activity, namely somatosensory-evoked potential (SSEP), interhemispheric coherence, and alpha-delta ratio (ADR) in response to forepaw stimulation. Our results confirmed the neuroprotective effect of bilateral forepaw stimulation at 2 mA as indicated by the 82% recovery of ADR and 95% improvement in perfusion into the region of penumbra. This experimental model can be used to study other potential interventions such as therapeutic hypertension and hypercarbia. PMID:26157965

High-density lipoprotein-based therapy reduces the hemorrhagic complications associated with tissue plasminogen activator treatment in experimental stroke.

PubMed

Lapergue, Bertrand; Dang, Bao Quoc; Desilles, Jean-Philippe; Ortiz-Munoz, Guadalupe; Delbosc, Sandrine; Loyau, Stéphane; Louedec, Liliane; Couraud, Pierre-Olivier; Mazighi, Mikael; Michel, Jean-Baptiste; Meilhac, Olivier; Amarenco, Pierre

2013-03-01

We have previously reported that intravenous injection of high-density lipoproteins (HDLs) was neuroprotective in an embolic stroke model. We hypothesized that HDL vasculoprotective actions on the blood-brain barrier (BBB) may decrease hemorrhagic transformation-associated with tissue plasminogen activator (tPA) administration in acute stroke. We used tPA alone or in combination with HDLs in vivo in 2 models of focal middle cerebral artery occlusion (MCAO) (embolic and 4-hour monofilament MCAO) and in vitro in a model of BBB. Sprague-Dawley rats were submitted to MCAO, n=12 per group. The rats were then randomly injected with tPA (10 mg/kg) or saline with or without human plasma purified-HDL (10 mg/kg). The therapeutic effects of HDL and BBB integrity were assessed blindly 24 hours later. The integrity of the BBB was also tested using an in vitro model of human cerebral endothelial cells under oxygen-glucose deprivation. tPA-treated groups had significantly higher mortality and rate of hemorrhagic transformation at 24 hours in both MCAO models. Cotreatment with HDL significantly reduced stroke-induced mortality versus tPA alone (by 42% in filament MCAO, P=0.009; by 73% in embolic MCAO, P=0.05) and tPA-induced intracerebral parenchymal hematoma (by 92% in filament MCAO, by 100% in embolic MCAO; P<0.0001). This was consistent with an improved BBB integrity. In vitro, HDLs decreased oxygen-glucose deprivation-induced BBB permeability (P<0.05) and vascular endothelial cadherin disorganization. HDL injection decreased tPA-induced hemorrhagic transformation in rat models of MCAO. Both in vivo and in vitro results support the vasculoprotective action of HDLs on BBB under ischemic conditions.

Vector-Free and Transgene-Free Human iPS Cells Differentiate into Functional Neurons and Enhance Functional Recovery after Ischemic Stroke in Mice

PubMed Central

Mohamad, Osama; Faulkner, Ben; Chen, Dongdong; Yu, Shan Ping; Wei, Ling

2013-01-01

Stroke is a leading cause of human death and disability in the adult population in the United States and around the world. While stroke treatment is limited, stem cell transplantation has emerged as a promising regenerative therapy to replace or repair damaged tissues and enhance functional recovery after stroke. Recently, the creation of induced pluripotent stem (iPS) cells through reprogramming of somatic cells has revolutionized cell therapy by providing an unlimited source of autologous cells for transplantation. In addition, the creation of vector-free and transgene-free human iPS (hiPS) cells provides a new generation of stem cells with a reduced risk of tumor formation that was associated with the random integration of viral vectors seen with previous techniques. However, the potential use of these cells in the treatment of ischemic stroke has not been explored. In the present investigation, we examined the neuronal differentiation of vector-free and transgene-free hiPS cells and the transplantation of hiPS cell-derived neural progenitor cells (hiPS-NPCs) in an ischemic stroke model in mice. Vector-free hiPS cells were maintained in feeder-free and serum-free conditions and differentiated into functional neurons in vitro using a newly developed differentiation protocol. Twenty eight days after transplantation in stroke mice, hiPS-NPCs showed mature neuronal markers in vivo. No tumor formation was seen up to 12 months after transplantation. Transplantation of hiPS-NPCs restored neurovascular coupling, increased trophic support and promoted behavioral recovery after stroke. These data suggest that using vector-free and transgene-free hiPS cells in stem cell therapy are safe and efficacious in enhancing recovery after focal ischemic stroke in mice. PMID:23717557

Retinal microvascular changes and subsequent vascular events after ischemic stroke.

PubMed

De Silva, D A; Manzano, J J F; Liu, E Y; Woon, F-P; Wong, W-X; Chang, H-M; Chen, C; Lindley, R I; Wang, J J; Mitchell, P; Wong, T-Y; Wong, M-C

2011-08-30

Retinal microvasculature changes are associated with vascular events including stroke in healthy populations. It is not known whether retinal microvascular changes predict recurrent vascular events after ischemic stroke. We examined the relationship between retinal microvascular signs and subsequent vascular events in a prospective cohort of 652 acute ischemic stroke patients admitted to a tertiary hospital in Singapore from 2005 to 2007. Retinal photographs taken within 1 week of stroke onset were assessed in a masked manner for quantitative and qualitative measures. Follow-up data over 2-4 years were obtained by standardized telephone interview and then were verified from medical records. Predictors of recurrent vascular events (cerebrovascular, coronary, vascular death, and composite vascular events) were determined using Cox regression models. Follow-up data over a median of 29 months were obtained for 89% (652 patients) of the cohort. After adjustment for covariates including traditional risk factors and index stroke etiology, patients with severe arteriovenous nicking (AVN) were more likely to have a recurrent cerebrovascular event (hazard ratio [HR] 2.28, 95% confidence interval [CI] 1.20-4.33) compared with those without AVN. Patients with severe focal arteriolar narrowing (FAN) were more likely to have a recurrent cerebrovascular event (HR 2.75, 95% CI 1.14-6.63) or subsequent composite vascular event (HR 2.77, 95% CI 1.31-5.86) compared to those without FAN. Retinal microvascular changes predicted subsequent vascular events after ischemic stroke, independent of traditional risk factors and stroke subtype. Thus, retinal imaging has a potential role in predicting the risk of recurrent vascular events after ischemic stroke and in understanding novel vascular risk factors.

Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.

PubMed

Chen, Zheng-Zhen; Yang, Dan-Dan; Zhao, Zhan; Yan, Hui; Ji, Juan; Sun, Xiu-Lan

2016-04-01

Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine. We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions. Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine. These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Non-invasive detection of matrix-metalloproteinase activity in a mouse model of cerebral ischemia using multispectral optoacoustic tomography

NASA Astrophysics Data System (ADS)

Ni, Ruiqing; Vaas, Markus; Ren, Wuwei; Klohs, Jan

2018-02-01

Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of cerebral ischemia. Here we visualized in vivo MMP activity in the transient middle cerebral artery occlusion (tMCAO) mouse model using multispectral optoacoustic imaging (MSOT) with a MMP-activatable probe. MSOT data was co-registered with structural magnetic resonance imaging (MRI) obtained at 7 T for localization of signal distribution. We demonstrated upregulated MMP signal within the focal ischemic lesion in the tMCAO mouse model using MSOT/MRI multimodal imaging. This convenient non-invasive method will allow repetitive measurement following the time course of MMP-lesion development in ischemic stroke animal model.

[Primary emergencies: management of acute ischemic stroke].

PubMed

Leys, Didier; Goldstein, Patrick

2012-01-01

The emergency diagnostic strategy for acute ischemic stroke consists of:--identification of stroke, based on clinical examination (sudden onset of a focal neurological deficit);--identification of the ischemic or hemorrhagic nature by MRI or CT;--determination of the early time-course (clinical examination) and the cause. In all strokes (ischemic or hemorrhagic), treatment consists of:--the same general management (treatment of a life-threatening emergency, ensuring normal biological parameters except for blood pressure, and prevention of complications);--decompressive surgery in the rare cases of intracranial hypertension. For proven ischemic stroke, other therapies consist of: rt-PA for patients admitted with 4.5 hours of stroke onset who have no contraindications, and aspirin (160 to 300 mg) for patients who are not eligible for rt-PA. These treatments should be administered within a few hours. A centralized emergency call system (phone number 15 in France) is the most effective way of achieving this objective.

Effects of the combined treatment of bone marrow stromal cells with mild exercise and thyroid hormone on brain damage and apoptosis in a mouse focal cerebral ischemia model.

PubMed

Akhoundzadeh, Kobar; Vakili, Abedin; Sameni, Hamid Reza; Vafaei, Abbas Ali; Rashidy-Pour, Ali; Safari, Manouchehr; Mohammadkhani, Razieh

2017-08-01

This study examined whether post-stroke bone marrow stromal cells (BMSCs) therapy combined with exercise (EX) and/or thyroid hormone (TH) could reduce brain damage in an experimental ischemic stroke in mice. Focal cerebral ischemia was induced under Laser Doppler Flowmetry (LDF) guide by 45 min of middle cerebral artery occlusion (MCAO), followed by 7 days of reperfusion in albino mice. BMSCs were injected into the right cerebral ventricle 24 h after MCAO, followed by daily injection of T3 (20 μg/100 g weight S.C) and 6 days of running on a treadmill. Infarct size, neurobehavioral test, TUNEL and BrdU positive cells were evaluated at 7 days after MCAO. Treatment with BMSCs and mild EX alone significantly reduced the infarct volume by 23% and 44%, respectively (both, p < 0.001). The BMSCs + TH, BMSCs + EX, and BMSCs + EX + TH combination therapies significantly reduced the infarct volume by 26%, 51%, and 70%, respectively (all, p < 0.001). A significant improvement in the neurobehavioral functioning was observed in the EX, BMSCs + EX, and BMSCs + EX+ TH groups (p < 0.001). The number of TUNEL-positive cells (a marker of apoptosis) was significantly reduced in the EX, BMSCs, BMSCs + EX, BMSCs + TH, and BMSCs + EX + TH groups (all, p < 0.001). Moreover, the combination therapy considerably increased BrdU-labeled cells in the subventricular zone (SVZ) (p < 0.01). Our findings indicated that the combined treatment of BMSCs with mild EX and TH more efficiently reduces the cerebral infarct size after stroke. More likely, these effects mediate via enchaining generation of new neuronal cells and the attenuation of apoptosis in ischemia stroke in young mice.

(-)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury.

PubMed

Chang, Cheng-Fu; Lai, Jing-Huei; Wu, John Chung-Che; Greig, Nigel H; Becker, Robert E; Luo, Yu; Chen, Yen-Hua; Kang, Shuo-Jhen; Chiang, Yung-Hsiao; Chen, Kai-Yun

2017-12-15

Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury. Published by Elsevier B.V.

Metformin Preconditioning of Human induced Pluripotent Stem Cell-derived Neural Stem Cells Promotes Their Engraftment and Improves Post-Stroke Regeneration and Recovery.

PubMed

Ould-Brahim, Fares; Sarma, Sailendra Nath; Syal, Charvi; Lu, Kevin Jiaqi; Seegobin, Matthew; Carter, Anthony; Jeffers, Matthew S; Doré, Carole; Stanford, William; Corbett, Dale; Wang, Jing

2018-06-12

While transplantation of hiPSC-derived neural stem cells (hiPSC-NSCs) shows therapeutic potential in animal stroke models, major concerns for translating hiPSC therapy to the clinic are efficacy and safety. Therefore, there is a demand to develop an optimal strategy to enhance the engraftment and regenerative capacity of transplanted hiPSC-NSCs in order to produce fully differentiated neural cells to replace lost brain tissues. Metformin, an FDA approved drug, is an optimal neuroregenerative agent that not only promotes NSC proliferation but also drives NSC towards differentiation. In this regard, we hypothesize that preconditioning of hiPSC-NSCs with metformin before transplantation into the stroke-damaged brain will improve engraftment and regenerative capabilities of hiPSC-NSCs, ultimately enhancing functional recovery. Here we show that pretreatment of hiPSC-NSCs with metformin enhances the proliferation and differentiation of hiPSC-NSCs in culture. Furthermore, metformin-preconditioned hiPSC-NSCs show increased engraftment 1-week post-transplant in a rat endothelin-1 focal ischemic stroke model. In addition, metformin preconditioned cell grafts exhibit increased survival compared to naïve cell grafts at 7-week post-transplant. Analysis of the grafts demonstrates that metformin preconditioning enhances the differentiation of hiPSC-NSCs. As an outcome, rats receiving metformin preconditioned cells display accelerated gross motor recovery and reduced infarct volume. These studies represent a vital step forward in the optimization of hiPSC-NSC based transplantation to promote post-stroke recovery.

Enhanced Motor Recovery After Stroke With Combined Cortical Stimulation and Rehabilitative Training Is Dependent on Infarct Location.

PubMed

Boychuk, Jeffery A; Schwerin, Susan C; Thomas, Nagheme; Roger, Alexandra; Silvera, Geoffrey; Liverpool, Misha; Adkins, DeAnna L; Kleim, Jeffrey A

2016-02-01

Cortical electrical stimulation of the motor cortex in combination with rehabilitative training (CS/RT) has been shown to enhance motor recovery in animal models of focal cortical stroke, yet in clinical trials, the effects are much less robust. The variability of stroke location in human patient populations that include both cortical and subcortical brain regions may contribute to the failure to find consistent effects clinically. This study sought to determine whether infarct location influences the enhanced motor recovery previously observed in response to CS/RT. The efficacy of CS/RT to promote improvements in motor function was examined in 2 different rat models of stroke that varied the amount and location of cortical and subcortical damage. Ischemic infarctions were induced by injecting the vasoconstricting peptide endothelin-1 either (1) onto the middle cerebral artery (MCA) producing damage to the frontal cortex and lateral striatum or (2) into a subcortical region producing damage to the posterior thalamus and internal capsule (subcortical capsular ischemic injury [SCII]). Daily CS/RT or RT alone was then given for 20 days, during which time performance on a skilled reaching task was assessed. Animals with MCA occlusion infarctions exhibited enhanced improvements on a skilled reaching task in response to CS/RT relative to RT alone. No such enhancement was observed in animals with SCII infarctions across the 20 days of treatment. The efficacy of CS for enhancing motor recovery after stroke may depend in part on the extent and location of the ischemic infarct. © The Author(s) 2015.

Electroacupuncture ameliorates cognitive impairment through inhibition of NF-κB-mediated neuronal cell apoptosis in cerebral ischemia-reperfusion injured rats.

PubMed

Feng, Xiaodong; Yang, Shanli; Liu, Jiao; Huang, Jia; Peng, Jun; Lin, Jiumao; Tao, Jing; Chen, Lidian

2013-05-01

Cognitive impairment is a serious mental deficit following stroke that severely affects the quality of life of stroke survivors. Nuclear factor‑κB (NF-κB)-mediated neuronal cell apoptosis is involved in the development of post-stroke cognitive impairment; therefore, it has become a promising target for the treatment of impaired cognition. Acupuncture at the Baihui (DU20) and Shenting (DU24) acupoints is commonly used in China to clinically treat post‑stroke cognitive impairment; however, the precise mechanism of its action is largely unknown. In the present study, we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and investigated the underlying molecular mechanisms using a rat model of focal cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture at Baihui and Shenting was identified to significantly ameliorate neurological deficits and reduce cerebral infarct volume. Additionally, electroacupuncture improved learning and memory ability in cerebral I/R injured rats, demonstrating its therapeutic efficacy against post-stroke cognitive impairment. Furthermore, electroacupuncture significantly suppressed the I/R-induced activation of NF-κB signaling in ischemic cerebral tissues. The inhibitory effect of electroacupuncture on NF-κB activation led to the inhibition of cerebral cell apoptosis. Finally, electroacupuncture markedly downregulated the expression of pro-apoptotic Bax and Fas, two critical downstream target genes of the NF-κB pathway. Collectively, our findings suggest that inhibition of NF-κB‑mediated neuronal cell apoptosis may be one mechanism via which electroacupuncture at Baihui and Shenting exerts a therapeutic effect on post-stroke cognitive impairment.

Photothrombosis-Induced Infarction of the Mouse Cerebral Cortex Is Not Affected by the Nrf2-Activator Sulforaphane

PubMed Central

Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

2012-01-01

Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage. PMID:22911746

Photothrombosis-induced infarction of the mouse cerebral cortex is not affected by the Nrf2-activator sulforaphane.

PubMed

Porritt, Michelle J; Andersson, Helene C; Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

2012-01-01

Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage.

A free radical scavenger edaravone suppresses systemic inflammatory responses in a rat transient focal ischemia model

PubMed Central

Fujiwara, Norio; Som, Angel T.; Pham, Loc-Duyen D.; Lee, Brian J.; Mandeville, Emiri T.; Lo, Eng H.; Arai, Ken

2017-01-01

A free radical scavenger edaravone is clinically used in Japan for acute stroke, and several basic researches have carefully examined the mechanisms of edaravone's protective effects. However, its actions on pro-inflammatory responses under stroke are still understudied. In this study, we subjected adult male Sprague-Dawley rats to 90-min middle cerebral artery (MCA) occlusion followed by reperfusion. Edaravone was treated twice via tail vein; after MCA occlusion and after reperfusion. As expected, edaravone-treated group showed less infarct volume and edema formation compared with control group at 24-hour after ischemic onset. Furthermore, edaravone reduced the levels of plasma interleukin (IL)-1β and matrix metalloproteinase-9 at 3-hour after ischemic onset. Several molecules besides IL-1β and MMP-9 are involved in inflammatory responses under stroke conditions. Therefore, we also examined whether edaravone treatment could decrease a wide range of pro-inflammatory cytokines/chemokines by testing rat plasma samples with a rat cytokine array. MCAO rats showed elevations in plasma levels of CINC-1, Fractalkine, IL-1α, IL-1ra, IL-6, IL-10, IP-10, MIG, MIP-1α, and MIP-3α, and all these increases were reduced by edaravone treatment. These data suggest that free radical scavengers may reduce systemic inflammatory responses under acute stroke conditions, and therefore, oxidative stress can be still a viable target for acute stroke therapy. PMID:27589890

Spatial and temporal MRI profile of ischemic tissue after the acute stages of a permanent mouse model of stroke.

PubMed

Bogaert-Buchmann, A; Poittevin, M; Po, C; Dupont, D; Sebrié, C; Tomita, Y; Trandinh, A; Seylaz, J; Pinard, E; Méric, P; Kubis, N; Gillet, B

2013-01-01

To characterize the progression of injured tissue resulting from a permanent focal cerebral ischemia after the acute phase, Magnetic Resonance Imaging (MRI) monitoring was performed on adult male C57BL/6J mice in the subacute stages, and correlated to histological analyses. Lesions were induced by electrocoagulation of the middle cerebral artery. Serial MRI measurements and weighted-images (T2, T1, T2* and Diffusion Tensor Imaging) were performed on a 9.4T scanner. Histological data (Cresyl-Violet staining and laminin-, Iba1- and GFAP-immunostainings) were obtained 1 and 2 weeks after the stroke. Two days after stroke, tissues assumed to correspond to the infarct core, were detected as a hyperintensity signal area in T2-weighted images. One week later, low-intensity signal areas appeared. Longitudinal MRI study showed that these areas remained present over the following week, and was mainly linked to a drop of the T2 relaxation time value in the corresponding tissues. Correlation with histological data and immuno-histochemistry showed that these areas corresponded to microglial cells. The present data provide, for the first time detailed MRI parameters of microglial cells dynamics, allowing its non-invasive monitoring during the chronic stages of a stroke. This could be particularly interesting in regards to emerging anti-inflammatory stroke therapies.

Spatial and Temporal MRI Profile of Ischemic Tissue after the Acute Stages of a Permanent Mouse Model of Stroke

PubMed Central

Bogaert-Buchmann, A; Poittevin, M; Po, C; Dupont, D; Sebrié, C; Tomita, Y; TranDinh, A; Seylaz, J; Pinard, E; Méric, P; Kubis, N; Gillet, B

2013-01-01

Object: To characterize the progression of injured tissue resulting from a permanent focal cerebral ischemia after the acute phase, Magnetic Resonance Imaging (MRI) monitoring was performed on adult male C57BL/6J mice in the subacute stages, and correlated to histological analyses. Material and methods: Lesions were induced by electrocoagulation of the middle cerebral artery. Serial MRI measurements and weighted-images (T2, T1, T2* and Diffusion Tensor Imaging) were performed on a 9.4T scanner. Histological data (Cresyl-Violet staining and laminin-, Iba1- and GFAP-immunostainings) were obtained 1 and 2 weeks after the stroke. Results: Two days after stroke, tissues assumed to correspond to the infarct core, were detected as a hyperintensity signal area in T2-weighted images. One week later, low-intensity signal areas appeared. Longitudinal MRI study showed that these areas remained present over the following week, and was mainly linked to a drop of the T2 relaxation time value in the corresponding tissues. Correlation with histological data and immuno-histochemistry showed that these areas corresponded to microglial cells. Conclusion: The present data provide, for the first time detailed MRI parameters of microglial cells dynamics, allowing its non-invasive monitoring during the chronic stages of a stroke. This could be particularly interesting in regards to emerging anti-inflammatory stroke therapies. PMID:23459141

Interferon-β Modulates Inflammatory Response in Cerebral Ischemia.

PubMed

Kuo, Ping-Chang; Scofield, Barbara A; Yu, I-Chen; Chang, Fen-Lei; Ganea, Doina; Yen, Jui-Hung

2016-01-08

Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke. We investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. Our results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

The TriAGe+ Score for Vertigo or Dizziness: A Diagnostic Model for Stroke in the Emergency Department.

PubMed

Kuroda, R; Nakada, T; Ojima, T; Serizawa, M; Imai, N; Yagi, N; Tasaki, A; Aoki, M; Oiwa, T; Ogane, T; Mochizuki, K; Kobari, M; Miyajima, H

2017-05-01

Vertigo or dizziness is a common occurrence, but it remains a challenging symptom when encountered in the emergency department (ED). A diagnostic score for stroke with high accuracy is therefore required. A single-center observational study (498 patients) was conducted. The predictor variables were derived from a multivariate logistic regression analysis with Akaike information criterion. The outcome was the occurrence of stroke. We evaluated the utility of a new diagnostic score (TriAGe+) and compared it with the ABCD2 score. The cohorts included 498 patients (147 with stroke [29.4%]). Eight variables were included: triggers, atrial fibrillation, male gender, blood pressure ≥140/90 mm Hg, brainstem or cerebellar dysfunction, focal weakness or speech impairment, dizziness, and no history of vertigo or dizziness or labyrinth or vestibular disease. We derived the TriAGe+ score from these variables. In the cohort, the prevalence of stroke increased significantly using the diagnostic score: 5.9% for a score of 0-4; 9.1% for 5-7; 24.7% for 8-9; and 57.3% for 10-17. At a cutoff value of 10 points, the sensitivity of the score was 77.5%, the specificity was 72.1%, and the positive likelihood ratio was 3.2. When the cutoff was defined as 5 points, the score obtained a high sensitivity (96.6%) with a good negative likelihood ratio (.15). The new score outperformed the ABCD2 score for the occurrence of stroke (C statistic, .818 versus .726; P < .001). The TriAGe+ score can identify the occurrence of stroke in patients with vertigo or dizziness presenting to the ED. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Rapid resolution of diffusion weighted MRI abnormality in a patient with a stuttering stroke

PubMed Central

Peters, Jurriaan M; MacLean, Ainsley V; Young, Geoffrey S

2010-01-01

We report the unusually rapid and spontaneous normalisation of low diffusivity that accompanied resolution of acute neurological deficits in a stroke patient who underwent two magnetic resonance imaging examinations within 24 h of symptom onset. Diffusion weighted imaging obtained within hours of onset of left sided weakness demonstrated a focal right capsular area of low diffusivity that resolved within 24 h, coinciding with resolution of the patient’s symptoms. PMID:22315635

Transplanted Dental Pulp Stem Cells Migrate to Injured Area and Express Neural Markers in a Rat Model of Cerebral Ischemia.

PubMed

Zhang, Xuemei; Zhou, Yinglian; Li, Hulun; Wang, Rui; Yang, Dan; Li, Bing; Cao, Xiaofang; Fu, Jin

2018-01-01

Ischemic stroke is a major cause of disability and mortality worldwide, while effective restorative treatments are limited at present. Stem cell transplantation holds therapeutic potential for ischemic vascular diseases and may provide an opportunity for neural regeneration. Dental pulp stem cells (DPSCs) origin from neural crest and have neuro-ectodermal features including proliferation and multilineage differentiation potentials. The rat model of middle cerebral artery occlusion (MCAO) was used to evaluate whether intravenous administration of DPSCs can reduce infarct size and to estimate the migration and trans-differentiation into neuron-like cells in focal cerebral ischemia models. Brain tissues were collected at 4 weeks following cell transplantation and analyzed with immunofluorescence, immunohistochemistry and real-time polymerase chain reaction (RT-PCR) methods. Intravenously administration of rat-derived DPSCs were found to migrate into the boundary of ischemic areas and expressed neural specific markers, reducing infarct volume and cerebral edema. These results suggest that DPSCs treatment may serve as a potential therapy for clinical stroke patients in the future. © 2018 The Author(s). Published by S. Karger AG, Basel.

Pre-treatment with the synthetic antioxidant T-butyl bisphenol protects cerebral tissues from experimental ischemia reperfusion injury.

PubMed

Duong, Thi Thuy Hong; Chami, Belal; McMahon, Aisling C; Fong, Genevieve M; Dennis, Joanne M; Freedman, Saul B; Witting, Paul K

2014-09-01

Treatments to inhibit or repair neuronal cell damage sustained during focal ischemia/reperfusion injury in stroke are largely unavailable. We demonstrate that dietary supplementation with the antioxidant di-tert-butyl-bisphenol (BP) before injury decreases infarction and vascular complications in experimental stroke in an animal model. We confirm that BP, a synthetic polyphenol with superior radical-scavenging activity than vitamin E, crosses the blood-brain barrier and accumulates in rat brain. Supplementation with BP did not affect blood pressure or endogenous vitamin E levels in plasma or cerebral tissue. Pre-treatment with BP significantly lowered lipid, protein and thiol oxidation and decreased infarct size in animals subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. This neuroprotective action was accompanied by down-regulation of hypoxia inducible factor-1α and glucose transporter-1 mRNA levels, maintenance of neuronal tissue ATP concentration and inhibition of pro-apoptotic factors that together enhanced cerebral tissue viability after injury. That pre-treatment with BP ameliorates oxidative damage and preserves cerebral tissue during focal ischemic insult indicates that oxidative stress plays at least some causal role in promoting tissue damage in experimental stroke. The data strongly suggest that inhibition of oxidative stress through BP scavenging free radicals in vivo contributes significantly to neuroprotection. We demonstrate that pre-treatment with ditert-butyl bisphenol(Di-t-Bu-BP) inhibits lipid, protein, and total thiol oxidation and decreases caspase activation and infarct size in rats subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. These data suggest that inhibition of oxidative stress contributes significantly to neuroprotection. © 2014 International Society for Neurochemistry.

Focal neurological deficits

MedlinePlus

... include: Abnormal blood vessels (vascular malformation) Brain tumor Cerebral palsy Degenerative nerve illness (such as multiple sclerosis) Disorders of a single nerve or nerve group (for example, carpal tunnel syndrome ) Infection of the brain (such as meningitis or encephalitis) Injury Stroke Home ...

Inability to empathize: brain lesions that disrupt sharing and understanding another’s emotions

PubMed Central

2014-01-01

Emotional empathy—the ability to recognize, share in, and make inferences about another person’s emotional state—is critical for all social interactions. The neural mechanisms underlying emotional empathy have been widely studied with functional imaging of healthy participants. However, functional imaging studies reveal correlations between areas of activation and performance of a task, so that they can only reveal areas engaged in a task, rather than areas of the brain that are critical for the task. Lesion studies complement functional imaging, to identify areas necessary for a task. Impairments in emotional empathy have been mostly studied in neurological diseases with fairly diffuse injury, such as traumatic brain injury, autism and dementia. The classic ‘focal lesion’ is stroke. There have been scattered studies of patients with impaired empathy after stroke and other focal injury, but these studies have included small numbers of patients. This review will bring together data from these studies, to complement evidence from functional imaging. Here I review how focal lesions affect emotional empathy. I will show how lesion studies contribute to the understanding of the cognitive and neural mechanisms underlying emotional empathy, and how they contribute to the management of patients with impaired emotional empathy. PMID:24293265

Transient ischemic attack: reviewing the evolution of the definition, diagnosis, risk stratification, and management for the emergency physician.

PubMed

Siket, Matthew S; Edlow, Jonathan A

2012-08-01

A transient ischemic attack (TIA) is an episode of reversible neurologic deficit caused by temporary focal central nervous system hypoperfusion. TIA is a medical emergency. Because patients with TIA in the emergency department (ED) have a high risk for stroke within the next 48 hours, it is imperative for the clinician to recognize this golden opportunity to prevent a disabling stroke. This article reviews our conceptual understanding of TIA, its definition, diagnosis, ways to stratify stroke risk, the acute management and disposition in the ED, and the potential future role of diagnostic biomarkers. Copyright © 2012 Elsevier Inc. All rights reserved.

Acute imaging does not improve ASTRAL score's accuracy despite having a prognostic value.

PubMed

Ntaios, George; Papavasileiou, Vasileios; Faouzi, Mohamed; Vanacker, Peter; Wintermark, Max; Michel, Patrik

2014-10-01

The ASTRAL score was recently shown to reliably predict three-month functional outcome in patients with acute ischemic stroke. The study aims to investigate whether information from multimodal imaging increases ASTRAL score's accuracy. All patients registered in the ASTRAL registry until March 2011 were included. In multivariate logistic-regression analyses, we added covariates derived from parenchymal, vascular, and perfusion imaging to the 6-parameter model of the ASTRAL score. If a specific imaging covariate remained an independent predictor of three-month modified Rankin score>2, the area-under-the-curve (AUC) of this new model was calculated and compared with ASTRAL score's AUC. We also performed similar logistic regression analyses in arbitrarily chosen patient subgroups. When added to the ASTRAL score, the following covariates on admission computed tomography/magnetic resonance imaging-based multimodal imaging were not significant predictors of outcome: any stroke-related acute lesion, any nonstroke-related lesions, chronic/subacute stroke, leukoaraiosis, significant arterial pathology in ischemic territory on computed tomography angiography/magnetic resonance angiography/Doppler, significant intracranial arterial pathology in ischemic territory, and focal hypoperfusion on perfusion-computed tomography. The Alberta Stroke Program Early CT score on plain imaging and any significant extracranial arterial pathology on computed tomography angiography/magnetic resonance angiography/Doppler were independent predictors of outcome (odds ratio: 0·93, 95% CI: 0·87-0·99 and odds ratio: 1·49, 95% CI: 1·08-2·05, respectively) but did not increase ASTRAL score's AUC (0·849 vs. 0·850, and 0·8563 vs. 0·8564, respectively). In exploratory analyses in subgroups of different prognosis, age or stroke severity, no covariate was found to increase ASTRAL score's AUC, either. The addition of information derived from multimodal imaging does not increase ASTRAL score's accuracy to predict functional outcome despite having an independent prognostic value. More selected radiological parameters applied in specific subgroups of stroke patients may add prognostic value of multimodal imaging. © 2014 World Stroke Organization.

Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke

PubMed Central

Gottesman, Rebecca F; Hillis, Argye E

2013-01-01

Stroke remains a primary cause of morbidity throughout the world mainly because of its effect on cognition. Individuals can recover from physical disability resulting from stroke, but might be unable to return to their previous occupations or independent life because of cognitive impairments. Cognitive dysfunction ranges from focal deficits, resulting directly from an area of infarction or from hypoperfusion in adjacent tissue, to more global cognitive dysfunction. Global dysfunction is likely to be related to other underlying subclinical cerebrovascular disease, such as white-matter disease or subclinical infarcts. Study of cognitive dysfunction after stroke is complicated by varying definitions and lack of measurement of cognition before stroke. Additionally, stroke can affect white-matter connectivity, so newer imaging techniques, such as diffusion-tensor imaging and magnetisation transfer imaging, that can be used to assess this subclinical injury are important tools in the assessment of cognitive dysfunction after stroke. As research is increasingly focused on the role of preventable risk factors in the development of dementia, the role of stroke in the development of cognitive impairment and dementia could be another target for prevention. PMID:20723846

Normobaric hyperoxia retards the evolution of ischemic brain tissue toward infarction in a rat model of transient focal cerebral ischemia.

PubMed

Xu, Ji; Zhang, Yuan; Liang, Zhouyuan; Wang, Ting; Li, Weiping; Ren, Lijie; Huang, Shaonong; Liu, Wenlan

2016-01-01

Oxygen therapy has been long considered a logical therapy for ischemic stroke. Our previous studies showed that normobaric hyperoxia (normobaric hyperoxia (NBO), 95% O2 with 5% CO2) treatment during ischemia reduced ischemic neuronal death and cerebromicrovascular injury in animal stroke models. In this study, we studied the effects of NBO on the evolution of ischemic brain tissue to infarction in a rat model of transient focal cerebral ischemia. Male Sprague-Dawley rats were given NBO (95% O2) or normoxia (21% O2) during 90-min filament occlusion of the middle cerebral artery (MCAO), followed by 3 or 22.5 h of reperfusion. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to evaluate the longitudinal evolution of tissue infarction. Results： In normoxic rats, MCA-supplied cortical and striatal tissue was infarcted after 90-min MCAO with 22.5 h of reperfusion. NBO-treated rats showed a 61.4% reduction in infarct size and tissue infarction mainly occurred in the ischemic striatum. When infarction was assessed at an earlier time point, i.e. at 3 h of reperfusion, normoxic rats showed significantly smaller but mature infarction (no TTC staining, white color), with the infarction mainly occurring in the striatum. Unexpectedly, NBO-treated rats only showed immature lesion (partially stained by TTC, light white color) in the ischemic striatum, indicating that NBO treatment also retarded the process of neuronal death in the ischemic core. Of note, NBO-preserved striatal tissue underwent infarction after prolonged reperfusion. Conclusions： Our results demonstrate that NBO treatment given during cerebral ischemia retards the evolution of ischemic brain tissue toward infarction and NBO-preserved cortical tissue survives better than NBO-preserved striatal tissue during the phase of reperfusion.

Ultrasonographic measurements of subclinical carotid atherosclerosis in prediction of ischemic stroke.

PubMed

Mathiesen, E B; Johnsen, S H

2009-01-01

Carotid intima-media thickness (IMT) and plaque measurements are widely used to quantify atherosclerosis and assess the risk of future stroke, and are used as surrogate endpoints for clinical disease. In recent years, it has become clear that carotid IMT and plaque reflect biologically and genetically different aspects of the atherosclerotic process, and are differentially related to risk factors and cardiovascular disease. Plaques are focal manifestations of atherosclerosis while increased IMT represents mainly hypertensive medial hypertrophy. Several prospective studies have showed that IMT and plaque measurements, such as total plaque area and plaque number, are predictive of future stroke. Plaque echogenicity predicts future stroke independent of plaque size. The contribution of IMT and plaque measurements in individual stroke risk prediction in the general population seems to be limited, but may be useful as a tool for individual stratification of high-risk patients.

Multidisciplinary rehabilitation following botulinum toxin and other focal intramuscular treatment for post-stroke spasticity.

PubMed

Demetrios, Marina; Khan, Fary; Turner-Stokes, Lynne; Brand, Caroline; McSweeney, Shane

2013-06-05

Spasticity may affect stroke survivors by contributing to activity limitations, caregiver burden, pain and reduced quality of life (QoL). Spasticity management guidelines recommend multidisciplinary (MD) rehabilitation programmes following botulinum toxin (BoNT) treatment for post-stroke spasticity. However, the evidence base for the effectiveness of MD rehabilitation is unclear. To assess the effectiveness of MD rehabilitation, following BoNT and other focal intramuscular treatments such as phenol, in improving activity limitations and other outcomes in adults and children with post-stroke spasticity. To explore what settings, types and intensities of rehabilitation programmes are effective. We searched the Cochrane Stroke Group Trials Register (February 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 12), MEDLINE (1948 to December 2011), EMBASE (1980 to January 2012), CINAHL (1982 to January 2012), AMED (1985 to January 2012), LILACS (1982 to September 2012), PEDro, REHABDATA and OpenGrey (September 2012). In an effort to identify further published, unpublished and ongoing trials we searched trials registries and reference lists, handsearched journals and contacted authors. We included randomised controlled trials (RCTs) that compared MD rehabilitation (delivered by two or more disciplines in conjunction with medical input) following BoNT and other focal intramuscular treatments for post-stroke spasticity with placebo, routinely available local services, or lower levels of intervention; or studies that compared MD rehabilitation in different settings, of different types, or at different levels of intensity. We excluded RCTs that assessed the effectiveness of unidisciplinary therapy (for example physiotherapy only) or a single modality (for example stretching, casting, electrical stimulation or splinting only). The primary outcomes were validated measures of activity level (active and passive function) according to the World Health Organization's International Classification of Functioning, Disability and Health. Secondary outcomes included measures of symptoms, impairments, participation, QoL, impact on caregivers and adverse events. We independently selected the trials, extracted data, and assessed methodological quality using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Due to the limited number of included studies, with clinical, methodological and statistical heterogeneity, quantitative meta-analysis was not possible. Therefore, GRADE provided qualitative synthesis of 'best evidence'. We included three RCTs involving 91 participants. All three studies scored 'low quality' on the methodological quality assessment, implying high risk of bias. All studies investigated various types and intensities of outpatient rehabilitation programmes following BoNT for upper limb spasticity in adults with chronic stroke. Rehabilitation programmes included: modified constraint-induced movement therapy (mCIMT) compared with a neurodevelopmental therapy programme; task practice therapy with cyclic functional electrical stimulation (FES) compared with task practice therapy only; and occupational, manual therapy with dynamic elbow extension splinting compared with occupational therapy only. There was 'low quality' evidence for mCIMT improving upper limb motor function and spasticity in chronic stroke survivors with residual voluntary upper limb activity, up to six months, and 'very low quality' evidence for dynamic elbow splinting and occupational therapy reducing elbow range of movement at 14 weeks. Task practice therapy with cyclic FES did not improve upper limb function more than task practice therapy alone, only at 12 weeks. No studies addressed interventions in children and those with lower limb spasticity, or after other focal intramuscular treatments for spasticity. At best there was 'low level' evidence for the effectiveness of outpatient MD rehabilitation in improving active function and impairments following BoNT for upper limb spasticity in adults with chronic stroke. No trials explored the effect of MD rehabilitation on 'passive function' (caring for the affected limb), caregiver burden, or the individual's priority goals for treatment. The optimal types (modalities, therapy approaches, settings) and intensities of therapy for improving activity (active and passive function) in adults and children with post-stroke spasticity, in the short and longer term, are unclear. Further research is required to build evidence in this area.

High-mobility group box 1 from reactive astrocytes enhances the accumulation of endothelial progenitor cells in damaged white matter.

PubMed

Hayakawa, Kazuhide; Miyamoto, Nobukazu; Seo, Ji Hae; Pham, Loc-Duyen D; Kim, Kyu-Won; Lo, Eng H; Arai, Ken

2013-04-01

High-mobility group box 1 (HMGB1) was initially described as a damage-associated-molecular-pattern (DAMP) mediator that worsens acute brain injury after stroke. But, recent findings suggest that HMGB1 can play a surprisingly beneficial role during stroke recovery by promoting endothelial progenitor cell (EPC) function and vascular remodeling in cortical gray matter. Here, we ask whether HMGB1 may also influence EPC responses in white matter injury. The standard lysophosphatidylcholine (LPC) injection model was used to induce focal demyelination in the corpus callosum of mice. Immunostaining showed that within the focal white matter lesions, HMGB1 was up-regulated in GFAP-positive reactive astrocytes, along with the accumulation of Flk1/CD34-double-positive EPCs that expressed pro-recovery mediators such as brain-derived neurotrophic factor and basic fibroblast growth factor. Astrocyte-EPC signaling required the HMGB1 receptor RAGE as treatment with RAGE-neutralizing antibody significantly decreased EPC accumulation. Moreover, suppression of HMGB1 with siRNA in vivo significantly decreased EPC numbers in damaged white matter as well as proliferated endothelial cell numbers. Finally, in vitro cell culture systems confirmed that HMGB1 directly affected EPC function such as migration and tube formation. Taken together, our findings suggest that HMGB1 from reactive astrocytes may attract EPCs to promote recovery after white matter injury. © 2012 International Society for Neurochemistry.

Animal models of cerebral ischemia

NASA Astrophysics Data System (ADS)

Khodanovich, M. Yu.; Kisel, A. A.

2015-11-01

Cerebral ischemia remains one of the most frequent causes of death and disability worldwide. Animal models are necessary to understand complex molecular mechanisms of brain damage as well as for the development of new therapies for stroke. This review considers a certain range of animal models of cerebral ischemia, including several types of focal and global ischemia. Since animal models vary in specificity for the human disease which they reproduce, the complexity of surgery, infarct size, reliability of reproduction for statistical analysis, and adequate models need to be chosen according to the aim of a study. The reproduction of a particular animal model needs to be evaluated using appropriate tools, including the behavioral assessment of injury and non-invasive and post-mortem control of brain damage. These problems also have been summarized in the review.

Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats.

PubMed

Gupta, Sangeetha; Gupta, Yogendra Kumar

2017-02-02

Traditionally, Zizyphus jujuba is used for anticonvulsant, hypnotic-sedative, anxiolytic, tranquilizer, antioxidant and anti-inflammatory properties. Likewise silymarin is popularly used for its potent antioxidant and hepatoprotective effects. Stroke being a multifactorial disease with unsatisfactory treatment outcomes, necessitates development of multimodal therapeutic interventions. Thus, we evaluated the therapeutic benefits of herbal combination of Z. jujuba and silymarin in a focal cerebral ischemia model. To evaluate the neuroprotective potential of hydroalcoholic extract of Z. jujuba (HEZJ) fruit and silymarin alone and in combination in middle cerebral artery occlusion (MCAo) model of focal cerebral ischemia in rats. Male Wistar rats were pretreated with HEZJ (100, 250 and 500mg/kg, p.o.) or silymarin (250mg/kg, p.o.) for 3 days prior to induction of MCAo. Neurological deficit score, motor impairment and cerebral infarction were assessed 24h following MCAo. HEZJ (250mg/kg) co-administered with silymarin (250mg/kg) for 3 days prior to induction of MCAo was also evaluated for above parameters and oxidative stress. Malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD) levels in the cortex, striatum and hippocampal brain regions were estimated 24h post MCAo. Pretreatment with HEZJ and silymarin reduced the neurological deficit score, motor impairment and cerebral infarction volume. HEZJ and silymarin pretreatment also ameliorated the oxidative stress in different brain regions, which was evident from increased SOD levels, decreased MDA and NO levels as compared to MCAo control rats. Interestingly neuroprotective efficacy was potentiated by pretreatment with HEZJ and silymarin combination. Pretreatment with HEZJ and silymarin combination was observed to have better neuroprotection mediated via amelioration of oxidative stress in the focal cerebral ischemia model. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment.

PubMed

Vahid-Ansari, Faranak; Albert, Paul R

2018-01-01

Poststroke depression (PSD) is a common outcome of stroke that limits recovery and is only partially responsive to chronic antidepressant treatment. In order to elucidate changes in the cortical-limbic circuitry associated with PSD and its treatment, we examined a novel mouse model of persistent PSD. Focal endothelin-1-induced ischemia of the left medial prefrontal cortex (mPFC) in male C57BL6 mice resulted in a chronic anxiety and depression phenotype. Here, we show severe cognitive impairment in spatial learning and memory in the stroke mice. The behavioral and cognitive phenotypes were reversed by chronic (4-week) treatment with fluoxetine, alone or with voluntary exercise (free-running wheel), but not by exercise alone. To assess chronic cellular activation, FosB + cells were co-labeled for markers of glutamate/pyramidal (VGluT1-3/CaMKIIα), γ-aminobutyric acid (GAD67), and serotonin (TPH). At 6 weeks poststroke versus sham (or 4 days poststroke), left mPFC stroke induced widespread FosB activation, more on the right (contralesional) than on the left side. Stroke activated glutamate cells of the mPFC, nucleus accumbens, amygdala, hippocampus, and raphe serotonin neurons. Chronic fluoxetine balanced bilateral neuronal activity, reducing total FosB and FosB/CamKII + cells (mPFC, nucleus accumbens), and unlike exercise, increasing FosB/GAD67 + cells (septum, amygdala) or both (hippocampus, raphe). In summary, chronic antidepressant but not exercise mediates recovery in this unilateral ischemic PSD model that is associated with region-specific reversal of stroke-induced pyramidal cell hyperactivity and increase in γ-aminobutyric acidergic activity. Targeted brain stimulation to restore brain activity could provide a rational approach for treating clinical PSD.

Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice

PubMed Central

Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Wei, Ling

2015-01-01

Apelin is a peptide originally isolated from bovine stomach tissue extracts and identified as an endogenous ligand of the APJ receptor; recent work showed that apelin ameliorates the ischemic injury in the heart and the brain. Being an analogue to the angiotensin II receptor, the apelin/APJ signaling may mediate angiogenesis process. We explored the noninvasive intranasal brain delivery method and investigated therapeutic effects of apelin-13 in a focal ischemic stroke model of mice. Intranasal administration of apelin-13 (4 mg/kg) was given 30 min after the onset of stroke and repeated once daily. Three days after stroke, mice received apelin-13 had significantly reduced infarct volume and less neuronal death in the penumbra. Western blot analyses showed upregulated levels of apelin, apelin receptor APLNR, and Bcl-2 and decreased caspase-3 activation in the apelin-13-treated brain. The proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1β, and chemokine monocyte chemoattractant protein-1 mRNA increased in the ischemic brain, which were significantly attenuated by apelin-13. Apelin-13 remarkably reduced microglia recruitment and activation in the penumbra according to morphological features of Iba-1-positive cells 3 days after ischemia. Apelin-13 significantly increased the expression of angiogenic factor vascular endothelial growth factor and matrix metalloproteinase-9 14 days after stroke. Angiogenesis illustrated by collagen IV + /5-bromo-2′-deoxyuridin + colabeled cells was significantly increased by the apelin-13 treatment 21 days after stroke. Finally, apelin-13 promoted the local cerebral blood flow restoration and long-term functional recovery. This study demonstrates a noninvasive intranasal delivery of apelin-13 after stroke, suggesting that the reduced inflammatory activities, decreased cell death, and increased angiogenesis contribute to the therapeutic benefits of apelin-13. PMID:26391329

Secondary brain injuries in thalamus and hippocampus after focal ischemia caused by mild, transient extradural compression of the somatosensori cortex in the rat.

PubMed

Holmberg, Per; Liljequist, Sture; Wägner, Anna

2009-02-01

The development and distribution of secondary brain lesions, subsequent to ischemic stroke, are of considerable clinical interest but so far only a limited number of studies have investigated the distribution and development of these secondary lesions in detail. In this study, we used an animal model of focal ischemia caused by extradural compression of the sensorimotor cortex. This paradigm of focal ischemia was shown to produce a consistent pattern of secondary lesions located distally from the primary lesion. Functionally the primary brain lesion produced a transient neurological deficit, which was evaluated by daily beam walking tests. Morphological changes were assessed in parallel after the ischemic event using Fluoro-Jade (FJ) staining as a marker of neuronal cell death. Secondary brain lesions were observed in the thalamus as well as in the hippocampus. The first sign of the slowly developing secondary brain lesions was present on day 3 with subsequent lesions being identified until day 16 after the primary ischemia. In addition to the identification of neuronal cell death by the FJ assays, immunostaining for parvalbumin (PA), a marker of GABAergic interneurons, revealed a loss of PA-staining in the pyramidal layer of CA1 on day 3, thus showing a similar time pattern for loss of PA-staining as for the loss of FJ stained cells. Based upon our present results, we suggest that the current animal model of focal ischemia represents a valuable tool for studies concerning the development of secondary remote brain lesions and their association to impaired motor and cognitive functions.

Hemopexin induces neuroprotection in the rat subjected to focal cerebral ischemia.

PubMed

Dong, Beibei; Cai, Min; Fang, Zongping; Wei, Haidong; Zhu, Fangyun; Li, Guochao; Dong, Hailong; Xiong, Lize

2013-06-10

The plasma protein hemopexin (HPX) exhibits the highest binding affinity to free heme. In vitro experiments and gene-knock out technique have suggested that HPX may have a neuroprotective effect. However, the expression of HPX in the brain was not well elucidated and its expression after cerebral ischemia-reperfusion injury was also poorly studied. Furthermore, no in vivo data were available on the effect of HPX given centrally on the prognosis of focal cerebral ischemia. In the present study, we systematically investigated expression of HPX in normal rat brain by immunofluorescent staining. The results showed that HPX was mainly expressed in vascular system and neurons, as well as in a small portion of astrocytes adjacent to the vessels in normal rat brain. Further, we determined the role of HPX in the process of focal cerebral ischemic injury and explored the effects of HPX treatment in a rat model of transient focal cerebral ischemia. After 2 h' middle cerebral artery occlusion (MCAO) followed by 24 h' reperfusion, the expression of HPX was increased in the neurons and astrocytes in the penumbra area, as demonstrated by immunohistochemistry and Western blot techniques. Intracerebroventricular injection of HPX at the onset of reperfusion dose-dependently reduced the infarct volumes and improved measurements of neurological function of the rat subjected to transient focal cerebral ischemia. The neuroprotective effects of HPX sustained for up to 7 days after experiments. Our study provides a new insight into the potential neuroprotective role of HPX as a contributing factor of endogenous protective mechanisms against focal cerebral ischemia injury, and HPX might be developed as a potential agent for treatment of ischemic stroke.

Stroke injury, cognitive impairment and vascular dementia☆

PubMed Central

Kalaria, Raj N.; Akinyemi, Rufus; Ihara, Masafumi

2016-01-01

The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25–30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood–brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26806700

A free radical scavenger edaravone suppresses systemic inflammatory responses in a rat transient focal ischemia model.

PubMed

Fujiwara, Norio; Som, Angel T; Pham, Loc-Duyen D; Lee, Brian J; Mandeville, Emiri T; Lo, Eng H; Arai, Ken

2016-10-28

A free radical scavenger edaravone is clinically used in Japan for acute stroke, and several basic researches have carefully examined the mechanisms of edaravone's protective effects. However, its actions on pro-inflammatory responses under stroke are still understudied. In this study, we subjected adult male Sprague-Dawley rats to 90-min middle cerebral artery (MCA) occlusion followed by reperfusion. Edaravone was treated twice via tail vein; after MCA occlusion and after reperfusion. As expected, edaravone-treated group showed less infarct volume and edema formation compared with control group at 24-h after an ischemic onset. Furthermore, edaravone reduced the levels of plasma interleukin (IL)-1β and matrix metalloproteinase-9 at 3-h after ischemic onset. Several molecules besides IL-1β and MMP-9 are involved in inflammatory responses under stroke conditions. Therefore, we also examined whether edaravone treatment could decrease a wide range of pro-inflammatory cytokines/chemokines by testing rat plasma samples with a rat cytokine array. MCAO rats showed elevations in plasma levels of CINC-1, Fractalkine, IL-1α, IL-1ra, IL-6, IL-10, IP-10, MIG, MIP-1α, and MIP-3α, and all these increases were reduced by edaravone treatment. These data suggest that free radical scavengers may reduce systemic inflammatory responses under acute stroke conditions, and therefore, oxidative stress can be still a viable target for acute stroke therapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy: new categories to be enrolled.

PubMed

Gancia, Paolo; Pomero, Giulia

2012-10-01

Therapeutic hypothermia is now the standard of care for brain injury control in term infants with perinatal hypoxic ischemic encephalopathy (HIE). Accumulated evidence shows a reduction in mortality and long-term neurodevelopmental disability at 12-24 months of age, with more favourable effects in the less severe forms of HIE. Only few trials recruited newborns <36 weeks gestational age, or mild-to-moderate encephalopathy with base deficit (BD) <16. The new categories of patients to be enrolled should include (late) preterm infants, neonates with unexpected postnatal collapse, and newborns with stroke. Preterm HIE: Therapeutic hypothermia shows a good safety profile in clinical studies, and no adverse effects were noted in the preterm fetal animal model. Recently, it has been shown that mild hypothermia in preterm newborns with necrotizing enterocolitis (NEC) and multiple organ dysfunction syndrome (MODS) does not increase mortality, bleeding, infection, or need for inotropes in cooled newborns. A pilot study (NCT00620711) is currently recruiting newborns of > 32 but < 36 weeks gestation with standard criteria for HIE. Postnatal Collapse: The postnatal collapse (PNC) is a rare (0.03-0.5/1000 live births) but life-threatening hypoxic-ischemic event. No clinical trials of therapeutic hypothermia have specifically addressed to PNC. Nevertheless, a beneficial effect of brain cooling is expectable, and it has been proposed to include in brain hypothermia trials the infants with PNC fulfilling the entry criteria for HIE. Stroke: Perinatal arterial ischemic stroke is the most common cause of cerebral palsy (CP) in term and near-term newborn. In a systematic review and meta-analysis of animal studies of focal cerebral ischemia, hypothermia reduced the infarct size by 44%. No specific neuroprotective interventions are available for the management of acute perinatal stroke. Hypothermia may decrease seizures in newborns with encephalopathy and a focal infarct, potentially improving the long-term outcome for these infants. Future studies of therapeutic hypothermia should include the categories of newborns excluded from the published clinical trials, that is infants <36 weeks gestation, PNC or stroke, or admitted outside of the established 6-hour window, and with encephalopathy not imputable to HIE. New entry criteria will allow significant number of newborns to benefit from the treatment.

Irisin Peptide Protects Brain Against Ischemic Injury Through Reducing Apoptosis and Enhancing BDNF in a Rodent Model of Stroke.

PubMed

Asadi, Yasin; Gorjipour, Fazel; Behrouzifar, Sedigheh; Vakili, Abedin

2018-06-07

Evidence has shown therapeutic potential of irisin in cerebral stroke. The present study aimed to assess the effects of recombinant irisin on the infarct size, neurological outcomes, blood-brain barrier (BBB) permeability, apoptosis and brain-derived neurotrophic factor (BDNF) expression in a mouse model of stroke. Transient focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 45 min and followed reperfusion for 23 h in mice. Recombinant irisin was administrated at doses of 0.1, 0.5, 2.5, 7.5, and 15 µg/kg, intracerebroventricularly (ICV), on the MCAO beginning. Neurological outcomes, infarct size, brain edema and BBB permeability were evaluated by modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride (TTC) staining and Evans blue (EB) extravasation methods, respectively, at 24 h after ischemia. Apoptotic cells and BDNF protein were detected by TUNEL assay and immunohistochemistry techniques. The levels of Bcl-2, Bax and caspase-3 proteins were measured by immunoblotting technique. ICV irisin administration at doses of 0.5, 2.5, 7.5 and 15 µg/kg, significantly reduced infarct size, whereas only in 7.5 and 15 µg/kg improved neurological outcome (P < 0.001). Treatment with irisin (7.5 µg/kg) reduced brain edema (P < 0.001) without changing BBB permeability (P > 0.05). Additionally, irisin (7.5 µg/kg) significantly diminished apoptotic cells and increased BDNF immunoreactivity in the ischemic brain cortex (P < 0.004). Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein. The present study indicated that irisin attenuates brain damage via reducing apoptosis and increasing BDNF protein of brain cortex in the experimental model of stroke in mice.

Protective effects of geniposide and ginsenoside Rg1 combination treatment on rats following cerebral ischemia are mediated via microglial microRNA‑155‑5p inhibition.

PubMed

Wang, Jun; Li, Dan; Hou, Jincai; Lei, Hongtao

2018-02-01

Geniposide, an active component of Gardenia, has been reported to protect against cerebral ischemia in animals. Ginsenoside Rg1, a component of Panax notoginseng, is usually administered in combination with Gardenia for the treatment of acute ischemic stroke; however, there are unknown effects of ginsenoside Rg1 that require further investigation. In the present study, the effects of geniposide and ginsensoide Rg1 combination treatment on focal cerebral ischemic stroke were investigated. For in vivo analysis, male rats were separated into three groups, including the (control), model and geniposide + ginsenoside Rg1 groups (n=8 per group). A middle cerebral artery occlusion model was established as the model group. The treatment group was treated with geniposide (30 mg/kg, tail vein injection) + ginsenoside Rg1 (6 mg/kg, tail vein injection), and the model group received saline instead. Neurobehavioral deficits, infarct volume, brain edema, and the expression of microRNA (miR)‑155‑5p and CD11b by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry, were assessed following 24 h of ischemia. For in vitro analysis, BV2 mouse microglial cells were cultured and exposed to geniposide (40 µg/ml) + ginsenoside Rg1 (8 µg/ml) during various durations of oxygen‑glucose deprivation (OGD). The expression levels of miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 were detected by RT‑qPCR. The results demonstrated that increases in brain infarct volume, edema volume, CD11b‑positive cells and miR‑155‑5p levels were alleviated following geniposide + ginsenoside administration in rats exposed to ischemia. Furthermore, geniposide + ginsenoside Rg1 treatment suppressed the miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 expression levels in OGD‑injured BV2 microglial cells. The results of the present study demonstrated that tail vein administration of geniposide in combination with ginsenoside Rg1 protected against focal cerebral ischemia in rats through inhibition of microglial miR‑155‑5p following ischemic injury, which may serve as a novel therapeutic agent for the treatment of strokes.

Long-term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice.

PubMed

Jiang, Michael Qize; Zhao, Ying-Ying; Cao, Wenyuan; Wei, Zheng Zachory; Gu, Xiaohuan; Wei, Ling; Yu, Shan Ping

2017-07-01

Focal cerebral ischemia results in an ischemic core surrounded by the peri-infarct region (penumbra). Most research attention has been focused on penumbra while the pattern of cell fates inside the ischemic core is poorly defined. In the present investigation, we tested the hypothesis that, inside the ischemic core, some neuronal and vascular cells could survive the initial ischemic insult while regenerative niches might exist many days after stroke in the adult brain. Adult mice were subjected to focal cerebral ischemia induced by permanent occlusion of distal branches of the middle cerebral artery (MCA) plus transient ligations of bilateral common carotid artery (CCA). The ischemic insult uniformly reduced the local cerebral blood flow (LCBF) by 90%. Massive cell death occurred due to multiple mechanisms and a significant infarction was cultivated in the ischemic cortex 24 h later. Nevertheless, normal or even higher levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) persistently remained in the core tissue, some NeuN-positive and Glut-1/College IV-positive cells with intact ultrastructural features resided in the core 7-14 days post stroke. BrdU-positive but TUNEL-negative neuronal and endothelial cells were detected in the core where extensive extracellular matrix infrastructure developed. Meanwhile, GFAP-positive astrocytes accumulated in the penumbra and Iba-1-positive microglial/macrophages invaded the core several days after stroke. The long term survival of neuronal and vascular cells inside the ischemic core was also seen after a severe ischemic stroke induced by permanent embolic occlusion of the MCA. We demonstrate that a therapeutic intervention of pharmacological hypothermia could save neurons/endothelial cells inside the core. These data suggest that the ischemic core is an actively regulated brain region with residual and newly formed viable neuronal and vascular cells acutely and chronically after at least some types of ischemic strokes. © 2016 International Society of Neuropathology.

Chronic stress induced disruption of the peri-infarct neurovascular unit following experimentally induced photothrombotic stroke.

PubMed

Zhao, Zidan; Ong, Lin Kooi; Johnson, Sarah; Nilsson, Michael; Walker, Frederick R

2017-12-01

How stress influences brain repair is an issue of considerable importance, as patients recovering from stroke are known to experience high and often unremitting levels of stress post-event. In the current study, we investigated how chronic stress modified the key cellular components of the neurovascular unit. Using an experimental model of focal cortical ischemia in male C57BL/6 mice, we examined how exposure to a persistently aversive environment, induced by the application of chronic restraint stress, altered the cortical remodeling post-stroke. We focused on systematically investigating changes in the key components of the neurovascular unit (i.e. neurons, microglia, astrocytes, and blood vessels) within the peri-infarct territories using both immunohistochemistry and Western blotting. The results from our study indicated that exposure to chronic stress exerted a significant suppressive effect on each of the key cellular components involved in neurovascular remodeling. Co-incident with these cellular changes, we observed that chronic stress was associated with an exacerbation of motor impairment 42 days post-event. Collectively, these results highlight the vulnerability of the peri-infarct neurovascular unit to the negative effects of chronic stress.

Predicting Language Outcome and Recovery After Stroke (PLORAS)

PubMed Central

Price, CJ; Seghier, ML; Leff, AP

2013-01-01

The ability of comprehend and produce speech after stroke depends on whether the areas of the brain that support language have been damaged. Here we review two different ways to predict language outcome after stroke. The first depends on understanding the neural circuits that support language. This model-based approach is a challenging endeavor because language is a complex cognitive function that involves the interaction of many different brain areas. The second approach does not require an understanding of why a lesion impairs language, instead, predictions are made on the basis of how previous patients with the same lesion recovered. This requires a database storing the speech and language abilities of a large population of patients who have, between them, incurred a comprehensive range of focal brain damage. In addition it requires a system that converts an MRI scan from a new patient into a 3D description of the lesion and then compares this lesion to all others on the database. The outputs of this system are the longitudinal language outcomes of corresponding patients in the database. This will provide a new patient, their carers and the clinician team managing them the range of likely recovery patterns over a variety of language measures. PMID:20212513

Experimental stroke protection induced by 4-hydroxybenzyl alcohol is cancelled by bacitracin.

PubMed

Descamps, Elodie; Petrault-Laprais, Maud; Maurois, Pierre; Pages, Nicole; Bac, Pierre; Bordet, Régis; Vamecq, Joseph

2009-06-01

Induction of protein disulfide isomerase (PDI) is validated as a main mechanism by which 4-hydroxybenzyl alcohol (4-HBA), an active principle of Gastrodia elata Blume, reduces cerebral infarct volumes in a murine model of focal brain ischemia/reperfusion. In contrast to its position isomers, i.e. 3-hydroxybenzyl alcohol (3-HBA) and 2-hydroxybenzyl alcohol (2-HBA), and to aliphatic diols (1,4-butanediol and 1,5-pentanediol), 4-HBA administered intravenously at 25 mg/kg protected mice, significantly reducing total, cortical and sub-cortical infarct volumes by 42, 28 and 55%, respectively. All compounds, 4-HBA included, were devoid of antioedematous properties. Only the stroke protective 4-HBA, but neither 3-HBA nor 2-HBA, was capable of significantly inducing PDI in intact mouse brains. Stroke protection was fully prevented by bacitracin (500 mg/kg), a known inhibitor of PDI, which, without affecting basal brain PDI levels, altered the ability of 4-HBA to induce significantly PDI in intact brains. Taken as a whole, our data indicate that stroke protection induced by 4-HBA involves PDI as a key player, making this protein a valuable target to control brain injury disorders. The fact that 4-HBA, at doses up to 200mg/kg, was devoid of neurotoxicity in the rotarod test is also a decisive element to promote the neuroprotective use of this plant compound.

Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a

PubMed Central

Chassagnon, Irène R.; McCarthy, Claudia A.; Chin, Yanni K.-Y.; Pineda, Sandy S.; Mobli, Mehdi; Pham, Vi; De Silva, T. Michael; Lynch, Joseph W.; Widdop, Robert E.; Rash, Lachlan D.

2017-01-01

Stroke is the second-leading cause of death worldwide, yet there are no drugs available to protect the brain from stroke-induced neuronal injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor in mammalian brain and a key mediator of acidosis-induced neuronal damage following cerebral ischemia. Genetic ablation and selective pharmacologic inhibition of ASIC1a reduces neuronal death following ischemic stroke in rodents. Here, we demonstrate that Hi1a, a disulfide-rich spider venom peptide, is highly neuroprotective in a focal model of ischemic stroke. Nuclear magnetic resonance structural studies reveal that Hi1a comprises two homologous inhibitor cystine knot domains separated by a short, structurally well-defined linker. In contrast with known ASIC1a inhibitors, Hi1a incompletely inhibits ASIC1a activation in a pH-independent and slowly reversible manner. Whole-cell, macropatch, and single-channel electrophysiological recordings indicate that Hi1a binds to and stabilizes the closed state of the channel, thereby impeding the transition into a conducting state. Intracerebroventricular administration to rats of a single small dose of Hi1a (2 ng/kg) up to 8 h after stroke induction by occlusion of the middle cerebral artery markedly reduced infarct size, and this correlated with improved neurological and motor function, as well as with preservation of neuronal architecture. Thus, Hi1a is a powerful pharmacological tool for probing the role of ASIC1a in acid-mediated neuronal injury and various neurological disorders, and a promising lead for the development of therapeutics to protect the brain from ischemic injury. PMID:28320941

Neuronal Dysregulation in Stroke-Associated Pseudobulbar Affect (PBA): Diagnostic Scales and Current Treatment Options.

PubMed

Lapchak, Paul A

2015-10-01

Until recently there was little understanding of the exact pathophysiology and treatment choices for stroke patients with Pseudobulbar affect (PBA). PBA is typically characterized by outbursts or uncontrollable laughing or crying and in the majority of patients, the outbursts being involuntary and incompatible with the patients' emotional state. PBA is a behavioral syndrome reported to be displayed in 28-52% of stroke patients with first or multiple strokes, and incidence may be higher in patients who have had prior stroke events, and higher in females. There is typically involvement of glutaminergic, serotoninergic and dopaminergic neuronal circuits of the corticolimbic-subcorticothalamic-pontocerebellar network. PBA is now understood to be a disinhibition syndrome in which specific pathways involving serotonin and glutamate are disrupted or modulated causing reduced cortical inhibition of a cerebellar/brainstem-situated "emotional" laughing or crying focal center. Stroke-induced disruption of one or more neuronal pathway circuits may "disinhibit" voluntary laughing and crying making the process involuntary. With a "new" treatment currently being marketed to treat PBA patients, this article will delve into the neurological and physiological basis for PBA in stroke, and review progress with the diagnosis and treatment of PBA.

Neuronal Dysregulation in Stroke-Associated Pseudobulbar Affect (PBA): Diagnostic Scales and Current Treatment Options

PubMed Central

Lapchak, Paul A

2015-01-01

Until recently there was little understanding of the exact pathophysiology and treatment choices for stroke patients with Pseudobulbar affect (PBA). PBA is typically characterized by outbursts or uncontrollable laughing or crying and in the majority of patients, the outbursts being involuntary and incompatible with the patients’ emotional state. PBA is a behavioral syndrome reported to be displayed in 28–52% of stroke patients with first or multiple strokes, and incidence may be higher in patients who have had prior stroke events, and higher in females. There is typically involvement of glutaminergic, serotoninergic and dopaminergic neuronal circuits of the corticolimbic-subcorticothalamic-pontocerebellar network. PBA is now understood to be a disinhibition syndrome in which specific pathways involving serotonin and glutamate are disrupted or modulated causing reduced cortical inhibition of a cerebellar/brainstem-situated “emotional” laughing or crying focal center. Stroke-induced disruption of one or more neuronal pathway circuits may “disinhibit” voluntary laughing and crying making the process involuntary. With a “new” treatment currently being marketed to treat PBA patients, this article will delve into the neurological and physiological basis for PBA in stroke, and review progress with the diagnosis and treatment of PBA. PMID:26693049

Angiogenesis-regulating microRNAs and ischemic stroke

PubMed Central

Yin, Ke-Jie; Hamblin, Milton; Chen, Y. Eugene

2014-01-01

Stroke is a leading cause of death and disability worldwide. Ischemic stroke is the dominant subtype of stroke and results from focal cerebral ischemia due to occlusion of major cerebral arteries. Thus, the restoration or improvement of reduced regional cerebral blood supply in a timely manner is very critical for improving stroke outcomes and post-stroke functional recovery. The recovery from ischemic stroke largely relies on appropriate restoration of blood flow via angiogenesis. Newly formed vessels would allow increased cerebral blood flow, thus increasing the amount of oxygen and nutrients delivered to affected brain tissue. Angiogenesis is strictly controlled by many key angiogenic factors in the central nervous system, and these molecules have been well-documented to play an important role in the development of angiogenesis in response to various pathological conditions. Promoting angiogenesis via various approaches that target angiogenic factors appears to be a useful treatment for experimental ischemic stroke. Most recently, microRNAs (miRs) have been identified as negative regulators of gene expression in a post-transcriptional manner. Accumulating studies have demonstrated that miRs are essential determinants of vascular endothelial cell biology/angiogenesis as well as contributors to stroke pathogenesis. In this review, we summarize the knowledge of stroke-associated angiogenic modulators, as well as the role and molecular mechanisms of stroke-associated miRs with a focus on angiogenesis-regulating miRs. Moreover, we further discuss their potential impact on miR-based therapeutics in stroke through targeting and enhancing post-ischemic angiogenesis. PMID:26156265

Post-stroke epilepsy in Burkina Faso (West Africa).

PubMed

Napon, Christian; Dabilgou, Anselme; Kyelem, Julie; Kaboré, Jean

2016-09-15

Post-stroke epilepsy (PSE) is defined as "recurrent seizures following stroke with confirmed diagnosis of epilepsy". Our objective was to describe the epidemiological, clinical and therapeutic PSE aspects at the Yalgado Ouedraogo Teaching Hospital, the main reference centre for neurological conditions in Burkina Faso. We conducted a retrospective study from January 2006 to December 2014. The data on thirty-two (32) cases of PSE was collected from a total of 1616 patients hospitalized for stroke, representing a rate of 1.98%. The patients' ages ranged from 25 to 77years old with a mean age of 58±10.39. There were 21 men and 11 women, with a gender ratio of 1.9. The time of occurrence of PSE ranged between 10 and 3600days (10years). The brain CT scan helped distinguish the different subtypes of stroke. Sixty-four percent (64%) of the cases experienced ischemic stroke and 36% of the cases cerebral hemorrhage. With regard to medical treatment, 23 patients received monotherapy, and 4 patients dual therapy. Exactly 96.87% of seizures were stabilized during the hospitalization period. PSE is a symptomatic type of epilepsy occurring during stroke sequelae. It is important not to lose sight of this before the occurrence of any focal or generalized seizure after a stroke. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuroblast survival depends on mature vascular network formation after mouse stroke: role of endothelial and smooth muscle progenitor cell co-administration.

PubMed

Nih, Lina R; Deroide, Nicolas; Leré-Déan, Carole; Lerouet, Dominique; Soustrat, Mathieu; Levy, Bernard I; Silvestre, Jean-Sébastien; Merkulova-Rainon, Tatiana; Pocard, Marc; Margaill, Isabelle; Kubis, Nathalie

2012-04-01

Pro-angiogenic cell-based therapies constitute an interesting and attractive approach to enhancing post-stroke neurogenesis and decreasing neurological deficit. However, most new stroke-induced neurons die during the first few weeks after ischemia, thus impairing total recovery. Although the neovascularization process involves different cell types and various growth factors, most cell therapy protocols are based on the biological effects of single-cell-type populations or on the administration of heterogeneous populations of progenitors, namely human cord blood-derived CD34(+) cells, with scarce vascular progenitor cells. Tight cooperation between endothelial cells and smooth muscle cells/pericytes is critical for the development of functional neovessels. We hypothesized that neuroblast survival in stroke brain depends on mature vascular network formation. In this study, we injected a combination of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs), isolated from human umbilical cord blood, into a murine model of permanent focal ischemia induced by middle cerebral artery occlusion. The co-administration of SMPCs and EPCs induced enhanced angiogenesis and vascular remodeling in the peri-infarct and infarct areas, where vessels exhibited a more mature phenotype. This activation of vessel growth resulted in the maintenance of neurogenesis and neuroblast migration to the peri-ischemic cortex. Our data suggest that a mature vascular network is essential for neuroblast survival after cerebral ischemia, and that co-administration of EPCs and SMPCs may constitute a novel therapeutic strategy for improving the treatment of stroke. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Anterior Temporal Lobe Connectivity Correlates with Functional Outcome after Aphasic Stroke

ERIC Educational Resources Information Center

Warren, Jane E.; Crinion, Jennifer T.; Ralph, Matthew A. Lambon; Wise, Richard J. S.

2009-01-01

Focal brain lesions are assumed to produce language deficits by two basic mechanisms: local cortical dysfunction at the lesion site, and remote cortical dysfunction due to disruption of the transfer and integration of information between connected brain regions. However, functional imaging studies investigating language outcome after aphasic…

A Simple Rule for Dendritic Spine and Axonal Bouton Formation Can Account for Cortical Reorganization after Focal Retinal Lesions

PubMed Central

Butz, Markus; van Ooyen, Arjen

2013-01-01

Lasting alterations in sensory input trigger massive structural and functional adaptations in cortical networks. The principles governing these experience-dependent changes are, however, poorly understood. Here, we examine whether a simple rule based on the neurons' need for homeostasis in electrical activity may serve as driving force for cortical reorganization. According to this rule, a neuron creates new spines and boutons when its level of electrical activity is below a homeostatic set-point and decreases the number of spines and boutons when its activity exceeds this set-point. In addition, neurons need a minimum level of activity to form spines and boutons. Spine and bouton formation depends solely on the neuron's own activity level, and synapses are formed by merging spines and boutons independently of activity. Using a novel computational model, we show that this simple growth rule produces neuron and network changes as observed in the visual cortex after focal retinal lesions. In the model, as in the cortex, the turnover of dendritic spines was increased strongest in the center of the lesion projection zone, while axonal boutons displayed a marked overshoot followed by pruning. Moreover, the decrease in external input was compensated for by the formation of new horizontal connections, which caused a retinotopic remapping. Homeostatic regulation may provide a unifying framework for understanding cortical reorganization, including network repair in degenerative diseases or following focal stroke. PMID:24130472

Hypothermia blocks beta-catenin degradation after focal ischemia in rats.

PubMed

Zhang, Hanfeng; Ren, Chuancheng; Gao, Xuwen; Takahashi, Tetsuya; Sapolsky, Robert M; Steinberg, Gary K; Zhao, Heng

2008-03-10

Dephosphorylated and activated glycogen synthase kinase (GSK) 3beta hyperphosphorylates beta-catenin, leading to its ubiquitin-proteosome-mediated degradation. beta-catenin-knockdown increases while beta-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of beta-catenin are reduced in the brain of Alzheimer's patients. However, whether beta-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK 3beta and beta-catenin, and the protective effect of moderate hypothermia (30 degrees C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK 3beta was dephosphorylated at 5 and 24 h after stroke in the normothermic (37 degrees C) brain; hypothermia augmented GSK 3beta dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK 3beta dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK 3beta protein. Corresponding to GSK 3beta activity in normothermic rats, beta-catenin phosphorylation transiently increased at 5 h in both the ischemic penumbra and core, and the total protein level of beta-catenin degraded after normothermic stroke. Hypothermia did not inhibit beta-catenin phosphorylation, but it blocked beta-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize beta-catenin, which may contribute to the protective effect of moderate hypothermia.

Experimental acute thrombotic stroke in baboons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Del Zoppo, G.J.; Copeland, B.R.; Harker, L.A.

1986-11-01

To study the effects of antithrombotic therapy in experimental stroke, we have characterized a baboon model of acute cerebrovascular thrombosis. In this model an inflatable silastic balloon cuff has been implanted by transorbital approach around the right middle cerebral artery (MCA), proximal to the take-off of the lenticulostriate arteries (LSA). Inflation of the balloon for 3 hours in six animals produced a stereotypic sustained stroke syndrome characterized by contralateral hemiparesis. An infarction volume of 3.2 +/- 1.5 cm3 in the ipsilateral corpus striatum was documented by computerized tomographic (CT) scanning at 10 days following stroke induction and 3.9 +/- 1.9more » cm3 (n = 4) at 14 days by morphometric neuropathologic determinations of brain specimens fixed in situ by pressure-perfusion with 10% buffered formalin. Immediate pressure-perfusion fixation following deflation of the balloon was performed in 16 additional animals given Evans blue dye intravenously prior to the 3 hour MCA balloon occlusion. Light microscopy and transmission electron microscopy consistently confirmed the presence of thrombotic material occluding microcirculatory branches of the right LSA in the region of Evans blue stain, but not those of the contralateral corpus striatum. When autologous 111In-platelets were infused intravenously in four animals from the above group prior to the transient 3 hour occlusion of the right MCA, gamma scintillation camera imaging of each perfused-fixed whole brain demonstrated the presence of a single residual focus of 111In-platelet activity involving only the Evans blue-stained right corpus striatum. Focal right hemispheric activity was equivalent to 0.55 +/- 0.49 ml of whole blood, and the occlusion score derived from histologic examination of the microcirculation of the Evans blue-stained corpus striatum averaged 34.8 +/- 2.8.« less

Regulation of Therapeutic Hypothermia on Inflammatory Cytokines, Microglia Polarization, Migration and Functional Recovery after Ischemic Stroke in Mice

PubMed Central

Lee, Jin Hwan; Wei, Zheng Z; Cao, Wenyuan; Won, Soonmi; Gu, Xiaohuan; Winter, Megan; Dix, Thomas A.; Wei, Ling; Yu, Shan Ping

2016-01-01

Stroke is a leading threat to human life and health in the US and around the globe, while very few effective treatments are available for stroke patients. Preclinical and clinical studies have shown that therapeutic hypothermia (TH) is a potential treatment for stroke. Using novel neurotensin receptor 1 (NTR1) agonists, we have demonstrated pharmacologically induced hypothermia and protective effects against brain damages after ischemic stroke, hemorrhage stroke, and traumatic brain injury (TBI) in rodent models. To further characterize the mechanism of TH-induced brain protection, we examined the effect of TH (at ±33°C for 6 hrs) induced by the NTR1 agonist HPI-201 or physical (ice/cold air) cooling on inflammatory responses after ischemic stroke in mice and oxygen glucose deprivation (OGD) in cortical neuronal cultures. Seven days after focal cortical ischemia, microglia activation in the penumbra reached a peak level, which was significantly attenuated by TH treatments commenced 30 min after stroke. The TH treatment decreased the expression of M1 type reactive factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-12, IL-23, and inducible nitric oxide synthase (iNOS) measured by RT-PCR and Western blot analyses. Meanwhile, TH treatments increased the expression of M2 type reactive factors including IL-10, Fizz1, Ym1, and arginase-1. In the ischemic brain and in cortical neuronal/BV2 microglia cultures subjected to OGD, TH attenuated the expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), two key chemokines in the regulation of microglia activation and infiltration. Consistently, physical cooling during OGD significantly decreased microglia migration 16 hrs after OGD. Finally, TH improved functional recovery at 1, 3, and 7 days after stroke. This study reveals the first evidence for hypothermia mediated regulation on inflammatory factor expression, microglia polarization, migration and indicates that the anti-inflammatory effect is an important mechanism underlying the brain protective effects of a TH therapy. PMID:27659107

Sustained diffusion reversal with in-bore reperfusion in monkey stroke models: Confirmed by prospective magnetic resonance imaging

PubMed Central

Yi, Kyung Sik; Choi, Chi-Hoon; Lee, Sang-Rae; Lee, Hong Jun; Lee, Youngjeon; Jeong, Kang-Jin; Hwang, Jinwoo; Chang, Kyu-Tae

2016-01-01

Although early diffusion lesion reversal after recanalization treatment of acute ischaemic stroke has been observed in clinical settings, the reversibility of lesions observed by diffusion-weighted imaging remains controversial. Here, we present consistent observations of sustained diffusion lesion reversal after transient middle cerebral artery occlusion in a monkey stroke model. Seven rhesus macaques were subjected to endovascular transient middle cerebral artery occlusion with in-bore reperfusion confirmed by repeated prospective diffusion-weighted imaging. Early diffusion lesion reversal was defined as lesion reversal at 3 h after reperfusion. Sustained diffusion lesion reversal was defined as the difference between the ADC-derived pre-reperfusion maximal ischemic lesion volume (ADCD-P Match) and the lesion on 4-week follow-up FLAIR magnetic resonance imaging. Diffusion lesions were spatiotemporally assessed using a 3-D voxel-based quantitative technique. The ADCD-P Match was 9.7 ± 6.0% (mean ± SD) and the final infarct was 1.2–6.0% of the volume of the ipsilateral hemisphere. Early diffusion lesion reversal and sustained diffusion lesion reversal were observed in all seven animals, and the calculated percentages compared with their ADCD-P Match ranged from 8.3 to 51.9% (mean ± SD, 26.9 ± 15.3%) and 41.7–77.8% (mean ± SD, 65.4 ± 12.2%), respectively. Substantial sustained diffusion lesion reversal and early reversal were observed in all animals in this monkey model of transient focal cerebral ischaemia. PMID:27401804

Posterior reversible encephalopathy syndrome mimicking a left middle cerebral artery stroke.

PubMed

Terranova, Santo; Kumar, Jai Dev; Libman, Richard B

2012-01-01

Certain Acute Clinical presentations are highly suggestive of stroke caused by specific mechanisms. One example of this would be the sudden onset of aphasia without hemiparesis often reflecting cerebral embolism, frequently from a cardiac source. Posterior reversible encephalopathy syndrome (PRES) describes a usually reversible neurologic syndrome with a variety of presenting symptoms from headache, altered mental status, seizures, vomiting, diminished spontaneity and speech, abnormalities of visual perception and visual loss. We report a patient presenting with elevated blood pressure, CT characteristics of PRES but a highly circumscribed neurologic syndrome (Wernicke's Aphasia without hemiparesis) suggestive of a cardioembolic stroke affecting the left MCA territory. That is, PRES mimicked a focal stroke syndrome. The importance of recognizing this possibility is that his deficits resolved with blood pressure control, while other treatments, such as intensifying his anticoagulation would have been inappropriate. In addition, allowing his blood pressure to remain elevated as is often done in the setting of an acute stroke might have perpetuated the underlying pathophysiology of PRES leading to a worse clinical outcome. For this reason PRES needs to be recognized quickly and treated appropriately.

Prefrontal and Executive Attention Network Lesions and the Development of Attention-Deficit/hyperactivity Symptomatology.

ERIC Educational Resources Information Center

Max, Jeffrey E.; Manes, Facundo F.; Robertson, Brigitte A.M.; Mathews, Katherine; Fox, Peter T.; Lancaster, Jack

2005-01-01

Objective: To investigate the association between focal stroke lesions of Posner's executive attention network and a specific region of interest in the frontal lobes (orbital frontal and mesial frontal) and either attention-deficit/hyperactivity disorder (ADHD) or traits of the disorder (ADHD symptomatology). Method: Twenty-nine children with…

The Janus Face of VEGF in Stroke

PubMed Central

Geiseler, Samuel J.; Morland, Cecilie

2018-01-01

The family of vascular endothelial growth factors (VEGFs) are known for their regulation of vascularization. In the brain, VEGFs are important regulators of angiogenesis, neuroprotection and neurogenesis. Dysregulation of VEGFs is involved in a large number of neurodegenerative diseases and acute neurological insults, including stroke. Stroke is the main cause of acquired disabilities, and normally results from an occlusion of a cerebral artery or a hemorrhage, both leading to focal ischemia. Neurons in the ischemic core rapidly undergo necrosis. Cells in the penumbra are exposed to ischemia, but may be rescued if adequate perfusion is restored in time. The neuroprotective and angiogenic effects of VEGFs would theoretically make VEGFs ideal candidates for drug therapy in stroke. However, contradictory to what one might expect, endogenously upregulated levels of VEGF as well as the administration of exogenous VEGF is detrimental in acute stroke. This is probably due to VEGF-mediated blood–brain-barrier breakdown and vascular leakage, leading to edema and increased intracranial pressure as well as neuroinflammation. The key to understanding this Janus face of VEGF function in stroke may lie in the timing; the harmful effect of VEGFs on vessel integrity is transient, as both VEGF preconditioning and increased VEGF after the acute phase has a neuroprotective effect. The present review discusses the multifaceted action of VEGFs in stroke prevention and therapy. PMID:29734653

High-mobility group box-1 as an autocrine trophic factor in white matter stroke.

PubMed

Choi, Jun Young; Cui, Yuexian; Chowdhury, Samma Tasneem; Kim, Byung Gon

2017-06-20

Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD-induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions.

Left hemisphere regions are critical for language in the face of early left focal brain injury.

PubMed

Raja Beharelle, Anjali; Dick, Anthony Steven; Josse, Goulven; Solodkin, Ana; Huttenlocher, Peter R; Levine, Susan C; Small, Steven L

2010-06-01

A predominant theory regarding early stroke and its effect on language development, is that early left hemisphere lesions trigger compensatory processes that allow the right hemisphere to assume dominant language functions, and this is thought to underlie the near normal language development observed after early stroke. To test this theory, we used functional magnetic resonance imaging to examine brain activity during category fluency in participants who had sustained pre- or perinatal left hemisphere stroke (n = 25) and in neurologically normal siblings (n = 27). In typically developing children, performance of a category fluency task elicits strong involvement of left frontal and lateral temporal regions and a lesser involvement of right hemisphere structures. In our cohort of atypically developing participants with early stroke, expressive and receptive language skills correlated with activity in the same left inferior frontal regions that support language processing in neurologically normal children. This was true independent of either the amount of brain injury or the extent that the injury was located in classical cortical language processing areas. Participants with bilateral activation in left and right superior temporal-inferior parietal regions had better language function than those with either predominantly left- or right-sided unilateral activation. The advantage conferred by left inferior frontal and bilateral temporal involvement demonstrated in our study supports a strong predisposition for typical neural language organization, despite an intervening injury, and argues against models suggesting that the right hemisphere fully accommodates language function following early injury.

Visualization of cell death in mice with focal cerebral ischemia using fluorescent annexin A5, propidium iodide, and TUNEL staining.

PubMed

Bahmani, Peyman; Schellenberger, Eyk; Klohs, Jan; Steinbrink, Jens; Cordell, Ryan; Zille, Marietta; Müller, Jochen; Harhausen, Denise; Hofstra, Leo; Reutelingsperger, Chris; Farr, Tracy Deanne; Dirnagl, Ulrich; Wunder, Andreas

2011-05-01

To monitor stroke-induced brain damage and assess neuroprotective therapies, specific imaging of cell death after cerebral ischemia in a noninvasive manner is highly desirable. Annexin A5 has been suggested as a marker for imaging cell death under various disease conditions including stroke. In this study, C57BL6/N mice received middle cerebral artery occlusion (MCAO) and were injected intravenously with either active or inactive Cy5.5-annexin A5 48 hours after reperfusion. Some mice also received propidium iodide (PI), a cell integrity marker. Only in mice receiving active Cy5.5-annexin A5 were fluorescence intensities significantly higher over the hemisphere ipsilateral to MCAO than on the contralateral side. This was detected noninvasively and ex vivo 4 and 8 hours after injection. The majority of cells positive for fluorescent annexin A5 were also positive for PI and fragmented DNA as detected by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining. This study demonstrates the high specificity of annexin A5 for visualization of cell death in a mouse model of stroke. To our knowledge, this is the first study to compare the distribution of injected active and inactive annexin A5, PI, and TUNEL staining. It provides important information on the experimental and potential clinical applications of annexin A5-based imaging agents in stroke.

Visualization of cell death in mice with focal cerebral ischemia using fluorescent annexin A5, propidium iodide, and TUNEL staining

PubMed Central

Bahmani, Peyman; Schellenberger, Eyk; Klohs, Jan; Steinbrink, Jens; Cordell, Ryan; Zille, Marietta; Müller, Jochen; Harhausen, Denise; Hofstra, Leo; Reutelingsperger, Chris; Farr, Tracy Deanne; Dirnagl, Ulrich; Wunder, Andreas

2011-01-01

To monitor stroke-induced brain damage and assess neuroprotective therapies, specific imaging of cell death after cerebral ischemia in a noninvasive manner is highly desirable. Annexin A5 has been suggested as a marker for imaging cell death under various disease conditions including stroke. In this study, C57BL6/N mice received middle cerebral artery occlusion (MCAO) and were injected intravenously with either active or inactive Cy5.5-annexin A5 48 hours after reperfusion. Some mice also received propidium iodide (PI), a cell integrity marker. Only in mice receiving active Cy5.5-annexin A5 were fluorescence intensities significantly higher over the hemisphere ipsilateral to MCAO than on the contralateral side. This was detected noninvasively and ex vivo 4 and 8 hours after injection. The majority of cells positive for fluorescent annexin A5 were also positive for PI and fragmented DNA as detected by terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling (TUNEL) staining. This study demonstrates the high specificity of annexin A5 for visualization of cell death in a mouse model of stroke. To our knowledge, this is the first study to compare the distribution of injected active and inactive annexin A5, PI, and TUNEL staining. It provides important information on the experimental and potential clinical applications of annexin A5-based imaging agents in stroke. PMID:21245871

Acute CT perfusion changes in seizure patients presenting to the emergency department with stroke-like symptoms: correlation with clinical and electroencephalography findings.

PubMed

Payabvash, S; Oswood, M C; Truwit, C L; McKinney, A M

2015-10-01

To determine acute computed tomography perfusion (CTP) changes in seizure patients presenting with stroke-like symptoms and to correlate those changes with clinical presentation and electroencephalography (EEG). The medical records of all patients who presented to the emergency department with acute stroke-like symptoms and underwent CTP (n=1085) over a 5.5-year period were reviewed. Patients were included who had primary seizure as the final diagnosis, and underwent CTP within 3 hours of symptom onset. A subset of patients had a follow-up EEG within 7 days. The perfusion changes and EEG findings were compared between different clinical presentations. Eighteen of 1085 patients (1.7%) who underwent CTP following an acute stroke-like presentation were included. The abnormality on CTP was usually focal, unilateral hyperperfusion - increased relative cerebral blood flow (rCBF) and volume (rCBV) (n=14/18), which most often affected the temporal lobe. Those patients who presented with a motor or speech deficit (n=12) had a higher temporal lobe rCBV, and rCBF, and lower relative mean transit time (rMTT) compared to those with non-focal neurological deficit at presentation. Early EEG was available in 13 patients; a sharp-spike epileptiform EEG discharge pattern (n=5) was associated with higher temporal lobe ipsilateral rCBF and rCBV, and lower rMTT on admission CTP examination. Seizure patients who present with a unilateral motor or speech deficit most commonly have contralateral hyperperfusion in the corresponding eloquent brain regions on the acute-stage CTP examination. In such patients, epileptiform discharges on the early follow-up EEG are associated with ipsilateral hyperperfusion on the admission CTP. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Ischemic Stroke: From Next Generation Sequencing and GWAS to Community Genomics?

PubMed

Black, Michael; Wang, Wenzhi; Wang, Wei

2015-08-01

Stroke is a major cause of mortality and morbidity in both the developed and developing world. Next generation sequencing (NGS) and multi-omics integrative biology research offer new opportunities in the way we research and understand stroke. These biotechnologies also signal a shift from genetics to genomics of stroke, which is highlighted in this review. Stroke is a focal neurological deficit resulting from disruption of the cerebral blood supply. There are two main types of common stroke, ischemic stroke (IS), which comprises 80% of cases, and hemorrhagic stroke (HS) that accounts for about 20% of cases. IS is a complex multi-factorial disease with multiple environmental and genomic determinants. We discuss here IS from genomics and bioinformatics perspectives, including the highlights of the genome wide association studies (GWAS), NGS progress to date, and exome studies. While both 'common variant, common disease' and 'rare variant, common disease' approaches need to be assessed in tandem, future studies into IS omics should also consider pedigree and/or community based sampling to take account of the complex diversity of IS genetics. We conclude by presenting an example of such community genomics research from China in an extended pedigree sample, and the ways in which the intersection of genomics and global society can usefully inform our understanding of IS pathophysiology and potential preventive medicine interventions in the future.

Homeostatic structural plasticity can account for topology changes following deafferentation and focal stroke.

PubMed

Butz, Markus; Steenbuck, Ines D; van Ooyen, Arjen

2014-01-01

After brain lesions caused by tumors or stroke, or after lasting loss of input (deafferentation), inter- and intra-regional brain networks respond with complex changes in topology. Not only areas directly affected by the lesion but also regions remote from the lesion may alter their connectivity-a phenomenon known as diaschisis. Changes in network topology after brain lesions can lead to cognitive decline and increasing functional disability. However, the principles governing changes in network topology are poorly understood. Here, we investigated whether homeostatic structural plasticity can account for changes in network topology after deafferentation and brain lesions. Homeostatic structural plasticity postulates that neurons aim to maintain a desired level of electrical activity by deleting synapses when neuronal activity is too high and by providing new synaptic contacts when activity is too low. Using our Model of Structural Plasticity, we explored how local changes in connectivity induced by a focal loss of input affected global network topology. In accordance with experimental and clinical data, we found that after partial deafferentation, the network as a whole became more random, although it maintained its small-world topology, while deafferentated neurons increased their betweenness centrality as they rewired and returned to the homeostatic range of activity. Furthermore, deafferentated neurons increased their global but decreased their local efficiency and got longer tailed degree distributions, indicating the emergence of hub neurons. Together, our results suggest that homeostatic structural plasticity may be an important driving force for lesion-induced network reorganization and that the increase in betweenness centrality of deafferentated areas may hold as a biomarker for brain repair.

Small strokes causing severe vertigo: frequency of false-negative MRIs and nonlacunar mechanisms.

PubMed

Saber Tehrani, Ali S; Kattah, Jorge C; Mantokoudis, Georgios; Pula, John H; Nair, Deepak; Blitz, Ari; Ying, Sarah; Hanley, Daniel F; Zee, David S; Newman-Toker, David E

2014-07-08

Describe characteristics of small strokes causing acute vestibular syndrome (AVS). Ambispective cross-sectional study of patients with AVS (acute vertigo or dizziness, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with at least one stroke risk factor from 1999 to 2011 at a single stroke referral center. Patients underwent nonquantitative HINTS "plus" examination (head impulse, nystagmus, test-of-skew plus hearing), neuroimaging to confirm diagnoses (97% by MRI), and repeat MRI in those with initially normal imaging but clinical signs of a central lesion. We identified patients with diffusion-weighted imaging (DWI) strokes ≤10 mm in axial diameter. Of 190 high-risk AVS presentations (105 strokes), we found small strokes in 15 patients (median age 64 years, range 41-85). The most common vestibular structure infarcted was the inferior cerebellar peduncle (73%); the most common stroke location was the lateral medulla (60%). Focal neurologic signs were present in only 27%. The HINTS "plus" battery identified small strokes with greater sensitivity than early MRI-DWI (100% vs 47%, p < 0.001). False-negative initial MRIs (6-48 hours) were more common with small strokes than large strokes (53% [n = 8/15] vs 7.8% [n = 7/90], p < 0.001). Nonlacunar stroke mechanisms were responsible in 47%, including 6 vertebral artery occlusions or dissections. Small strokes affecting central vestibular projections can present with isolated AVS. The HINTS "plus" hearing battery identifies these patients with greater accuracy than early MRI-DWI, which is falsely negative in half, up to 48 hours after onset. We found nonlacunar mechanisms in half, suggesting greater risk than might otherwise be assumed for patients with such small infarctions. © 2014 American Academy of Neurology.

Focal Low and Global High Permeability Predict the Possibility, Risk, and Location of Hemorrhagic Transformation following Intra-Arterial Thrombolysis Therapy in Acute Stroke.

PubMed

Li, Y; Xia, Y; Chen, H; Liu, N; Jackson, A; Wintermark, M; Zhang, Y; Hu, J; Wu, B; Zhang, W; Tu, J; Su, Z; Zhu, G

2017-09-01

The contrast volume transfer coefficient ( K trans ), which reflects blood-brain barrier permeability, is influenced by circulation and measurement conditions. We hypothesized that focal low BBB permeability values can predict the spatial distribution of hemorrhagic transformation and global high BBB permeability values can predict the likelihood of hemorrhagic transformation. We retrospectively enrolled 106 patients with hemispheric stroke who received intra-arterial thrombolytic treatment. K trans maps were obtained with first-pass perfusion CT data. The K trans values at the region level, obtained with the Alberta Stroke Program Early CT Score system, were compared to determine the differences between the hemorrhagic transformation and nonhemorrhagic transformation regions. The K trans values of the whole ischemic region based on baseline perfusion CT were obtained as a variable to hemorrhagic transformation possibility at the global level. Forty-eight (45.3%) patients had hemorrhagic transformation, and 21 (19.8%) had symptomatic intracranial hemorrhage. At the region level, there were 82 ROIs with hemorrhagic transformation and parenchymal hemorrhage with a mean K trans , 0.5 ± 0.5/min, which was significantly lower than that in the nonhemorrhagic transformation regions ( P < .01). The mean K trans value of 615 nonhemorrhagic transformation ROIs was 0.7 ± 0.6/min. At the global level, there was a significant difference ( P = .01) between the mean K trans values of patients with symptomatic intracranial hemorrhage (1.3 ± 0.9) and those without symptomatic intracranial hemorrhage (0.8 ± 0.4). Only a high K trans value at the global level could predict the occurrence of symptomatic intracranial hemorrhage ( P < .01; OR = 5.04; 95% CI, 2.01-12.65). Global high K trans values can predict the likelihood of hemorrhagic transformation or symptomatic intracranial hemorrhage at the patient level, whereas focal low K trans values can predict the spatial distributions of hemorrhagic transformation at the region level. © 2017 by American Journal of Neuroradiology.

Brain metabolic pattern analysis using a magnetic resonance spectra classification software in experimental stroke.

PubMed

Jiménez-Xarrié, Elena; Davila, Myriam; Candiota, Ana Paula; Delgado-Mederos, Raquel; Ortega-Martorell, Sandra; Julià-Sapé, Margarida; Arús, Carles; Martí-Fàbregas, Joan

2017-01-13

Magnetic resonance spectroscopy (MRS) provides non-invasive information about the metabolic pattern of the brain parenchyma in vivo. The SpectraClassifier software performs MRS pattern-recognition by determining the spectral features (metabolites) which can be used objectively to classify spectra. Our aim was to develop an Infarct Evolution Classifier and a Brain Regions Classifier in a rat model of focal ischemic stroke using SpectraClassifier. A total of 164 single-voxel proton spectra obtained with a 7 Tesla magnet at an echo time of 12 ms from non-infarcted parenchyma, subventricular zones and infarcted parenchyma were analyzed with SpectraClassifier ( http://gabrmn.uab.es/?q=sc ). The spectra corresponded to Sprague-Dawley rats (healthy rats, n = 7) and stroke rats at day 1 post-stroke (acute phase, n = 6 rats) and at days 7 ± 1 post-stroke (subacute phase, n = 14). In the Infarct Evolution Classifier, spectral features contributed by lactate + mobile lipids (1.33 ppm), total creatine (3.05 ppm) and mobile lipids (0.85 ppm) distinguished among non-infarcted parenchyma (100% sensitivity and 100% specificity), acute phase of infarct (100% sensitivity and 95% specificity) and subacute phase of infarct (78% sensitivity and 100% specificity). In the Brain Regions Classifier, spectral features contributed by myoinositol (3.62 ppm) and total creatine (3.04/3.05 ppm) distinguished among infarcted parenchyma (100% sensitivity and 98% specificity), non-infarcted parenchyma (84% sensitivity and 84% specificity) and subventricular zones (76% sensitivity and 93% specificity). SpectraClassifier identified candidate biomarkers for infarct evolution (mobile lipids accumulation) and different brain regions (myoinositol content).

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis.

PubMed

Dong, Mei-Xue; Hu, Qing-Chuan; Shen, Peng; Pan, Jun-Xi; Wei, You-Dong; Liu, Yi-Yun; Ren, Yi-Fei; Liang, Zi-Hong; Wang, Hai-Yang; Zhao, Li-Bo; Xie, Peng

2016-01-01

Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger's test were obtained to detect publication bias. We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis

PubMed Central

Wei, You-Dong; Liu, Yi-Yun; Ren, Yi-Fei; Liang, Zi-Hong; Wang, Hai-Yang; Zhao, Li-Bo; Xie, Peng

2016-01-01

Background and Purpose Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Methods Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger’s test were obtained to detect publication bias. Results We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. Conclusions This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA. PMID:27387385

Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation.

PubMed

Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

2017-01-01

Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway.

Task-specific compensation and recovery following focal motor cortex lesion in stressed rats.

PubMed

Kirkland, Scott W; Smith, Lori K; Metz, Gerlinde A

2012-03-01

One reason for the difficulty to develop effective therapies for stroke is that intrinsic factors, such as stress, may critically influence pathological mechanisms and recovery. In cognitive tasks, stress can both exaggerate and alleviate functional loss after focal ischemia in rodents. Using a comprehensive motor assessment in rats, this study examined if chronic stress and corticosterone treatment affect skill recovery and compensation in a task-specific manner. Groups of rats received daily restraint stress or oral corticosterone supplementation for two weeks prior to a focal motor cortex lesion. After lesion, stress and corticosterone treatments continued for three weeks. Motor performance was assessed in two skilled reaching tasks, skilled walking, forelimb inhibition, forelimb asymmetry and open field behavior. The results revealed that persistent stress and elevated corticosterone levels mainly limit motor recovery. Treated animals dropped larger amounts of food in successful reaches and showed exaggerated loss of forelimb inhibition early after lesion. Stress also caused a moderate, but non-significant increase in infarct size. By contrast, stress and corticosterone treatments promoted reaching success and other quantitative measures in the tray reaching task. Comparative analysis revealed that improvements are due to task-specific development of compensatory strategies. These findings suggest that stress and stress hormones may partially facilitate task-specific and adaptive compensatory movement strategies. The observations support the notion that hypothalamic-pituitary-adrenal axis activation may be a key determinant of recovery and motor system plasticity after ischemic stroke.

Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke.

PubMed

Ge, Ruimin; Tornero, Daniel; Hirota, Masao; Monni, Emanuela; Laterza, Cecilia; Lindvall, Olle; Kokaia, Zaal

2017-07-28

Choroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer's disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown. Adult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx 3 cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed using flow cytometry. Infiltration of MDMs into CP and CSF were validated using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. CD115+ monocytes were isolated using a magnetic cell separation system from bone marrow of Cx 3 cr1-GFP or wild-type C57BL/6 donor mice. The freshly isolated monocytes or M2-like MDMs primed in vitro with IL4 and IL13 were stereotaxically injected into the lateral ventricle of stroke-affected mice to trace for their migration into ischemic hemisphere or to assess their effect on post-stroke recovery using open field, corridor, and active avoidance behavioral tests. We found that CP responded to cortical stroke by upregulation of gene expression for several possible mediators of MDM trafficking and, concomitantly, MDMs increased in CP and cerebrospinal fluid (CSF). We then confirmed that MDMs infiltrated from blood into CP and CSF after the insult using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. When MDMs were directly administered into CSF following stroke, they homed to the ischemic hemisphere. If they had been primed in vitro prior to their administration to become M2-like macrophages, they promoted post-stroke recovery of motor and cognitive function without influencing infarct volume. Our findings suggest the possibility that autologous transplantation of M2-like MDMs into CSF might be developed into a new strategy for promoting recovery also in patients with stroke.

Mental Number Line Disruption in a Right-Neglect Patient after a Left-Hemisphere Stroke

ERIC Educational Resources Information Center

Pia, Lorenzo; Corazzini, Luca Latini; Folegatti, Alessia; Gindri, Patrizia; Cauda, Franco

2009-01-01

A right-neglect patient with focal left-hemisphere damage to the posterior superior parietal lobe was assessed for numerical knowledge and tested on the bisection of numerical intervals and visual lines. The semantic and verbal knowledge of numbers was preserved, whereas the performance in numerical tasks that strongly emphasize the visuo-spatial…

Predictive value of vertebral artery extracranial color-coded duplex sonography for ischemic stroke-related vertigo.

PubMed

Liou, Li-Min; Lin, Hsiu-Fen; Huang, I-Fang; Chang, Yang-Pei; Lin, Ruey-Tay; Lai, Chiou-Lian

2013-12-01

Vertigo can be a major presentation of posterior circulation stroke and can be easily misdiagnosed because of its complicated presentation. We thus prospectively assessed the predictive value of vertebral artery extracranial color-coded duplex sonography (ECCS) for the prediction of ischemic stroke-related vertigo. The inclusion criteria were: (1) a sensation of whirling (vertigo); (2) intractable vertigo for more than 1 hour despite appropriate treatment; and (3) those who could complete cranial magnetic resonance imaging (MRI) and vertebral artery (V2 segment) ECCS studies. Eventually, 76 consecutive participants with vertigo were enrolled from Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan between August 2010 and August 2011. Demographic data, neurological symptoms, neurologic examinations, and V2 ECCS were assessed. We chose the parameters of peak systolic velocity (PSV), end diastolic velocity (EDV), PSV/EDV, mean velocity (MV), resistance index (RI), and pulsatility index (PI) to represent the hemodynamics. Values from both sides of V2 segments were averaged. We then calculated the average RI (aRI), average PI (aPI), average PSV (aPSV)/EDV, and average (aMV). Axial and coronal diffusion-weighted MRI findings determined the existence of acute ischemic stroke. We grouped and analyzed participants in two ways (way I and way II analyses) based on the diffusion-weighted MRI findings (to determine whether there was acute stroke) and neurological examinations. Using way I analysis, the "MRI (+)" group had significantly higher impedance (aRI, aPI, and aPSV/EDV ratio) and lower velocity (aPSV, aEDV, and aMV(PSV + EDV/2)), compared to the "MRI (-)" group. The cutoff value/sensitivity/specificity of aPSV, aEDV, aMV, aPI, aRI, and aPSV/EDV between the MRI (+) and MRI (-) groups were 41.15/61.5/66.0 (p = 0.0101), 14.55/69.2/72.0 (p = 0.0003), 29.10/92.1/38.0 (p = 0.0013), 1.07/76.9/64.0 (p = 0.0066), 0.62/76.9/64.0 (p = 0.0076), and 2.69/80.8/66.0 (p = 0.0068), respectively. Using way II analysis, lower aEDV and aMV, and higher aRI, aPI, and aPSV/EDV ratio could determine the "MRI (+) without focal signs" group. The cutoff value/sensitivity/specificity of aEDV, aMV, aPI, aRI, and aPSV/EDV between the MRI (+) without focal signs and MRI (-) groups were 9.10/71.4/96.0 (p = 0.0005), 15.65/57.1/96.0 (p = 0.0124), 1.10/100/70.0 (p = 0.0002), 0.64/100/70.0 (p = 0.0023), and 2.80/100/70.0 (p = 0.0017), respectively. In conclusion, using demographic data and clinical symptoms, it was difficult to determine the patients with ischemic stroke-related vertigo. Although neurological examinations still have diagnostic value, the high impedance and low velocity pattern of V2 ECCS can be an add-on method for the screening of acute ischemic stroke-related vertigo, even for those without focal neurological signs. Copyright © 2013. Published by Elsevier B.V.

The PLAN score: a bedside prediction rule for death and severe disability following acute ischemic stroke.

PubMed

O'Donnell, Martin J; Fang, Jiming; D'Uva, Cami; Saposnik, Gustavo; Gould, Linda; McGrath, Emer; Kapral, Moira K

2012-11-12

We sought to develop and validate a simple clinical prediction rule for death and severe disability after acute ischemic stroke that can be used by general clinicians at the time of hospital admission. We analyzed data from a registry of 9847 patients (4943 in the derivation cohort and 4904 in the validation cohort) hospitalized with acute ischemic stroke and included in the Registry of the Canadian Stroke Network (July 1, 2003, to March 31, 2008; 11 regional stroke centers in Ontario, Canada). Outcome measures were 30-day and 1-year mortality and a modified Rankin score of 5 to 6 at discharge. Overall 30-day mortality was 11.5% (derivation cohort) and 13.5% (validation cohort). In the final multivariate model, we included 9 clinical variables that could be categorized as preadmission comorbidities (5 points for preadmission dependence [1.5], cancer [1.5], congestive heart failure [1.0], and atrial fibrillation [1.0]), level of consciousness (5 points for reduced level of consciousness), age (10 points, 1 point/decade), and neurologic focal deficit (5 points for significant/total weakness of the leg [2], weakness of the arm [2], and aphasia or neglect [1]). Maximum score is 25. In the validation cohort, the PLAN score (derived from preadmission comorbidities, level of consciousness, age, and neurologic deficit) predicted 30-day mortality (C statistic, 0.87), death or severe dependence at discharge (0.88), and 1-year mortality (0.84). The PLAN score also predicted favorable outcome (modified Rankin score, 0-2) at discharge (C statistic, 0.80). The PLAN clinical prediction rule identifies patients who will have a poor outcome after hospitalization for acute ischemic stroke. The score comprises clinical data available at the time of admission and may be determined by nonspecialist clinicians. Additional studies to independently validate the PLAN rule in different populations and settings are required.

Herpes Simplex Virus Encephalitis: Atypical Presentation as a Right Middle Cerebral Artery Stroke.

PubMed

Shoaib, Maria; Kraus, Jacqueline J; Khan, Muhammad T

2018-01-15

Herpes simplex virus encephalitis (HSVE) is a medical emergency associated with high mortality and morbidity. Definitive diagnosis is established by history, clinical examination, neuroimaging studies, supportive electroencephalogram (EEG) findings, and cerebrospinal fluid (CSF) analysis. We report a case of HSVE presenting as a stroke mimic in a 76-year-old female with a history of atrial fibrillation on warfarin. She was admitted to our medical intensive care unit with intermittent fever, lethargy, and new onset left-sided hemiparesis. A computed tomography (CT) of the head showed a right middle cerebral artery (MCA) acute ischemic stroke with midline shift and a dense right MCA sign. Brain magnetic resonance imaging (MRI) showed evidence of acute stroke with consideration of herpes encephalitis. CSF analysis was positive for herpes simplex virus (HSV) type one. She recovered with high-dose intravenous acyclovir therapy. Our patient was a diagnostic dilemma, initially being diagnosed with an acute ischemic stroke and yet found to have HSVE, which mimicked an acute ischemic stroke. Delay in treatment may result in devastating clinical outcomes that may include severe cognitive, focal neurological deficits, persistent seizures, and even death. This case highlights the importance of a multidisciplinary approach and the need for increased awareness of an atypical presentation of HSVE among emergency physicians, neurologist, intensivists, and radiologists.

How I treat and manage strokes in sickle cell disease

PubMed Central

Kassim, Adetola A.; Galadanci, Najibah A.; Pruthi, Sumit

2015-01-01

Neurologic complications are a major cause of morbidity and mortality in sickle cell disease (SCD). In children with sickle cell anemia, routine use of transcranial Doppler screening, coupled with regular blood transfusion therapy, has decreased the prevalence of overt stroke from ∼11% to 1%. Limited evidence is available to guide acute and chronic management of individuals with SCD and strokes. Current management strategies are based primarily on single arm clinical trials and observational studies, coupled with principles of neurology and hematology. Initial management of a focal neurologic deficit includes evaluation by a multidisciplinary team (a hematologist, neurologist, neuroradiologist, and transfusion medicine specialist); prompt neuro-imaging and an initial blood transfusion (simple followed immediately by an exchange transfusion or only exchange transfusion) is recommended if the hemoglobin is >4 gm/dL and <10 gm/dL. Standard therapy for secondary prevention of strokes and silent cerebral infarcts includes regular blood transfusion therapy and in selected cases, hematopoietic stem cell transplantation. A critical component of the medical care following an infarct is cognitive and physical rehabilitation. We will discuss our strategy of acute and long-term management of strokes in SCD. PMID:25824688

YC‑1 reduces inflammatory responses by inhibiting nuclear factor‑κB translocation in mice subjected to transient focal cerebral ischemia.

PubMed

Lee, Wei-Ting; Tai, Shih-Huang; Lin, Yu-Wen; Wu, Tian-Shung; Lee, E-Jian

2018-06-15

3‑(5‑hydroxymethyl‑2‑furyl)‑1‑benzyl‑indazole (YC‑1) is understood to protect against ischemic stroke, but the molecular basis for its neuroprotection remains to be fully characterized. The present study investigated the influence of YC‑1 on inflammatory responses following experimental stroke. Previous studies indicated that nuclear factor (NF)‑κB‑driven signals serve a pivotal role in mediating inflammatory responses following stroke. Ischemic stroke results in activation of NF‑κB to induce gene expression of factors including inducible nitric oxide synthase, interleukin (IL)‑1β, IL‑6 and matrix metalloproteinases (MMPs). The results of the present study demonstrated that YC‑1 effectively reduced brain infarction and brain edema, and improved blood‑brain barrier leakage. Additionally, animals treated with YC‑1 exhibited significant reductions in neutrophil and macrophage infiltration into the ischemic brain. Furthermore, YC‑1 effectively inhibited NF‑κB translocation and binding activity, and the activity and expression of MMP‑9 following ischemic stroke. In conclusion, YC‑1 may effectively attenuate NF‑κB‑induced inflammatory damage following cerebral ischemia‑reperfusion.

Neuroprotective effect of humic Acid on focal cerebral ischemia injury: an experimental study in rats.

PubMed

Ozkan, Adile; Sen, Halil Murat; Sehitoglu, Ibrahim; Alacam, Hasan; Guven, Mustafa; Aras, Adem Bozkurt; Akman, Tarik; Silan, Coşkun; Cosar, Murat; Karaman, Handan Isin Ozisik

2015-02-01

Stroke is still a major cause of death and permanent neurological disability. As humic acids are well-known antioxidant molecules, the purpose of this study was to investigate the potential neuroprotective effects of humic acid in a focal cerebral ischemia model. Twenty-four rats were divided equally into three groups. A middle cerebral artery occlusion model was performed in this study where control (group II) and humic acid (group III) were administered intraperitoneally following an ischemic experimental procedure. Group I was evaluated as sham. Malondialdehyde (MDA), superoxide dismutase (SOD), and nuclear respiratory factor-1 (NRF-1) levels were analyzed biochemically on the right side of the ischemic cerebral hemisphere, while ischemic histopathological studies were completed on the left side to investigate the antioxidant status. Biochemical results showed that SOD and NRF-1 levels were significantly increased in the humic acid group (III) compared with the control group (II) while MDA levels were significantly decreased. On histopathological examination, cerebral edema, vacuolization, degeneration, and destruction of neural elements were decreased in the humic acid group (III) compared with the control group (II). Cerebral ischemia was attenuated by humic acid administration. These observations indicate that humic acid may have potential as a therapeutic agent in cerebral ischemia by preventing oxidative stress.

Neuroprotective effect of oxaloacetate in a focal brain ischemic model in the rat.

PubMed

Knapp, L; Gellért, L; Kocsis, K; Kis, Z; Farkas, T; Vécsei, L; Toldi, J

2015-01-01

During an ischemic event, the well-regulated glutamate (Glu) homeostasis is disturbed, which gives rise to extremely high levels of this excitatory neurotransmitter in the brain tissues. It was earlier reported that the administration of oxaloacetate (OxAc) as a Glu scavenger reduces the Glu level in the brain by enhancing the brain-to-blood Glu efflux. Here, we studied the neuroprotective effect of OxAc administration in a new focal ischemic model in rats. Occlusion of the middle cerebral artery resulted in immediate reduction of the somatosensory-evoked responses (SERs), and the amplitudes remained at the reduced level throughout the whole ischemic period. On reperfusion, the SERs started to increase, but never reached the control level. OxAc proved to be protective, since the amplitudes started to recover even during the ischemia, and finally fully regained the control level. The findings of the histological measurements were in accordance with the electrophysiological data. After Fluoro Jade C staining, significantly fewer labeled cells were detected in the OxAc-treated group relative to the control. These results provide new evidence of the neuroprotective effect of OxAc against ischemic injury, which strengthens the likelihood of its future applicability as a novel neuroprotective agent for the treatment of ischemic stroke patients.

Cerebrolysin and aquaporin 4 inhibition improve pathological and motor recovery after ischemic stroke.

PubMed

Catalin, Bogdan; Rogoveanu, O C; Pirici, Ionica; Balseanu, Tudor Adrian; Stan, Adina; Tudorica, Valerica; Balea, Maria; Mindrila, Ion; Albu, Carmen Valeria; Mohamed, Guleed; Pirici, Daniel; Muresanu, Dafin Fior

2018-04-25

Edema represents one of the earliest negative markers of survival and consecutive neurological deficit following stroke. The mixture of cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema, which leaves parenteral administration of a hypertonic solution as the only non-surgical alternative. New insights into water metabolism in the brain have opened the way for molecular targeted treatment, with aquaporin 4 channels (AQP4) taking center stage. We aimed here to assess the effect of inhibiting AQP4 together with the administration of a neurotropic factor (Cerebrolysin) in ischemic stroke. Using a permanent medial cerebral artery occlusion rat model, we administrated a single dose of the AQP4 inhibitor TGN-020 (100 mg/kg) at 15 minutes after ischemia followed by daily Cerebrolysin dosing (5ml/kg) for seven days. Rotarod motor testing and neuropathology examinations were next performed. We showed first that the combination treatment animals have a better motor function preservation at seven days after permanent ischemia. We have also identified distinct cellular contributions that represent the bases of behavior testing, such as less astrocyte scarring and a larger neuronal-survival phenotype rate in animals treated with both compounds than in animals treated with Cerebrolysin alone or untreated animals. Our data shows that water diffusion inhibition and Cerebrolysin administration after focal ischemic stroke reduces infarct size, leading to a higher neuronal survival in the peri-core glial scar region. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Depletion of Cultivatable Gut Microbiota by Broad-Spectrum Antibiotic Pretreatment Worsens Outcome After Murine Stroke

PubMed Central

Winek, Katarzyna; Engel, Odilo; Koduah, Priscilla; Heimesaat, Markus M.; Fischer, André; Bereswill, Stefan; Dames, Claudia; Kershaw, Olivia; Gruber, Achim D.; Curato, Caterina; Oyama, Naoki; Meisel, Christian; Meisel, Andreas

2016-01-01

Background and Purpose— Antibiotics disturbing microbiota are often used in treatment of poststroke infections. A bidirectional brain–gut microbiota axis was recently suggested as a modulator of nervous system diseases. We hypothesized that gut microbiota may be an important player in the course of stroke. Methods— We investigated the outcome of focal cerebral ischemia in C57BL/6J mice after an 8-week decontamination with quintuple broad-spectrum antibiotic cocktail. These microbiota-depleted animals were subjected to 60 minutes middle cerebral artery occlusion or sham operation. Infarct volume was measured using magnetic resonance imaging, and mice were monitored clinically throughout the whole experiment. At the end point, tissues were preserved for further analysis, comprising histology and immunologic investigations using flow cytometry. Results— We found significantly decreased survival in the middle cerebral artery occlusion microbiota-depleted mice when the antibiotic cocktail was stopped 3 days before surgery (compared with middle cerebral artery occlusion specific pathogen-free and sham-operated microbiota-depleted mice). Moreover, all microbiota-depleted animals in which antibiotic treatment was terminated developed severe acute colitis. This phenotype was rescued by continuous antibiotic treatment or colonization with specific pathogen-free microbiota before surgery. Further, infarct volumes on day one did not differ between any of the experimental groups. Conclusions— Conventional microbiota ensures intestinal protection in the mouse model of experimental stroke and prevents development of acute and severe colitis in microbiota-depleted mice not given antibiotic protection after cerebral ischemia. Our experiments raise the clinically important question as to whether microbial colonization or specific microbiota are crucial for stroke outcome. PMID:27056982

Cerebrovascular complications of alcohol and sympathomimetic drug abuse.

PubMed

Bruno, Askiel

2003-01-01

Alcohol abuse has been linked to intracranial hemorrhage, both intracerebral and subarachnoid. Some studies have found a dose-response relationship, so that increasing levels of abuse are associated with greater risk of hemorrhage. However, alcohol abuse has not been clearly linked to cerebral infarction, and some studies find that mild-to-moderate drinking appears to be associated with a decreased risk of cerebral infarction. Intravenous administration of drugs of abuse predisposes to endocarditis, which may lead to embolic stroke. Associations have been reported between various sympathomimetic drugs and cerebral infarction. A possible mechanism for cerebral infarction is focal arterial vasoconstriction and occasionally cerebral vasculitis. Associations have also been reported between various sympathomimetic drugs and intracranial hemorrhage. A likely mechanism for intracranial hemorrhage is acute arterial hypertension. With the exception of endocarditis, management of stroke related to drug abuse is largely supportive, with emphasis on supportive care to prevent stroke complications, physical and occupational therapy, and aggressive addiction rehabilitation.

High-altitude cerebral oedema mimicking stroke.

PubMed

Yanamandra, Uday; Gupta, Amul; Patyal, Sagarika; Varma, Prem Prakash

2014-03-26

High-altitude cerebral oedema (HACO) is the most fatal high-altitude illness seen by rural physicians practising in high-altitude areas. HACO presents clinically with cerebellar ataxia, features of raised intracranial pressure (ICP) and coma. Early identification is important as delay in diagnosis can be fatal. We present two cases of HACO presenting with focal deficits mimicking stroke. The first patient presented with left-sided hemiplegia associated with the rapid deterioration in the sensorium. Neuroimaging revealed features suggestive of vasogenic oedema. The second patient presented with monoplegia of the lower limb. Neuroimaging revealed perfusion deficit in anterior cerebral artery territory. Both patients were managed with dexamethasone and they improved dramatically. Clinical picture and neuroimaging closely resembled acute ischaemic stroke in both cases. Thrombolysis in these patients would have been disastrous. Recent travel to high altitude, young age, absence of atherosclerotic risk factors and features of raised ICP concomitantly directed the diagnosis to HACO.

[Clinical efficiency of Vasonat in neurometabolic therapy of patients with ischemic stroke at early rehabilitation period].

PubMed

Abasova, G B; Tyksanbaeva, G U; Orazalieva, D B; Kasymova, S K

2011-01-01

Research of efficiency and safety of Vasonat has been carried out. 31 patients aged 46-75 years who had had hemispheric athero- thrombotic or hemodynamic schemic stroke with moderate severity and being treated in 2-5-month of early rehabilitation period have been observed. The control group of patients received placebo. Results of the study, 4 weeks treatment using Vasonat in the dosage of 500 mg/day have shown positive effect on common signs of the disease by decreasing headache intensity, dizziness, a nausea, and on focal neurological symptoms by decreasing hemiparesis degree; psychoemotional and mnestic activity (main memory and attention) improved as well. It was more distinct in patients with localization of the stroke in the right hemisphere of the brain. It was also noted more rapid improvement of motion function and quality of life of patients.

Motor recovery and cortical plasticity after functional electrical stimulation in a rat model of focal stroke.

PubMed

Cecatto, Rebeca Boltes; Maximino, Jessica Ruivo; Chadi, Gerson

2014-09-01

The aim of this study was to investigate the functional responses and plastic cortical changes in a sample of animals with sequelae of cerebral ischemia that were subjected to a model of functional electrical stimulation (FES). Rats received an ischemic cortical lesion (Rose Bengal method) and were randomized and submitted to an FES stimulation (1-2 mA, 30 Hz, 20-40 mins for 14 days) or sham stimulation. The Foot Fault Test was performed before inducing the cortical lesion and also before and after FES. Brain immunochemistry labeling with microtubule-associated protein-2 and neurofilament-200 markers was performed after FES. The authors found a decreased percentage of errors in the Foot Fault Test (P < 0.001) in the stimulated group compared with the sham group after FES. FES has not altered the lesion size. Spontaneous motor parameters returned to basal values in both groups. The qualitative analysis showed an increased amount of radial microtubule-associated protein-2 immunoreactive fibers in the preserved cortex adjacent to stroke site in the stimulated animals. Regarding the measurements of neurofilament-200 immunostaining, there were no differences between the hemispheres or groups in area or intensity. Acute and short period of FES led to motor recovery of ankle joint neurodisability. The extent to which compensatory plasticity occurs after stroke or after FES and the extent to which it contributes to functional recovery are yet unclear. The changes induced by the stimulation may improve the ability of the nervous system to undergo spontaneous recovery, which is of substantial interest for neurorehabilitation strategies.

Neurotherapeutic activity of the recombinant heat shock protein Hsp70 in a model of focal cerebral ischemia in rats.

PubMed

Shevtsov, Maxim A; Nikolaev, Boris P; Yakovleva, Ludmila Y; Dobrodumov, Anatolii V; Dayneko, Anastasiy S; Shmonin, Alexey A; Vlasov, Timur D; Melnikova, Elena V; Vilisov, Alexander D; Guzhova, Irina V; Ischenko, Alexander M; Mikhrina, Anastasiya L; Galibin, Oleg V; Yakovenko, Igor V; Margulis, Boris A

2014-01-01

Recombinant 70 kDa heat shock protein (Hsp70) is an antiapoptotic protein that has a cell protective activity in stress stimuli and thus could be a useful therapeutic agent in the management of patients with acute ischemic stroke. The neuroprotective and neurotherapeutic activity of recombinant Hsp70 was explored in a model of experimental stroke in rats. Ischemia was produced by the occlusion of the middle cerebral artery for 45 minutes. To assess its neuroprotective capacity, Hsp70, at various concentrations, was intravenously injected 20 minutes prior to ischemia. Forty-eight hours after ischemia, rats were sacrificed and brain tissue sections were stained with 2% triphenyl tetrazolium chloride. Preliminary treatment with Hsp70 significantly reduced the ischemic zone (optimal response at 2.5 mg/kg). To assess Hsp70's neurotherapeutic activity, we intravenously administered Hsp70 via the tail vein 2 hours after reperfusion (2 hours and 45 minutes after ischemia). Rats were then kept alive for 72 hours. The ischemic region was analyzed using a high-field 11 T MRI scanner. Administration of the Hsp70 decreased the infarction zone in a dose-dependent manner with an optimal (threefold) therapeutic response at 5 mg/kg. Long-term treatment of the ischemic rats with Hsp70 formulated in alginate granules with retarded release of protein further reduced the infarct volume in the brain as well as apoptotic area (annexin V staining). Due to its high neurotherapeutic potential, prolonged delivery of Hsp70 could be useful in the management of acute ischemic stroke.

Transient Beneficial Effects of Excitatory Theta Burst Stimulation in a Patient with Phonological Agraphia after Left Supramarginal Gyrus Infarction

ERIC Educational Resources Information Center

Nardone, Raffaele; De Blasi, Pierpaolo; Zuccoli, Giulio; Tezzon, Frediano; Golaszewski, Stefan; Trinka, Eugen

2012-01-01

We report a patient showing isolated phonological agraphia after an ischemic stroke involving the left supramarginal gyrus (SMG). In this patient, we investigated the effects of focal repetitive transcranial magnetic stimulation (rTMS) given as theta burst stimulation (TBS) over the left SMG, corresponding to the Brodmann area (BA) 40. The patient…

Protective effects of angiopoietin-like 4 on the blood-brain barrier in acute ischemic stroke treated with thrombolysis in mice.

PubMed

Zhang, Bin; Xu, Xiaofeng; Chu, Xiuli; Yu, Xiaoyang; Zhao, Yuwu

2017-04-03

Given the risk of blood-brain barrier damage (BBB) caused by ischemic and tissue plasminogen activator thrombolysis, the preservation of vascular integrity is important. Angiopoietin-like 4 (ANGPTL4), a protein secreted in hypoxia, is involved in the regulation of vascular permeability. We hypothesized that Angptl4 might exert a protective effect in thrombolysis through stabilizing blood-brain barrier and inhibit hyper-permeability. We investigated the role of Angptl4 in stroke using a transient focal cerebral ischemia mouse model. The treated mice were administered Angptl4 1h after the ischemic event upon reperfusion. Our results showed that Angptl4 combined with thrombolysis greatly reduced the infarct volume and consequent neurological deficit. Western blot analyses and gelatin zymography revealed that Angptl4 protected the integrity of the endothelium damaged by thrombolysis. Angptl4 inhibited the up-regulation of vascular endothelial growth factor (VEGF) in the vascular endothelium after stroke, which was suppressed by counteracting VEGFR signaling and diminishing downstream Src signaling, and led to the increased stability of junctions and improved endothelial cell barrier integrity. These findings demonstrated that Angptl4 protects the permeability of the BBB damaged by ischemic and thrombolysis. Suggested that Angptl4 might be a promising target molecule in therapies for vasoprotection after thrombolysis treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Apixaban decreases brain thrombin activity in a male mouse model of acute ischemic stroke.

PubMed

Bushi, Doron; Chapman, Joab; Wohl, Anton; Stein, Efrat Shavit; Feingold, Ekaterina; Tanne, David

2018-05-14

Factor Xa (FXa) plays a critical role in the coagulation cascade by generation of thrombin. During focal ischemia thrombin levels increase in the brain tissue and cause neural damage. This study examined the hypothesis that administration of the FXa inhibitor, apixaban, following focal ischemic stroke may have therapeutic potential by decreasing brain thrombin activity and infarct volume. Male mice were divided into a treated groups that received different doses of apixaban (2, 20, 100 mg/kg administered I.P.) or saline (controls) immediately after blocking the middle cerebral artery (MCA). Thrombin activity was measured by a fluorescence assay on fresh coronal slices taken from the mice brains 24 hr following the MCA occlusion. Infarct volume was assessed using triphenyltetrazolium chloride staining. A high dose of apixaban (100 mg/kg) significantly decreased thrombin activity levels in the ipsilateral hemisphere compared to the control group (Slice#5, p = .016; Slice#6, p = .016; Slice#7, p = .016; Slice#8, p = .036; by the nonparametric Mann-Whitney test). In addition, treatment with apixaban doses of both 100 mg/kg (32 ± 8% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .005 by the nonparametric Mann-Whitney test) and 20 mg/kg (43 ± 7% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .019 by the nonparametric Mann-Whitney test) decreased infarct volumes in areas surrounding the ischemic core (Slices #3 and #8). No brain hemorrhages were observed either in the treated or control groups. In summary, I.P. administration of high dose of apixaban immediately after MCA occlusion decreases brain thrombin activity and reduces infarct size. © 2018 Wiley Periodicals, Inc.

Sodium phenylbutyrate ameliorates focal cerebral ischemic/reperfusion injury associated with comorbid type 2 diabetes by reducing endoplasmic reticulum stress and DNA fragmentation.

PubMed

Srinivasan, Krishnamoorthy; Sharma, Shyam S

2011-11-20

Endoplasmic reticulum (ER) stress has been postulated to play a crucial role in the pathophysiology of cerebral ischemic/reperfusion (I/R) injury and diabetes. Diabetes is a major risk factor and also common amongst the people who suffer from stroke. In this study, we have investigated the neuroprotective potential of sodium 4-phenylbutyrate (SPB; 30-300mg/kg), a chemical chaperone by targeting ER stress in a rat model of transient focal cerebral ischemia associated with comorbid type 2 diabetes. Intraperitoneal treatment with SPB (100 and 300mg/kg) significantly ameliorated brain I/R damage as evidenced by reduction in cerebral infarct and edema volume. It also significantly improved the functional recovery of various neurobehavioral impairments (neurological deficit score, grip strength and rota rod) evoked by I/R compared with vehicle-treatment. Further, SPB (100mg/kg) significantly reduced the DNA fragmentation as shown by prominent reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells. This effect was observed concomitantly with significant attenuation in upregulation of 78kDa glucose regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-12, specific markers of ER stress/apoptosis. The neuroprotection observed with SPB was independent of its effect on cerebral blood flow and blood glucose. In conclusion, this study demonstrates the neuroprotective effect of SPB owing to amelioration of ER stress and DNA fragmentation. It also suggest that targeting ER stress might offer a promising therapeutic approach and benefits against ischemic stroke associated with comorbid type 2 diabetes. Copyright © 2011 Elsevier B.V. All rights reserved.

Breviscapine confers a neuroprotective efficacy against transient focal cerebral ischemia by attenuating neuronal and astrocytic autophagy in the penumbra.

PubMed

Pengyue, Zhang; Tao, Guo; Hongyun, He; Liqiang, Yang; Yihao, Deng

2017-06-01

Breviscapine is a flavonoid derived from a traditional Chinese herb Erigerin breviscapus (Vant.) Hand-Mazz, and has been extensively used in clinical treatment for cerebral stroke in China, but the underlying pharmacological mechanisms are still unclear. In present study, we investigated whether breviscapine could confer a neuroprotection against cerebral ischemia injury by targeting autophagy mechanisms. A cerebral stroke model in Sprague-Dawley rats was prepared by middle cerebral artery occlusion (MCAO), rats were then randomly divided into 5 groups: MCAO+Bre group, rats were treated with breviscapine; MCAO+Tat-Beclin-1 group, animals were administrated with specific autophagy inducer Tat-Beclin-1; MCAO+Bre+Tat-Beclin-1 group, rats were treated with both breviscapine and Tat-Beclin-1, MCAO+saline group, rats received the same volume of physiological saline, and Sham surgery group. The autophagy levels in infarct penumbra were evaluated by western blotting, real-time PCR and immunofluorescence 7days after the insult. Meanwhile, infarct volume, brain water content and neurological deficit score were assessed. The results illustrated that the infarct volume, brain water content and neurofunctional deficiency were significantly reduced by 7days of breviscapine treatment in MCAO+Bre group, compared with those in MCAO+saline group. Meanwhile, the western blotting, quantitative PCR and immunofluorescence showed that the autophagy in both neurons and astrocytes at the penumbra were markedly attenuated by breviscapine admininstration. Moreover, these pharmacological effects of breviscapine could be counteracted by autophagy inducer Tat-Beclin-1. Our study suggests that breviscapine can provide a neuroprotection against transient focal cerebral ischemia, and this biological function is associated with attenuating autophagy in both neurons and astrocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Preconditioning of bone marrow-derived mesenchymal stromal cells by tetramethylpyrazine enhances cell migration and improves functional recovery after focal cerebral ischemia in rats.

PubMed

Li, Lin; Chu, Lisheng; Fang, Yan; Yang, Yan; Qu, Tiebing; Zhang, Jianping; Yin, Yuanjun; Gu, Jingjing

2017-05-12

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is one of the new therapeutic strategies for treating ischemic stroke. However, the relatively poor migratory capacity of BMSCs toward infarcted regions limited the therapeutic potential of this approach. Pharmacological preconditioning can increase the expression of CXC chemokine receptor 4 (CXCR4) in BMSCs and enhance cell migration toward the injury site. In the present study, we investigated whether tetramethylpyrazine (TMP) preconditioning could enhance BMSCs migration to the ischemic brain and improve functional recovery through upregulating CXCR4 expression. BMSCs were identified by flow cytometry analysis. BMSCs migration was evaluated in vitro by transwell migration assay, and CXCR4 expression was measured by quantitative reverse transcription-polymerase chain reaction and western blot analysis. In rats with focal cerebral ischemia, the neurological function was evaluated by the modified neurological severity score, the adhesive removal test and the corner test. The homing BMSCs and angiogenesis were detected by immunofluorescence, and expression of stromal cell-derived factor-1 (SDF-1) and CXCR4 was measured by western blot analysis. Flow cytometry analysis demonstrated that BMSCs expressed CD29 and CD90, but not CD34 and CD45. TMP pretreatment dose-dependently induced BMSCs migration and CXCR4 expression in vitro, which was significantly inhibited by AMD3100, a CXCR4 antagonist. In rat stroke models, we found more TMP-preconditioned BMSCs homing toward the infarcted regions than nonpreconditioned cells, leading to improved neurological performance and enhanced angiogenesis. Moreover, TMP-preconditioned BMSCs significantly upregulated the protein expression of SDF-1 and CXCR4 in the ischemic boundary regions. These beneficial effects of TMP preconditioning were blocked by AMD3100. TMP preconditioning enhances the migration and homing ability of BMSCs, increases CXCR4 expression, promotes angiogenesis, and improves neurological performance. Therefore, TMP preconditioning may be an effective strategy to improve the therapeutic potency of BMSCs for ischemic stroke due to enhanced BMSCs migration to ischemic regions.

18F-NaF PET Demonstrating Unusual Focal Tracer Activity in the Brain.

PubMed

Thenkondar, Anuradha; Jafari, Lida; Sooriash, Robbie; Hajsadeghi, Fereshteh; Berenji, Gholam R; Li, Yuxin

2017-02-01

A 60-year-old man with enlarged prostate, hypertension, and diabetes was referred for F-NaF PET/CT to evaluate possible metastatic lesions. The patient appeared asymptomatic on the day of the study, without any signs indicating stroke. Patient also had no known history of malignancy or cerebrovascular disease. He had mild elevation of the prostate-specific antigen level, and biopsy of his prostate was not performed. Patient had long-standing history of chronic back pain and abdominal pain. The PET bone scan demonstrated a large area of very intense tracer uptake in the brain. A subsequent brain MRI revealed prior stroke in the same area.

Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia.

PubMed

Moraga, Ana; Pradillo, Jesús M; García-Culebras, Alicia; Palma-Tortosa, Sara; Ballesteros, Ivan; Hernández-Jiménez, Macarena; Moro, María A; Lizasoain, Ignacio

2015-05-10

Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young- (2 to 3 months) and middle-aged mice (13 to 14 months). Aging increased both microglial proliferation, as shown by a higher number of BrdU(+) cells and BrdU/Iba1(+) cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1(+)/epidermal growth factor receptor (EGFR)(+)/nestin(+)/glial fibrillary acidic protein (GFAP)(+) cells) and type-C cells (prominin-1(+)/EGFR(+)/nestin(-)/Mash1(+) cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX(+) cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN(+)/BrdU(+) and GAD67(+) cells) in the peri-infarct cortical area 14 days after stroke. Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in the cortical peri-infarct area. Thus, our results highlight the importance of using aged animals for translation to clinical studies.

The Neural Cell Adhesion Molecule-Derived (NCAM)-Peptide FG Loop (FGL) Mobilizes Endogenous Neural Stem Cells and Promotes Endogenous Regenerative Capacity after Stroke.

PubMed

Klein, Rebecca; Mahlberg, Nicolas; Ohren, Maurice; Ladwig, Anne; Neumaier, Bernd; Graf, Rudolf; Hoehn, Mathias; Albrechtsen, Morten; Rees, Stephen; Fink, Gereon Rudolf; Rueger, Maria Adele; Schroeter, Michael

2016-12-01

The neural cell adhesion molecule (NCAM)-derived peptide FG loop (FGL) modulates synaptogenesis, neurogenesis, and stem cell proliferation, enhances cognitive capacities, and conveys neuroprotection after stroke. Here we investigated the effect of subcutaneously injected FGL on cellular compartments affected by degeneration and regeneration after stroke due to middle cerebral artery occlusion (MCAO), namely endogenous neural stem cells (NSC), oligodendrocytes, and microglia. In addition to immunohistochemistry, we used non-invasive positron emission tomography (PET) imaging with the tracer [ 18 F]-fluoro-L-thymidine ([ 18 F]FLT) to visualize endogenous NSC in vivo. FGL significantly increased endogenous NSC mobilization in the neurogenic niches as evidenced by in vivo and ex vivo methods, and it induced remyelination. Moreover, FGL affected neuroinflammation. Extending previous in vitro results, our data show that the NCAM mimetic peptide FGL mobilizes endogenous NSC after focal ischemia and enhances regeneration by amplifying remyelination and modulating neuroinflammation via affecting microglia. Results suggest FGL as a promising candidate to promote recovery after stroke.

Stroke as the First Clinical Manifestation of Takayasu's Arteritis.

PubMed

Pereira, Vanessa Caldeira; de Freitas, Carlos Clayton Macedo; Luvizutto, Gustavo José; Sobreira, Marcone Lima; Peixoto, Daniel Escobar Bueno; Magalhães, Inaldo do Nascimento; Bazan, Rodrigo; Braga, Gabriel Pereira

2014-09-01

Takayasu's arteritis is a chronic inflammatory disease, and neurological symptoms occur in 50% of cases, most commonly including headache, dizziness, visual disturbances, convulsive crisis, transient ischemic attack, stroke and posterior reversible encephalopathy syndrome. The aim of this study was to report the case of a young Brazilian female with a focal neurological deficit. She presented with asymmetry of brachial and radial pulses, aphasia, dysarthria and right hemiplegia. Stroke was investigated extensively in this young patient. Only nonspecific inflammatory markers such as velocity of hemosedimentation and C-reactive protein were elevated. During hospitalization, clinical treatment was performed with pulse therapy showing improvement in neurological recuperation on subsequent days. In the chronic phase, the patient was submitted to medicated angioplasty of the brachiocephalic trunk with paclitaxel, with significant improvement of the stenosis. At the 6-month follow-up, the neurological exam presented mild dysarthria, faciobrachial predominant disproportionate hemiparesis, an NIHSS score of 4 and a modified Rankin Scale score of 3 (moderate incapacity). In conclusion, Takayasu's arteritis must be recognized as a potential cause of ischemic stroke in young females.

Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

PubMed

Simpkins, Alexis N; Dias, Christian; Leigh, Richard

2016-09-01

Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption. Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression. Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013). This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator. © 2016 American Heart Association, Inc.

Down-regulation of NOX4 by betulinic acid protects against cerebral ischemia-reperfusion in mice.

PubMed

Lu, Pei; Zhang, Chen-Chen; Zhang, Xiao-Min; Li, Hui-Ge; Luo, Ai-Lin; Tian, Yu-Ke; Xu, Hui

2017-10-01

Ischemic stroke leads to high potentiality of mortality and disability. The current treatment for ischemic stroke is mainly focused on intravenous thrombolytic therapy. However, ischemia/ reperfusion induces neuronal damage, which significantly influences the outcome of patients with ischemic stroke, and the exact mechanism implicated in ischemia/reperfusion injury remains unclear, although evidence shows that oxidative stress is likely to be involved. Betulinic acid is mainly known for its anti-tumor and anti-inflammatory activities. Our previous study showed that betulinic acid could decrease the reactive oxygen species (ROS) production by regulating the expression of NADPH oxidase. Thus, we hypothesized that betulinic acid may protect against brain ischemic injury in the animal model of stroke. Focal cerebral ischemia was achieved by using the standard intraluminal occlusion method and reperfusion enabled after 2 h ischemia. Neurological deficits were scored. Infarct size was determined with 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and the mRNA expression of NADPH oxidase 4 (NOX4) was determined by RT-PCR in infarct tissue. ROS generation and apoptosis in ischemic tissue were analyzed by measuring the oxidative conversion of cell permeable 2',7'-dichloro-fluorescein diacetate (DCF-DA) to fluorescent dichlorofluorescein (DCF) in fluorescence microplate reader and TUNEL assay, respectively. In Kunming mice, 2 h of middle cerebral artery (MCA) occlusion followed by 24 or 72 h of reperfusion led to an enhanced NOX4 expression in the ischemic hemisphere. This was associated with elevated levels of ROS generation and neuronal apoptosis. Pre-treatment with betulinic acid (50 mg/kg/day for 7 days via gavage) prior to MCA occlusion prevented the ischemia/reperfusion-induced up-regulation of NOX4 and ROS production. In addition, treatment with betulinic acid could markedly blunt the ischemia/reperfusion-induced neuronal apoptosis. Finally, betulinic acid reduced infarct volume and ameliorated the neurological deficit in this stroke mouse model. Our results suggest that betulinic acid protects against cerebral ischemia/reperfusion injury in mice and the down-regulation of NOX4 may represent a mechanism contributing to this effect.

Mobilization of Endogenous Bone Marrow Derived Endothelial Progenitor Cells and Therapeutic Potential of Parathyroid Hormone after Ischemic Stroke in Mice

PubMed Central

Wang, Li-Li; Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Alaaeddine, Ghina; Li, Jimei; Wei, Ling; Yu, Shan Ping

2014-01-01

Stroke is a major neurovascular disorder threatening human life and health. Very limited clinical treatments are currently available for stroke patients. Stem cell transplantation has shown promising potential as a regenerative treatment after ischemic stroke. The present investigation explores a new concept of mobilizing endogenous stem cells/progenitor cells from the bone marrow using a parathyroid hormone (PTH) therapy after ischemic stroke in adult mice. PTH 1-34 (80 µg/kg, i.p.) was administered 1 hour after focal ischemia and then daily for 6 consecutive days. After 6 days of PTH treatment, there was a significant increase in bone marrow derived CD-34/Fetal liver kinase-1 (Flk-1) positive endothelial progenitor cells (EPCs) in the peripheral blood. PTH treatment significantly increased the expression of trophic/regenerative factors including VEGF, SDF-1, BDNF and Tie-1 in the brain peri-infarct region. Angiogenesis, assessed by co-labeled Glut-1 and BrdU vessels, was significantly increased in PTH-treated ischemic brain compared to vehicle controls. PTH treatment also promoted neuroblast migration from the subventricular zone (SVZ) and increased the number of newly formed neurons in the peri-infarct cortex. PTH-treated mice showed significantly better sensorimotor functional recovery compared to stroke controls. Our data suggests that PTH therapy improves endogenous repair mechanisms after ischemic stroke with functional benefits. Mobilizing endogenous bone marrow-derived stem cells/progenitor cells using PTH and other mobilizers appears an effective and feasible regenerative treatment after ischemic stroke. PMID:24503654

Neurofunctional changes after a single mirror therapy intervention in chronic ischemic stroke.

PubMed

Novaes, Morgana M; Palhano-Fontes, Fernanda; Peres, Andre; Mazzetto-Betti, Kelley; Pelicioni, Maristela; Andrade, Kátia C; Dos Santos, Antonio Carlos; Pontes-Neto, Octavio; Araujo, Draulio

2018-03-20

Mirror therapy (MT) is becoming an alternative rehabilitation strategy for various conditions, including stroke. Although recent studies suggest the positive benefit of MT in chronic stroke motor recovery, little is known about its neural mechanisms. To identify functional brain changes induced by a single MT intervention in ischemic stroke survivors, assessed by both transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI). TMS and fMRI were used to investigate 15 stroke survivors immediately before and after a single 30-min MT session. We found statistically significant increase in post-MT motor evoked potential (MEP) amplitude (increased excitability) from the affected primary motor cortex (M1), when compared to pre-MT MEP. Post-MT fMRI maps were associated with a more organized and constrained pattern, with a more focal M1 activity within the affected hemisphere after MT, limited to the cortical area of hand representation. Furthermore, we find a change in the balance of M1 activity toward the affected hemisphere. In addition, significant correlation was found between decreased fMRI β-values and increased MEP amplitude post-MT, in the affected hemisphere. Our study suggests that a single MT intervention in stroke survivors is related to increased MEP of the affected limb, and a more constrained activity of the affected M1, as if activity had become more constrained and limited to the affected hemisphere.

Docosahexaenoic acid complexed to albumin provides neuroprotection after experimental stroke in aged rats.

PubMed

Eady, Tiffany N; Khoutorova, Larissa; Obenaus, Andre; Mohd-Yusof, Alena; Bazan, Nicolas G; Belayev, Ludmila

2014-02-01

Recently we have shown that docosahexaenoic acid complexed to albumin (DHA-Alb) is neuroprotective after experimental stroke in young rats. The purpose of this study was to determine whether treatment with DHA-Alb would be protective in aged rats after focal cerebral ischemia. Isoflurane/nitrous oxide-anesthetized normothermic (brain temperature 36-36.5°C) Sprague-Dawley aged rats (18-months old) received 2h middle cerebral artery occlusion (MCAo) by poly-l-lysine-coated intraluminal suture. The neurological status was evaluated during occlusion (60min) and on days 1, 2, 3 and 7 after MCAo; a grading scale of 0-12 was employed. DHA (5mg/kg), Alb (0.63g/kg), DHA-Alb (5mg/kg+0.63g/kg) or saline was administered i.v. 3h after onset of stroke (n=8-10 per group). Ex vivo T2-weighted imaging (T2WI) of the brains was conducted on an 11.7T MRI on day 7 and 3D reconstructions were generated. Infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/microphages), NeuN (neurons)-positive cells and SMI-71 (positive vessels) were counted in the cortex and striatum at the level of the central lesion. Physiological variables were entirely comparable between groups. Animals treated with DHA-Alb showed significantly improved neurological scores compared to vehicle rats; 33% improvement on day 1; 39% on day 2; 41% on day 3; and 45% on day 7. Total and cortical lesion volumes computed from T2WI were significantly reduced by DHA-Alb treatment (62 and 69%, respectively). In addition, treatment with DHA-Alb reduced cortical and total brain infarction while promoting cell survival. We conclude that DHA-Alb therapy is highly neuroprotective in aged rats following focal cerebral ischemia and has potential for the effective treatment of ischemic stroke in aged individuals. © 2013. Published by Elsevier Inc. All rights reserved.

TIA model is attainable in Wistar rats by intraluminal occlusion of the MCA for 10min or shorter.

PubMed

Durukan Tolvanen, A; Tatlisumak, E; Pedrono, E; Abo-Ramadan, U; Tatlisumak, T

2017-05-15

Transient ischemic attack (TIA) has received only little attention in the experimental research field. Recently, we introduced a TIA model for mice, and here we set similar principles for simulating this human condition in Wistar rats. In the model: 1) transient nature of the event is ensured, and 2) 24h after the event animals are free from any sensorimotor deficit and from any detectable lesion by magnetic resonance imaging (MRI). Animals experienced varying durations of ischemia (5, 10, 12.5, 15, 25, and 30min, n=6-8pergroup) by intraluminal middle cerebral artery occlusion (MCAO). Ischemia severity and reperfusion rates were controlled by cerebral blood flow measurements. Sensorimotor neurological evaluations and MRI at 24h differentiated between TIA and ischemic stroke. Hematoxylin and eosin staining and apoptotic cell counts revealed pathological correlates of the event. We found that already 12.5min of ischemia was long enough to induce ischemic stroke in Wistar rats. Ten min or shorter durations induced neither gross neurological deficits nor infarcts visible on MRI, but histologically caused selective neuronal necrosis. A separate group of animals with 10min of ischemia followed up to 1week after reperfusion remained free of infarction and any MRI signal change. Thus, 10min or shorter focal cerebral ischemia induced by intraluminal MCAO in Wistar rats provides a clinically relevant TIA the rat. This model is useful for studying molecular correlates of TIA. Copyright © 2017 Elsevier B.V. All rights reserved.

CE Neuropsychological and neurobehavioral outcome following childhood arterial ischemic stroke: Attention deficits, emotional dysregulation, and executive dysfunction

PubMed Central

Liégeois, Frédérique; Eve, Megan; Ganesan, Vijeya; King, John; Murphy, Tara

2013-01-01

Objectives To investigate neuropsychological and neurobehavioral outcome in children with arterial ischemic stroke (AIS). Background Childhood stroke can have consequences on motor, cognitive, and behavioral development. We present a cross-sectional study of neuropsychological and neurobehavioral outcome at least one year poststroke in a uniquely homogeneous sample of children who had experienced AIS. Method Forty-nine children with AIS aged 6 to 18 years were recruited from a specialist clinic. Neuropsychological measures of intelligence, reading comprehension, attention, and executive function were administered. A triangulation of data collection included questionnaires completed by the children, their parents, and teachers, rating behavior, executive functions, and emotions. Key Findings Focal neuropsychological vulnerabilities in attention (response inhibition and dual attention) and executive function were found, beyond general intellectual functioning, irrespective of hemispheric side of stroke. Difficulties with emotional and behavioral regulation were also found. Consistent with an “early plasticity” hypothesis, earlier age of stroke was associated with better performance on measures of executive function. Conclusions A significant proportion of children poststroke are at long-term risk of difficulties with emotional regulation, executive function, and attention. Data also suggest that executive functions are represented in widespread networks in the developing brain and are vulnerable to unilateral injury. PMID:24028185

(1)H NMR-based metabonomics revealed protective effect of Naodesheng bioactive extract on ischemic stroke rats.

PubMed

Luo, Lan; Zhen, Lifeng; Xu, Yatao; Yang, Yongxia; Feng, Suxiang; Wang, Shumei; Liang, Shengwang

2016-06-20

Stroke is a leading cause of death and disability in the world. However, current therapies are limited. Naodesheng, a widely used traditional Chinese medicine prescription, has shown a good clinical curative effect on ischemic stroke. Also, Naodesheng has been suggested to have neuroprotective effect on focal cerebral ischemia rats, but the underlying molecular mechanism remains unclear. The present study was designed to evaluate the effect of Naodesheng bioactive extract on the metabolic changes in brain tissue, plasma and urine induced by cerebral ischemia perfusion injury, and explore the possible metabolic mechanisms by using a (1)H NMR-based metabonomics approach. A middle cerebral artery occlusion rat model was established and confirmed by the experiments of neurobehavioral abnormality evaluation, brain tissue TTC staining and pathological examination. The metabolic changes in brain tissue, plasma and urine were then assessed by a (1)H NMR technique combined with multivariate statistical analysis method. These NMR data showed that cerebral ischemia reperfusion induced great metabolic disorders in brain tissue, plasma and urine metabolisms. However, Naodesheng bioactive extract could reverse most of the imbalanced metabolites. Meanwhile, it was found that both the medium and high dosages of Naodesheng bioactive extract were more effective on the metabolic changes than the low dosage, consistent with histopathological assessments. These results revealed that Naodesheng had protective effect on ischemic stroke rats and the underlying mechanisms involved multiple metabolic pathways, including energy metabolism, amino acid metabolism, oxidative stress and inflammatory injury. The present study could provide evidence that metabonomics revealed its capacity to evaluate the holistic efficacy of traditional Chinese medicine and explore the underlying mechanisms. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A method to differentiate the causes of stiff-knee gait in stroke patients.

PubMed

Campanini, I; Merlo, A; Damiano, B

2013-06-01

Stiff-knee gait (SKG) is a common abnormal gait pattern in patients after stroke characterized by insufficient knee flexion (KF) during swing. Overactivity of the rectus femoris (RF) is considered the primary cause of SKG. Inadequate push-off has been indicated as an additional cause in the recent literature, as KF depends on knee flexion velocity in preswing (KFV). We used the peak of vertical acceleration of the malleolus (PMVA) as a kinematic-based indirect measure of push-off and studied its relationship with KF and KFV in a sample of 20 healthy subjects walking fast (v = 95 ± 5%heights(-1)), at self-selected speed (v = 74 ± 5%heights(-1)), slow (v = 54 ± 6%heights(-1)) and very slow (v = 38 ± 5%heights(-1)) and in a sample of 52 stroke patients with SKG (age 60 ± 11, v = 20 ± 11%heights(-1)). In healthy subjects PMVA occurred before knee flexion acceleration (p<0.001) and hip flexion acceleration (p<0.001). KF appeared as a bottom-up mechanism driven by the ankle push-off. From a regression analysis, the PMVA-KFV cause-effect relationship resulted strictly linear, with R(2) = 0.967, KFV = 0+7.1×PMVA, P<0.0001. Data from SKG patients were compared to this normal cause-effect model. For 44/52 patients the reduced KFV was combined with lack of push-off. Data from 8/52 patients only were statistically outside the 95%CI of the model, thus requiring for a braking mechanism to explain KFV reduction. In stroke adults of our sample the push-off impairment (85% of cases) and not the inappropriate knee extension moment produced by the thigh muscles was the primary cause of SKG. This result could explain the low average efficacy (<10°) of focal and surgical treatments at the quadriceps. The presented model could be used to differentiate the primary cause of SKG between inadequate push-off and braking activity of the thigh muscles, thus increasing the effectiveness of the selected treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

Cardiac magnetic resonance imaging has limited additional yield in cryptogenic stroke evaluation after transesophageal echocardiography.

PubMed

Liberman, Ava L; Kalani, Rizwan E; Aw-Zoretic, Jessie; Sondag, Matthew; Daruwalla, Vistasp J; Mitter, Sumeet S; Bernstein, Richard; Collins, Jeremy D; Prabhakaran, Shyam

2017-12-01

Background The use of cardiac magnetic resonance imaging is increasing, but its role in the diagnostic work-up following ischemic stroke has received limited study. We aimed to explore the added yield of cardiac magnetic resonance imaging to identify cardio-aortic sources not detected by transesophageal echocardiography among patients with cryptogenic stroke. Methods A retrospective single-center cohort study was performed from 01 January 2009 to 01 March 2013. Consecutive patients who had both a stroke protocol cardiac magnetic resonance imaging and a transesophageal echocardiography preformed during a single hospitalization were included. All cardiac magnetic resonance imaging studies underwent independent, blinded review by two investigators. We applied the causative classification system for ischemic stroke to all patients, first blinded to cardiac magnetic resonance imaging results; we then reapplied the causative classification system using cardiac magnetic resonance imaging. Standard statistical tests to evaluate stroke subtype reclassification rates were used. Results Ninety-three patients were included in the final analysis; 68.8% were classified as cryptogenic stroke after initial diagnostic evaluation. Among patients with cryptogenic stroke, five (7.8%) were reclassified due to cardiac magnetic resonance imaging findings: one was reclassified as "cardio-aortic embolism evident" due to the presence of a patent foramen ovale and focal cardiac infarct and four were reclassified as "cardio-aortic embolism possible" due to mitral valve thickening (n = 1) or hypertensive cardiomyopathy (n = 3). Overall, findings on cardiac magnetic resonance imaging reduced the percentage of patients with cryptogenic stroke by slightly more than 1%. Conclusion Our stroke subtype reclassification rate after the addition of cardiac magnetic resonance imaging results to a diagnostic work-up which includes transesophageal echocardiography was very low. Prospective studies evaluating the role of cardiac magnetic resonance imaging and transesophageal echocardiography among patients with cryptogenic stroke should be considered.

Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats

PubMed Central

Selvamani, Amutha; Sohrabji, Farida

2009-01-01

While human observational studies and animal studies report a neuroprotective role for estrogen therapy in stroke, the multicenter placebo-controlled Women's Health Initiative (WHI) study concluded that hormone therapy increased the risk for stroke in postmenopausal women. The present study therefore tested the hypothesis that estrogen replacement would increase the severity of a stroke-like injury in females when this replacement occurs after a prolonged hypoestrogenic period, such as the menopause or reproductive senescence, but not when given to females that were normally cycling immediately prior to the hormone replacement. Two groups of female rats were used: multiparous females with normal but lengthened estrus cycles (mature adults), and older multiparous females currently in a persistent acyclic state (reproductive senescent). Animals were either used intact, or were bilaterally ovariectomized and immediately replaced with a 17β-estradiol pellet or control pellet. Animals were subject to a forelimb placing test (a test for sensorimotor deficit) and thereafter to middle cerebral artery occlusion (MCAo) by stereotaxic injection of the vasoconstrictive peptide endothelin-1, adjacent to the MCA. One week after stroke, behavioral tests were performed again. Cortical and striatal infarct volume, measured from brain slices, was significantly greater in intact reproductive senescent females as compared to intact mature adults. Furthermore, estrogen treatment to ovariectomized mature adult females significantly reduced the cortical infarct volume. Paradoxically, estrogen treatment to ovariectomized reproductive senescent females significantly increased cortical and striatal infarct volumes as compared to control pellet replaced senescent females. Significant post-stroke behavioral deficit was observed in all groups on the side contralateral to the lesion, while senescent females also exhibited deficits on the ipsilateral side, in the cross-midline forelimb placement test. Using an animal model that approximates the natural ovarian aging process, these findings strongly support the hypothesis that the effectiveness of estrogen therapy in protecting brain health may depend critically on the time of initiation with respect to a female's reproductive status. PMID:18829137

Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhawan, J.; Biegon, A.; Dhawan, J.

2010-03-04

Stroke is accompanied by neuroinflammation in humans and animal models. To examine the temporal and anatomical profile of neuroinflammation and NMDA receptors (NMDAR) in a stroke model, rats (N = 17) were subjected to a 90 min occlusion of the middle cerebral artery (MCAO) and compared to sham (N = 5) and intact (N = 4) controls. Striatal and parietal cortical infarction was confirmed by MRI 24 h after reperfusion. Animals were killed 14 or 30-40 days later and consecutive coronal cryostat sections were processed for quantitative autoradiography with the neuroinflammation marker [{sup 3}H]PK11195 and the NMDAR antagonist [{sup 3}H]MK801.more » Significantly increased specific binding of [{sup 3}H]PK11195 relative to non-ischemic controls was observed in the ipsilateral striatum (> 3 fold, p < 0.0001), substantia innominata (> 2 fold) with smaller (20%-80%) but statistically significant (p = 0.002-0.04) ipsilateral increases in other regions partially involved in the infarct such as the parietal and piriform cortex, and in the lateral septum, which was not involved in the infarct. Trends for increases in PBR density were also observed in the contralateral hemisphere. In the same animals, NMDAR specific binding was significantly decreased bilaterally in the septum, substantia innominata and ventral pallidum. Significant decreases were also seen in the ipsilateral striatum, accumbens, frontal and parietal cortex. The different anatomical distribution of the two phenomena suggests that neuroinflammation does not cause the observed reduction in NMDAR, though loss of NMDAR may be locally augmented in ipsilateral regions with intense neuroinflammation. Persistent, bilateral loss of NMDAR, probably reflecting receptor down regulation and internalization, may be responsible for some of the effects of stroke on cognitive function which cannot be explained by infarction alone.« less

Neurally dissociable cognitive components of reading deficits in subacute stroke.

PubMed

Boukrina, Olga; Barrett, A M; Alexander, Edward J; Yao, Bing; Graves, William W

2015-01-01

According to cognitive models of reading, words are processed by interacting orthographic (spelling), phonological (sound), and semantic (meaning) information. Despite extensive study of the neural basis of reading in healthy participants, little group data exist on patients with reading deficits from focal brain damage pointing to critical neural systems for reading. Here, we report on one such study. We have performed neuropsychological testing and magnetic resonance imaging on 11 patients with left-hemisphere stroke (<=5 weeks post-stroke). Patients completed tasks assessing cognitive components of reading such as semantics (matching picture or word choices to a target based on meaning), phonology (matching word choices to a target based on rhyming), and orthography (a two-alternative forced choice of the most plausible non-word). They also read aloud pseudowords and words with high or low levels of usage frequency, imageability, and spelling-sound consistency. As predicted by the cognitive model, when averaged across patients, the influence of semantics was most salient for low-frequency, low-consistency words, when phonological decoding is especially difficult. Qualitative subtraction analyses revealed lesion sites specific to phonological processing. These areas were consistent with those shown previously to activate for phonology in healthy participants, including supramarginal, posterior superior temporal, middle temporal, inferior frontal gyri, and underlying white matter. Notable divergence between this analysis and previous functional imaging is the association of lesions in the mid-fusiform gyrus and anterior temporal lobe with phonological reading deficits. This study represents progress toward identifying brain lesion-deficit relationships in the cognitive components of reading. Such correspondences are expected to help not only better understand the neural mechanisms of reading, but may also help tailor reading therapy to individual neurocognitive deficit profiles.

Neuroprotective effect of p-coumaric acid in rat model of embolic cerebral ischemia

PubMed Central

Guven, Mustafa; Aras, Adem Bozkurt; Akman, Tarik; Sen, Halil Murat; Ozkan, Adile; Salis, Osman; Sehitoglu, Ibrahim; Kalkan, Yildiray; Silan, Coskun; Deniz, Mustafa; Cosar, Murat

2015-01-01

Objective(s): Stroke poses a crucial risk for mortality and morbidity. Our study aimed to investigate the effect of p-coumaric acid on focal cerebral ischemia in rats. Material and Methods: Rats were randomly divided into four groups, namely Group I (control rats), Group II (ischemia rats), Group III (6 hr ischemia + p-coumaric acid rats) and Group IV (24 hr ischemia + p-coumaric acid rats). Cerebral ischemia was induced via intraluminal monofilament occlusion model. In all groups, the brain was removed after the procedure and rats were sacrificed. Malondialdehyde, superoxide dismutase and nuclear respiratory factor-1 were measured in the ischemic hemisphere. The histopathological changes were observed in the right hemisphere within the samples. Functional assessment was performed for neurological deficit scores. Results: Following the treatment, biochemical factors changed significantly. Histopathologically, it was shown that p-coumaric acid decreased the oxidative damage. The neurological deficit scores of p-coumaric acid-treated rats were significantly improved after cerebral ischemia. Conclusion: Our results showed that p-coumaric acid is a neuroprotective agent on account of its strong anti-oxidant and anti-apoptotic features. Moreover, p-coumaric acid decreased the focal ischemia. Extra effort should be made to introduce p-coumaric acid as a promising therapeutic agent to be utilized for treatment of human cerebral ischemia in the future. PMID:26019798

Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats

PubMed Central

2010-01-01

Background Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. Methods The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus) extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. Results Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. Conclusions These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis. PMID:20955613

Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats.

PubMed

Liu, Zhenquan; Li, Pengtao; Zhao, Dan; Tang, Huiling; Guo, Jianyou

2010-10-19

Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus) extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis.

Neuroprotective Role of a Brain-Enriched Tyrosine Phosphatase, STEP, in Focal Cerebral Ischemia

PubMed Central

Deb, Ishani; Manhas, Namratta; Poddar, Ranjana; Rajagopal, Sathyanarayanan; Allan, Andrea M.; Lombroso, Paul J.; Rosenberg, Gary A.; Candelario-Jalil, Eduardo

2013-01-01

The striatal-enriched phosphatase (STEP) is a component of the NMDA-receptor-mediated excitotoxic signaling pathway, which plays a key role in ischemic brain injury. Using neuronal cultures and a rat model of ischemic stroke, we show that STEP plays an initial role in neuroprotection, during the insult, by disrupting the p38 MAPK pathway. Degradation of active STEP during reperfusion precedes ischemic brain damage and is associated with secondary activation of p38 MAPK. Application of a cell-permeable STEP-derived peptide that is resistant to degradation and binds to p38 MAPK protects cultured neurons from hypoxia-reoxygenation injury and reduces ischemic brain damage when injected up to 6 h after the insult. Conversely, genetic deletion of STEP in mice leads to sustained p38 MAPK activation and exacerbates brain injury and neurological deficits after ischemia. Administration of the STEP-derived peptide at the onset of reperfusion not only prevents the sustained p38 MAPK activation but also reduces ischemic brain damage in STEP KO mice. The findings indicate a neuroprotective role of STEP and suggest a potential role of the STEP-derived peptide in stroke therapy. PMID:24198371

18TH Annual Meeting of the European Neuroscience Association.

DTIC Science & Technology

1996-01-01

propagation of ictal-like seizure activity oný the neocottex of anaesthetised rats in viva. Epileptifotot events in the Global cerebral isehemia in rats...for the study of stroke -related brain injury . Novel MR] techniques, 40 neurological patients suspected clinically to suffer from inherited...head injury . MRI scan of start, runway and goal chamber with 2 drinking indicates diffuse cerebral damage, with focal abnormality spouts. The goal had

Hyperperfusion syndrome after MCA embolectomy – a rare complication?

PubMed Central

Backhaus, Roland; Boy, Sandra; Fuchs, Kornelius; Ulrich, Bogdahn; Schuierer, Gerhard; Schlachetzki, Felix

2013-01-01

Patient: Female, 78 Final Diagnosis: Cerebral hyperperfusion syndrome Symptoms: — Medication: — Clinical Procedure: Endovascular embolectomy Specialty: Neurology Objective: Unknown ethiology Background: Cerebral hyperperfusion syndrome (cHS) is a well known but rare complication after carotid endarterectomy, carotid angioplasty with stenting, and stenting of intracranial arterial stenosis. The clinical presentation may vary from acute onset of focal oedema (stroke-like presentation) and intracerbral hemorrhage to delayed (>24h hours after the procedure) presentation with seizures, focal motor weakness, or late intracerebral hemorrhage. The incidence of cHS after carotid endarterectomy ranges from 0–3% and defined as an increase of the ipsilateral cerebral blood flow up to 40% over baseline in ultrasound. Case Report: We present a case of a 78-year-old woman with an acute ischemic stroke due to left side middle cerebral artery territory with right sided hemiparesis and aphasia (NIHSS 16). After systemic thrombolysis embolectomy using a retractable stent (Solitaire® device) was performed and resulted in complete and successful recanalization of MCA including its branches about 210 minutes after symptom onset but, partial dislocation of thrombotic material into the anterior cerebral artery (ACA). Conclusions: Cerebral hyperperfusion syndrome should be considered in patients with clinical deterioration after successful recanalisation and the early diagnosis and treatment may be important for neurological outcome after endovascular embolectomy PMID:24340127

Conditioned Medium Derived from Neural Progenitor Cells Induces Long-term Post-ischemic Neuroprotection, Sustained Neurological Recovery, Neurogenesis, and Angiogenesis.

PubMed

Doeppner, Thorsten R; Traut, Viktorija; Heidenreich, Alexander; Kaltwasser, Britta; Bosche, Bert; Bähr, Mathias; Hermann, Dirk M

2017-03-01

Adult neural progenitor cells (NPCs) induce post-ischemic long-term neuroprotection and brain remodeling by releasing of survival- and plasticity-promoting mediators. To evaluate whether secreted factors may mimic neuroprotective and restorative effects of NPCs, we exposed male C57BL6 mice to focal cerebral ischemia and intravenously applied conditioned medium (CM) derived from subventricular zone NPCs. CM dose-dependently reduced infarct volume and brain leukocyte infiltration after 48 h when delivered up to 12 h after focal cerebral ischemia. Neuroprotection persisted in the post-acute stroke phase yielding enhanced neurological recovery that lasted throughout the 28-day observation period. Increased Bcl-2, phosphorylated Akt and phosphorylated STAT-3 abundance, and reduced caspase-3 activity and Bax abundance were noted in ischemic brains of CM-treated mice at 48 h post-stroke, indicative of enhanced cell survival signaling. Long-term neuroprotection was associated with increased brain glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) concentrations at 28 days resulting in increased neurogenesis and angiogenesis. The observation that NPC-derived CM induces sustained neuroprotection and neurological recovery suggests that cell transplantation may be dispensable when secreted factors are instead administered.

Stroke in thrombotic thrombocytopenic purpura induced by thyrotoxicosis: a case report.

PubMed

Bellante, Flavio; Redondo Saez, Patricia; Springael, Cecile; Dethy, Sophie

2014-07-01

Thrombotic thrombocytopenic purpura (TTP) is a hematologic disease involving the platelet aggregation and resulting in hemolytic anemia, thrombocytopenia, and microvascular occlusion. Although frequent neurologic features are headache and confusion, focal deficit is described in 30% of the cases. There are a lot of causes inducing thrombotic thrombocytopenic, but reports are lacking when associated with Grave disease. We describe the case of a 51-year-old Caucasian woman presenting a 24-hour story of sudden onset of dysarthria and left superior limb palsy. Four months before, she developed severe hyperthyroidism associated with petechiae, hemolytic anemia, thrombocytopenia, and schistocytes at blood film examination. Relapse of TTP in association with Grave disease was diagnosed. There are few reports describing association between Grave disease and TTP with only mild neurologic involvement. We described, to our knowledge, the first case of acute ischemic stroke secondary to thrombotic thrombocytopenic induced by thyrotoxicosis. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass surgery in patients with occlusion of the internal carotid artery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vorstrup, S.; Brun, B.; Lassen, N.A.

1986-11-01

Cerebral blood flow (CBF) was measured by xenon-133 inhalation tomography in 18 patients with cerebrovascular disease before and 4 months after extracranial-intracranial bypass surgery. Only patients who showed a reduced CBF in areas that were intact on the CT scan and relevant to the clinical and angiographical findings were operated. The majority of the patients had suffered a minor stroke with or without subsequent transient ischemic attacks. They were studied at least 6 weeks following the stroke. All patients had an occlusion of the relevant internal carotid artery. To identify preoperatively the patients with a compromised collateral circulation and hencemore » reduced CBF due to reduced perfusion pressure, a cerebral vasodilatory stress test was performed using acetazolamide (Diamox). In normal subjects, Diamox has been shown to increase tomographic CBF without change of the flow distribution. In the present series 9 patients showed a significant redistribution of flow in favor of the non-occluded side (positive Diamox test). Two of these 9 patients showed even a paradoxical decrease in focal CBF preoperatively, i.e., a steal effect. These 2 patients were the only patients who improved in focal CBF after shunting. The remaining 9 patients all showed uniform flow responses (negative Diamox test), and none of these increased in focal CBF postoperatively. The finding of an unchanged flow map postoperatively confirmed that the low flow areas were not due to restricted flow via collateral pathways. However, an increase in the regional vasodilatory capacity was observed postoperatively in the majority of patients.« less

Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat.

PubMed

Zhang, Ruilan; Wang, Lei; Zhang, Li; Chen, Jieli; Zhu, Zhenping; Zhang, Zhenggang; Chopp, Michael

2003-02-21

We investigated the effects of NO on angiogenesis and the synthesis of vascular endothelial growth factor (VEGF) in a model of focal embolic cerebral ischemia in the rat. Compared with control rats, systemic administration of an NO donor, DETANONOate, to rats 24 hours after stroke significantly enlarged vascular perimeters and increased the number of proliferated cerebral endothelial cells and the numbers of newly generated vessels in the ischemic boundary regions, as evaluated by 3-dimensional laser scanning confocal microscopy. Treatment with DETANONOate significantly increased VEGF levels in the ischemic boundary regions as measured by ELISA. A capillary-like tube formation assay was used to investigate whether DETANONOate increases angiogenesis in ischemic brain via activation of soluble guanylate cyclase. DETANONOate-induced capillary-like tube formation was completely inhibited by a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Blocking VEGF activity by a neutralized antibody against VEGF receptor 2 significantly attenuated DETANONOate-induced capillary-like tube formation. Moreover, systemic administration of a phosphodiesterase type 5 inhibitor (Sildenafil) to rats 24 hours after stroke significantly increased angiogenesis in the ischemic boundary regions. Sildenafil and an analog of cyclic guanosine monophosphate (cGMP) also induced capillary-like tube formation. These findings suggest that exogenous NO enhances angiogenesis in ischemic brain, which is mediated by the NO/cGMP pathway. Furthermore, our data suggest that NO, in part via VEGF, may enhance angiogenesis in ischemic brain.

Implicit sequence-specific motor learning after sub-cortical stroke is associated with increased prefrontal brain activations: An fMRI study

PubMed Central

Meehan, Sean K.; Randhawa, Bubblepreet; Wessel, Brenda; Boyd, Lara A.

2010-01-01

Implicit motor learning is preserved after stroke, but how the brain compensates for damage to facilitate learning is unclear. We used a random effects analysis to determine how stroke alters patterns of brain activity during implicit sequence-specific motor learning as compared to general improvements in motor control. Nine healthy participants and 9 individuals with chronic, right focal sub-cortical stroke performed a continuous joystick-based tracking task during an initial fMRI session, over 5 days of practice, and a retention test during a separate fMRI session. Sequence-specific implicit motor learning was differentiated from general improvements in motor control by comparing tracking performance on a novel, repeated tracking sequences during early practice and again at the retention test. Both groups demonstrated implicit sequence-specific motor learning at the retention test, yet substantial differences were apparent. At retention, healthy control participants demonstrated increased BOLD response in left dorsal premotor cortex (BA 6) but decreased BOLD response left dorsolateral prefrontal cortex (DLPFC; BA 9) during repeated sequence tracking. In contrast, at retention individuals with stroke did not show this reduction in DLPFC during repeated tracking. Instead implicit sequence-specific motor learning and general improvements in motor control were associated with increased BOLD response in the left middle frontal gyrus BA 8, regardless of sequence type after stroke. These data emphasize the potential importance of a prefrontal-based attentional network for implicit motor learning after stroke. The present study is the first to highlight the importance of the prefrontal cortex for implicit sequence-specific motor learning after stroke. PMID:20725908

Comprehensive stroke units: a review of comparative evidence and experience.

PubMed

Chan, Daniel K Y; Cordato, Dennis; O'Rourke, Fintan; Chan, Daniel L; Pollack, Michael; Middleton, Sandy; Levi, Chris

2013-06-01

Stroke unit care offers significant benefits in survival and dependency when compared to general medical ward. Most stroke units are either acute or rehabilitation, but comprehensive (combined acute and rehabilitation) model (comprehensive stroke unit) is less common. To examine different levels of evidence of comprehensive stroke unit compared to other organized inpatient stroke care and share local experience of comprehensive stroke units. Cochrane Library and Medline (1980 to December 2010) review of English language articles comparing stroke units to alternative forms of stroke care delivery, different types of stroke unit models, and differences in processes of care within different stroke unit models. Different levels of comparative evidence of comprehensive stroke units to other models of stroke units are collected. There are no randomized controlled trials directly comparing comprehensive stroke units to other stroke unit models (either acute or rehabilitation). Comprehensive stroke units are associated with reduced length of stay and greatest reduction in combined death and dependency in a meta-analysis study when compared to other stroke unit models. Comprehensive stroke units also have better length of stay and functional outcome when compared to acute or rehabilitation stroke unit models in a cross-sectional study, and better length of stay in a 'before-and-after' comparative study. Components of stroke unit care that improve outcome are multifactorial and most probably include early mobilization. A comprehensive stroke unit model has been successfully implemented in metropolitan and rural hospital settings. Comprehensive stroke units are associated with reductions in length of stay and combined death and dependency and improved functional outcomes compared to other stroke unit models. A comprehensive stroke unit model is worth considering as the preferred model of stroke unit care in the planning and delivery of metropolitan and rural stroke services. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Hippocampal volume and memory performance in children with perinatal stroke.

PubMed

Gold, Jeffrey J; Trauner, Doris A

2014-01-01

Pediatric neurologists and neonatologists often are asked to predict cognitive outcome after perinatal brain injury (including likely memory and learning outcomes). However, relatively few data exist on how accurate predictions can be made. Furthermore, although the consequences of brain injury on hippocampal volume and memory performance have been studied extensively in adults, little work has been done in children. We measured the volume of the hippocampus in 27 children with perinatal stroke and 19 controls, and measured their performance on standardized verbal and non-verbal memory tests. We discovered the following: (1) As a group, children with perinatal stroke had smaller left and right hippocampi compared with control children. (2) Individually, children with perinatal stroke demonstrated 1 of 3 findings: no hippocampal loss, unilateral hippocampal loss, or bilateral hippocampal volume loss compared with control children. (3) Hippocampal volume inversely correlated with memory test performance in the perinatal stroke group, with smaller left and right hippocampal volumes related to poorer verbal and non-verbal memory test performance, respectively. (4) Seizures played a significant role in determining memory deficit and extent of hippocampal volume reduction in patients with perinatal stroke. These findings support the view that, in the developing brain, the left and right hippocampi preferentially support verbal and nonverbal memory respectively, a consistent finding in the adult literature but a subject of debate in the pediatric literature. This is the first work to report that children with focal brain injury incurred from perinatal stroke have volume reduction in the hippocampus and impairments in certain aspects of declarative memory. Copyright © 2014 Elsevier Inc. All rights reserved.

Large-Scale Phase Synchrony Reflects Clinical Status After Stroke: An EEG Study.

PubMed

Kawano, Teiji; Hattori, Noriaki; Uno, Yutaka; Kitajo, Keiichi; Hatakenaka, Megumi; Yagura, Hajime; Fujimoto, Hiroaki; Yoshioka, Tomomi; Nagasako, Michiko; Otomune, Hironori; Miyai, Ichiro

2017-06-01

Stroke-induced focal brain lesions often exert remote effects via residual neural network activity. Electroencephalographic (EEG) techniques can assess neural network modifications after brain damage. Recently, EEG phase synchrony analyses have shown associations between the level of large-scale phase synchrony of brain activity and clinical symptoms; however, few reports have assessed such associations in stroke patients. The aim of this study was to investigate the clinical relevance of hemispheric phase synchrony in stroke patients by calculating its correlation with clinical status. This cross-sectional study included 19 patients with post-acute ischemic stroke admitted for inpatient rehabilitation. Interhemispheric phase synchrony indices (IH-PSIs) were computed in 2 frequency bands (alpha [α], and beta [β]), and associations between indices and scores of the Functional Independence Measure (FIM), the National Institutes of Health Stroke Scale (NIHSS), and the Fugl-Meyer Motor Assessment (FMA) were analyzed. For further assessments of IH-PSIs, ipsilesional intrahemispheric PSIs (IntraH-PSIs) as well as IH- and IntraH-phase lag indices (PLIs) were also evaluated. IH-PSIs correlated significantly with FIM scores and NIHSS scores. In contrast, IH-PSIs did not correlate with FMA scores. IntraH-PSIs correlate with FIM scores after removal of the outlier. The results of analysis with PLIs were consistent with IH-PSIs. The PSIs correlated with performance on the activities of daily living scale but not with scores on a pure motor impairment scale. These results suggest that large-scale phase synchrony represented by IH-PSIs provides a novel surrogate marker for clinical status after stroke.

[Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

PubMed

Ichikawa, Hiroo

2016-02-01

Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels.

Physical Therapy for an Adult with Chronic Stroke after Botulinum Toxin Injection for Spasticity: A Case Report

PubMed Central

Phadke, Chetan P.; Ismail, Farooq; Boulias, Chris

2015-01-01

ABSTRACT Purpose: In this case report, we describe the type and duration of a physical therapy and botulinum toxin type A (BoNTA) intervention directed at lower limb spasticity and the gait and balance improvement in a patient post-stroke. Treatment of focal spasticity with BoNTA intramuscular injections combined with physical therapy is recommended by rehabilitation experts. However, the optimal type and duration of physical therapy intervention to optimize any functional gains that follow chemodenervation induced by BoNTA has not been established. Method: One individual with chronic stroke who received BoNTA injections for upper and lower extremity spasticity was included. Physical therapy intervention consisted of 45- to 60-min sessions twice weekly for 12 weeks, based on the Bobath–neurodevelopmental therapy approach, and an activity-based home program. Results: After BoNTA injections and physical therapy, the patient made clinically significant improvements in balance and gait speed and became more independent with his ambulation. Conclusions: This case report demonstrates that physical therapy after BoNTA injections can result in significant functional improvements for individuals with spasticity after chronic stroke that may not be possible with BoNTA injections alone. PMID:25931655

Combined treatment of botulinumtoxin and robot-assisted rehabilitation therapy on poststroke, upper limb spasticity

PubMed Central

Lee, So Young; Jeon, Young Tae; Kim, Bo Ryun; Han, Eun Young

2017-01-01

Abstract Rationale: Spasticity is a major complication after stroke, and botulinumtoxin A (BoNT-A) injection is commonly used to manage focal spasticity. However, it is uncertain whether BoNT-A can improve voluntary motor control or activities of daily living function of paretic upper limbs. This study investigated whether BoNT-A injection combined with robot-assisted upper limb therapy improves voluntary motor control or functions of upper limbs after stroke. Patient concerns: Two subacute stroke patients were transferred to the Department of Rehabilitation. Diagnoses: Patients demonstrated spasticity in the upper extremity on the affected side. Interventions: BoNT-A was injected into the paretic muscles of the shoulder, arm, and forearm of the 2 patients at the subacute stage. Conventional rehabilitation therapy and robot-assisted upper limb training were performed during the rehabilitation period. Outcomes: Manual dexterity, grip strength, muscle tone, and activities of daily living function were improved after multidisciplinary rehabilitation treatment. Lessons: BoNT-A injection in combination with multidisciplinary rehabilitation treatment, including robot-assisted arm training, should be recommended for subacute spastic stroke patients to enhance appropriate motor recovery. PMID:29390585

Protective effects of alkaloid extract from Leonurus heterophyllus on cerebral ischemia reperfusion injury by middle cerebral ischemic injury (MCAO) in rats.

PubMed

Liang, Hao; Liu, Ping; Wang, Yunshan; Song, Shuliang; Ji, Aiguo

2011-07-15

The neuronal damage following cerebral ischemia is a serious risk to stroke patients. The aim of this study was to investigate the neuroprotective effects of alkaloid extract from Leonurus heterophyllus (LHAE) on cerebral ischemic injury. After 24 h of reperfusion following ischemia for 2 h induced by middle cerebral artery occlusion (MCAO), some rats were intraperitoneally administered different doses of LHAE (3.6, 7.2, 14.4 mg/kg, respectively). Neurological examination was measured in all animals. Infarct volume, myeloperoxidase (MPO) activity, levels of nitrate/nitrite metabolite (NO) and apoptosis ratio of nerve fiber in brain were determined. The results showed that LHAE at 7.2 mg/kg or 14.4 mg/kg exerted significantly decreasing neurological deficit scores and reducing the infarct volume on rats with focal cerebral ischemic injury (p<0.05). At those dose, the MPO content were significantly decreased in ischemic brain as compared with model group (p<0.05). LHAE at 14.4 mg/kg significantly decreased the NO level compared with the model group (p<0.05). In addition, LHAE significantly decreased the apoptosis ratio of nerve fiber compared with the model group (p<0.05). This study suggests that LHAE may be used for treatment of ischemic stroke as a neuroprotective agent. Further studies are warranted to assess the efficacy and safety of LHAE in patients. Copyright © 2011 Elsevier GmbH. All rights reserved.

Epilepsy Characteristics and Clinical Outcome in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS).

PubMed

Lee, Ha Neul; Eom, Soyong; Kim, Se Hoon; Kang, Hoon-Chul; Lee, Joon Soo; Kim, Heung Dong; Lee, Young-Mock

2016-11-01

Epileptic seizures in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) are heterogeneous with no pathognomonic features. We reviewed epilepsy characteristics and clinical outcome exclusively in a pediatric population. Twenty-two children and adolescents (13 males) with confirmed mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes due to mitochondrial DNA A3243G mutation and epilepsy were recruited. Clinical data including seizure semiology, treatment response, neuroimaging findings, and electroencephalography were analyzed. We also examined the effect of the age at seizure onset and initial symptoms on the clinical variables. Seizure semiology and electroencephalography abnormalities showed no syndrome-specific findings. Focal seizures occurred in 21 of 22 subjects (95.5%), whereas generalized seizures developed in seven of 22 subjects (31.8%). Twenty of 22 subjects (90.9%) achieved partial to complete reduction of clinical seizures for more than one year with a combination of more than two antiepileptic drugs. The subgroup with earlier seizure onset presented significantly earlier and showed significantly higher rates of drug-resistant epilepsy compared with the late onset group, although there were no significant differences in the initial symptoms. The subjects with severe epileptic conditions tended to have more severe clinical dysfunction and more severe organ involvement. Both focal and generalized seizures occurred in patients with MELAS. Epilepsy in this population is drug resistant, but a certain degree of clinical seizure reduction was achievable with antiepileptic drugs, with more favorable outcomes than historically expected. Close observation and active epilepsy treatment of individuals with MELAS episodes and earlier seizure onset might improve the prognosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Beyond erythropoiesis: novel applications for recombinant human erythropoietin.

PubMed

Cerami, A

2001-07-01

Erythropoietin (EPO) primarily is produced in the kidney and acts as a principal mediator of the physiologic response to hypoxia by increasing red blood cell production. Astrocytes and neurons in the central nervous system (CNS) also are known to produce EPO in response to hypoxia/ischemia. EPO appears to play a neuroprotective role based on preclinical data demonstrating the ability of recombinant human erythropoietin (r-HuEPO) to shield neurons from hypoxic/ischemic stress when administered intracerebraventricularly. In CNS models, systemically administered r-HuEPO has not been intensely investigated because large glycosylated molecules generally were deemed incapable of crossing the blood-brain barrier (BBB). A collaborative research effort identified expression of EPO receptors on human brain capillaries and a specific receptor-mediated transport of r-HuEPO across the BBB after a single intraperitoneal (IP) injection in rodents, with subsequent protection against various types of neuronal damage. For example, administration of r-HuEPO 24 hours before or up to 6 hours after focal ischemic stroke significantly reduced the extent of infarction. r-HuEPO also attenuated concussive brain injury, kainate-induced seizure activity, and autoimmune encephalomyelitis. These preclinical findings suggest that r-HuEPO may have therapeutic potential for stroke, head trauma, and epilepsy; additional studies are needed to confirm and extend these encouraging observations in animal models. Copyright 2001 by W.B. Saunders Company.

A novel approach to induction and rehabilitation of deficits in forelimb function in a rat model of ischemic stroke.

PubMed

Livingston-Thomas, Jessica Mary; Hume, Andrew Wilson; Doucette, Tracy Ann; Tasker, Richard Andrew

2013-01-01

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.

Histological quantification of brain tissue inflammatory cell infiltration after focal cerebral infarction: a systematic review.

PubMed

Russek, Natanya S; Jensen, Matthew B

2014-03-01

Ischemic stroke is a leading cause of death and disability, and current treatments to limit tissue injury and improve recovery are limited. Cerebral infarction is accompanied by intense brain tissue inflammation involving many inflammatory cell types that may cause both negative and positive effects on outcomes. Many potential neuroprotective and neurorestorative treatments may affect, and be affected by, this inflammatory cell infiltration, so that accurate quantification of this tissue response is needed. We performed a systematic review of histological methods to quantify brain tissue inflammatory cell infiltration after cerebral infarction. We found reports of multiple techniques to quantify different inflammatory cell types. We found no direct comparison studies and conclude that more research is needed to optimize the assessment of this important stroke outcome.

Talampanel improves the functional deficit after transient focal cerebral ischemia in rats. A 30-day follow up study.

PubMed

Erdo, Franciska; Berzsenyi, Pál; Német, László; Andrási, Ferenc

2006-01-15

The neuroprotective effect of talampanel, a negative allosteric modulator of alpha-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid (AMPA) receptors has been described previously. However, in these studies the histological changes and not the functional consequences of the brain damage were evaluated. The aim of present investigation was to analyze the sensorimotor function after stroke and to test the influence of talampanel (GYKI-53773, LY-300164) by 30-day monitoring in rats. After 1h middle cerebral artery occlusion (MCAO) general 'well-being', neurological status, spontaneous motor activity, rotation, motor coordination, balancing, muscle strength and reaction time were followed for 1 month. Talampanel (6 x 10 mg/kg i.p. given on the day of stroke) improved the motor coordination in rotarod (p < 0.01) and beam walking (p < 0.01) tests, reduced the number of stroke-induced rotations (p < 0.05), shortened the reflex time on the forelimb contralateral to brain ischemia and improved the survival rate comparing with vehicle treated control. After stroke, serious sensorimotor deficits appeared in rats but they showed partial spontaneous recovery after 30 days. Talampanel treatment enhanced the rate of functional improvement without changing the morphology at the end of the experiment. Our results indicate that modulation of AMPA receptors by talampanel can be a promising therapeutic approach to the treatment of stroke.

A review and empirical study of the composite scales of the Das-Naglieri cognitive assessment system.

PubMed

McCrea, Simon M

2009-01-01

Alexander Luria's model of the working brain consisting of three functional units was formulated through the examination of hundreds of focal brain-injury patients. Several psychometric instruments based on Luria's syndrome analysis and accompanying qualitative tasks have been developed since the 1970s. In the mid-1970s, JP Das and colleagues defined a specific cognitive processes model based directly on Luria's two coding units termed simultaneous and successive by studying diverse cross-cultural, ability, and socioeconomic strata. The cognitive assessment system is based on the PASS model of cognitive processes and consists of four composite scales of Planning-Attention-Simultaneous-Successive (PASS) devised by Naglieri and Das in 1997. Das and colleagues developed the two new scales of planning and attention to more closely model Luria's theory of higher cortical functions. In this paper a theoretical review of Luria's theory, Das and colleagues elaboration of Luria's model, and the neural correlates of PASS composite scales based on extant studies is summarized. A brief empirical study of the neuropsychological specificity of the PASS composite scales in a sample of 33 focal cortical stroke patients using cluster analysis is then discussed. Planning and simultaneous were sensitive to right hemisphere lesions. These findings were integrated with recent functional neuroimaging studies of PASS scales. In sum it was found that simultaneous is strongly dependent on dual bilateral occipitoparietal interhemispheric coordination whereas successive demonstrated left frontotemporal specificity with some evidence of interhemispheric coordination across the prefrontal cortex. Hence, support for the validity of the PASS composite scales was found as well as for the axiom of the independence of code content from code type originally specified in 1994 by Das, Naglieri, and Kirby.

A review and empirical study of the composite scales of the Das–Naglieri cognitive assessment system

PubMed Central

McCrea, Simon M

2009-01-01

Alexander Luria’s model of the working brain consisting of three functional units was formulated through the examination of hundreds of focal brain-injury patients. Several psychometric instruments based on Luria’s syndrome analysis and accompanying qualitative tasks have been developed since the 1970s. In the mid-1970s, JP Das and colleagues defined a specific cognitive processes model based directly on Luria’s two coding units termed simultaneous and successive by studying diverse cross-cultural, ability, and socioeconomic strata. The cognitive assessment system is based on the PASS model of cognitive processes and consists of four composite scales of Planning–Attention–Simultaneous–Successive (PASS) devised by Naglieri and Das in 1997. Das and colleagues developed the two new scales of planning and attention to more closely model Luria’s theory of higher cortical functions. In this paper a theoretical review of Luria’s theory, Das and colleagues elaboration of Luria’s model, and the neural correlates of PASS composite scales based on extant studies is summarized. A brief empirical study of the neuropsychological specificity of the PASS composite scales in a sample of 33 focal cortical stroke patients using cluster analysis is then discussed. Planning and simultaneous were sensitive to right hemisphere lesions. These findings were integrated with recent functional neuroimaging studies of PASS scales. In sum it was found that simultaneous is strongly dependent on dual bilateral occipitoparietal interhemispheric coordination whereas successive demonstrated left frontotemporal specificity with some evidence of interhemispheric coordination across the prefrontal cortex. Hence, support for the validity of the PASS composite scales was found as well as for the axiom of the independence of code content from code type originally specified in 1994 by Das, Naglieri, and Kirby. PMID:22110322

Stroke rehabilitation at home before and after discharge reduced disability and improved quality of life: a randomised controlled trial.

PubMed

Rasmussen, Rune Skovgaard; Østergaard, Ann; Kjær, Pia; Skerris, Anja; Skou, Christina; Christoffersen, Jane; Seest, Line Skou; Poulsen, Mai Bang; Rønholt, Finn; Overgaard, Karsten

2016-03-01

To evaluate if home-based rehabilitation of inpatients improved outcome compared to standard care. Interventional, randomised, safety/efficacy open-label trial. University hospital stroke unit in collaboration with three municipalities. Seventy-one eligible stroke patients (41 women) with focal neurological deficits hospitalised in a stroke unit for more than three days and in need of rehabilitation. Thirty-eight patients were randomised to home-based rehabilitation during hospitalization and for up to four weeks after discharge to replace part of usual treatment and rehabilitation services. Thirty-three control patients received treatment and rehabilitation following usual guidelines for the treatment of stroke patients. Ninety days post-stroke the modified Rankin Scale score was the primary endpoint. Other outcome measures were the modified Barthel-100 Index, Motor Assessment Scale, CT-50 Cognitive Test, EuroQol-5D, Body Mass Index and treatment-associated economy. Thirty-one intervention and 30 control patients completed the study. Patients in the intervention group achieved better modified Rankin Scale score (Intervention median = 2, IQR = 2-3; Control median = 3, IQR = 2-4; P=0.04). EuroQol-5D quality of life median scores were improved in intervention patients (Intervention median = 0.77, IQR = 0.66-0.79; Control median = 0.66, IQR = 0.56 - 0.72; P=0.03). The total amount of home-based training in minutes highly correlated with mRS, Barthel, Motor Assessment Scale and EuroQol-5D™ scores (P-values ranging from P<0.00001 to P=0.01). Economical estimations of intervention costs were lower than total costs of standard treatment. Early home-based rehabilitation reduced disability and increased quality of life. Compared to standard care, home-based stroke rehabilitation was more cost-effective. © The Author(s) 2015.

Structural integrity of the contralesional hemisphere predicts cognitive impairment in ischemic stroke at three months.

PubMed

Dacosta-Aguayo, Rosalia; Graña, Manuel; Fernández-Andújar, Marina; López-Cancio, Elena; Cáceres, Cynthia; Bargalló, Núria; Barrios, Maite; Clemente, Immaculada; Monserrat, Pere Toran; Sas, Maite Alzamora; Dávalos, Antoni; Auer, Tibor; Mataró, Maria

2014-01-01

After stroke, white matter integrity can be affected both locally and distally to the primary lesion location. It has been shown that tract disruption in mirror's regions of the contralateral hemisphere is associated with degree of functional impairment. Fourteen patients suffering right hemispheric focal stroke (S) and eighteen healthy controls (HC) underwent Diffusion Weighted Imaging (DWI) and neuropsychological assessment. The stroke patient group was divided into poor (SP; n = 8) and good (SG; n = 6) cognitive recovery groups according to their cognitive improvement from the acute phase (72 hours after stroke) to the subacute phase (3 months post-stroke). Whole-brain DWI data analysis was performed by computing Diffusion Tensor Imaging (DTI) followed by Tract Based Spatial Statistics (TBSS). Assessment of effects was obtained computing the correlation of the projections on TBSS skeleton of Fractional Anisotropy (FA) and Radial Diffusivity (RD) with cognitive test results. Significant decrease of FA was found only in right brain anatomical areas for the S group when compared to the HC group. Analyzed separately, stroke patients with poor cognitive recovery showed additional significant FA decrease in several left hemisphere regions; whereas SG patients showed significant decrease only in the left genu of corpus callosum when compared to the HC. For the SG group, whole brain analysis revealed significant correlation between the performance in the Semantic Fluency test and the FA in the right hemisphere as well as between the performance in the Grooved Pegboard Test (GPT) and the Trail Making Test-part A and the FA in the left hemisphere. For the SP group, correlation analysis revealed significant correlation between the performance in the GPT and the FA in the right hemisphere.

Structural Integrity of the Contralesional Hemisphere Predicts Cognitive Impairment in Ischemic Stroke at Three Months

PubMed Central

Dacosta-Aguayo, Rosalia; Graña, Manuel; Fernández-Andújar, Marina; López-Cancio, Elena; Cáceres, Cynthia; Bargalló, Núria; Barrios, Maite; Clemente, Immaculada; Monserrat, Pere Toran; Sas, Maite Alzamora; Dávalos, Antoni

2014-01-01

After stroke, white matter integrity can be affected both locally and distally to the primary lesion location. It has been shown that tract disruption in mirror’s regions of the contralateral hemisphere is associated with degree of functional impairment. Fourteen patients suffering right hemispheric focal stroke (S) and eighteen healthy controls (HC) underwent Diffusion Weighted Imaging (DWI) and neuropsychological assessment. The stroke patient group was divided into poor (SP; n = 8) and good (SG; n = 6) cognitive recovery groups according to their cognitive improvement from the acute phase (72 hours after stroke) to the subacute phase (3 months post-stroke). Whole-brain DWI data analysis was performed by computing Diffusion Tensor Imaging (DTI) followed by Tract Based Spatial Statistics (TBSS). Assessment of effects was obtained computing the correlation of the projections on TBSS skeleton of Fractional Anisotropy (FA) and Radial Diffusivity (RD) with cognitive test results. Significant decrease of FA was found only in right brain anatomical areas for the S group when compared to the HC group. Analyzed separately, stroke patients with poor cognitive recovery showed additional significant FA decrease in several left hemisphere regions; whereas SG patients showed significant decrease only in the left genu of corpus callosum when compared to the HC. For the SG group, whole brain analysis revealed significant correlation between the performance in the Semantic Fluency test and the FA in the right hemisphere as well as between the performance in the Grooved Pegboard Test (GPT) and theTrail Making Test-part A and the FA in the left hemisphere. For the SP group, correlation analysis revealed significant correlation between the performance in the GPT and the FA in the right hemisphere. PMID:24475078

Fungal Infections Associated with Contaminated Methylprednisolone in Tennessee

PubMed Central

Kainer, Marion A.; Reagan, David R.; Nguyen, Duc B.; Wiese, Andrew D.; Wise, Matthew E.; Ward, Jennifer; Park, Benjamin J.; Kanago, Meredith L.; Baumblatt, Jane; Schaefer, Melissa K.; Berger, Brynn E.; Marder, Ellyn P.; Min, Jea-Young; Dunn, John R.; Smith, Rachel M.; Dreyzehner, John; Jones, Timothy F.

2015-01-01

BACKGROUND We investigated an outbreak of fungal infections of the central nervous system that occurred among patients who received epidural or paraspinal glucocorticoid injections of preservative-free methylprednisolone acetate prepared by a single compounding pharmacy. METHODS Case patients were defined as patients with fungal meningitis, posterior circulation stroke, spinal osteomyelitis, or epidural abscess that developed after epidural or paraspinal glucocorticoid injections. Clinical and procedure data were abstracted. A cohort analysis was performed. RESULTS The median age of the 66 case patients was 69 years (range, 23 to 91). The median time from the last epidural glucocorticoid injection to symptom onset was 18 days (range, 0 to 56). Patients presented with meningitis alone (73%), the cauda equina syndrome or focal infection (15%), or posterior circulation stroke with or without meningitis (12%). Symptoms and signs included headache (in 73% of the patients), new or worsening back pain (in 50%), neurologic symptoms (in 48%), nausea (in 39%), and stiff neck (in 29%). The median cerebrospinal fluid white-cell count on the first lumbar puncture among patients who presented with meningitis, with or without stroke or focal infection, was 648 per cubic millimeter (range, 6 to 10,140), with 78% granulocytes (range, 0 to 97); the protein level was 114 mg per deciliter (range, 29 to 440); and the glucose concentration was 44 mg per deciliter (range, 12 to 121) (2.5 mmol per liter [range, 0.7 to 6.7]). A total of 22 patients had laboratory confirmation of Exserohilum rostratum infection (21 patients) or Aspergillus fumigatus infection (1 patient). The risk of infection increased with exposure to lot 06292012@26, older vials, higher doses, multiple procedures, and translaminar approach to epidural glucocorticoid injection. Voriconazole was used to treat 61 patients (92%); 35 patients (53%) were also treated with liposomal amphotericin B. Eight patients (12%) died, seven of whom had stroke. CONCLUSIONS We describe an outbreak of fungal meningitis after epidural or paraspinal glucocorticoid injection with methylprednisolone from a single compounding pharmacy. Rapid recognition of illness and prompt initiation of therapy are important to prevent complications. (Funded by the Tennessee Department of Health and the Centers for Disease Control and Prevention.) PMID:23131029

Evaluation of acute ischemic stroke using quantitative EEG: a comparison with conventional EEG and CT scan.

PubMed

Murri, L; Gori, S; Massetani, R; Bonanni, E; Marcella, F; Milani, S

1998-06-01

The sensitivity of quantitative electroencephalogram (EEG) was compared with that of conventional EEG in patients with acute ischaemic stroke. In addition, a correlation between quantitative EEG data and computerized tomography (CT) scan findings was carried out for all the areas of lesion in order to reassess the actual role of EEG in the evaluation of stroke. Sixty-five patients were tested with conventional and quantitative EEG within 24 h from the onset of neurological symptoms, whereas CT scan was performed within 4 days from the onset of stroke. EEG was recorded from 19 electrodes placed upon the scalp according to the International 10-20 System. Spectral analysis was carried out on 30 artefact-free 4-sec epochs. For each channel absolute and relative power were calculated for the delta, theta, alpha and beta frequency bands and such data were successively represented in colour-coded maps. Ten patients with extensive lesions documented by CT scan were excluded. The results indicated that conventional EEG revealed abnormalities in 40 of 55 cases, while EEG mapping showed abnormalities in 46 of 55 cases: it showed focal abnormalities in five cases and nonfocal abnormalities in one of six cases which had appeared to be normal according to visual inspection of EEG. In a further 11 cases, where the conventional EEG revealed abnormalities in one hemisphere, the quantitative EEG and maps allowed to further localize abnormal activity in a more localized way. The sensitivity of both methods was higher for frontocentral, temporal and parieto-occipital cortical-subcortical infarctions than for basal ganglia and internal capsule lesions; however, quantitative EEG was more efficient for all areas of lesion in detecting cases that had appeared normal by visual inspection and was clearly superior in revealing focal abnormalities. When we considered the electrode related to which the maximum power of the delta frequency band is recorded, a fairly close correlation was found between the localization of the maximum delta power and the position of lesions documented by CT scan for all areas of lesion excepting those located in the striatocapsular area.

A review of stroke and pregnancy: incidence, management and prevention.

PubMed

Moatti, Zoe; Gupta, Manish; Yadava, Rajendra; Thamban, Sujatha

2014-10-01

Stroke, defined as a focal or global disturbance of cerebral function lasting over 24h resulting from disruption of its blood supply, is a devastating event for a pregnant woman. This can result in long-term disability or death, and impact on her family and unborn child. In addition to pre-existing patient risk factors, the hypercoagulable state and pre-eclampsia need to be taken into account. The patterns and types of stroke affect pregnant women differ from the non-pregnant female population of child-bearing age. Like other thrombo-embolic diseases in pregnancy, stroke is essentially a disease of the puerperium. Population studies have estimated the risk of stroke at between 21.2 and 46.2 per 100,000. The US Nationwide Inpatient Sample, identified 2850 pregnancies complicated by stroke in the United States in 2000-2001, for a rate of 34.2 per 100,000 deliveries. There were 117 deaths, a mortality rate of 1.4 per 100,000. Both the mortality and disability rates were higher than previously reported, with 10-13% of women dying. With the increasing prevalence of obesity, hypertension and cardiac disease amongst women of child-bearing age, so is the incidence of stroke during pregnancy and the puerperium. In the United States, an alarming trend toward higher numbers of stroke hospitalizations during the last decade was demonstrated in studies from 1995 to 1996 and 2006 to 2007. The rate of all types of stroke increased by 47% among antenatal hospitalizations, and by 83% among post-partum hospitalizations. Hypertensive disorders, obesity and heart disease complicated 32% of antenatal admissions and 53% of post-partum admissions. In addition to pre-existing patient risk factors, the hypercoagulable state and pre-eclampsia need to be taken into account. The patterns and types of stroke affect pregnant women differ from the non-pregnant female population of child-bearing age. Like other thrombo-embolic diseases in pregnancy, stroke is essentially a disease of the puerperium. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Magnolol Reduces Glutamate-Induced Neuronal Excitotoxicity and Protects against Permanent Focal Cerebral Ischemia Up to 4 Hours

PubMed Central

Lee, E-Jian; Hung, Yu-Chang; Tai, Shih-Huang; Chen, Hung-Yi; Chen, Tsung-Ying; Wu, Tian-Shung

2012-01-01

Neuroprotective efficacy of magnolol, 5,5′-dially-2,2′-dihydroxydiphenyl, was investigated in a model of stroke and cultured neurons exposed to glutamate-induced excitotoxicity. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO). Magnolol or vehicle was administered intraperitoneally, at 1 hr pre-insult or 1–6 hrs post-insult. Brain infarction was measured upon sacrifice. Relative to controls, animals pre-treated with magnolol (50–200 mg/kg) had significant infarct volume reductions by 30.9–37.8% and improved neurobehavioral outcomes (P<0.05, respectively). Delayed treatment with magnolol (100 mg/kg) also protected against ischemic brain damage and improved neurobehavioral scores, even when administered up to 4 hrs post-insult (P<0.05, respectively). Additionally, magnolol (0.1 µM) effectively attenuated the rises of intracellular Ca2+ levels, [Ca2+](i), in cultured neurons exposed to glutamate. Consequently, magnolol (0.1–1 µM) significantly attenuated glutamate-induced cytotoxicity and cell swelling (P<0.05). Thus, magnolol offers neuroprotection against permanent focal cerebral ischemia with a therapeutic window of 4 hrs. This neuroprotection may be, partly, mediated by its ability to limit the glutamate-induced excitotoxicity. PMID:22808077

Hexane extracts of Polygonum multiflorum improve tissue and functional outcome following focal cerebral ischemia in mice.

PubMed

Lee, Soo Vin; Choi, Kyung Ha; Choi, Young Whan; Hong, Jin Woo; Baek, Jin Ung; Choi, Byung Tae; Shin, Hwa Kyoung

2014-04-01

Polygonum multiflorum is a traditional Korean medicine that has been utilized widely in East Asian countries as a longevity agent. Clinical studies have demonstrated that Polygonum multiflorum improves hypercholesterolemia, coronary heart disease, neurosis and other diseases commonly associated with aging. However, scientific evidence defining the protective effects and mechanisms of Polygonum multiflorum against ischemic stroke is incomplete. In the present study, we investigated the cerebrovascular protective effects of Polygonum multiflorum against ischemic brain injury using an in vivo photothrombotic mouse model. To examine the underlying mechanism of action, we utilized an in vitro human brain microvascular endothelial cell (HBMEC) culture system. Hexane extracts (HEPM), ethyl acetate extracts (EAEPM) and methanol extracts (MEPM) of Polygonum multiflorum (100 mg/kg) were administered intraperitoneally 30 min prior to ischemic insult. Focal cerebral ischemia was induced in C57BL/6J mice and endothelial nitric oxide synthase knockout (eNOS KO) mice by photothrombotic cortical occlusion. We evaluated the infarct volume, as well as neurological and motor function, 24 h after ischemic brain injury. Following ischemic insult, HEPM induced a significant reduction in infarct volume and subsequent neurological deficits, compared with EAEPM and MEPM. HEPM significantly decreased infarct size and improved neurological and motor function, which was not observed in eNOS KO mice, suggesting that this cerebroprotective effect is primarily an eNOS-dependent mechanism. In vitro, HEPM effectively promoted NO production, however these effects were inhibited by the NOS inhibitor, L-NAME and the PI3K/Akt inhibitor, LY-294002. Furthermore, HEPM treatment resulted in increased phosphorylation-dependent activation of Akt and eNOS in HBMEC, suggesting that HEPM increased NO production via phosphorylation-dependent activation of Akt and eNOS. In conclusion, HEPM prevents cerebral ischemic damage through an eNOS-dependent mechanism, and thus may have clinical applications as a protective agent against neurological injury in stroke.

Emergence of realism: Enhanced visual artistry and high accuracy of visual numerosity representation after left prefrontal damage.

PubMed

Takahata, Keisuke; Saito, Fumie; Muramatsu, Taro; Yamada, Makiko; Shirahase, Joichiro; Tabuchi, Hajime; Suhara, Tetsuya; Mimura, Masaru; Kato, Motoichiro

2014-05-01

Over the last two decades, evidence of enhancement of drawing and painting skills due to focal prefrontal damage has accumulated. It is of special interest that most artworks created by such patients were highly realistic ones, but the mechanism underlying this phenomenon remains to be understood. Our hypothesis is that enhanced tendency of realism was associated with accuracy of visual numerosity representation, which has been shown to be mediated predominantly by right parietal functions. Here, we report a case of left prefrontal stroke, where the patient showed enhancement of artistic skills of realistic painting after the onset of brain damage. We investigated cognitive, functional and esthetic characteristics of the patient׳s visual artistry and visual numerosity representation. Neuropsychological tests revealed impaired executive function after the stroke. Despite that, the patient׳s visual artistry related to realism was rather promoted across the onset of brain damage as demonstrated by blind evaluation of the paintings by professional art reviewers. On visual numerical cognition tasks, the patient showed higher performance in comparison with age-matched healthy controls. These results paralleled increased perfusion in the right parietal cortex including the precuneus and intraparietal sulcus. Our data provide new insight into mechanisms underlying change in artistic style due to focal prefrontal lesion. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neuroprotective effect of chondroitinase ABC on primary and secondary brain injury after stroke in hypertensive rats.

PubMed

Chen, Xin-ran; Liao, Song-jie; Ye, Lan-xiang; Gong, Qiong; Ding, Qiao; Zeng, Jin-sheng; Yu, Jian

2014-01-16

Focal cerebral infarction causes secondary damage in the ipsilateral ventroposterior thalamic nucleus (VPN). Chondroitin sulfate proteoglycans (CSPGs) are a family of putative inhibitory components, and its degradation by chondroitinase ABC (ChABC) promotes post-injury neurogenesis. This study investigated the role of ChABC in the primary and secondary injury post stroke in hypertension. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO), and were subjected to continuous intra-infarct infusion of ChABC (0.12 U/d for 7 days) 24 h later. Neurological function was evaluated by a modified neurologic severity score. Neurons were counted in the peri-infarct region and the ipsilateral VPN 8 and 14 days after MCAO by Nissl staining and NeuN labeling. The expressions of CSPGs, growth-associated protein-43 (GAP-43) and synaptophysin (SYN) were detected with immunofluorescence or Western blotting. The intra-infarct infusion of ChABC, by degrading accumulated CSPGs, rescued neuronal loss and increased the levels of GAP-43 and SYN in both the ipsilateral cortex and VPN, indicating enhancd neuron survival as well as augmented axonal growth and synaptic plasticity, eventually improving overall neurological function. The study demonstrated that intra-infarct ChABC infusion could salvage the brain from both primary and secondary injury by the intervention on the neuroinhibitory environment post focal cerebral infarction. © 2013 Published by Elsevier B.V.

Identification of Sleep-Modulated Pathways Involved in Neuroprotection from Stroke.

PubMed

Pace, Marta; Baracchi, Francesca; Gao, Bo; Bassetti, Claudio

2015-11-01

Sleep deprivation (SDp) performed before stroke induces an ischemic tolerance state as observed in other forms of preconditioning. As the mechanisms underlying this effect are not well understood, we used DNA oligonucleotide microarray analysis to identify the genes and the gene-pathways underlying SDp preconditioning effects. Gene expression was analyzed 3 days after stroke in 4 experimental groups: (i) SDp performed before focal cerebral ischemia (IS) induction; (ii) SDp performed before sham surgery; (iii) IS without SDp; and (iv) sham surgery without SDp. SDp was performed by gentle handling during the last 6 h of the light period, and ischemia was induced immediately after. Basic sleep research laboratory. Stroke induced a massive alteration in gene expression both in sleep deprived and non-sleep deprived animals. However, compared to animals that underwent ischemia alone, SDp induced a general reduction in transcriptional changes with a reduction in the upregulation of genes involved in cell cycle regulation and immune response. Moreover, an upregulation of a new neuroendocrine pathway which included melanin concentrating hormone, glycoprotein hormones-α-polypeptide and hypocretin was observed exclusively in rats sleep deprived before stroke. Our data indicate that sleep deprivation before stroke reprogrammed the signaling response to injury. The inhibition of cell cycle regulation and inflammation are neuroprotective mechanisms reported also for other forms of preconditioning treatment, whereas the implication of the neuroendocrine function is novel and has never been described before. These results therefore provide new insights into neuroprotective mechanisms involved in ischemic tolerance mechanisms. © 2015 Associated Professional Sleep Societies, LLC.

How Commonly Is Stroke Found in Patients with Isolated Vertigo or Dizziness Attack?

PubMed

Doijiri, Ryosuke; Uno, Hisakazu; Miyashita, Kotaro; Ihara, Masafumi; Nagatsuka, Kazuyuki

2016-10-01

The sudden development of vertigo or dizziness without focal neurological symptoms is generally attributable to vestibular diseases such as benign paroxysmal positional vertigo. Isolated vertigo or dizziness attack needs more attention than vestibular diseases. This retrospective study was performed to elucidate the frequency of strokes in patients with isolated vertigo or dizziness attack. We enrolled 221 patients (men, 119; women, 102; mean age, 68.4 ± 10.3 years) who were admitted to our hospital over the last 10 years because of sudden isolated vertigo or dizziness attack without other neurological symptoms except for nystagmus, deafness, or tinnitus. We investigated the clinical features, final diagnosis, neuroimaging findings, and short- or long-term outcome of these patients. One hundred eighteen patients had vertigo whereas the other 103 had dizziness. Brain computed tomography or magnetic resonance imaging revealed recent stroke lesions in 25 patients (11.3%) (ischemic, 21; hemorrhagic, 4).The lesions were generally small and localized in the cerebellum (n = 21), pons (n = 1), medulla oblongata (n = 1), or corona radiata (n = 1). Of the 25 patients, 19 (76%) had dizzy-type spells; none had neurological dysfunction at the time of discharge. In the remaining 196 patients, no stroke was detected on computed tomography or magnetic resonance imaging. Stroke was found in 11% of patients with isolated vertigo or dizziness attack. The posterior inferior cerebellar artery area was the most frequently implicated for isolated vertigo or dizziness. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

MRI as a Translational Tool for the Study of Neonatal Stroke

PubMed Central

Dzietko, Mark; Wendland, Michael; Derugin, Nikita; Ferriero, Donna M.; Vexler, Zinaida S.

2013-01-01

More than half of neonatal stroke survivors have long-term sequelae, including seizures and neurological deficits. Although the immature brain has tremendous potential for recovery, mechanisms governing repair are essentially unexplored. We explored whether magnetic resonance imaging (MRI) early or late after transient middle cerebral arterial occlusion in 10-day-old (P10) rats can serve as an intermediate endpoint for long-term studies. Injured animals selected by diffusion-weighted MRI during middle cerebral arterial occlusion were scanned using T2-weighted MRI at P18 and P25 (injury volumes on MRI and histology were compared), or were subjected to contrast-enhanced MRI at P13 to characterize cerebral microcirculatory disturbances and blood-brain barrier leakage. Injury volume did not predict histological outcome at 2 weeks. Major reductions occurred by P18, with no further changes by P25. Cerebral perfusion was significantly reduced in the injured caudate but blood-brain barrier leakage was small. Therefore, conventional T2-weighted MRI performed during a subchronic injury phase predicts long-term histological outcome after experimental neonatal focal stroke. PMID:21670390

Identification of proteins in hyperglycemia and stroke animal models.

PubMed

Sung, Jin-Hee; Shah, Fawad-Ali; Gim, Sang-Ah; Koh, Phil-Ok

2016-01-01

Stroke is a major cause of disability and death in adults. Diabetes mellitus is a metabolic disorder that strongly increases the risk of severe vascular diseases. This study compared changes in proteins of the cerebral cortex during ischemic brain injury between nondiabetic and diabetic animals. Adult male rats were injected with streptozotocin (40 mg/kg) via the intraperitoneal route to induce diabetes and underwent surgical middle cerebral artery occlusion (MCAO) 4 wk after streptozotocin treatment. Cerebral cortex tissues were collected 24 h after MCAO and cerebral cortex proteins were analyzed by two-dimensional gel electrophoresis and mass spectrometry. Several proteins were identified as differentially expressed between nondiabetic and diabetic animals. Among the identified proteins, we focused on the following metabolism-related enzymes: isocitrate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, adenosylhomocysteinase, pyruvate kinase, and glucose-6-phosphate isomerase (neuroleukin). Expression of these proteins was decreased in animals that underwent MCAO. Moreover, protein expression was reduced to a greater extent in diabetic animals than in nondiabetic animals. Reverse transcription-polymerase chain reaction analysis confirmed that the diabetic condition exacerbates the decrease in expression of metabolism-related proteins after MCAO. These results suggest that the diabetic condition may exacerbate brain damage during focal cerebral ischemia through the downregulation of metabolism-related proteins. Copyright © 2016 Elsevier Inc. All rights reserved.

External validation of a six simple variable model of stroke outcome and verification in hyper-acute stroke.

PubMed

Reid, J M; Gubitz, G J; Dai, D; Reidy, Y; Christian, C; Counsell, C; Dennis, M; Phillips, S J

2007-12-01

We aimed to validate a previously described six simple variable (SSV) model that was developed from acute and sub-acute stroke patients in our population that included hyper-acute stroke patients. A Stroke Outcome Study enrolled patients from 2001 to 2002. Functional status was assessed at 6 months using the modified Rankin Scale (mRS). SSV model performance was tested in our cohort. 538 acute ischaemic (87%) and haemorrhagic stroke patients were enrolled, 51% of whom presented to hospital within 6 h of symptom recognition. At 6 months post-stroke, 42% of patients had a good outcome (mRS < or = 2). Stroke patients presenting within 6 h of symptom recognition were significantly older with higher stroke severity. In our Stroke Outcome Study dataset, the SSV model had an area under the curve of 0.792 for 6 month outcomes and performed well for hyper-acute or post-acute stroke, age < or > or = 75 years, haemorrhagic or ischaemic stroke, men or women, moderate and severe stroke, but poorly for mild stroke. This study confirms the external validity of the SSV model in our hospital stroke population. This model can therefore be utilised for stratification in acute and hyper-acute stroke trials.

Vascular cognitive disorders and depression after first-ever stroke: the Fogarty-Mexico Stroke Cohort.

PubMed

Arauz, Antonio; Rodríguez-Agudelo, Yaneth; Sosa, Ana Luisa; Chávez, Mireya; Paz, Francisco; González, Margarita; Coral, Juliana; Díaz-Olavarrieta, Claudia; Román, Gustavo C

2014-01-01

Stroke is the major cause of vascular behavior and cognitive disorders worldwide. In developing countries, there is a dearth of information regarding the public health magnitude of stroke. The aim of the Fogarty-Mexico cohort was to assess the prevalence of vascular behavioral and cognitive disorders, ranging from mild vascular cognitive impairment (VCI) to vascular dementia (VaD), in a cohort of acute first-ever symptomatic stroke patients in Mexico. A total of 165 consecutive, first-ever stroke patients admitted to the National Institute of Neurology and Neurosurgery in Mexico City, were included in the cohort. Patients were eligible if they had an ischemic stroke, primary intracerebral hemorrhage, or cerebral venous thrombosis (CVT). Stroke diagnosis required the presence of an acute focal deficit lasting more than 24 h, confirmed by a corresponding lesion on CT/MRI. Stroke severity was established with the NIH Stroke Scale. The pre-stroke functional status was determined by the IQCODE. Three months after the occurrence of stroke, 110 survivor patients returned for follow-up and were able to undergo functional outcome (modified Rankin scale, Barthel index), along with neurological, psychiatric, neuropsychological, laboratory, and imaging assessments. We compared depression, demographic, and clinical and imaging features between patients with and without dementia, and between patients with VCI and those with intact cognition. Of the 110 patients (62% men, mean age 56 ± 17.8, education 7.7 ± 5.2 years) 93 (84%) had ischemic strokes, 14 (13%) intracerebral hemorrhage, and 3 (3%) CVT. The main risk factors were hypertension (50%), smoking (40%), hypercholesterolemia (29%), hyperhomocysteinemia (24%), and diabetes (22%). Clinical and neuropsychological evaluations demonstrated post-stroke depression in 56%, VCI in 41%, and VaD in 12%; 17% of the latter had pre-stroke functional impairment (IQCODE >3.5). Cognitive deficits included executive function in 69%, verbal memory in 49%, language in 38%, perception in 36%, and attention in 38%. Executive dysfunction occurred in 36% of non-demented subjects, 65% of them with mild-moderate deficits in daily living activities. Female gender (p ≤ 0.054), older age (mean age 65.6 years vs. 49.3, p < 0.001), diabetes (p ≤ 0.004), illiteracy and lower education (p ≤ 0.001), and PSD (p = 0.03) were significantly higher in VCI-VaD compared with cognitively intact post-stroke subjects. We could not demonstrate an association with lesion site and distribution of the cognitive deficits. The Fogarty-Mexico cohort recruited relatively young acute stroke patients, compared with other Mexican stroke cohorts. PSD and VCI occurred frequently but prevalence of VaD (12%) was lower than expected. A high prevalence of treatable stroke risk factors suggests that preventive interventions are advisable. © 2014 S. Karger AG, Basel.

Progesterone induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in rats.

PubMed

Andrabi, Syed Suhail; Parvez, Suhel; Tabassum, Heena

2017-06-01

Organelle damage and increases in mitochondrial permeabilization are key events in the development of cerebral ischemic tissue injury because they cause both modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetic processes can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found to be neuroprotective in various models of neurological diseases, through a number of mechanisms. This influenced us to investigate the possible role of P4 in the mitochondria-mediated neuroprotective mechanism in an ischemic stroke model of rat. In this study, we have shown the positive effect of P4 administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). After induction of tMCAO, the rats received an initial intraperitoneal injection of P4 (8 mg/kg body weight) or vehicle at 1 h post-occlusion followed by subcutaneous injections at 6, 12 and 18 h. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Findings revealed a significant improvement with P4 treatment in tMCAO animals. Staining of isolated brain slices from P4-treated rats with 2,3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. P4 treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that P4 has a positive effect on mitochondrial bioenergetics. In conclusion, these results demonstrate that P4 treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies. © 2017. Published by The Company of Biologists Ltd.

Inhibition of VEGF Signaling Reduces Diabetes-Exacerbated Brain Swelling, but Not Infarct Size, in Large Cerebral Infarction in Mice.

PubMed

Kim, Eunhee; Yang, Jiwon; Park, Keun Woo; Cho, Sunghee

2017-12-30

In light of repeated translational failures with preclinical neuroprotection-based strategies, this preclinical study reevaluates brain swelling as an important pathological event in diabetic stroke and investigates underlying mechanism of the comorbidity-enhanced brain edema formation. Type 2 (mild), type 1 (moderate), and mixed type 1/2 (severe) diabetic mice were subjected to transient focal ischemia. Infarct volume, brain swelling, and IgG extravasation were assessed at 3 days post-stroke. Expression of vascular endothelial growth factor (VEGF)-A, endothelial-specific molecule-1 (Esm1), and the VEGF receptor 2 (VEGFR2) was determined in the ischemic brain. Additionally, SU5416, a VEGFR2 inhibitor, was treated in the type 1/2 diabetic mice, and stroke outcomes were determined. All diabetic groups displayed bigger infarct volume and brain swelling compared to nondiabetic mice, and the increased swelling was disproportionately larger relative to infarct enlargement. Diabetic conditions significantly increased VEGF-A, Esm1, and VEGFR2 expressions in the ischemic brain compared to nondiabetic mice. Notably, in diabetic mice, VEGFR2 mRNA levels were positively correlated with brain swelling, but not with infarct volume. Treatment with SU5416 in diabetic mice significantly reduced brain swelling. The study shows that brain swelling is a predominant pathological event in diabetic stroke and that an underlying event for diabetes-enhanced brain swelling includes the activation of VEGF signaling. This study suggests consideration of stroke therapies aiming at primarily reducing brain swelling for subjects with diabetes.

Migraine prophylaxis, ischemic depolarizations and stroke outcomes in mice

PubMed Central

Eikermann-Haerter, Katharina; Lee, Jeong Hyun; Yalcin, Nilufer; Yu, Esther Sori; Daneshmand, Ali; Wei, Ying; Zheng, Yi; Can, Anil; Sengul, Buse; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.; Ayata, Cenk

2014-01-01

Background and Purpose Migraine with aura is an established stroke risk factor, and excitatory mechanisms such as spreading depression are implicated in the pathogenesis of both migraine and stroke. Spontaneous spreading depression waves originate within the peri-infarct tissue and exacerbate the metabolic mismatch during focal cerebral ischemia. Genetically enhanced spreading depression susceptibility facilitates anoxic depolarizations and peri-infarct spreading depressions and accelerates infarct growth, suggesting that susceptibility to spreading depression is a critical determinant of vulnerability to ischemic injury. Because chronic treatment with migraine prophylactic drugs suppresses spreading depression susceptibility, we tested whether migraine prophylaxis can also suppress ischemic depolarizations and improve stroke outcome. Methods We measured the cortical susceptibility to spreading depression and ischemic depolarizations, and determined tissue and neurological outcome after middle cerebral artery occlusion in wild type and familial hemiplegic migraine type 1 knock-in mice treated with vehicle, topiramate or lamotrigine daily for 7 weeks or as a single dose shortly before testing. Results Chronic treatment with topiramate or lamotrigine reduces the susceptibility to KCl- or electrical stimulation-induced spreading depressions as well as ischemic depolarizations in both wild-type and familial hemiplegic migraine type 1 mutant mice. Consequently, both tissue and neurological outcomes are improved. Notably, treatment with a single dose of either drug is ineffective. Conclusions These data underscore the importance of hyperexcitability as a mechanism for increased stroke risk in migraineurs, and suggest that migraine prophylaxis may not only prevent migraine attacks but also protect migraineurs against ischemic injury. PMID:25424478

Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study.

PubMed

Fang, Qing; Yan, Xu; Li, Shaowu; Sun, Yilin; Xu, Lixin; Shi, Zhongfang; Wu, Min; Lu, Yi; Dong, Liping; Liu, Ran; Yuan, Fang; Yang, Shao-Hua

2016-01-01

The neuroprotective effect of methylene blue (MB) has been identified against various brain disorders, including ischemic stroke. In the present study, we evaluated the effects of MB on postischemic brain edema using magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Adult male rats were subjected to transient focal cerebral ischemia induced by 1 h middle cerebral artery occlusion (MCAO), followed by reperfusion. MB was infused intravenously immediately after reperfusion (3 mg/kg) and again at 3 h post-occlusion (1.5 mg/kg). Normal saline was administered as vehicle control. Sequential MRIs, including apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI), were obtained at 0.5, 2.5, and 48 h after the onset of stroke. Separated groups of animals were sacrificed at 2.5 and 48 h after stroke for ultrastructural analysis by TEM. In addition, final lesion volumes were analyzed by triphenyltetrazolium chloride (TTC) staining at 48 h after stroke. Ischemic stroke induced ADC lesion volume at 0.5 h during MCAOs that were temporally recovered at 1.5 h after reperfusion. No significant difference in ADC-defined lesion was observed between vehicle and MB treatment groups. At 48 h after stroke, MB significantly reduced ADC lesion and T2WI lesion volume and attenuated cerebral swelling. Consistently, MB treatment significantly decreased TTC-defined lesion volume at 48 h after stroke. TEM revealed remarkable swollen astrocytes, astrocytic perivascular end-feet, and concurrent shrunken neurons in the penumbra at 2.5 and 48 h after MCAO. MB treatment attenuated astrocyte swelling, the perivascular astrocytic foot process, and endothelium and also alleviated neuron degeneration. This study demonstrated that MB could decrease postischemic brain edema and provided additional evidence that future clinical investigation of MB for the treatment of ischemic stroke is warrented.

Neuroprotective mechanism of BNG-1 against focal cerebral ischemia: a neuroimaging and neurotrophin study.

PubMed

Chi, Nai-Fang; Liu, Ho-Ling; Yang, Jen-Tsung; Lin, Jr-Rung; Liao, Shu-Li; Peng, Bo-Han; Lee, Yen-Tung; Lee, Tsong-Hai

2014-01-01

BNG-1 is a herb complex used in traditional Chinese medicine to treat stroke. In this study, we attempted to identify the neuroprotective mechanism of BNG-1 by using neuroimaging and neurotrophin analyses of a stroke animal model. Rats were treated with either saline or BNG-1 for 7 d after 60-min middle cerebral artery occlusion by filament model. The temporal change of magnetic resonance (MR) imaging of brain was studied using a 7 Tesla MR imaging (MRI) system and the temporal expressions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in brain were analyzed before operation and at 4 h, 2 d, and 7 d after operation. Compared with the saline group, the BNG-1 group exhibited a smaller infarction volume in the cerebral cortex in T2 image from as early as 4 h to 7 d, less edema in the cortex in diffusion weighted image from 2 to 7 d, earlier reduction of postischemic hyperperfusion in both the cortex and striatum in perfusion image at 4 h, and earlier normalization of the ischemic pattern in the striatum in susceptibility weighted image at 2 d. NT-3 and BDNF levels were higher in the BNG-1 group than the saline group at 7 d. We concluded that the protective effect of BNG-1 against cerebral ischemic injury might act through improving cerebral hemodynamics and recovering neurotrophin generation.

Diabetic microangiopathy: impact of impaired cerebral vasoreactivity and delayed angiogenesis after permanent middle cerebral artery occlusion on stroke damage and cerebral repair in mice.

PubMed

Poittevin, Marine; Bonnin, Philippe; Pimpie, Cynthia; Rivière, Léa; Sebrié, Catherine; Dohan, Anthony; Pocard, Marc; Charriaut-Marlangue, Christiane; Kubis, Nathalie

2015-03-01

Diabetes increases the risk of stroke by three, increases related mortality, and delays recovery. We aimed to characterize functional and structural alterations in cerebral microvasculature before and after experimental cerebral ischemia in a mouse model of type 1 diabetes. We hypothesized that preexisting brain microvascular disease in patients with diabetes might partly explain increased stroke severity and impact on outcome. Diabetes was induced in 4-week-old C57Bl/6J mice by intraperitoneal injections of streptozotocin (60 mg/kg). After 8 weeks of diabetes, the vasoreactivity of the neurovascular network to CO2 was abolished and was not reversed by nitric oxide (NO) donor administration; endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) mRNA, phospho-eNOS protein, nNOS, and phospho-nNOS protein were significantly decreased; angiogenic and vessel maturation factors (vascular endothelial growth factor a [VEGFa], angiopoietin 1 (Ang1), Ang2, transforming growth factor-β [TGF-β], and platelet-derived growth factor-β [PDGF-β]) and blood-brain barrier (BBB) occludin and zona occludens 1 (ZO-1) expression were significantly decreased; and microvessel density was increased without changes in ultrastructural imaging. After permanent focal cerebral ischemia induction, infarct volume and neurological deficit were significantly increased at D1 and D7, and neuronal death (TUNEL+ / NeuN+ cells) and BBB permeability (extravasation of Evans blue) at D1. At D7, CD31+ / Ki67+ double-immunolabeled cells and VEGFa and Ang2 expression were significantly increased, indicating delayed angiogenesis. We show that cerebral microangiopathy thus partly explains stroke severity in diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury

PubMed Central

2012-01-01

Background An increase in intracellular calcium concentration [Ca2+]i is one of the first events to take place after brain ischemia. A key [Ca2+]i-regulated signaling molecule is the phosphatase calcineurin (CN), which plays important roles in the modulation of inflammatory cascades. Here, we have analyzed the role of endogenous regulator of CN 1 (Rcan1) in response to experimental ischemic stroke induced by middle cerebral artery occlusion. Methods Animals were subjected to focal cerebral ischemia with reperfusion. To assess the role of Rcan1 after stroke, we measured infarct volume after 48 h of reperfusion in Rcan1 knockout (KO) and wild-type (WT) mice. In vitro studies were performed in astrocyte-enriched cortical primary cultures subjected to 3% oxygen (hypoxia) and glucose deprivation (HGD). Adenoviral vectors were used to analyze the effect of overexpression of Rcan1-4 protein. Protein expression was examined by immunohistochemistry and immunoblotting and expression of mRNA by quantitative real-time Reverse-Transcription Polymerase Chain Reaction (real time qRT-PCR). Results Brain ischemia/reperfusion (I/R) injury in vivo increased mRNA and protein expression of the calcium-inducible Rcan1 isoform (Rcan1-4). I/R-inducible expression of Rcan1 protein occurred mainly in astroglial cells, and in an in vitro model of ischemia, HGD treatment of primary murine astrocyte cultures induced Rcan1-4 mRNA and protein expression. Exogenous Rcan1-4 overexpression inhibited production of the inflammatory marker cyclo-oxygenase 2. Mice lacking Rcan1 had higher expression of inflammation associated genes, resulting in larger infarct volumes. Conclusions Our results support a protective role for Rcan1 during the inflammatory response to stroke, and underline the importance of the glial compartment in the inflammatory reaction that takes place after ischemia. Improved understanding of non-neuronal mechanisms in ischemic injury promises novel approaches to the treatment of acute ischemic stroke. PMID:22397398

Diffusion tensor imaging of early changes in corpus callosum after acute cerebral hemisphere lesions in newborns.

PubMed

Righini, Andrea; Doneda, Chiara; Parazzini, Cecilia; Arrigoni, Filippo; Matta, Ursula; Triulzi, Fabio

2010-11-01

The main purpose was to investigate any early diffusion tensor imaging (DTI) changes in corpus callosum (CC) associated with acute cerebral hemisphere lesions in term newborns. We retrospectively analysed 19 cases of term newborns acutely affected by focal or multi-focal lesions: hypoxic-ischemic encephalopathy, hypoglycaemic encephalopathy, focal ischemic stroke and deep medullary vein associated lesions. DTI was acquired at 1.5 Tesla with dedicated neonatal coil. DTI metrics (apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial λ(∐) and radial λ(⟂) diffusivity) were measured in the hemisphere lesions and in the CC. The control group included seven normal newborns. The following significant differences were found between patients and normal controls in the CC: mean ADC was lower in patients (0.88 SD 0.23 versus 1.18 SD 0.07 μm(2)/s) and so was mean FA (0.50 SD 0.1 versus 0.67 SD 0.05) and mean λ(∐) value (1.61 SD 0.52 versus 2.36 SD 0.14 μm(2)/s). In CC the percentage of ADC always diminished independently of lesion age (with one exception), whereas in hemisphere lesions, it was negative in earlier lesions, but exceeded normal values in the older lesions. CC may undergo early DTI changes in newborns with acute focal or multi-focal hemisphere lesions of different aetiology. Although a direct insult to CC cannot be totally ruled out, DTI changes in CC (in particular λ(∐)) may also be compatible with very early Wallerian degeneration or pre-Wallerian degeneration.

Stroke survivors' endorsement of a "stress belief model" of stroke prevention predicts control of risk factors for recurrent stroke.

PubMed

Phillips, L Alison; Tuhrim, Stanley; Kronish, Ian M; Horowitz, Carol R

2014-01-01

Perceptions that stress causes and stress-reduction controls hypertension have been associated with poorer blood pressure (BP) control in hypertension populations. The current study investigated these "stress-model perceptions" in stroke survivors regarding prevention of recurrent stroke and the influence of these perceptions on patients' stroke risk factor control. Stroke and transient ischemic attack survivors (N=600) participated in an in-person interview in which they were asked about their beliefs regarding control of future stroke; BP and cholesterol were measured directly after the interview. Counter to expectations, patients who endorsed a "stress-model" but not a "medication-model" of stroke prevention were in better control of their stroke risk factors (BP and cholesterol) than those who endorsed a medication-model but not a stress-model of stroke prevention (OR for poor control=.54, Wald statistic=6.07, p=.01). This result was not explained by between group differences in patients' reported medication adherence. The results have implications for theory and practice, regarding the role of stress belief models and acute cardiac events, compared to chronic hypertension.

Mediodorsal thalamus and cognition in non-human primates

PubMed Central

Baxter, Mark G.

2013-01-01

Several recent studies in non-human primates have provided new insights into the role of the medial thalamus in different aspects of cognitive function. The mediodorsal nucleus of the thalamus (MD), by virtue of its connectivity with the frontal cortex, has been implicated in an array of cognitive functions. Rather than serving as an engine or relay for the prefrontal cortex, this area seems to be more specifically involved in regulating plasticity and flexibility of prefrontal-dependent cognitive functions. Focal damage to MD may also exacerbate the effects of damage to other subcortical relays. Thus, a wide range of distributed circuits and cognitive functions may be disrupted from focal damage within the medial thalamus (for example as a consequence of stroke or brain injury). Conversely, this region may make an interesting target for neuromodulation of cognitive function via deep brain stimulation or related methods, in conditions associated with dysfunction of these neural circuits. PMID:23964206

Mediodorsal thalamus and cognition in non-human primates.

PubMed

Baxter, Mark G

2013-01-01

Several recent studies in non-human primates have provided new insights into the role of the medial thalamus in different aspects of cognitive function. The mediodorsal nucleus of the thalamus (MD), by virtue of its connectivity with the frontal cortex, has been implicated in an array of cognitive functions. Rather than serving as an engine or relay for the prefrontal cortex, this area seems to be more specifically involved in regulating plasticity and flexibility of prefrontal-dependent cognitive functions. Focal damage to MD may also exacerbate the effects of damage to other subcortical relays. Thus, a wide range of distributed circuits and cognitive functions may be disrupted from focal damage within the medial thalamus (for example as a consequence of stroke or brain injury). Conversely, this region may make an interesting target for neuromodulation of cognitive function via deep brain stimulation or related methods, in conditions associated with dysfunction of these neural circuits.

The protective effect of dexanabinol (HU-211) on nitric oxide and cysteine protease-mediated neuronal death in focal cerebral ischemia.

PubMed

Durmaz, Ramazan; Ozden, Hilmi; Kanbak, Güngör; Aral, Erinç; Arslan, Okan Can; Kartkaya, Kazim; Uzuner, Kubilay

2008-09-01

We hypothesized that dexanabinol can prevent neuronal death by protecting neuronal lysosomes from nitric oxide (NO)-mediated toxicity, and in turn, by suppressing the release of cathepsins during cerebral ischemia. Focal cerebral ischemia was induced in two sets of animals by permanent middle cerebral artery occlusion. The first set was used to monitor NO concentration and cathepsin activity, while the second was used for histological examination with hematoxylin and eosin, and TUNEL staining. In post-ischemic brain tissue, NO content and cathepsin B and L activity increased (p < 0.05). Dexanabinol treatment reduced NO concentration and cathepsin activity to the control level (p > 0.05). The number of eosinophilic and apoptotic neurons increased in the post-ischemic cerebral cortex (p < 0.05). However, dexanabinol treatment lowered both of these (p < 0.05). We conclude that dexanabinol might be a useful agent for the treatment of stroke patients.

Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.

PubMed

Jin, Rong; Xiao, Adam Y; Chen, Rui; Granger, D Neil; Li, Guohong

2017-12-01

Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function-blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood-brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduced thrombosis and increased cerebral perfusion, and (3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced NF-κB (nuclear factor κB) activation, MMP-9 (matrix metalloproteinase-9) activity, and PAI-1 (plasminogen activator inhibitor-1) expression in brain microvascular endothelial cells. Inhibition of CD147 ameliorates acute ischemic stroke by reducing thromboinflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thromboinflammatory disorders. © 2017 American Heart Association, Inc.

Simple prediction scores predict good and devastating outcomes after stroke more accurately than physicians.

PubMed

Reid, John Michael; Dai, Dingwei; Delmonte, Susanna; Counsell, Carl; Phillips, Stephen J; MacLeod, Mary Joan

2017-05-01

physicians are often asked to prognosticate soon after a patient presents with stroke. This study aimed to compare two outcome prediction scores (Five Simple Variables [FSV] score and the PLAN [Preadmission comorbidities, Level of consciousness, Age, and focal Neurologic deficit]) with informal prediction by physicians. demographic and clinical variables were prospectively collected from consecutive patients hospitalised with acute ischaemic or haemorrhagic stroke (2012-13). In-person or telephone follow-up at 6 months established vital and functional status (modified Rankin score [mRS]). Area under the receiver operating curves (AUC) was used to establish prediction score performance. five hundred and seventy-five patients were included; 46% female, median age 76 years, 88% ischaemic stroke. Six months after stroke, 47% of patients had a good outcome (alive and independent, mRS 0-2) and 26% a devastating outcome (dead or severely dependent, mRS 5-6). The FSV and PLAN scores were superior to physician prediction (AUCs of 0.823-0.863 versus 0.773-0.805, P < 0.0001) for good and devastating outcomes. The FSV score was superior to the PLAN score for predicting good outcomes and vice versa for devastating outcomes (P < 0.001). Outcome prediction was more accurate for those with later presentations (>24 hours from onset). the FSV and PLAN scores are validated in this population for outcome prediction after both ischaemic and haemorrhagic stroke. The FSV score is the least complex of all developed scores and can assist outcome prediction by physicians. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com

An Effective Solution to Discover Synergistic Drugs for Anti-Cerebral Ischemia from Traditional Chinese Medicinal Formulae

PubMed Central

Lu, Peng; Chen, Chang; Fu, Meihong; Fang, Jing; Gao, Jian; Zhu, Li; Liang, Rixin; Shen, Xin; Yang, Hongjun

2013-01-01

Recently, the pharmaceutical industry has shifted to pursuing combination therapies that comprise more than one active ingredient. Interestingly, combination therapies have been used for more than 2500 years in traditional Chinese medicine (TCM). Understanding optimal proportions and synergistic mechanisms of multi-component drugs are critical for developing novel strategies to combat complex diseases. A new multi-objective optimization algorithm based on least angle regression-partial least squares was proposed to construct the predictive model to evaluate the synergistic effect of the three components of a novel combination drug Yi-qi-jie-du formula (YJ), which came from clinical TCM prescription for the treatment of encephalopathy. Optimal proportion of the three components, ginsenosides (G), berberine (B) and jasminoidin (J) was determined via particle swarm optimum. Furthermore, the combination mechanisms were interpreted using PLS VIP and principal components analysis. The results showed that YJ had optimal proportion 3(G): 2(B): 0.5(J), and it yielded synergy in the treatment of rats impaired by middle cerebral artery occlusion induced focal cerebral ischemia. YJ with optimal proportion had good pharmacological effects on acute ischemic stroke. The mechanisms study demonstrated that the combination of G, B and J could exhibit the strongest synergistic effect. J might play an indispensable role in the formula, especially when combined with B for the acute stage of stroke. All these data in this study suggested that in the treatment of acute ischemic stroke, besides restoring blood supply and protecting easily damaged cells in the area of the ischemic penumbra as early as possible, we should pay more attention to the removal of the toxic metabolites at the same time. Mathematical system modeling may be an essential tool for the analysis of the complex pharmacological effects of multi-component drug. The powerful mathematical analysis method could greatly improve the efficiency in finding new combination drug from TCM. PMID:24236065

[Speech syndrome and its course in patients who have sustained an ischemic stroke (clinico-tomographic study)].

PubMed

Stoliarova, L G; Varakin, Iu Ia; Vavilov, S B

1981-01-01

Clinical and tomographic examinations of 40 patients with aphasia developed after an ischemic stroke were carried out. In more than half of them no correlation between the aphasia gravity and character on the one hand, and the size and localization of the ischemic focus (or foci) in the brain on the other was noted. With similar character and gravity of the speech disorder the size and localization of the ischemic foci may be different, ad vice versa. It has been shown that the interrelations between the focal pathology of the brain and the character and gravity of speech disorders are very complicated. One should take into consideration the possibility of individual organization of the speech functions, the degree of the speech activity automatism before the disease, and the state of the cerebrovascular system as a whole.

Emission computed tomography of /sup 18/F-fluorodeoxyglucose and /sup 13/N-ammonia in stroke and epilepsy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuhl, D.E.; Phelps, M.E.; Engel, J. Jr.

1980-01-01

The ECAT Positron Tomograph was used to scan normal control subjects, stroke patients at various times during recovery, and patients with partial epilepsy during EEG monitoring. /sup 18/F-fluorodeoxyglucose (/sup 18/FDG) and /sup 13/N-Ammonia (/sup 13/NH/sub 3/) were used as indicators of abnormalities in local cerebral glucose utilization (LCMR/sub glc/) and relative perfusion, respectively. Hypometabolism, due to deactivation or minimal damage, was demonstrated with the /sup 18/FDG scan in deep structures and broad zones of cerebral cortex which appeared normal on x-ray CT (XCT) and /sup 99m/Tc pertechnetate scans. In patients with partial epilepsy, who had unilateral or focal electrical abnormalities,more » interictal /sup 18/FDG scan patterns clearly showed localized regions of decreased (20 to 50%) LCMR/sub glc/, which correlated anatomically with the eventual EEG localization.« less

Pain as the only manifestation of internal carotid artery dissection.

PubMed

Biousse, V; Woimant, F; Amarenco, P; Touboul, P J; Bousser, M G

1992-10-01

Internal carotid artery dissection is a major cause of ischemic stroke in the young. Pain is the leading symptom and is associated with other focal signs such as Horner's syndrome and painful tinnitus or with signs of cerebral or retinal ischemia. We report two patients with angiographically confirmed extracranial internal carotid artery dissection presenting with cephalic pain as the only manifestation. The first patient had a diffuse headache and a latero-cervical pain lasting for 12 days, reminiscent of carotidynia. The second patient experienced an exploding headache suggestive of subarachnoid hemorrhage, which was ruled out by computed tomography of the head and cerebrospinal fluid study. These patients demonstrate that recognition of carotid artery dissection as a cause of carotidynia and headache suggestive of subarachnoid hemorrhage may permit an earlier diagnosis and possibly the prevention of a stroke through the use of anticoagulation.

Changes in resting-state functional connectivity after stroke in a mouse brain lacking extracellular matrix components.

PubMed

Quattromani, Miriana Jlenia; Hakon, Jakob; Rauch, Uwe; Bauer, Adam Q; Wieloch, Tadeusz

2018-04-01

In the brain, focal ischemia results in a local region of cell death and disruption of both local and remote functional neuronal networks. Tissue reorganization following stroke can be limited by factors such as extracellular matrix (ECM) molecules that prevent neuronal growth and synaptic plasticity. The brain's ECM plays a crucial role in network formation, development, and regeneration of the central nervous system. Further, the ECM is essential for proper white matter tract development and for the formation of structures called perineuronal nets (PNNs). PNNs mainly surround parvalbumin/GABA inhibitory interneurons, of importance for processing sensory information. Previous studies have shown that downregulating PNNs after stroke reduces the neurite-inhibitory environment, reactivates plasticity, and promotes functional recovery. Resting-state functional connectivity (RS-FC) within and across hemispheres has been shown to correlate with behavioral recovery after stroke. However, the relationship between PNNs and RS-FC has not been examined. Here we studied a quadruple knock-out mouse (Q4) that lacks four ECM components: brevican, neurocan, tenascin-C and tenascin-R. We applied functional connectivity optical intrinsic signal (fcOIS) imaging in Q4 mice and wild-type (129S1 mice) before and 14 days after photothrombotic stroke (PT) to understand how the lack of crucial ECM components affects neuronal networks and functional recovery after stroke. Limb-placement ability was evaluated at 2, 7 and 14 days of recovery through the paw-placement test. Q4 mice exhibited significantly impaired homotopic RS-FC compared to wild-type mice, especially in the sensory and parietal regions. Changes in RS-FC were significantly correlated with the number of interhemispheric callosal crossings in those same regions. PT caused unilateral damage to the sensorimotor cortex and deficits of tactile-proprioceptive placing ability in contralesional fore- and hindlimbs, but the two experimental groups did not present significant differences in infarct size. Two weeks after PT, a general down-scaling of regional RS-FC as well as the number of regional functional connections was visible for all cortical regions and most notable in the somatosensory areas of both Q4 and wild-type mice. Q4 mice exhibited higher intrahemispheric RS-FC in contralesional sensory and motor cortices compared to control mice. We propose that the lack of growth inhibiting ECM components in the Q4 mice potentially worsen behavioral outcome in the early phase after stroke, but subsequently facilitates modulation of contralesional RS-FC which is relevant for recovery of sensory motor function. We conclude that Q4 mice represent a valuable model to study how the elimination of ECM genes compromises neuronal function and plasticity mechanisms after stroke. Copyright © 2018 Elsevier Inc. All rights reserved.

Chloride Cotransporters as a Molecular Mechanism underlying Spreading Depolarization-Induced Dendritic Beading.

PubMed

Steffensen, Annette B; Sword, Jeremy; Croom, Deborah; Kirov, Sergei A; MacAulay, Nanna

2015-09-02

Spreading depolarizations (SDs) are waves of sustained neuronal and glial depolarization that propagate massive disruptions of ion gradients through the brain. SD is associated with migraine aura and recently recognized as a novel mechanism of injury in stroke and brain trauma patients. SD leads to neuronal swelling as assessed in real time with two-photon laser scanning microscopy (2PLSM). Pyramidal neurons do not express aquaporins and thus display low inherent water permeability, yet SD rapidly induces focal swelling (beading) along the dendritic shaft by unidentified molecular mechanisms. To address this issue, we induced SD in murine hippocampal slices by focal KCl microinjection and visualized the ensuing beading of dendrites expressing EGFP by 2PLSM. We confirmed that dendritic beading failed to arise during large (100 mOsm) hyposmotic challenges, underscoring that neuronal swelling does not occur as a simple osmotic event. SD-induced dendritic beading was not prevented by pharmacological interference with the cytoskeleton, supporting the notion that dendritic beading may result entirely from excessive water influx. Dendritic beading was strictly dependent on the presence of Cl(-), and, accordingly, combined blockade of Cl(-)-coupled transporters led to a significant reduction in dendritic beading without interfering with SD. Furthermore, our in vivo data showed a strong inhibition of dendritic beading during pharmacological blockage of these cotransporters. We propose that SD-induced dendritic beading takes place as a consequence of the altered driving forces and thus activity for these cotransporters, which by transport of water during their translocation mechanism may generate dendritic beading independently of osmotic forces. Spreading depolarization occurs during pathological conditions such as stroke, brain injury, and migraine and is characterized as a wave of massive ion translocation between intracellular and extracellular space in association with recurrent transient focal swelling (beading) of dendrites. Numerous ion channels have been demonstrated to be involved in generation and propagation of spreading depolarization, but the molecular machinery responsible for the dendritic beading has remained elusive. Using real-time in vitro and in vivo two-photon laser scanning microscopy, we have identified the transport mechanisms involved in the detrimental focal swelling of dendrites. These findings have clear clinical significance because they may point to a new class of pharmacological targets for prevention of neuronal swelling that consequently will serve as neuroprotective agents. Copyright © 2015 the authors 0270-6474/15/3512172-16$15.00/0.

Neurogenesis and angiogenesis within the ipsilateral thalamus with secondary damage after focal cortical infarction in hypertensive rats.

PubMed

Ling, Li; Zeng, Jinsheng; Pei, Zhong; Cheung, Raymond T F; Hou, Qinghua; Xing, Shihui; Zhang, Suping

2009-09-01

Neurogenesis and angiogenesis in the subventricular zone and peri-infarct region have been confirmed. However, newly formed neuronal cells and blood vessels that appear in the nonischemic ipsilateral ventroposterior nucleus (VPN) of the thalamus with secondary damage after stroke has not been previously studied. Twenty-four stroke-prone renovascular hypertensive rats were subjected to distal right middle cerebral artery occlusion (MCAO) or sham operation. 5'-Bromo-2'-deoxyuridine (BrdU) was used to label cell proliferation. Rats were killed at 7 or 14 days after the operation. Neuronal nuclei (NeuN), OX-42, BrdU, nestin, laminin(+), BrdU(+)/nestin(+), BrdU(+)/NeuN(+), nestin(+)/GFAP(+)(glial fibrillary acidic protein), and BrdU(+)/laminin(+) immunoreactive cells were detected within the ipsilateral VPN. The primary infarction was confined to the right somatosensory cortex. Within the ipsilateral VPN of the ischemic rats, the number of NeuN(+) neurons decreased, the OX-42(+) microglia cells were activated, and BrdU(+) and nestin(+) cells were detected at day 7 after MCAO and increased in number at day 14. Moreover, BrdU(+)/nestin(+) cells and BrdU(+)/NeuN(+) cells were detected at day 14 after MCAO. In addition, the ischemic rats showed a significant increase in vascular density in the ipsilateral VPN compared with the sham-operated rats. These results suggest that secondary damage with neurogenesis and angiogenesis of the ipsilateral VPN of the thalamus occurs after focal cortical infarction.

Eriodictyol-7-O-glucoside activates Nrf2 and protects against cerebral ischemic injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jing, Xu; Ren, Dongmei; Wei, Xinbing

Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependentmore » genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke. - Highlights: • E7G activates Nrf2 in astrocytes. • E7G stimulates expression of Nrf2-mediated cytoprotective proteins in astrocytes. • E7G protects astrocytes against OGD-induced cell death and apoptosis. • The neuroprotective effect of E7G involves the Nrf2/ARE pathway. • E7G protects rats against cerebral ischemic injury.« less

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

PubMed Central

Jiang, Xiaoyan; Zhang, Lili; Pu, Hongjian; Hu, Xiaoming; Zhang, Wenting; Cai, Wei; Gao, Yanqin; Leak, Rehana K.; Keep, Richard F.; Bennett, Michael V. L.; Chen, Jun

2017-01-01

The damage borne by the endothelial cells (ECs) forming the blood–brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs—namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30–60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs—but not within neurons—ameliorated BBB impairment 1–24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown. PMID:28137866

Hyperglycemia decreases expression of 14-3-3 proteins in an animal model of stroke.

PubMed

Jeon, Seong-Jun; Sung, Jin-Hee; Koh, Phil-Ok

2016-07-28

Diabetes is a severe metabolic disorder and a major risk factor for stroke. Stroke severity is worse in patients with diabetes compared to the non-diabetic population. The 14-3-3 proteins are a family of conserved acidic proteins that are ubiquitously expressed in cells and tissues. These proteins are involved in many cellular processes including metabolic pathways, signal transduction, protein trafficking, protein synthesis, and cell cycle control. This study investigated 14-3-3 proteins expression in the cerebral cortex of animals with diabetes, cerebral ischemic injury and a combination of both diabetes and cerebral ischemic injury. Diabetes was induced by intraperitoneal injection of streptozotocin (40mg/kg) in adult male rats. After 4 weeks of treatment, middle cerebral artery occlusion (MCAO) was performed for the induction of focal cerebral ischemia and cerebral cortex tissue was collected 24h after MCAO. We confirmed that diabetes increases infarct volume following MCAO compared to non-diabetic animals. In diabetic animals with MCAO injury, reduction of 14-3-3 β/α, 14-3-3 ζ/δ, 14-3-3 γ, and 14-3-3 ε isoforms was detected. The expression of these proteins was significantly decreased in diabetic animals with MCAO injury compared to diabetic-only and MCAO-only animals. Moreover, Western blot analysis ascertained the decreased expression of 14-3-3 family proteins in diabetic animals with MCAO injury, including β/α, ζ/δ, γ, ε, τ, and η isoforms. These results show the changes of 14-3-3 proteins expression in streptozotocin-induced diabetic animals with MCAO injury. Thus, these findings suggest that decreases in 14-3-3 proteins might be involved in the regulation of 14-3-3 proteins under the presence of diabetes following MCAO. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Neuroprotective effects of chloroform and petroleum ether extracts of Nigella sativa seeds in stroke model of rat

PubMed Central

Akhtar, Mohammad; Maikiyo, Aliyu Muhammad; Najmi, Abul Kalam; Khanam, Razia; Mujeeb, Mohd; Aqil, Mohd

2013-01-01

PURPOSE: Stroke still remains a challenge for the researchers and scientists for developing ideal drug. Several new drugs are being evaluated showing excellent results in preclinical studies but when tested in clinical trials, they failed. Many herbal drugs in different indigenous system of medicine claim to have beneficial effects but not extensively evaluated for stroke (cerebral ischemia). AIM: The present study was undertaken to evaluate chloroform and petroleum ether extract of Nigella sativa seeds administered at a dose of 400 mg/kg, per orally for seven days in middle cerebral artery occluded (MCAO) rats for its neuroprotective role in cerebral ischemia. MATERIALS AND METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion for two hours followed by reperfusion for 22 hours. After 24 hours, grip strength, locomotor activity tests were performed in different treatment groups of rats. After completing behavioral tests, animals were sacrificed; brains were removed for the measurement of infarct volume followed by the estimation of markers of oxidative stress. RESULTS: Both chloroform and petroleum ether extracts-pretreated rats showed improvement in locomotor activity and grip strength, reduced infarct volume when compared with MCAO rats. MCA occlusion resulted in the elevation of levels of thiobarbituric acid reactive substance (TBARS), while a reduction in the levels of glutathione (GSH) and antioxidant enzymes viz. superoxide dismutase (SOD) and catalase levels were observed. Pre-treatment of both extracts of Nigella sativa showed reduction in TBARS, elevation in glutathione, SOD, and catalase levels when compared with MCAO rats. CONCLUSION: The chloroform and petroleum ether extract of Nigella sativa showed the protective effects in cerebral ischemia. The present study confirms the antioxidant, free radical scavenging, and anti-inflammatory properties of Nigella sativa already reported. PMID:23833517

A leader-return-stroke consistent macroscopic model for calculations of return stroke current and its optical and electromagnetic emissions

NASA Astrophysics Data System (ADS)

Cai, Shuyao; Chen, Mingli; Du, Yaping; Qin, Zilong

2017-08-01

A downward lightning flash usually starts with a downward leader and an upward connecting leader followed by an upward return stroke. It is the preceding leader that governs the following return stroke property. Besides, the return stroke property evolves with height and time. These two aspects, however, are not well addressed in most existing return stroke models. In this paper, we present a leader-return stroke consistent model based on the time domain electric field integral equation, which is a growth and modification of Kumar's macroscopic model. The model is further extended to simulate the optical and electromagnetic emissions of a return stroke by introducing a set of equations relating the return stroke current and conductance to the optical and electromagnetic emissions. With a presumed leader initiation potential, the model can then simulate the temporal and spatial evolution of the current, charge transfer, channel size, and conductance of the return stroke, furthermore the optical and electromagnetic emissions. The model is tested with different leader initiation potentials ranging from -10 to -140 MV, resulting in different return stroke current peaks ranging from 2.6 to 209 kA with different return stroke speed peaks ranging from 0.2 to 0.8 speed of light and different optical power peaks ranging from 4.76 to 248 MW/m. The larger of the leader initiation potential, the larger of the return stroke current and speed. Both the return stroke current and speed attenuate exponentially as it propagates upward. All these results are qualitatively consistent with those reported in the literature.

Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling

PubMed Central

Wesley, Umadevi V.; Vemuganti, Raghu; Ayvaci, Rabia; Dempsey, Robert J.

2013-01-01

Focal cerebral ischemia initiates self-repair mechanisms that include the production of neurotrophic factors and cytokines. Galectin-3 is an important angiogenic cytokine. We have previously demonstrated that expression of galectin 3 (Gal-3), a carbohydrate binding protein is significantly upregulated in activated microglia in the brains of rats subjected to focal ischemia. Further blocking of Gal-3 function with Gal-3 neutralizing antibody decreased the microvessel density in ischemic brain. We currently show that Gal-3 significantly increases the viability of microglia BV2 cells subjected to oxygen glucose deprivation (OGD) and re-oxygenation. Exogenous Gal-3 promoted the formation of pro-angiogenic structures in an in vitro human umbilical vein endothelial (HUVEC) and BV2 cell co-culture model. Gal-3 induced angiogenesis was associated with increased expression of vascular endothelial growth factor. The conditioned medium of BV2 cells exposed to OGD contained increased Gal-3 levels, and promoted the formation of pro-angiogenic structures in an in vitro HUVEC culture model. Gal-3 also augmented the in vitro migratory potential of BV2 microglia. Gal-3 mediated functions were associated with increased levels of integrin-linked kinase (ILK) signaling as demonstrated by the impaired angiogenesis and migration of BV2 cells following targeted silencing of ILK expression by SiRNA. Furthermore, we show that ILK levels correlate with the levels of phos-AKT and ERK1/2 that are downstream effectors of ILK pathway. Taken together, our studies indicate that Gal-3 contributes to angiogenesis and microglia migration that may have implications in post stroke repair. PMID:23246924

Molecular imaging of inflammation in the ApoE -/- mouse model of atherosclerosis with IodoDPA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foss, Catherine A., E-mail: cfoss1@jhmi.edu; Bedja, Djahida; Faculty of Medicine and Health Sciences, Macquarie University, Sydney

Background: Atherosclerosis is a common and serious vascular disease predisposing individuals to myocardial infarction and stroke. Intravascular plaques, the pathologic lesions of atherosclerosis, are largely composed of cholesterol-laden luminal macrophage-rich infiltrates within a fibrous cap. The ability to detect those macrophages non-invasively within the aorta, carotid artery and other vessels would allow physicians to determine plaque burden, aiding management of patients with atherosclerosis. Methods and results: We previously developed a low-molecular-weight imaging agent, [{sup 125}I]iodo-DPA-713 (iodoDPA), which selectively targets macrophages. Here we use it to detect both intravascular macrophages and macrophage infiltrates within the myocardium in the ApoE -/- mousemore » model of atherosclerosis using single photon emission computed tomography (SPECT). SPECT data were confirmed by echocardiography, near-infrared fluorescence imaging and histology. SPECT images showed focal uptake of radiotracer at the aortic root in all ApoE -/- mice, while the age-matched controls were nearly devoid of radiotracer uptake. Focal radiotracer uptake along the descending aorta and within the myocardium was also observed in affected animals. Conclusions: IodoDPA is a promising new imaging agent for atherosclerosis, with specificity for the macrophage component of the lesions involved. - Highlights: • [{sup 125}I]iodoDPA SPECT detects atherosclerotic plaques in ApoE -/- mice with high contrast. • Plaques are detected in ApoE -/- mice regardless of diet with iodoDPA. • iodoDPA has very low uptake in healthy tissue including healthy TSPO + tissues at 24 h.« less

Angiographic Features, Collaterals, and Infarct Topography of Symptomatic Occlusive Radiation Vasculopathy

PubMed Central

Zou, Winnie X.Y.; Leung, Thomas W.; Yu, Simon C.H.; Wong, Edward H.C.; Leung, S.F.; Soo, Yannie O.Y.; Ip, Vincent H.L.; Chan, Anne Y.Y.; Lam, Wynnie W.M.; Siu, Deyond Y.W.; Abrigo, Jill; Lee, Kwok Tung; Liebeskind, David S.; Wong, Ka Sing

2014-01-01

Background and Purpose Occlusive radiation vasculopathy (ORV) predisposes head-and-neck cancer survivors to ischemic strokes. Methods We analyzed the digital subtraction angiography acquired in 96 patients who had first-ever transient ischemic attack or ischemic strokes attributed to ORV. Another age-matched 115 patients who had no radiotherapy but symptomatic high-grade (>70%) carotid stenoses were enrolled as referent subjects. Digital subtraction angiography was performed within 2 months from stroke onset and delineated carotid and vertebrobasilar circulations from aortic arch up to intracranial branches. Two reviewers blinded to group assignment recorded all vascular lesions, collateral status, and infarct pattern. Results ORV patients had less atherosclerotic risk factors at presentation. In referent patients, high-grade stenoses were mostly focal at the proximal internal carotid artery. In contrast, high-grade ORV lesions diffusely involved the common carotid artery and internal carotid artery and were more frequently bilateral (54% versus 22%), tandem (23% versus 10%), associated with complete occlusion in one or both carotid arteries (30% versus 9%), vertebral artery (VA) steno-occlusions (28% versus 16%), and external carotid artery stenosis (19% versus 5%) (all P<0.05). With comparable rates of vascular anomaly, ORV patients showed more established collateral circulations through leptomeningeal arteries, anterior communicating artery, posterior communicating artery, suboccipital/costocervical artery, and retrograde flow in ophthalmic artery. In terms of infarct topography, the frequencies of cortical or subcortical watershed infarcts were similar in both groups. Conclusions ORV angiographic features and corresponding collaterals are distinct from atherosclerotic patterns at initial stroke presentation. Clinical decompensation, despite more extensive collateralization, may precipitate stroke in ORV. PMID:23306321

Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke.

PubMed

Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

2010-07-08

Cannabis contains the psychoactive component delta⁸-tetrahydrocannabinol (delta⁸-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta⁸-THC and other cannabinoid CB₁ receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta⁸-THC also mediates psychological effects through the activation of the CB₁ receptor in the central nervous system. In addition to the CB₁ receptor agonists, cannabis also contains therapeutically active components which are CB₁ receptor independent. Of the CB₁ receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson's disease, Alzheimer's disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB₁ receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.

Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke

PubMed Central

Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

2010-01-01

Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke. PMID:27713349

A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion

PubMed Central

2013-01-01

Background Microglia cells continuously survey the healthy brain in a ramified morphology and, in response to injury, undergo progressive morphological and functional changes that encompass microglia activation. Although ideally positioned for immediate response to ischemic stroke (IS) and reperfusion, their progressive morphological transformation into activated cells has not been quantified. In addition, it is not well understood if diverse microglia morphologies correlate to diverse microglia functions. As such, the dichotomous nature of these cells continues to confound our understanding of microglia-mediated injury after IS and reperfusion. The purpose of this study was to quantitatively characterize the spatiotemporal pattern of microglia morphology during the evolution of cerebral injury after IS and reperfusion. Methods Male C57Bl/6 mice were subjected to focal cerebral ischemia and periods of reperfusion (0, 8 and 24 h). The microglia process length/cell and number of endpoints/cell was quantified from immunofluorescent confocal images of brain regions using a skeleton analysis method developed for this study. Live cell morphology and process activity were measured from movies acquired in acute brain slices from GFP-CX3CR1 transgenic mice after IS and 24-h reperfusion. Regional CD11b and iNOS expressions were measured from confocal images and Western blot, respectively, to assess microglia proinflammatory function. Results Quantitative analysis reveals a significant spatiotemporal relationship between microglia morphology and evolving cerebral injury in the ipsilateral hemisphere after IS and reperfusion. Microglia were both hyper- and de-ramified in striatal and cortical brain regions (respectively) after 60 min of focal cerebral ischemia. However, a de-ramified morphology was prominent when ischemia was coupled to reperfusion. Live microglia were de-ramified, and, in addition, process activity was severely blunted proximal to the necrotic core after IS and 24 h of reperfusion. CD11b expression, but not iNOS expression, was increased in regions of hyper- and de-ramified microglia during the course of ischemic stroke and 24 h of reperfusion. Conclusions Our findings illustrate that microglia activation after stroke includes both increased and decreased cell ramification. Importantly, quantitative analyses of microglial morphology and activity are feasible and, in future studies, would assist in the comprehensive identification and stratification of their dichotomous contribution toward cerebral injury and recovery during IS and reperfusion. PMID:23311642

[News in neurology 2013].

PubMed

Spatola, Marianna; Rossetti, Andrea O; Michel, Patrick; Kuntzer, Thierry; Benninger, David; Nater, Bernard; Démonet, Jean-François; Schluep, Myriam; Du Pasquier, Renaud A; Vingerhoets, François

2014-01-15

In 2013, perampanel is approved as an add-on treatment for generalised and focal seizures in pharmaco-resistant epilepsy. New anticoagulants are superior to antivitamin K in stroke secondary prevention in case of atrial fibrillation. DBS remains a valid therapeutic option for advanced Parkinson's disease. Intranasal ketamine seems to reduce the intensity of severe migraine aura. High concentrations of topic capsaicin improve post-herpetic neuralgia. In Alzheimer's disease, statins might deteriorate cognitive functions. Oral immuno-modifing treatments for relapsing remitting multiple sclerosis have shown to slow cerebral atrophy progression at two years.

[Hemiparesis and facial palsy caused by methotrexate].

PubMed

Rueda Arenas, E; García Corzo, J; Franco Ospina, L

2013-12-01

Methotrexate used in the treatment of acute lymphocytic leukemia, can cause neurotoxicity, including a rare presentation with hemiparesis. We describe two teenagers, who during the implementation of the M phase of the protocol, suffered hemiparesis, facial paresis and dysarthria which quickly reversed. Leukemia involvement of the central nervous system and stroke, were ruled out. We briefly review the pathophysiology of methotrexate neurotoxicity, the characteristics of the focal paresis presentation and magnetic resonance image findings. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

6-Mercaptopurine exerts an immunomodulatory and neuroprotective effect on permanent focal cerebral occlusion in rats.

PubMed

Chang, Chih-Zen; Kwan, Aij-Lie; Howng, Shen-Long

2010-08-01

A bursting cascade of inflammation imposes progressive neurological deterioration after experimental stroke has been demonstrated. In our study, 6-mercaptopurine (6-mp) has been successful in alleviating cerebral infarct in a rodent permanent middle cerebral artery occlusion (pMCAO) model. The present study was aimed to examine the effect of 6-mp on cytokine levels in experimental stroke. The rodent pMCAO model was employed. A dose of 2 mg/kg 6-mp or vehicle (0.1 mol/L PBS) was administered intraperitoneally 30 min after the induction of pMCAO. Neurological score, serum, and cerebrospinal fluid (CSF) cytokines such as IL-1beta, IL-6, and TNF-alpha and infarct volume were determined 48 h after pMCAO. Cerebral infarction volume was significantly decreased in animals treated with 6-mp (74.3%, p < 0.01), and the ratio of tissue edema was also decreased in 6-mp-treated groups (71%). Animals receiving 6-mp thus showed a significant decrease in IL-1 and TNF-alpha (18/43% and 48/64% in CSF/serum, respectively) when compared with the pMCAO groups (p < 0.01). This study demonstrates that 6-mp interposes the production of IL-1 and TNF-alpha in CSF and serum, attenuates ischemic brain injury, and thus alleviates neurological deficits in the pMCAO animals. These findings also offer first evidence that 6-mp may attenuate TNF-alpha-related neuron apoptosis and also support the notion that 6-mp and other anti-inflammatory agents could potentially have therapeutic uses in cases of cerebral infarct.

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.

PubMed

Ismael, Saifudeen; Zhao, Liang; Nasoohi, Sanaz; Ishrat, Tauheed

2018-04-13

Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60 min tMCAO followed by intraperitoneal administration of MCC950 (50 mg/kg) or saline at 1 h and 3 h post-occlusion. After 24 h of I/R, mice were tested for neurological outcome and were sacrificed for the analysis of infarct size and estimating NLRP3-inflammasome and apoptotic markers as well. Spectrophotometric method was used to determine hemoglobin (Hb) content as a marker of intracerebral hemorrhage. MCC950-treated mice showed a substantial reduction in infarction, edema and Hb content compared to saline controls in parallel with improved neurological deficits. MCC950 reduced expression of NLRP3-inflammasome cleavage products Caspase-1 and interlukin-1β (IL-1β) in penumbral region. These protective effects of MCC950 were associated with decreased TNF-α levels as well as poly (ADP-ribose) polymerase (PARP) and Caspase-3 cleavage and paralleled less phosphrylated NFκBp65 and IκBα levels. Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 has therapeutic potential in ischemic stroke models. Further investigations into the therapeutic efficacy and protocols are needed to confirm whether MCC950 treatment could be a promising candidate for clinical trials.

In-hospital risk prediction for post-stroke depression: development and validation of the Post-stroke Depression Prediction Scale.

PubMed

de Man-van Ginkel, Janneke M; Hafsteinsdóttir, Thóra B; Lindeman, Eline; Ettema, Roelof G A; Grobbee, Diederick E; Schuurmans, Marieke J

2013-09-01

The timely detection of post-stroke depression is complicated by a decreasing length of hospital stay. Therefore, the Post-stroke Depression Prediction Scale was developed and validated. The Post-stroke Depression Prediction Scale is a clinical prediction model for the early identification of stroke patients at increased risk for post-stroke depression. The study included 410 consecutive stroke patients who were able to communicate adequately. Predictors were collected within the first week after stroke. Between 6 to 8 weeks after stroke, major depressive disorder was diagnosed using the Composite International Diagnostic Interview. Multivariable logistic regression models were fitted. A bootstrap-backward selection process resulted in a reduced model. Performance of the model was expressed by discrimination, calibration, and accuracy. The model included a medical history of depression or other psychiatric disorders, hypertension, angina pectoris, and the Barthel Index item dressing. The model had acceptable discrimination, based on an area under the receiver operating characteristic curve of 0.78 (0.72-0.85), and calibration (P value of the U-statistic, 0.96). Transforming the model to an easy-to-use risk-assessment table, the lowest risk category (sum score, <-10) showed a 2% risk of depression, which increased to 82% in the highest category (sum score, >21). The clinical prediction model enables clinicians to estimate the degree of the depression risk for an individual patient within the first week after stroke.

Development and application of Model of Resource Utilization, Costs, and Outcomes for Stroke (MORUCOS): an Australian economic model for stroke.

PubMed

Mihalopoulos, Catherine; Cadilhac, Dominique A; Moodie, Marjory L; Dewey, Helen M; Thrift, Amanda G; Donnan, Geoffrey A; Carter, Robert C

2005-01-01

To outline the development, structure, data assumptions, and application of an Australian economic model for stroke (Model of Resource Utilization, Costs, and Outcomes for Stroke [MORUCOS]). The model has a linked spreadsheet format with four modules to describe the disease burden and treatment pathways, estimate prevalence-based and incidence-based costs, and derive life expectancy and quality of life consequences. The model uses patient-level, community-based, stroke cohort data and macro-level simulations. An interventions module allows options for change to be consistently evaluated by modifying aspects of the other modules. To date, model validation has included sensitivity testing, face validity, and peer review. Further validation of technical and predictive accuracy is needed. The generic pathway model was assessed by comparison with a stroke subtypes (ischemic, hemorrhagic, or undetermined) approach and used to determine the relative cost-effectiveness of four interventions. The generic pathway model produced lower costs compared with a subtypes version (total average first-year costs/case AUD$ 15,117 versus AUD$ 17,786, respectively). Optimal evidence-based uptake of anticoagulation therapy for primary and secondary stroke prevention and intravenous thrombolytic therapy within 3 hours of stroke were more cost-effective than current practice (base year, 1997). MORUCOS is transparent and flexible in describing Australian stroke care and can effectively be used to systematically evaluate a range of different interventions. Adjusting results to account for stroke subtypes, as they influence cost estimates, could enhance the generic model.

Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes

PubMed Central

Ergul, Adviye; Hafez, Sherif; Fouda, Abdelrahman; Fagan, Susan C.

2016-01-01

Human ischemic stroke is very complex and no single preclinical model can comprise all the variables known to contribute to stroke injury and recovery. Hypertension, diabetes and hyperlipidemia are leading comorbidities in stroke patients. The use of predominantly young adult and healthy animals in experimental stroke research has created a barrier for translation of findings to patients. As such, more and more disease models are being incorporated into the research design. This review highlights the major strengths and weaknesses of the most commonly used animal models of these conditions in preclinical stroke research. The goal is to provide guidance in choosing, reporting and executing appropriate disease models that will be subjected to different models of stroke injury. PMID:27026092

Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models

PubMed Central

Edwardson, Matthew A.; Wang, Ximing; Liu, Brent; Ding, Li; Lane, Christianne J.; Park, Caron; Nelsen, Monica A.; Jones, Theresa A; Wolf, Steven L; Winstein, Carolee J; Dromerick, Alexander W.

2017-01-01

Background Stroke patients with mild-moderate upper extremity (UE) motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective Determine whether stroke lesions in an UE rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, <1 % had lesions resembling proximal MCA or surface vessel occlusion models. Preclinical models of subcortical white matter injury best resembled the ICARE population (33%). Intracranial hemorrhage participants had small (median 12.5 mL) lesions that best matched the capsular hematoma preclinical model. Conclusions ICARE subjects are not representative of all stroke patients, but they represent a clinically and scientifically important subgroup. Compared to lesions in general stroke populations and widely-studied animal models of recovery, ICARE participants had smaller, more subcortically-based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models. PMID:28337932

Estimating the annual number of strokes and the issue of imperfect data: an example from Australia.

PubMed

Cadilhac, Dominique A; Vos, Theo; Thrift, Amanda G

2014-01-01

Estimates of strokes in Australia are typically obtained using 1996-1997 age-specific attack rates from the pilot North East Melbourne Stroke Incidence (NEMESIS) Study (eight postcode regions). Declining hospitalizations for stroke indicate the potential to overestimate cases. To illustrate how current methods may potentially overestimate the number of strokes in Australia. Hospital separations data (primary discharge ICD10 codes I60 to I64) and three stroke projection models were compared. Each model had age- and gender-specific attack rates from the NEMESIS study applied to the 2003 population. One model used the 2003 Burden of Disease approach where the ratio of the 1996-1997 NEMESIS study incidence to hospital separation rate in the same year was adjusted by the 2002/2003 hospital separation rate within the same geographic region using relevant ICD-primary diagnosis codes. Hospital separations data were inflated by 12·1% to account for nonhospitalized stroke, while the Burden of Disease model was inflated by 27·6% to account for recurrent stroke events in that year. The third model used 1997-1999 attack rates from the larger 22-postcode NEMESIS study region. In 2003, Australian hospitalizations for stroke (I60 to I64) were 33,022, and extrapolation to all stroke (hospitalized and nonhospitalized) was 37,568. Applying NEMESIS study attack rates to the 2003 Australian population, 50,731 strokes were projected. Fewer cases for 2003 were estimated with the Burden of Disease model (28,364) and 22-postcode NEMESIS study rates (41,332). Estimating the number of strokes in a country can be highly variable depending on the recency of data, the type of data available, and the methods used. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.

Middle cerebral artery occlusion in Macaca fascicularis: acute and chronic stroke evolution.

PubMed

D'Arceuil, Helen E; Duggan, Michael; He, Julian; Pryor, Johnny; de Crespigny, Alex

2006-04-01

An intravascular stroke model designed for magnetic resonance imaging was developed in Macaca fascicularis (M. fascicularis) to characterize serial stroke lesion evolution. This model produces a range of stroke lesion sizes which closely mimics human stroke evolution. This paper describes the care of animals undergoing this stroke procedure, the range of outcomes we experienced and the cause of mortality in this model. Anesthesia was induced with atropine and ketamine and maintained with isoflurane or propofol. Non-invasive blood pressure, oxygen saturation, heart rate, respiration rate, temperature and end tidal CO2 were monitored continuously. The stroke was created by occluding a distal branch of the middle cerebral artery. During catheter placement animals were heparinized and vasospasm was minimized using verapamil. Anesthetic induction and maintenance were smooth. Animals with small strokes showed very rapid recovery, were able to ambulate and self-feed within 2 hours of recovery. Animals with strokes of >or=4% of the hemispheric volume required lengthy observation during recovery and parenteral nutrition. Large strokes resulted in significant brain edema, herniation and brainstem compression. Intracerebral hemorrhage and or subarachnoid hemorrhage coupled with a stroke of any size was acutely fatal. In the absence of an effective acute stroke therapy, the spectrum of outcomes seen in our primate model is very similar to that observed in human stroke patients.

Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study.

PubMed

Bustamante, Alejandro; López-Cancio, Elena; Pich, Sara; Penalba, Anna; Giralt, Dolors; García-Berrocoso, Teresa; Ferrer-Costa, Carles; Gasull, Teresa; Hernández-Pérez, María; Millan, Mónica; Rubiera, Marta; Cardona, Pedro; Cano, Luis; Quesada, Helena; Terceño, Mikel; Silva, Yolanda; Castellanos, Mar; Garces, Moisés; Reverté, Silvia; Ustrell, Xavier; Marés, Rafael; Baiges, Joan Josep; Serena, Joaquín; Rubio, Francisco; Salas, Eduardo; Dávalos, Antoni; Montaner, Joan

2017-09-01

Stroke diagnosis could be challenging in the acute phase. We aimed to develop a blood-based diagnostic tool to differentiate between real strokes and stroke mimics and between ischemic and hemorrhagic strokes in the hyperacute phase. The Stroke-Chip was a prospective, observational, multicenter study, conducted at 6 Stroke Centers in Catalonia. Consecutive patients with suspected stroke were enrolled within the first 6 hours after symptom onset, and blood samples were drawn immediately after admission. A 21-biomarker panel selected among previous results and from the literature was measured by immunoassays. Outcomes were differentiation between real strokes and stroke mimics and between ischemic and hemorrhagic strokes. Predictive models were developed by combining biomarkers and clinical variables in logistic regression models. Accuracy was evaluated with receiver operating characteristic curves. From August 2012 to December 2013, 1308 patients were included (71.9% ischemic, 14.8% stroke mimics, and 13.3% hemorrhagic). For stroke versus stroke mimics comparison, no biomarker resulted included in the logistic regression model, but it was only integrated by clinical variables, with a predictive accuracy of 80.8%. For ischemic versus hemorrhagic strokes comparison, NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) >4.9 (odds ratio, 2.40; 95% confidence interval, 1.55-3.71; P <0.0001) and endostatin >4.7 (odds ratio, 2.02; 95% confidence interval, 1.19-3.45; P =0.010), together with age, sex, blood pressure, stroke severity, atrial fibrillation, and hypertension, were included in the model. Predictive accuracy was 80.6%. The studied biomarkers were not sufficient for an accurate differential diagnosis of stroke in the hyperacute setting. Additional discovery of new biomarkers and improvement on laboratory techniques seem necessary for achieving a molecular diagnosis of stroke. © 2017 American Heart Association, Inc.

Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion.

PubMed

Liu, Yanqun; Tang, Guanghui; Zhang, Zhijun; Wang, Yongting; Yang, Guo-Yuan

2014-09-05

Current studies demonstrated that metformin is not only a hypoglycemic drug, but also a neuro-protective agent. However, the effect of metformin during ischemic brain injury is unclear. The aim of the present study is to explore the effect of metformin during ischemic brain injury. Adult male CD1 mice underwent 90min transient middle cerebral artery occlusion. Metformin (200mg/kg) was given at the time of reperfusion daily until sacrifice. Results showed that metformin treatment significantly reduced ischemia-induced brain atrophy volume compared to the control (p<0.05). Immunostaining results showed that the microvessel density in the peri-focal region of metformin treated mice was greatly increased compared to the control (p<0.05). Similarly, the numbers of BrdU+/DCX+ and nestin+ cells in the subventricular zone were increased in metformin treated mice compared to the control (p<0.05). Furthermore, we demonstrated that metformin treatment activated AMPK signaling pathway and promoted eNOS phosphorylation. Thus, we concluded that metformin promoted focal angiogenesis and neurogenesis and attenuated ischemia-induced brain injury in mice after middle cerebral artery occlusion, suggesting that metformin is a potential new drug for ischemic stroke therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Functional and structural correlates of magnetic resonance patterns in a new in vitro model of cerebral ischemia by transient occlusion of the medial cerebral artery.

PubMed

Breschi, Gian Luca; Librizzi, Laura; Pastori, Chiara; Zucca, Ileana; Mastropietro, Alfonso; Cattalini, Alessandro; de Curtis, Marco

2010-08-01

Magnetic resonance imaging (MRI) during the acute phase of a stroke contributes to recognize ischemic regions and is potentially useful to predict clinical outcome. Yet, the functional significance of early MRI alterations during brain ischemia is not clearly understood. We achieved an experimental study to interpret MRI signals in a novel model of focal ischemia in the in vitro isolated guinea pig brain. By combining neurophysiological and morphological analysis with MR-imaging, we evaluated the suitability of MR to identify ischemic and peri-ischemic regions. Extracellular recordings demonstrated depolarizations in the ischemic core, but not in adjacent areas, where evoked activity was preserved and brief peri-infarct depolarizations occurred. Diffusion-weighted MRI and immunostaining performed after neurophysiological characterization showed changes restricted to the core region. Diffusion-weighted MR alterations did not include the penumbra region characterized by peri-infarct depolarizations. Therefore, by comparing neurophysiological, imaging and anatomical data, we can conclude that DW-MRI underestimates the extension of the tissue damage involved in brain ischemia.

Delayed histochemical alterations within the neurovascular unit due to transient focal cerebral ischemia and experimental treatment with neurotrophic factors.

PubMed

Michalski, Dominik; Pitsch, Roman; Pillai, Deepu R; Mages, Bianca; Aleithe, Susanne; Grosche, Jens; Martens, Henrik; Schlachetzki, Felix; Härtig, Wolfgang

2017-01-01

Current stroke therapy is focused on recanalizing strategies, but neuroprotective co-treatments are still lacking. Modern concepts of the ischemia-affected neurovascular unit (NVU) and surrounding penumbra emphasize the complexity during the transition from initial damaging to regenerative processes. While early treatment with neurotrophic factors was shown to result in lesion size reduction and blood-brain barrier (BBB) stabilization, cellular consequences from these treatments are poorly understood. This study explored delayed cellular responses not only to ischemic stroke, but also to an early treatment with neurotrophic factors. Rats underwent 60 minutes of focal cerebral ischemia. Fluorescence labeling was applied to sections from brains perfused 7 days after ischemia. Analyses focused on NVU constituents including the vasculature, astrocytes and microglia in the ischemic striatum, the border zone and the contralateral hemisphere. In addition to histochemical signs of BBB breakdown, a strong up-regulation of collagen IV and microglia activation occurred within the ischemic core with simultaneous degradation of astrocytes and their endfeet. Activated astroglia were mainly depicted at the border zone in terms of a glial scar formation. Early treatment with pigment epithelium-derived factor (PEDF) resulted in an attenuation of the usually up-regulated collagen IV-immunoreactivity. However, glial activation was not influenced by treatment with PEDF or the epidermal growth factor (EGF). In conclusion, these data on ischemia-induced cellular reactions within the NVU might help to develop treatments addressing the transition from injury towards regeneration. Thereby, the integrity of the vasculature in close relation to neighboring structures like astrocytes appears as a promising target.

Is Dynamic Cerebral Autoregulation Bilaterally Impaired after Unilateral Acute Ischemic Stroke?

PubMed

Xiong, Li; Tian, Ge; Lin, Wenhua; Wang, Wei; Wang, Lijuan; Leung, Thomas; Mok, Vincent; Liu, Jia; Chen, Xiangyan; Wong, Ka Sing

2017-05-01

Whether dynamic cerebral autoregulation (dCA) is impaired focally in the affected hemisphere or bilaterally in both the affected and nonaffected hemispheres after ischemic stroke remains controversial. We therefore investigated the pattern of dCA in acute ischemic stroke patients with different subtypes. Sixty acute ischemic stroke patients with unilateral anterior circulation infarct [30 with large artery atherosclerosis (LAA), 13 with small vessel disease (SVD), and 17 with coexisting LAA and SVD] and 16 healthy controls were enrolled. Spontaneous arterial blood pressure and cerebral blood flow velocity fluctuations in both bilateral middle cerebral arteries using transcranial Doppler were recorded over 10 minutes. Transfer function analysis was applied to obtain autoregulatory parameters, autoregulation index (ARI), phase difference (PD), and gain. PD was significantly lower on both the ipsilateral and contralateral sides in the LAA group (ipsilateral, 30.74 degrees; contralateral, 29.17 degrees) and the coexisting LAA and SVD group (20.23 degrees; 13.10 degrees) than that in healthy controls (left side, 51.66 degrees; right side, 58.48 degrees) (all P < .05), but there were no significant differences between the 2 sides when compared with each other in all groups. However, in the coexisting LAA and SVD group, phase on both sides was significantly lower when compared with that in the LAA and SVD groups, respectively. The results of ARI were consistent with the findings in PD. The results indicate that dCA is bilaterally impaired in acute ischemic patients with LAA, and the coexisting SVD may aggravate the bilateral impairment of dCA. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

In vivo animal stroke models: a rationale for rodent and non-human primate models

PubMed Central

Tajiri, Naoki; Dailey, Travis; Metcalf, Christopher; Mosley, Yusef I.; Lau, Tsz; Staples, Meaghan; van Loveren, Harry; Kim, Seung U.; Yamashima, Tetsumori; Yasuhara, Takao; Date, Isao; Kaneko, Yuji; Borlongan, Cesario V.

2013-01-01

On average, every four minutes an individual dies from a stroke, accounting for 1 out of every 18 deaths in the United States. Apporximately 795,000 Americans have a new or recurrent stroke each year, with just over 600,000 of these being first attack [1]. There have been multiple animal models of stroke demonstrating that novel therapeutics can help improve the clinical outcome. However, these results have failed to show the same outcomes when tested in human clinical trials. This review will discuss the current in vivo animal models of stroke, advantages and limitations, and the rationale for employing these animal models to satisfy translational gating items for examination of neuroprotective, as well as neurorestorative strategies in stroke patients. An emphasis in the present discussion of therapeutics development is given to stem cell therapy for stroke. PMID:23682299

Extracerebral Tissue Damage in the Intraluminal Filament Mouse Model of Middle Cerebral Artery Occlusion

PubMed Central

Vaas, Markus; Ni, Ruiqing; Rudin, Markus; Kipar, Anja; Klohs, Jan

2017-01-01

Middle cerebral artery occlusion is the most common model of focal cerebral ischemia in the mouse. In the surgical procedure, the external carotid artery (ECA) is ligated; however, its effect on the tissue supplied by the vessel has not been described so far. C57BL/6 mice underwent 1 h of transient MCAO (tMCAO) or sham surgery. Multi-spectral optoacoustic tomography was employed at 30 min after surgery to assess oxygenation in the temporal muscles. Microstructural changes were assessed with magnetic resonance imaging and histological examination at 24 h and 48 h after surgery. Ligation of the ECA resulted in decreased oxygenation of the left temporal muscle in most sham-operated and tMCAO animals. Susceptible mice of both groups exhibited increased T2 relaxation times in the affected muscle with histological evidence of myofibre degeneration, interstitial edema, and neutrophil influx. Ligatures had induced an extensive neutrophil-dominated inflammatory response. ECA ligation leads to distinct hypoxic degenerative changes in the tissue of the ECA territory and to ligature-induced inflammatory processes. An impact on outcome needs to be considered in this stroke model. PMID:28348545

A Program for Solving the Brain Ischemia Problem

PubMed Central

DeGracia, Donald J.

2013-01-01

Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of “master bifurcation diagrams” that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection. PMID:24961411

Development of an Algorithm for Stroke Prediction: A National Health Insurance Database Study in Korea.

PubMed

Min, Seung Nam; Park, Se Jin; Kim, Dong Joon; Subramaniyam, Murali; Lee, Kyung-Sun

2018-01-01

Stroke is the second leading cause of death worldwide and remains an important health burden both for the individuals and for the national healthcare systems. Potentially modifiable risk factors for stroke include hypertension, cardiac disease, diabetes, and dysregulation of glucose metabolism, atrial fibrillation, and lifestyle factors. We aimed to derive a model equation for developing a stroke pre-diagnosis algorithm with the potentially modifiable risk factors. We used logistic regression for model derivation, together with data from the database of the Korea National Health Insurance Service (NHIS). We reviewed the NHIS records of 500,000 enrollees. For the regression analysis, data regarding 367 stroke patients were selected. The control group consisted of 500 patients followed up for 2 consecutive years and with no history of stroke. We developed a logistic regression model based on information regarding several well-known modifiable risk factors. The developed model could correctly discriminate between normal subjects and stroke patients in 65% of cases. The model developed in the present study can be applied in the clinical setting to estimate the probability of stroke in a year and thus improve the stroke prevention strategies in high-risk patients. The approach used to develop the stroke prevention algorithm can be applied for developing similar models for the pre-diagnosis of other diseases. © 2018 S. Karger AG, Basel.

Power and energy dissipation in subsequent return strokes as predicted by a new return stroke model

NASA Technical Reports Server (NTRS)

Cooray, Vernon

1991-01-01

Recently, Cooray introduced a new return stroke model which is capable of predicting the temporal behavior of the return stroke current and the return stroke velocity as a function of the height along the return stroke channel. The authors employed this model to calculate the power and energy dissipation in subsequent return strokes. The results of these calculations are presented here. It was concluded that a large fraction of the total energy available for the dart leader-subsequent stroke process is dissipated in the dart leader stage. The peak power per unit length dissipated in a subsequent stroke channel element decreases with increasing height of that channel element from ground level. For a given channel element, the peak power dissipation increases with increasing current in that channel element. The peak electrical power dissipation in a typical subsequent return stroke is about 1.5 times 10(exp 11) W. The energy dissipation in a subsequent stroke increases with increasing current in the return stroke channel, and for a typical subsequent stroke, the energy dissipation per unit length is about 5.0 times 10(exp 3) J/m.

Self-Reported Sleep Duration in Relation to Incident Stroke Symptoms: Nuances by Body Mass and Race from the REGARDS Study

PubMed Central

Ruiter Petrov, Megan E.; Letter, Abraham J.; Howard, Virginia J.; Kleindorfer, Dawn

2013-01-01

Objectives Determine, amongst employed persons with low risk for obstructive sleep apnea (OSA), if sleep duration is associated with incident stroke symptoms, independent of body mass index (BMI), and if sleep duration mediates racial differences in stroke symptoms. Methods In 2008, 5,666 employed participants (US blacks and whites, ≥45years) from the longitudinal and nationally-representative REasons for Geographic And Racial Differences in Stroke (REGARDS) study, self-reported their average sleep duration. Participants had no history of stroke, transient ischemic attack, or stroke symptoms, and were low risk for OSA. After the sleep assessment, self-reported stroke symptoms were collected at six-month intervals, up to 3 years (M=751 days). Interval-censored, parametric survival models were conducted to estimate hazard ratios predicting time from sleep duration measurement (<6, 6-6.9, 7-7.9(reference), 8-8.9, ≥9 hours) to first stroke symptom. Adjusted models included demographics, stroke risk factors, psychological symptoms, health behaviors, and diet. Results During follow-up, 224 participants reported ≥1 stroke symptom. In the unadjusted model, short sleep (<6hrs) significantly predicted increased risk of stroke symptoms, but not in adjusted models. Stratification by BMI revealed a significant association between short sleep duration and stroke symptoms only for normal BMI persons in unadjusted (HR: 2.93, 95%CI: 1.38-6.22) and fully adjusted models (HR: 4.19, 95%CI: 1.62-10.84). The mediating effect of sleep duration on the relationship between race and stroke symptoms was borderline significant in normal weight participants. Conclusions Among middle-aged to older employed individuals of normal weight and low risk of OSA, self-reported short sleep duration is prospectively associated with increased risk of stroke symptoms. PMID:24119626

Stroke Location and Brain Function in an Embolic Rabbit Stroke Model

PubMed Central

Brown, Aliza T.; Skinner, Robert D.; Flores, Rene; Hennings, Leah; Borrelli, Michael J.; Lowery, John; Culp, William C.

2010-01-01

Purpose Current rabbit stroke models often depend on symptoms as endpoints for embolization and produce wide variation in location, size, and severity of strokes. To further refine our angiographic embolic stroke model we correlated localized infarctions to neurological deficits. Our goal is a rabbit model for long term studies of therapies after stroke. Materials and Methods New Zealand White rabbits (4–5 kg) (n=71) had selective internal carotid artery (ICA) angiography and a single clot was injected. At 24 hours neurological assessment scores (NAS) were measured on a 0=normal to 10=dead scale. Brains were removed and stained to identify stroke areas. All animals with single strokes, N=31, were analyzed by specific brain structure involvement and NAS values were correlated. Results Stroke incidence differed by location with cortex, subcortical, and basal ganglia regions highest. Distributions of middle cerebral artery (MCA) at 52% and anterior cerebral artery (ACA) at 29% were most commonly involved with largest stroke volumes in the ACA distribution. Brain stem and cerebellum strokes had disproportionately severe neurological deficits, scoring 2.25±1.0 vs. cortex (0.5±0.2), subcortical (1.3±0.4) and basal ganglia (0.5±0.3) all in the frontal or parietal regions on NAS (P≤0.02). Conclusions MCA and ACA distributions included 81% of strokes. These sites were relatively silent (potentially allowing longer term survival studies) while others in the posterior circulation produced disproportionately severe symptoms. Symptoms were not reliable indicators of stroke occurrence and other endpoints such as imaging may be required. These are important steps towards refinement of the rabbit stroke model. PMID:20417119

Post traumatic brain perfusion SPECT analysis using reconstructed ROI maps of radioactive microsphere derived cerebral blood flow and statistical parametric mapping

PubMed Central

McGoron, Anthony J; Capille, Michael; Georgiou, Michael F; Sanchez, Pablo; Solano, Juan; Gonzalez-Brito, Manuel; Kuluz, John W

2008-01-01

Background Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets. Methods The focal effects of moderate traumatic brain injury (TBI) on cerebral blood flow (CBF) by SPECT cerebral blood perfusion (CBP) imaging in an animal model were investigated by parallelized statistical techniques. Regional CBF was measured by radioactive microspheres and by SPECT 2 hours after injury in sham-operated piglets versus those receiving severe TBI by fluid-percussion injury to the left parietal lobe. Qualitative SPECT CBP accuracy was assessed against reference radioactive microsphere regional CBF measurements by map reconstruction, registration and smoothing. Cerebral hypoperfusion in the test group was identified at the voxel level using statistical parametric mapping (SPM). Results A significant area of hypoperfusion (P < 0.01) was found as a response to the TBI. Statistical mapping of the reference microsphere CBF data confirms a focal decrease found with SPECT and SPM. Conclusion The suitability of SPM for application to the experimental model and ability to provide insight into CBF changes in response to traumatic injury was validated by the SPECT SPM result of a decrease in CBP at the left parietal region injury area of the test group. Further study and correlation of this characteristic lesion with long-term outcomes and auxiliary diagnostic modalities is critical to developing more effective critical care treatment guidelines and automated medical imaging processing techniques. PMID:18312639

Post traumatic brain perfusion SPECT analysis using reconstructed ROI maps of radioactive microsphere derived cerebral blood flow and statistical parametric mapping.

PubMed

McGoron, Anthony J; Capille, Michael; Georgiou, Michael F; Sanchez, Pablo; Solano, Juan; Gonzalez-Brito, Manuel; Kuluz, John W

2008-02-29

Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets. The focal effects of moderate traumatic brain injury (TBI) on cerebral blood flow (CBF) by SPECT cerebral blood perfusion (CBP) imaging in an animal model were investigated by parallelized statistical techniques. Regional CBF was measured by radioactive microspheres and by SPECT 2 hours after injury in sham-operated piglets versus those receiving severe TBI by fluid-percussion injury to the left parietal lobe. Qualitative SPECT CBP accuracy was assessed against reference radioactive microsphere regional CBF measurements by map reconstruction, registration and smoothing. Cerebral hypoperfusion in the test group was identified at the voxel level using statistical parametric mapping (SPM). A significant area of hypoperfusion (P < 0.01) was found as a response to the TBI. Statistical mapping of the reference microsphere CBF data confirms a focal decrease found with SPECT and SPM. The suitability of SPM for application to the experimental model and ability to provide insight into CBF changes in response to traumatic injury was validated by the SPECT SPM result of a decrease in CBP at the left parietal region injury area of the test group. Further study and correlation of this characteristic lesion with long-term outcomes and auxiliary diagnostic modalities is critical to developing more effective critical care treatment guidelines and automated medical imaging processing techniques.

Neurofibromatosis 1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like symptoms.

PubMed

Waheed, Waqar; Nathan, Muriel H; Allen, Gilman B; Borden, Neil M; Babi, M Ali; Tandan, Rup

2015-11-03

A 37-year-old man with a known history of neurofibromatosis 1 (NF1) presented within 2 days of diarrhoeal illness followed by encephalopathy, facial twitching, hypoglycaemia, hypotension, tachycardia and low-grade fever. Examination showed multiple café-au-lait spots and neurofibromas over the trunk, arms and legs and receptive aphasia with right homonymous hemianopia, which resolved. Workup for cardiac, inflammatory and infectious aetiologies was unrevealing. A brain MRI showed gyral swelling with increased T2 fluid-attenuated inversion recovery signal and diffusion restriction in the left cerebral cortex. Neuroendocrine findings suggested panhypopituitarism with centrally derived adrenal insufficiency. Supportive treatment, hormone supplementation, antibiotics, antivirals and levetiracetam yielded clinical improvement. A follow-up brain MRI showed focal left parieto-occipital atrophy with findings of cortical laminar necrosis. In conclusion, we describe a case of NF1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like findings, hitherto unreported manifestations of NF1. Prompt recognition and treatment of these associated conditions can prevent devastating complications. 2015 BMJ Publishing Group Ltd.

Neurofibromatosis 1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like symptoms

PubMed Central

Waheed, Waqar; Nathan, Muriel H; Allen, Gilman B; Borden, Neil M; Babi, M Ali; Tandan, Rup

2015-01-01

A 37-year-old man with a known history of neurofibromatosis 1 (NF1) presented within 2 days of diarrhoeal illness followed by encephalopathy, facial twitching, hypoglycaemia, hypotension, tachycardia and low-grade fever. Examination showed multiple café-au-lait spots and neurofibromas over the trunk, arms and legs and receptive aphasia with right homonymous hemianopia, which resolved. Workup for cardiac, inflammatory and infectious aetiologies was unrevealing. A brain MRI showed gyral swelling with increased T2 fluid-attenuated inversion recovery signal and diffusion restriction in the left cerebral cortex. Neuroendocrine findings suggested panhypopituitarism with centrally derived adrenal insufficiency. Supportive treatment, hormone supplementation, antibiotics, antivirals and levetiracetam yielded clinical improvement. A follow-up brain MRI showed focal left parieto-occipital atrophy with findings of cortical laminar necrosis. In conclusion, we describe a case of NF1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like findings, hitherto unreported manifestations of NF1. Prompt recognition and treatment of these associated conditions can prevent devastating complications. PMID:26531733

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

PubMed Central

Shekhar, Shashank; Liu, Ruen; Travis, Olivia K; Roman, Richard J; Fan, Fan

2017-01-01

Aging and chronic hypertension are associated with dysfunction in vascular smooth muscle, endothelial cells, and neurovascular coupling. These dysfunctions induce impaired myogenic response and cerebral autoregulation, which diminish the protection of cerebral arterioles to the cerebral microcirculation from elevated pressure in hypertension. Chronic hypertension promotes cerebral focal ischemia in response to reductions in blood pressure that are often seen in sedentary elderly patients on antihypertensive therapy. Cerebral autoregulatory dysfunction evokes Blood-Brain Barrier (BBB) leakage, allowing the circulating inflammatory factors to infiltrate the brain to activate glia. The impaired cerebral autoregulation-induced inflammatory and ischemic injury could cause neuronal cell death and synaptic dysfunction which promote cognitive deficits. In this brief review, we summarize the pathogenesis and signaling mechanisms of cerebral autoregulation in hypertension and ischemic stroke-induced cognitive deficits, and discuss our new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the altered cerebral vascular function. PMID:29333537

SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients.

PubMed

Armstrong, Amy E; Gillan, Eileen; DiMario, Francis Joseph

2014-03-01

SMART syndrome (stroke-like migraine attacks after radiation therapy) is a rare condition that involves complex migraines with focal neurologic findings in patients following cranial irradiation for central nervous system malignancies. Little is known about the mechanisms behind the disorder, making successful treatment challenging. We report 2 new cases of SMART syndrome in pediatric patients as well as review all documented cases of the syndrome. Each of our 2 pediatric patients suffered multiple episodes. Attacks were characterized by severe headache, visual disturbance, aphasia, and weakness. Recovery occurred over several days to weeks. The data from all documented reports of SMART syndrome indicate a greater prevalence for male gender. An age-dependent pattern of onset was also observed, with a greater variability of syndrome onset in patients who received cranial irradiation at a younger age. SMART appears to be a reversible, recurrent long-term complication of radiation therapy with possible age- and gender-related influences.

An ensemble survival model for estimating relative residual longevity following stroke: Application to mortality data in the chronic dialysis population

PubMed Central

Phadnis, Milind A; Wetmore, James B; Shireman, Theresa I; Ellerbeck, Edward F; Mahnken, Jonathan D

2016-01-01

Time-dependent covariates can be modeled within the Cox regression framework and can allow both proportional and nonproportional hazards for the risk factor of research interest. However, in many areas of health services research, interest centers on being able to estimate residual longevity after the occurrence of a particular event such as stroke. The survival trajectory of patients experiencing a stroke can be potentially influenced by stroke type (hemorrhagic or ischemic), time of the stroke (relative to time zero), time since the stroke occurred, or a combination of these factors. In such situations, researchers are more interested in estimating lifetime lost due to stroke rather than merely estimating the relative hazard due to stroke. To achieve this, we propose an ensemble approach using the generalized gamma distribution by means of a semi-Markov type model with an additive hazards extension. Our modeling framework allows stroke as a time-dependent covariate to affect all three parameters (location, scale, and shape) of the generalized gamma distribution. Using the concept of relative times, we answer the research question by estimating residual life lost due to ischemic and hemorrhagic stroke in the chronic dialysis population. PMID:26403934

An ensemble survival model for estimating relative residual longevity following stroke: Application to mortality data in the chronic dialysis population.

PubMed

Phadnis, Milind A; Wetmore, James B; Shireman, Theresa I; Ellerbeck, Edward F; Mahnken, Jonathan D

2017-12-01

Time-dependent covariates can be modeled within the Cox regression framework and can allow both proportional and nonproportional hazards for the risk factor of research interest. However, in many areas of health services research, interest centers on being able to estimate residual longevity after the occurrence of a particular event such as stroke. The survival trajectory of patients experiencing a stroke can be potentially influenced by stroke type (hemorrhagic or ischemic), time of the stroke (relative to time zero), time since the stroke occurred, or a combination of these factors. In such situations, researchers are more interested in estimating lifetime lost due to stroke rather than merely estimating the relative hazard due to stroke. To achieve this, we propose an ensemble approach using the generalized gamma distribution by means of a semi-Markov type model with an additive hazards extension. Our modeling framework allows stroke as a time-dependent covariate to affect all three parameters (location, scale, and shape) of the generalized gamma distribution. Using the concept of relative times, we answer the research question by estimating residual life lost due to ischemic and hemorrhagic stroke in the chronic dialysis population.

Prolonged, 24-h delayed peripheral inflammation increases short- and long-term functional impairment and histopathological damage after focal ischemia in the rat.

PubMed

Langdon, Kristopher D; Maclellan, Crystal L; Corbett, Dale

2010-08-01

The incidence of infection among stroke patients is alarmingly high and both acute and delayed infections increase morbidity and mortality. Experimental studies support the acute clinical data, but little attention has focused on delayed systemic infections. Here, we investigated the effects of prolonged systemic inflammation either before or 24-h after ischemia. Systemic inflammation was induced by injecting rats with three separate doses of lipopolysaccharide (LPS; 50 mug/kg, i.p.) with core temperature monitoring for 48-h after middle cerebral artery occlusion (MCAo). Lipopolysaccharide injected before MCAo increased injury by approximately 30%, whereas delayed injection increased injury by approximately 85% (30-day survival). Proinflammatory cytokines assessed repeatedly for 72 h were significantly and persistently elevated with inflammation. This was accompanied by increases in microglia/macrophage and infiltrating leukocyte numbers in delayed LPS-treated animals. Behavioral assessments at 7 and 30 days revealed approximately 15% deficit in hindlimb function in animals treated with LPS 24-h after ischemia. Clearly, delayed and prolonged postischemic systemic inflammation has devastating effects on stroke outcome, in the absence of a prolonged febrile response. These findings, together with corroborative clinical data, emphasize the importance of early intervention to counteract the deleterious consequences of stroke-associated inflammation and infection.

Heart Rate Variability (HRV) modifications in adult hemiplegic patients after botulinum toxin type A (nt-201) injection.

PubMed

Invernizzi, M; Carda, S; Molinari, C; Stagno, D; Cisari, C; Baricich, A

2015-08-01

The most important adverse effect of BoNT-A is the systemic diffusion of the toxin. There is some evidence that the administration of high doses can increase the risk of systemic diffusion and the development of clinically evident adverse effects, however an international consensus does not exist about its maximum dose. The aim of this study was to evaluate changes in autonomic heart drive induced by high doses (higher than 600 units) of incobotulinumtoxinA injection in spastic stroke patients. Moreover, the treatment safety by monitoring adverse events occurrence was assessed. Case control study. Eleven stroke survivors with spastic hemiplegia. Patients were treated with intramuscular focal injections of IncobotulinumtoxinA (NT 201; Xeomin®, Merz Pharmaceuticals GmbH, Frankfurt, Germany). Doses were below 12 units/Kg. Each patient underwent an ECG recording before injection and 10 days after treatment. Linear and non-linear Heart Rate variability (HRV) measures were derived from ECGs with a dedicated software. None of the variable considered showed statistically significant changes after BoNT-A injection. The use of incobotulinumtoxinA in adult patients at doses up to 12 units/kg seems to be safe regarding autonomic heart drive. The use of IncobotulinumtoxinA up to 600 units could be a safe therapeutic option in spastic hemiplegic stroke survivors.

Chronic photoperiod disruption does not increase vulnerability to focal cerebral ischemia in young normotensive rats.

PubMed

Ku Mohd Noor, Ku Mastura; Wyse, Cathy; Roy, Lisa A; Biello, Stephany M; McCabe, Christopher; Dewar, Deborah

2017-11-01

Photoperiod disruption, which occurs during shift work, is associated with changes in metabolism or physiology (e.g. hypertension and hyperglycaemia) that have the potential to adversely affect stroke outcome. We sought to investigate if photoperiod disruption affects vulnerability to stroke by determining the impact of photoperiod disruption on infarct size following permanent middle cerebral artery occlusion. Adult male Wistar rats (210-290 g) were housed singly under two different light/dark cycle conditions ( n = 12 each). Controls were maintained on a standard 12:12 light/dark cycle for nine weeks. For rats exposed to photoperiod disruption, every three days for nine weeks, the lights were switched on 6 h earlier than in the previous photoperiod. T 2 -weighted magnetic resonance imaging was performed at 48 h after middle cerebral artery occlusion. Disruption of photoperiod in young healthy rats for nine weeks did not alter key physiological variables that can impact on ischaemic damage, e.g. blood pressure and blood glucose immediately prior to middle cerebral artery occlusion. There was no effect of photoperiod disruption on infarct size after middle cerebral artery occlusion. We conclude that any potentially adverse effect of photoperiod disruption on stroke outcome may require additional factors such as high fat/high sugar diet or pre-existing co-morbidities.

Combination of brain-computer interface training and goal-directed physical therapy in chronic stroke: a case report.

PubMed

Broetz, Doris; Braun, Christoph; Weber, Cornelia; Soekadar, Surjo R; Caria, Andrea; Birbaumer, Niels

2010-09-01

There is no accepted and efficient rehabilitation strategy to reduce focal impairments for patients with chronic stroke who lack residual movements. A 67-year-old hemiplegic patient with no active finger extension was trained with a brain-computer interface (BCI) combined with a specific daily life-oriented physiotherapy. The BCI used electrical brain activity (EEG) and magnetic brain activity (MEG) to drive an orthosis and a robot affixed to the patient's affected upper extremity, which enabled him to move the paralyzed arm and hand driven by voluntary modulation of micro-rhythm activity. In addition, the patient practiced goal-directed physiotherapy training. Over 1 year, he completed 3 training blocks. Arm motor function, gait capacities (using Fugl-Meyer Assessment, Wolf Motor Function Test, Modified Ashworth Scale, 10-m walk speed, and goal attainment score), and brain reorganization (functional MRI, MEG) were repeatedly assessed. The ability of hand and arm movements as well as speed and safety of gait improved significantly (mean 46.6%). Improvement of motor function was associated with increased micro-oscillations in the ipsilesional motor cortex. This proof-of-principle study suggests that the combination of BCI training with goal-directed, active physical therapy may improve the motor abilities of chronic stroke patients despite apparent initial paralysis.

Pilot study of intravenous glyburide in patients with a large ischemic stroke.

PubMed

Sheth, Kevin N; Kimberly, W Taylor; Elm, Jordan J; Kent, Thomas A; Mandava, Pitchaiah; Yoo, Albert J; Thomalla, Götz; Campbell, Bruce; Donnan, Geoffrey A; Davis, Stephen M; Albers, Gregory W; Jacobson, Sven; Simard, J Marc; Stern, Barney J

2014-01-01

Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection). We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm3, whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127≤10 hours. Recruitment was completed within 10 months. The mean age was 50.5 years, and baseline diffusion-weighted image lesion volume was 102±23 cm3. There were no serious adverse events related to drug and no symptomatic hypoglycemia. The increase in ipsilateral hemisphere volume was 50±33 cm3. The proportion of 90-day modified Rankin Scale≤4 was 90% (40% modified Rankin Scale, ≤3). RP-1127 at a dose of 3 mg/d was well tolerated and did not require any dose reductions. A clinical trial of RP-1127 is feasible. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01268683.

Animal models of post-ischemic forced use rehabilitation: methods, considerations, and limitations

PubMed Central

2013-01-01

Many survivors of stroke experience arm impairments, which can severely impact their quality of life. Forcing use of the impaired arm appears to improve functional recovery in post-stroke hemiplegic patients, however the mechanisms underlying improved recovery remain unclear. Animal models of post-stroke rehabilitation could prove critical to investigating such mechanisms, however modeling forced use in animals has proven challenging. Potential problems associated with reported experimental models include variability between stroke methods, rehabilitation paradigms, and reported outcome measures. Herein, we provide an overview of commonly used stroke models, including advantages and disadvantages of each with respect to studying rehabilitation. We then review various forced use rehabilitation paradigms, and highlight potential difficulties and translational problems. Lastly, we discuss the variety of functional outcome measures described by experimental researchers. To conclude, we outline ongoing challenges faced by researchers, and the importance of translational communication. Many stroke patients rely critically on rehabilitation of post-stroke impairments, and continued effort toward progression of rehabilitative techniques is warranted to ensure best possible treatment of the devastating effects of stroke. PMID:23343500

Comparison of risk scores for the prediction of stroke in African Americans: Findings from the Jackson Heart Study.

PubMed

Foraker, Randi E; Greiner, Melissa; Sims, Mario; Tucker, Katherine L; Towfighi, Amytis; Bidulescu, Aurelian; Shoben, Abigail B; Smith, Sakima; Talegawkar, Sameera; Blackshear, Chad; Wang, Wei; Hardy, Natalie Chantelle; O'Brien, Emily

2016-07-01

Evidence from existing cohort studies supports the prediction of incident coronary heart disease and stroke using 10-year cardiovascular disease (CVD) risk scores and the American Heart Association/American Stroke Association's cardiovascular health (CVH) metric. We included all Jackson Heart Study participants with complete scoring information at the baseline study visit (2000-2004) who had no history of stroke (n = 4,140). We used Kaplan-Meier methods to calculate the cumulative incidence of stroke and used Cox models to estimate hazard ratios and 95% CIs for stroke according to CVD risk and CVH score. We compared the discrimination of the 2 models according to the Harrell c index and plotted predicted vs observed stroke risk calibration plots for each of the 2 models. The median age of the African American participants was 54.5 years, and 65% were female. The cumulative incidence of stroke increased across worsening categories of CVD risk and CVH. A 1-unit increase in CVD risk increased the hazard of stroke (1.07, 1.06-1.08), whereas each 1-unit increase in CVH corresponded to a decreased hazard of stroke (0.76, 0.69-0.83). As evidenced by the c statistics, the CVH model was less discriminating than the CVD risk model (0.59 [0.55-0.64] vs 0.79 [0.76-0.83]). Both scores were associated with incident stroke in a dose-response fashion; however, the CVD risk model was more discriminating than the CVH model. The CVH score may still be preferable for its simplicity in application to broad patient populations and public health efforts. Copyright © 2016 Elsevier Inc. All rights reserved.

Development and validation of clinical prediction models for mortality, functional outcome and cognitive impairment after stroke: a study protocol

PubMed Central

Fahey, Marion; Rudd, Anthony; Béjot, Yannick; Wolfe, Charles; Douiri, Abdel

2017-01-01

Introduction Stroke is a leading cause of adult disability and death worldwide. The neurological impairments associated with stroke prevent patients from performing basic daily activities and have enormous impact on families and caregivers. Practical and accurate tools to assist in predicting outcome after stroke at patient level can provide significant aid for patient management. Furthermore, prediction models of this kind can be useful for clinical research, health economics, policymaking and clinical decision support. Methods 2869 patients with first-ever stroke from South London Stroke Register (SLSR) (1995–2004) will be included in the development cohort. We will use information captured after baseline to construct multilevel models and a Cox proportional hazard model to predict cognitive impairment, functional outcome and mortality up to 5 years after stroke. Repeated random subsampling validation (Monte Carlo cross-validation) will be evaluated in model development. Data from participants recruited to the stroke register (2005–2014) will be used for temporal validation of the models. Data from participants recruited to the Dijon Stroke Register (1985–2015) will be used for external validation. Discrimination, calibration and clinical utility of the models will be presented. Ethics Patients, or for patients who cannot consent their relatives, gave written informed consent to participate in stroke-related studies within the SLSR. The SLSR design was approved by the ethics committees of Guy’s and St Thomas’ NHS Foundation Trust, Kings College Hospital, Queens Square and Westminster Hospitals (London). The Dijon Stroke Registry was approved by the Comité National des Registres and the InVS and has authorisation of the Commission Nationale de l’Informatique et des Libertés. PMID:28821511

Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents

PubMed Central

Lee, Boyeon; Clarke, Douglas; Al Ahmad, Abraham; Kahle, Michael; Parham, Christi; Auckland, Lisa; Shaw, Courtney; Fidanboylu, Mehmet; Orr, Anthony Wayne; Ogunshola, Omolara; Fertala, Andrzej; Thomas, Sarah A.; Bix, Gregory J.

2011-01-01

Stroke is the leading cause of long-term disability and the third leading cause of death in the United States. While most research thus far has focused on acute stroke treatment and neuroprotection, the exploitation of endogenous brain self-repair mechanisms may also yield therapeutic strategies. Here, we describe a distinct type of stroke treatment, the naturally occurring extracellular matrix fragment of perlecan, domain V, which we found had neuroprotective properties and enhanced post-stroke angiogenesis, a key component of brain repair, in rodent models of stroke. In both rat and mouse models, Western blot analysis revealed elevated levels of perlecan domain V. When systemically administered 24 hours after stroke, domain V was well tolerated, reached infarct and peri-infarct brain vasculature, and restored stroke-affected motor function to baseline pre-stroke levels in these multiple stroke models in both mice and rats. Post-stroke domain V administration increased VEGF levels via a mechanism involving brain endothelial cell α5β1 integrin, and the subsequent neuroprotective and angiogenic actions of domain V were in turn mediated via VEGFR. These results suggest that perlecan domain V represents a promising approach for stroke treatment. PMID:21747167

Validation of simplified centre of mass models during gait in individuals with chronic stroke.

PubMed

Huntley, Andrew H; Schinkel-Ivy, Alison; Aqui, Anthony; Mansfield, Avril

2017-10-01

The feasibility of using a multiple segment (full-body) kinematic model in clinical gait assessment is difficult when considering obstacles such as time and cost constraints. While simplified gait models have been explored in healthy individuals, no such work to date has been conducted in a stroke population. The aim of this study was to quantify the errors of simplified kinematic models for chronic stroke gait assessment. Sixteen individuals with chronic stroke (>6months), outfitted with full body kinematic markers, performed a series of gait trials. Three centre of mass models were computed: (i) 13-segment whole-body model, (ii) 3 segment head-trunk-pelvis model, and (iii) 1 segment pelvis model. Root mean squared error differences were compared between models, along with correlations to measures of stroke severity. Error differences revealed that, while both models were similar in the mediolateral direction, the head-trunk-pelvis model had less error in the anteroposterior direction and the pelvis model had less error in the vertical direction. There was some evidence that the head-trunk-pelvis model error is influenced in the mediolateral direction for individuals with more severe strokes, as a few significant correlations were observed between the head-trunk-pelvis model and measures of stroke severity. These findings demonstrate the utility and robustness of the pelvis model for clinical gait assessment in individuals with chronic stroke. Low error in the mediolateral and vertical directions is especially important when considering potential stability analyses during gait for this population, as lateral stability has been previously linked to fall risk. Copyright © 2017 Elsevier Ltd. All rights reserved.

A photoelectric technique for measuring lightning-channel propagation velocities from a mobile laboratory

NASA Technical Reports Server (NTRS)

Mach, Douglas M.; Rust, W. David

1989-01-01

The present device for lightning channel propagation-velocity determination employs eight photodetectors mounted behind precision horizontal slits in the focal plane of a photographic camera lens. The eight photodetector pulses, IRIG-B time, and slow and fast electric field-change waveforms are recorded on a 14-track analog tape recorder. A comparison of the present results with those obtained by a streaking camera shows no significant differences between the velocities obtained from the same strokes with the two systems; neither is there any difference in pulse characteristics or in the velocities calculated from them.

Cerebral infarction due to smoker’s polycythemia

PubMed Central

Thakur, Kiran Teresa; Westover, M Brandon

2011-01-01

A 65-year-old man presented with fluctuating focal neurological deficits and neuroimaging findings of multiple small cerebral infarctions. His medical investigation revealed a >100 pack/year smoking history, and a haematocrit >60. Subsequent investigations led to a diagnosis of cerebral infarction due to smoker’s polycythemia, the third such case reported in the medical literature. The patient’s neurological deficits resolved completely with subsequent haematocrit reduction. This brief report reviews the differential diagnosis of polycythemia, current knowledge of the mechanisms by which smoker’s polycythemia may lead to ischemic stroke, and recommendations for management. PMID:22675101

External Validation of a Case-Mix Adjustment Model for the Standardized Reporting of 30-Day Stroke Mortality Rates in China.

PubMed

Yu, Ping; Pan, Yuesong; Wang, Yongjun; Wang, Xianwei; Liu, Liping; Ji, Ruijun; Meng, Xia; Jing, Jing; Tong, Xu; Guo, Li; Wang, Yilong

2016-01-01

A case-mix adjustment model has been developed and externally validated, demonstrating promise. However, the model has not been thoroughly tested among populations in China. In our study, we evaluated the performance of the model in Chinese patients with acute stroke. The case-mix adjustment model A includes items on age, presence of atrial fibrillation on admission, National Institutes of Health Stroke Severity Scale (NIHSS) score on admission, and stroke type. Model B is similar to Model A but includes only the consciousness component of the NIHSS score. Both model A and B were evaluated to predict 30-day mortality rates in 13,948 patients with acute stroke from the China National Stroke Registry. The discrimination of the models was quantified by c-statistic. Calibration was assessed using Pearson's correlation coefficient. The c-statistic of model A in our external validation cohort was 0.80 (95% confidence interval, 0.79-0.82), and the c-statistic of model B was 0.82 (95% confidence interval, 0.81-0.84). Excellent calibration was reported in the two models with Pearson's correlation coefficient (0.892 for model A, p<0.001; 0.927 for model B, p = 0.008). The case-mix adjustment model could be used to effectively predict 30-day mortality rates in Chinese patients with acute stroke.

The neurophysiology of language: Insights from non-invasive brain stimulation in the healthy human brain.

PubMed

Hartwigsen, Gesa

2015-09-01

With the advent of non-invasive brain stimulation (NIBS), a new decade in the study of language has started. NIBS allows for testing the functional relevance of language-related brain activation and enables the researcher to investigate how neural activation changes in response to focal perturbations. This review focuses on the application of NIBS in the healthy brain. First, some basic mechanisms will be introduced and the prerequisites for carrying out NIBS studies of language are addressed. The next section outlines how NIBS can be used to characterize the contribution of the stimulated area to a task. In this context, novel approaches such as multifocal transcranial magnetic stimulation and the condition-and-perturb approach are discussed. The third part addresses the combination of NIBS and neuroimaging in the study of plasticity. These approaches are particularly suited to investigate short-term reorganization in the healthy brain and may inform models of language recovery in post-stroke aphasia. Copyright © 2014 The Author. Published by Elsevier Inc. All rights reserved.

Magnetization Transfer Ratio Relates to Cognitive Impairment in Normal Elderly

PubMed Central

Seiler, Stephan; Pirpamer, Lukas; Hofer, Edith; Duering, Marco; Jouvent, Eric; Fazekas, Franz; Mangin, Jean-Francois; Chabriat, Hugues; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2014-01-01

Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38–86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia. PMID:25309438

Use-Dependent Dendritic Regrowth Is Limited after Unilateral Controlled Cortical Impact to the Forelimb Sensorimotor Cortex

PubMed Central

Jones, Theresa A.; Liput, Daniel J.; Maresh, Erin L.; Donlan, Nicole; Parikh, Toral J.; Marlowe, Dana

2012-01-01

Abstract Compensatory neural plasticity occurs in both hemispheres following unilateral cortical damage incurred by seizures, stroke, and focal lesions. Plasticity is thought to play a role in recovery of function, and is important for the utility of rehabilitation strategies. Such effects have not been well described in models of traumatic brain injury (TBI). We examined changes in immunoreactivity for neural structural and plasticity-relevant proteins in the area surrounding a controlled cortical impact (CCI) to the forelimb sensorimotor cortex (FL-SMC), and in the contralateral homotopic cortex over time (3–28 days). CCI resulted in considerable motor deficits in the forelimb contralateral to injury, and increased reliance on the ipsilateral forelimb. The density of dendritic processes, visualized with immunostaining for microtubule-associated protein-2 (MAP-2), were bilaterally decreased at all time points. Synaptophysin (SYN) immunoreactivity increased transiently in the injured hemisphere, but this reflected an atypical labeling pattern, and it was unchanged in the contralateral hemisphere compared to uninjured controls. The lack of compensatory neuronal structural plasticity in the contralateral homotopic cortex, despite behavioral asymmetries, is in contrast to previous findings in stroke models. In the cortex surrounding the injury (but not the contralateral cortex), decreases in dendrites were accompanied by neurodegeneration, as indicated by Fluoro-Jade B (FJB) staining, and increased expression of the growth-inhibitory protein Nogo-A. These studies indicate that, following unilateral CCI, the cortex undergoes neuronal structural degradation in both hemispheres out to 28 days post-injury, which may be indicative of compromised compensatory plasticity. This is likely to be an important consideration in designing therapeutic strategies aimed at enhancing plasticity following TBI. PMID:22352953

A Novel Dual NO-donating Oxime and c-Jun N-terminal Kinase Inhibitor Protects Against Cerebral Ischemia–Reperfusion Injury in Mice

PubMed Central

Atochin, Dmitriy N.; Schepetkin, Igor A.; Khlebnikov, Andrei I.; Seledtsov, Victor I.; Swanson, Helen; Quinn, Mark T.; Huang, Paul L.

2017-01-01

The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30 minutes) with subsequent reperfusion (48 hours). Mice were treated with IQ-1S (25 mg/kg) suspended in 10% solutol or with vehicle alone 30 minutes before and 24 hours after middle cerebral artery MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30 minutes of MCAO provoked by a filament and during the first 30 minutes of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48 hours of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury. PMID:26923672

Use-dependent dendritic regrowth is limited after unilateral controlled cortical impact to the forelimb sensorimotor cortex.

PubMed

Jones, Theresa A; Liput, Daniel J; Maresh, Erin L; Donlan, Nicole; Parikh, Toral J; Marlowe, Dana; Kozlowski, Dorothy A

2012-05-01

Compensatory neural plasticity occurs in both hemispheres following unilateral cortical damage incurred by seizures, stroke, and focal lesions. Plasticity is thought to play a role in recovery of function, and is important for the utility of rehabilitation strategies. Such effects have not been well described in models of traumatic brain injury (TBI). We examined changes in immunoreactivity for neural structural and plasticity-relevant proteins in the area surrounding a controlled cortical impact (CCI) to the forelimb sensorimotor cortex (FL-SMC), and in the contralateral homotopic cortex over time (3-28 days). CCI resulted in considerable motor deficits in the forelimb contralateral to injury, and increased reliance on the ipsilateral forelimb. The density of dendritic processes, visualized with immunostaining for microtubule-associated protein-2 (MAP-2), were bilaterally decreased at all time points. Synaptophysin (SYN) immunoreactivity increased transiently in the injured hemisphere, but this reflected an atypical labeling pattern, and it was unchanged in the contralateral hemisphere compared to uninjured controls. The lack of compensatory neuronal structural plasticity in the contralateral homotopic cortex, despite behavioral asymmetries, is in contrast to previous findings in stroke models. In the cortex surrounding the injury (but not the contralateral cortex), decreases in dendrites were accompanied by neurodegeneration, as indicated by Fluoro-Jade B (FJB) staining, and increased expression of the growth-inhibitory protein Nogo-A. These studies indicate that, following unilateral CCI, the cortex undergoes neuronal structural degradation in both hemispheres out to 28 days post-injury, which may be indicative of compromised compensatory plasticity. This is likely to be an important consideration in designing therapeutic strategies aimed at enhancing plasticity following TBI.

Developing a stroke severity index based on administrative data was feasible using data mining techniques.

PubMed

Sung, Sheng-Feng; Hsieh, Cheng-Yang; Kao Yang, Yea-Huei; Lin, Huey-Juan; Chen, Chih-Hung; Chen, Yu-Wei; Hu, Ya-Han

2015-11-01

Case-mix adjustment is difficult for stroke outcome studies using administrative data. However, relevant prescription, laboratory, procedure, and service claims might be surrogates for stroke severity. This study proposes a method for developing a stroke severity index (SSI) by using administrative data. We identified 3,577 patients with acute ischemic stroke from a hospital-based registry and analyzed claims data with plenty of features. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). We used two data mining methods and conventional multiple linear regression (MLR) to develop prediction models, comparing the model performance according to the Pearson correlation coefficient between the SSI and the NIHSS. We validated these models in four independent cohorts by using hospital-based registry data linked to a nationwide administrative database. We identified seven predictive features and developed three models. The k-nearest neighbor model (correlation coefficient, 0.743; 95% confidence interval: 0.737, 0.749) performed slightly better than the MLR model (0.742; 0.736, 0.747), followed by the regression tree model (0.737; 0.731, 0.742). In the validation cohorts, the correlation coefficients were between 0.677 and 0.725 for all three models. The claims-based SSI enables adjusting for disease severity in stroke studies using administrative data. Copyright © 2015 Elsevier Inc. All rights reserved.

Feasibility of using high-definition transcranial direct current stimulation (HD-tDCS) to enhance treatment outcomes in persons with aphasia.

PubMed

Richardson, Jessica; Datta, Abhishek; Dmochowski, Jacek; Parra, Lucas C; Fridriksson, Julius

2015-01-01

Transcranial direct current stimulation (tDCS) enhances treatment outcomes post-stroke. Feasibility and tolerability of high-definition (HD) tDCS (a technique that increases current focality and intensity) for consecutive weekdays as an adjuvant to behavioral treatment in a clinical population has not been demonstrated. To determine HD-tDCS feasibility outcomes: 1) ability to implement study as designed, 2) acceptability of repeated HD-tDCS administration to patients, and 3) preliminary efficacy. Eight patients with chronic post-stroke aphasia participated in a randomized crossover trial with two arms: conventional sponge-based (CS) tDCS and HD-tDCS. Computerized anomia treatment was administered for five consecutive days during each treatment arm. Individualized modeling/targeting procedures and an 8-channel HD-tDCS device were developed. CS-tDCS and HD-tDCS were comparable in terms of implementation, acceptability, and outcomes. Naming accuracy and response time improved for both stimulation conditions. Change in accuracy of trained items was numerically higher (but not statistically significant) for HD-tDCS compared to CS-tDCS for most patients. Regarding feasibility, HD-tDCS treatment studies can be implemented when designed similarly to documented CS-tDCS studies. HD-tDCS is likely to be acceptable to patients and clinicians. Preliminary efficacy data suggest that HD-tDCS effects, using only 4 electrodes, are at least comparable to CS-tDCS.

Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis

PubMed Central

Duan, Bo; Wang, Yi-Zhi; Yang, Tao; Chu, Xiang-Ping; Yu, Ye; Huang, Yu; Cao, Hui; Hansen, Jillian; Simon, Roger P.; Zhu, Michael X.; Xiong, Zhi-Gang; Xu, Tian-Le

2011-01-01

Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca2+ overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction. PMID:21307247

Feasibility of using high-definition transcranial direct current stimulation (HD-tDCS) to enhance treatment outcomes in persons with aphasia

PubMed Central

Richardson, Jessica; Datta, Abhishek; Dmochowski, Jacek; Parra, Lucas C.; Fridriksson, Julius

2018-01-01

BACKGROUND Transcranial direct current stimulation (tDCS) enhances treatment outcomes post-stroke. Feasibility and tolerability of high-definition (HD) tDCS (a technique that increases current focality and intensity) for consecutive weekdays as an adjuvant to behavioral treatment in a clinical population has not been demonstrated. OBJECTIVE To determine HD-tDCS feasibility outcomes: 1) ability to implement study as designed, 2) acceptability of repeated HD-tDCS administration to patients, and 3) preliminary efficacy. METHODS Eight patients with chronic post-stroke aphasia participated in a randomized crossover trial with two arms: conventional sponge-based (CS) tDCS and HD-tDCS. Computerized anomia treatment was administered for five consecutive days during each treatment arm. RESULTS Individualized modeling/targeting procedures and an 8-channel HD-tDCS device were developed. CS-tDCS and HD-tDCS were comparable in terms of implementation, acceptability, and outcomes. Naming accuracy and response time improved for both stimulation conditions. Change in accuracy of trained items was numerically higher (but not statistically significant) for HD-tDCS compared to CS-tDCS for most patients. CONCLUSIONS Regarding feasibility, HD-tDCS treatment studies can be implemented when designed similarly to documented CS-tDCS studies. HD-tDCS is likely to be acceptable to patients and clinicians. Preliminary efficacy data suggest that HD-tDCS effects, using only 4 electrodes, are at least comparable to CS-tDCS. PMID:25547776

Early post-stroke cognition in stroke rehabilitation patients predicts functional outcome at 13 months.

PubMed

Wagle, Jørgen; Farner, Lasse; Flekkøy, Kjell; Bruun Wyller, Torgeir; Sandvik, Leiv; Fure, Brynjar; Stensrød, Brynhild; Engedal, Knut

2011-01-01

To identify prognostic factors associated with functional outcome at 13 months in a sample of stroke rehabilitation patients. Specifically, we hypothesized that cognitive functioning early after stroke would predict long-term functional outcome independently of other factors. 163 stroke rehabilitation patients underwent a structured neuropsychological examination 2-3 weeks after hospital admittance, and their functional status was subsequently evaluated 13 months later with the modified Rankin Scale (mRS) as outcome measure. Three predictive models were built using linear regression analyses: a biological model (sociodemographics, apolipoprotein E genotype, prestroke vascular factors, lesion characteristics and neurological stroke-related impairment); a functional model (pre- and early post-stroke cognitive functioning, personal and instrumental activities of daily living, ADL, and depressive symptoms), and a combined model (including significant variables, with p value <0.05, from the biological and functional models). A combined model of 4 variables best predicted long-term functional outcome with explained variance of 49%: neurological impairment (National Institute of Health Stroke Scale; β = 0.402, p < 0.001), age (β = 0.233, p = 0.001), post-stroke cognitive functioning (Repeatable Battery of Neuropsychological Status, RBANS; β = -0.248, p = 0.001) and prestroke personal ADL (Barthel Index; β = -0.217, p = 0.002). Further linear regression analyses of which RBANS indexes and subtests best predicted long-term functional outcome showed that Coding (β = -0.484, p < 0.001) and Figure Copy (β = -0.233, p = 0.002) raw scores at baseline explained 42% of the variance in mRS scores at follow-up. Early post-stroke cognitive functioning as measured by the RBANS is a significant and independent predictor of long-term functional post-stroke outcome. Copyright © 2011 S. Karger AG, Basel.

The development and implementation of stroke risk prediction model in National Health Insurance Service's personal health record.

PubMed

Lee, Jae-Woo; Lim, Hyun-Sun; Kim, Dong-Wook; Shin, Soon-Ae; Kim, Jinkwon; Yoo, Bora; Cho, Kyung-Hee

2018-01-01

The purpose of this study was to build a 10-year stroke prediction model and categorize a probability of stroke using the Korean national health examination data. Then it intended to develop the algorithm to provide a personalized warning on the basis of each user's level of stroke risk and a lifestyle correction message about the stroke risk factors. Subject to national health examinees in 2002-2003, the stroke prediction model identified when stroke was first diagnosed by following-up the cohort until 2013 and estimated a 10-year probability of stroke. It sorted the user's individual probability of stroke into five categories - normal, slightly high, high, risky, very risky, according to the five ranges of average probability of stroke in comparison to total population - less than 50 percentile, 50-70, 70-90, 90-99.9, more than 99.9 percentile, and constructed the personalized warning and lifestyle correction messages by each category. Risk factors in stroke risk model include the age, BMI, cholesterol, hypertension, diabetes, smoking status and intensity, physical activity, alcohol drinking, past history (hypertension, coronary heart disease) and family history (stroke, coronary heart disease). The AUC values of stroke risk prediction model from the external validation data set were 0.83 in men and 0.82 in women, which showed a high predictive power. The probability of stroke within 10 years for men in normal group (less than 50 percentile) was less than 3.92% and those in very risky group (top 0.01 percentile) was 66.2% and over. The women's probability of stroke within 10 years was less than 3.77% in normal group (less than 50 percentile) and 55.24% and over in very risky group. This study developed the stroke risk prediction model and the personalized warning and the lifestyle correction message based on the national health examination data and uploaded them to the personal health record service called My Health Bank in the health information website - Health iN. By doing so, it urged medical users to strengthen the motivation of health management and induced changes in their health behaviors. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Mannitol infusion immediately after reperfusion suppresses the development of focal cortical infarction after temporary cerebral ischemia in gerbils

PubMed Central

Ito, Umeo; Hakamata, Yoji; Watabe, Kazuhiko; Oyanagi, Kiyomitsu

2014-01-01

Previously we found that, after temporary cerebral ischemia, microvasculogenic secondary focal cerebral cortical ischemia occurred, caused by microvascular obstruction due to compression by swollen astrocytic end-feet, resulting in focal infarction. Herein, we examined whether mannitol infusion immediately after restoration of blood flow could protect the cerebral cortex against the development of such an infarction. If so, the infusion of mannitol might improve the results of vascular reperfusion therapy. We selected stroke-positive animals during the first 10 min after left carotid occlusion performed twice with a 5-h interval, and allocated them into four groups: sham-operated control, no-treatment, mannitol-infusion, and saline-infusion groups. Light- and electron-microscopic studies were performed on cerebral cortices of coronal sections prepared at the chiasmatic level, where the focal infarction develops abruptly in the area where disseminated selective neuronal necrosis is maturing. Measurements were performed to determine the following: (A) infarct size in HE-stained specimens from all groups at 72 and 120 h after return of blood flow; (B) number of carbon-black-suspension-perfused microvessels in the control and at 0.5, 3, 5, 8, 12 and 24 h in the no-treatment and mannitol-infusion groups; (C) area of astrocytic end-feet; and (D) number of mitochondria in the astrocytic end-feet in electron microscopic pictures taken at 5 h. The average decimal fraction area ratio of infarct size in the mannitol group was significantly reduced at 72 and 120 h, associated with an increased decimal fraction number ratio of carbon-black-suspension-perfused microvessels at 3, 5 and 8 h, and a marked reduction in the size of the end-feet at 5 h. Mannitol infusion performed immediately after restitution of blood flow following temporary cerebral ischemia remarkably reduced the size of the cerebral cortical focal infarction by decreasing the swelling of the end-feet, thus preventing the microvascular compression and stasis and thereby microvasculogenic secondary focal cerebral ischemia. PMID:24661099

Stroke due to mitochondrial disorders in Saudi children.

PubMed

Salih, Mustafa A; Abdel-Gader, Abdel-Galil M; Zahraa, Jihad N; Al-Rayess, Molham M; Alorainy, Ibrahim A; Hassan, Hamdy H; Ruitenbeek, Wim; Zeviani, Massimo

2006-03-01

To report on the clinical and biochemical features of patients who presented with stroke due to mitochondrial disorders amongst a prospective and retrospective cohort of Saudi children. Children, who presented with stroke, were evaluated at the Division of Pediatric Neurology, or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia, during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Open muscle biopsies were obtained from patients suspected to have mitochondrial disorders, and examined using conventional histological and histochemical techniques. Biochemical, molecular pathological investigations, or both, of muscle could be arranged for only some of the patients. Mitochondrial disorders were the underlying risk factor for stroke in 4 (3.8%) of 104 children (aged one month to 12 years). Three patients (one male and 2 females) had Leigh syndrome (LS) and one had mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). At the time of stroke, the 3 children with LS were 11 months, 15 months, and 7 years old. They presented with psychomotor regression and seizures. Muscle histology and histochemistry showed mild non-specific changes but no ragged red fibers. Biochemical analysis of muscle (in one patient) revealed deficiency of pyruvate dehydrogenase complex. Analysis of mitochondrial DNA (mtDNA), [the other 2 patients] was negative for the 2 point mutations (T-G and T-C) at nucleotide position 8993, and for two T-C point mutations (at positions 8851 and 9176 of the ATPase 6 gene) that have been described in patients with LS. The girl with MELAS syndrome presented with a stroke-like episode at the age of 29 months and had focal brain lesions in the medial aspect of the left occipital and temporal lobes, and in the posteromedial aspect of the left thalamus, which resolved within 7 weeks. She had raised cerebrospinal fluid lactate but no ragged red fibers on muscle histochemistry. Biochemical assay of muscle homogenate showed reduction in respiratory chain complexes I, III and IV. Mutation screening of mtDNA at nucleotides 3243 (tRNA(Leu(UUR))) and 8344 (tRNA(Lys)) was negative. Mitochondrial disorders constitute a risk factor for stroke in Saudi children. However, demanding and highly specialized investigations are needed to confirm the diagnosis. These are better performed at supraregional centers where facilities for clinical, biochemical and molecular work-up are available.

Incorporating Stroke Severity Into Hospital Measures of 30-Day Mortality After Ischemic Stroke Hospitalization.

PubMed

Schwartz, Jennifer; Wang, Yongfei; Qin, Li; Schwamm, Lee H; Fonarow, Gregg C; Cormier, Nicole; Dorsey, Karen; McNamara, Robert L; Suter, Lisa G; Krumholz, Harlan M; Bernheim, Susannah M

2017-11-01

The Centers for Medicare & Medicaid Services publicly reports a hospital-level stroke mortality measure that lacks stroke severity risk adjustment. Our objective was to describe novel measures of stroke mortality suitable for public reporting that incorporate stroke severity into risk adjustment. We linked data from the American Heart Association/American Stroke Association Get With The Guidelines-Stroke registry with Medicare fee-for-service claims data to develop the measures. We used logistic regression for variable selection in risk model development. We developed 3 risk-standardized mortality models for patients with acute ischemic stroke, all of which include the National Institutes of Health Stroke Scale score: one that includes other risk variables derived only from claims data (claims model); one that includes other risk variables derived from claims and clinical variables that could be obtained from electronic health record data (hybrid model); and one that includes other risk variables that could be derived only from electronic health record data (electronic health record model). The cohort used to develop and validate the risk models consisted of 188 975 hospital admissions at 1511 hospitals. The claims, hybrid, and electronic health record risk models included 20, 21, and 9 risk-adjustment variables, respectively; the C statistics were 0.81, 0.82, and 0.79, respectively (as compared with the current publicly reported model C statistic of 0.75); the risk-standardized mortality rates ranged from 10.7% to 19.0%, 10.7% to 19.1%, and 10.8% to 20.3%, respectively; the median risk-standardized mortality rate was 14.5% for all measures; and the odds of mortality for a high-mortality hospital (+1 SD) were 1.51, 1.52, and 1.52 times those for a low-mortality hospital (-1 SD), respectively. We developed 3 quality measures that demonstrate better discrimination than the Centers for Medicare & Medicaid Services' existing stroke mortality measure, adjust for stroke severity, and could be implemented in a variety of settings. © 2017 American Heart Association, Inc.

External Validation of a Case-Mix Adjustment Model for the Standardized Reporting of 30-Day Stroke Mortality Rates in China

PubMed Central

Yu, Ping; Pan, Yuesong; Wang, Yongjun; Wang, Xianwei; Liu, Liping; Ji, Ruijun; Meng, Xia; Jing, Jing; Tong, Xu; Guo, Li; Wang, Yilong

2016-01-01

Background and Purpose A case-mix adjustment model has been developed and externally validated, demonstrating promise. However, the model has not been thoroughly tested among populations in China. In our study, we evaluated the performance of the model in Chinese patients with acute stroke. Methods The case-mix adjustment model A includes items on age, presence of atrial fibrillation on admission, National Institutes of Health Stroke Severity Scale (NIHSS) score on admission, and stroke type. Model B is similar to Model A but includes only the consciousness component of the NIHSS score. Both model A and B were evaluated to predict 30-day mortality rates in 13,948 patients with acute stroke from the China National Stroke Registry. The discrimination of the models was quantified by c-statistic. Calibration was assessed using Pearson’s correlation coefficient. Results The c-statistic of model A in our external validation cohort was 0.80 (95% confidence interval, 0.79–0.82), and the c-statistic of model B was 0.82 (95% confidence interval, 0.81–0.84). Excellent calibration was reported in the two models with Pearson’s correlation coefficient (0.892 for model A, p<0.001; 0.927 for model B, p = 0.008). Conclusions The case-mix adjustment model could be used to effectively predict 30-day mortality rates in Chinese patients with acute stroke. PMID:27846282

WE-EF-207-03: Design and Optimization of a CBCT Head Scanner for Detection of Acute Intracranial Hemorrhage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, J; Sisniega, A; Zbijewski, W

Purpose: To design a dedicated x-ray cone-beam CT (CBCT) system suitable to deployment at the point-of-care and offering reliable detection of acute intracranial hemorrhage (ICH), traumatic brain injury (TBI), stroke, and other head and neck injuries. Methods: A comprehensive task-based image quality model was developed to guide system design and optimization of a prototype head scanner suitable to imaging of acute TBI and ICH. Previously reported models were expanded to include the effects of x-ray scatter correction necessary for detection of low contrast ICH and the contribution of bit depth (digitization noise) to imaging performance. Task-based detectablity index provided themore » objective function for optimization of system geometry, x-ray source, detector type, anti-scatter grid, and technique at 10–25 mGy dose. Optimal characteristics were experimentally validated using a custom head phantom with 50 HU contrast ICH inserts imaged on a CBCT imaging bench allowing variation of system geometry, focal spot size, detector, grid selection, and x-ray technique. Results: The model guided selection of system geometry with a nominal source-detector distance 1100 mm and optimal magnification of 1.50. Focal spot size ∼0.6 mm was sufficient for spatial resolution requirements in ICH detection. Imaging at 90 kVp yielded the best tradeoff between noise and contrast. The model provided quantitation of tradeoffs between flat-panel and CMOS detectors with respect to electronic noise, field of view, and readout speed required for imaging of ICH. An anti-scatter grid was shown to provide modest benefit in conjunction with post-acquisition scatter correction. Images of the head phantom demonstrate visualization of millimeter-scale simulated ICH. Conclusions: Performance consistent with acute TBI and ICH detection is feasible with model-based system design and robust artifact correction in a dedicated head CBCT system. Further improvements can be achieved with incorporation of model-based iterative reconstruction techniques also within the scope of the task-based optimization framework. David Foos and Xiaohui Wang are employees of Carestream Health.« less

Network dysfunction predicts speech production after left hemisphere stroke.

PubMed

Geranmayeh, Fatemeh; Leech, Robert; Wise, Richard J S

2016-03-09

To investigate the role of multiple distributed brain networks, including the default mode, fronto-temporo-parietal, and cingulo-opercular networks, which mediate domain-general and task-specific processes during speech production after aphasic stroke. We conducted an observational functional MRI study to investigate the effects of a previous left hemisphere stroke on functional connectivity within and between distributed networks as patients described pictures. Study design included various baseline tasks, and we compared results to those of age-matched healthy participants performing the same tasks. We used independent component and psychophysiological interaction analyses. Although activity within individual networks was not predictive of speech production, relative activity between networks was a predictor of both within-scanner and out-of-scanner language performance, over and above that predicted from lesion volume, age, sex, and years of education. Specifically, robust functional imaging predictors were the differential activity between the default mode network and both the left and right fronto-temporo-parietal networks, respectively activated and deactivated during speech. We also observed altered between-network functional connectivity of these networks in patients during speech production. Speech production is dependent on complex interactions among widely distributed brain networks, indicating that residual speech production after stroke depends on more than the restoration of local domain-specific functions. Our understanding of the recovery of function following focal lesions is not adequately captured by consideration of ipsilesional or contralesional brain regions taking over lost domain-specific functions, but is perhaps best considered as the interaction between what remains of domain-specific networks and domain-general systems that regulate behavior. © 2016 American Academy of Neurology.

Perfusion status of the stroke-like lesion at the hyperacute stage in MELAS.

PubMed

Yeh, Hsu-Ling; Chen, Yen-Kung; Chen, Wei-Hung; Wang, Han-Cheng; Chiu, Hou-Chang; Lien, Li-Ming; Wei, Yau-Huei

2013-02-01

Hypoperfusion on single-photon emission computed tomography (SPECT) of the stroke-like lesion (SLL) at the hyperacute stage of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is considered to be a supportive evidence of the mitochondrial angiopathy theory. Our objectives were to examine whether other neuroimages, especially transcranial color-coded sonography (TCCS), done at the hyperacute stage of stroke-like episode (SLE) is consistent with hypoperfusion of the SLL. We reviewed the magnetic resonance imaging (MRI), SPECT, cerebral angiography, and TCCS of a patient with MELAS syndrome, all of which were performed at the hyperacute stage of one SLE. MRI on the 1st day post SLE showed right temporoparietal lesion with vasogenic edema. SPECT on the 2nd day showed focal decreased uptake of technetium-99m hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) in the same region, but cerebral angiography and TCCS on the 3rd day showed increased regional cerebral blood flow (rCBF) and distal arteriole dilation in the same region. TCCS can delineate increased rCBF of the SLL at the hyperacute stage of SLE. We propose that the discrepancy between the decreased (99m)Tc-HMPAO uptake and increased rCBF might be caused by mitochondrial dysfunction. The phenomenon of "hypoperfusion" on SPECT might be caused by cell dysfunction but not decreased rCBF. We suggest that SPECT can be complemented by angiography and TCCS in future studies to delineate the perfusion status of SLLs. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

[Medical care of patients with spasticity following stroke : Evaluation of the treatment situation in Germany with focus on the use of botulinum toxin].

PubMed

Kerkemeyer, L; Lux, G; Walendzik, A; Wasem, J; Neumann, A

2017-08-01

Upper limb spasticity is a common complication following stroke. Cohort studies found 19% of post-stroke patients had upper limb spasticity at 3 months and 38% of patients at 12 months. For focal spasticity, intramuscular injections of botulinum toxin are indicated. In Germany, it is assumed that patients with the described indication are undersupplied with botulinum toxin. The aim of the present study is to evaluate the medical care of patients with upper limb spasticity post-stroke with the focus on the use of botulinum toxin as one treatment option. A standardized questionnaire was developed and a postal survey of a representative national random sample of 800 neurologists to capture the actual medical care situation. The response rate amounted to 37% (n = 292). 59% of the neurologists surveyed had never used botulinum toxin. In total, 87% of neurologists noticed barriers regarding the use of botulinum toxin, where the amount of the doctor's remuneration in 40% and the lack of reimbursement of costs in off-label use in 60% were the most commonly used answers. The achievement of an advanced training in using botulinum toxin was also stated as a general obstacle for resident neurologists. Due to a response rate of 37% for the postal survey a selection bias cannot be excluded. Although botulinum toxin is recommended in the national treatment guidelines, many neurologists do not use botulinum toxin. The reasons can be seen from the barriers described.

Network dysfunction predicts speech production after left hemisphere stroke

PubMed Central

Leech, Robert; Wise, Richard J.S.

2016-01-01

Objective: To investigate the role of multiple distributed brain networks, including the default mode, fronto-temporo-parietal, and cingulo-opercular networks, which mediate domain-general and task-specific processes during speech production after aphasic stroke. Methods: We conducted an observational functional MRI study to investigate the effects of a previous left hemisphere stroke on functional connectivity within and between distributed networks as patients described pictures. Study design included various baseline tasks, and we compared results to those of age-matched healthy participants performing the same tasks. We used independent component and psychophysiological interaction analyses. Results: Although activity within individual networks was not predictive of speech production, relative activity between networks was a predictor of both within-scanner and out-of-scanner language performance, over and above that predicted from lesion volume, age, sex, and years of education. Specifically, robust functional imaging predictors were the differential activity between the default mode network and both the left and right fronto-temporo-parietal networks, respectively activated and deactivated during speech. We also observed altered between-network functional connectivity of these networks in patients during speech production. Conclusions: Speech production is dependent on complex interactions among widely distributed brain networks, indicating that residual speech production after stroke depends on more than the restoration of local domain-specific functions. Our understanding of the recovery of function following focal lesions is not adequately captured by consideration of ipsilesional or contralesional brain regions taking over lost domain-specific functions, but is perhaps best considered as the interaction between what remains of domain-specific networks and domain-general systems that regulate behavior. PMID:26962070

Anodal transcranial direct current stimulation to the cerebellum improves handwriting and cyclic drawing kinematics in focal hand dystonia.

PubMed

Bradnam, Lynley V; Graetz, Lynton J; McDonnell, Michelle N; Ridding, Michael C

2015-01-01

There is increasing evidence that the cerebellum has a role in the pathophysiology of primary focal hand dystonia and might provide an intervention target for non-invasive brain stimulation to improve function of the affected hand. The primary objective of this study was to determine if cerebellar transcranial direct current stimulation (tDCS) improves handwriting and cyclic drawing kinematics in people with hand dystonia, by reducing cerebellar-brain inhibition (CBI) evoked by transcranial magnetic stimulation (TMS). Eight people with dystonia (5 writer's dystonia, 3 musician's dystonia) and eight age-matched controls completed the study and underwent cerebellar anodal, cathodal and sham tDCS in separate sessions. Dystonia severity was assessed using the Writer's Cramp Rating Scale (WRCS) and the Arm Dystonia Disability Scale (ADDS). The kinematic measures that differentiated the groups were; mean stroke frequency during handwriting and fast cyclic drawing and average pen pressure during light cyclic drawing. TMS measures of cortical excitability were no different between people with FHD and controls. There was a moderate, negative relationship between TMS-evoked CBI at baseline and the WRCS in dystonia. Anodal cerebellar tDCS reduced handwriting mean stroke frequency and average pen pressure, and increased speed and reduced pen pressure during fast cyclic drawing. Kinematic measures were not associated with a decrease in CBI within an individual. In conclusion, cerebellar anodal tDCS appeared to improve kinematics of handwriting and circle drawing tasks; but the underlying neurophysiological mechanism remains uncertain. A study in a larger homogeneous population is needed to further investigate the possible therapeutic benefit of cerebellar tDCS in dystonia.

Anodal transcranial direct current stimulation to the cerebellum improves handwriting and cyclic drawing kinematics in focal hand dystonia

PubMed Central

Bradnam, Lynley V.; Graetz, Lynton J.; McDonnell, Michelle N.; Ridding, Michael C.

2015-01-01

There is increasing evidence that the cerebellum has a role in the pathophysiology of primary focal hand dystonia and might provide an intervention target for non-invasive brain stimulation to improve function of the affected hand. The primary objective of this study was to determine if cerebellar transcranial direct current stimulation (tDCS) improves handwriting and cyclic drawing kinematics in people with hand dystonia, by reducing cerebellar-brain inhibition (CBI) evoked by transcranial magnetic stimulation (TMS). Eight people with dystonia (5 writer’s dystonia, 3 musician’s dystonia) and eight age-matched controls completed the study and underwent cerebellar anodal, cathodal and sham tDCS in separate sessions. Dystonia severity was assessed using the Writer’s Cramp Rating Scale (WRCS) and the Arm Dystonia Disability Scale (ADDS). The kinematic measures that differentiated the groups were; mean stroke frequency during handwriting and fast cyclic drawing and average pen pressure during light cyclic drawing. TMS measures of cortical excitability were no different between people with FHD and controls. There was a moderate, negative relationship between TMS-evoked CBI at baseline and the WRCS in dystonia. Anodal cerebellar tDCS reduced handwriting mean stroke frequency and average pen pressure, and increased speed and reduced pen pressure during fast cyclic drawing. Kinematic measures were not associated with a decrease in CBI within an individual. In conclusion, cerebellar anodal tDCS appeared to improve kinematics of handwriting and circle drawing tasks; but the underlying neurophysiological mechanism remains uncertain. A study in a larger homogeneous population is needed to further investigate the possible therapeutic benefit of cerebellar tDCS in dystonia. PMID:26042019

Very late ischemic complications in flow-diverter stents: a retrospective analysis of a single-center series.

PubMed

Guédon, Alexis; Clarençon, Frédéric; Di Maria, Federico; Rosso, Charlotte; Biondi, Alessandra; Gabrieli, Joseph; Rojas, Patricia; Chiras, Jacques; Sourour, Nader

2016-10-01

OBJECTIVE The authors evaluate the rate and discuss the pathomechanisms of very late (≥ 4-month) ischemic complications after flow-diverter stent (FDS) placement for intracranial aneurysms. METHODS The authors retrospectively reviewed the clinical data of the patients treated at Pitié-Salpêtrière Hospital between January 2010 and September 2014, who underwent FDS placement for intracranial aneurysm. The patients received dual-antiplatelet therapy (clopidogrel and aspirin) 5 days before and 3-6 months after the procedure and then aspirin alone for 6-9 months. An ischemic complication was defined as a sudden focal neurological deficit documented on diffusion-weighted images. RESULTS Eighty-six consecutive patients were included. Three (3.5%) patients treated with the Pipeline embolization device experienced a delayed acute ischemic stroke (2 cases of perforator/side-wall branch infarction and 1 case of thromboembolic stroke) with an average delay of 384 days (4 months, 20 months, and 13 months, respectively). The aneurysm locations were the left superior cerebellar artery, the right anterior choroid artery, and the left internal carotid artery (paraclinoid segment), respectively. The complications occurred after the patients had completed the antiaggregation protocol, except for Patient 1, who was receiving aspirin alone because of a spontaneous hematoma. At the acute phase, no in-stent thromboses were found on digital subtraction angiography. In Patient 2, the treated anterior choroid artery was occluded 20 months after the procedure. In Patient 3, a focal stenosis (approximately 40%) of the distal aspect of the FDS, probably caused by intimal hyperplasia, was seen. CONCLUSIONS Very late ischemic complications after FDS treatment were observed in 3.5% of the cases in the authors' series, some of which occurred as late as more than 1 year after placement.

The permeability of puerarin loaded poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 on the blood-brain barrier and its protective effect against cerebral ischemia/reperfusion injury.

PubMed

Zhao, Li-xia; Liu, An-chang; Yu, Shu-wen; Wang, Zeng-xin; Lin, Xiao-qian; Zhai, Guang-xi; Zhang, Qing-zhu

2013-01-01

Puerarin (PUE) is a good candidate for treating stroke, but its low concentration in brain after administration limits its curative efficacy. The aim of the present work was to design and characterize PUE loaded poly(butylcyanoacrylate) nanoparticles (PBCN) coated with polysorbate 80 (Ps 80), and to evaluate the effect of PBCN on the permeability of PUE across the blood-brain barrier (BBB) and the effect of PUE loaded PBCN on the cerebral ischemia/reperfusion injury. PUE loaded PBCN were successfully prepared by anionic polymerization method with the mean particle size of 201.2 nm and the zeta potential of -7.72 mV. The in vitro release behavior of PUE from the nanoparticles showed a biphasic profile manner with an initial burst release followed by a sustained release. The results of pharmacokinetic and biodistribution to brain performed in mice after intravenous administration showed that the drug concentrations in blood and brain for PUE loaded PBCN were both greater than these for the free drug. Moreover, compared with free drug, the vein injection of PUE loaded PBCN exerted the better neuroprotective effect in rats with focal cerebral ischemic injury via significantly decreasing neurological deficit scores, increasing body weight, lowing brain water content, and reducing the infarct volume. The results indicated that this preparation may reduce the total dose required for the stroke therapy with concurrent reduction in dose related toxicity. All these findings suggest that PBCN could enhance the transport of PUE to brain and have a potential as a neuroprotective agent in the focal cerebral ischemic injury.

The Influence of Acute Hyperglycemia in an Animal Model of Lacunar Stroke That Is Induced by Artificial Particle Embolization

PubMed Central

Tsai, Ming-Jun; Lin, Ming-Wei; Huang, Yaw-Bin; Kuo, Yu-Min; Tsai, Yi-Hung

2016-01-01

Animal and clinical studies have revealed that hyperglycemia during ischemic stroke increases the stroke's severity and the infarct size in clinical and animal studies. However, no conclusive evidence demonstrates that acute hyperglycemia worsens post-stroke outcomes and increases infarct size in lacunar stroke. In this study, we developed a rat model of lacunar stroke that was induced via the injection of artificial embolic particles during full consciousness. We then used this model to compare the acute influence of hyperglycemia in lacunar stroke and diffuse infarction, by evaluating neurologic behavior and the rate, size, and location of the infarction. The time course of the neurologic deficits was clearly recorded from immediately after induction to 24 h post-stroke in both types of stroke. We found that acute hyperglycemia aggravated the neurologic deficit in diffuse infarction at 24 h after stroke, and also aggravated the cerebral infarct. Furthermore, the infarct volumes of the basal ganglion, thalamus, hippocampus, and cerebellum but not the cortex were positively correlated with serum glucose levels. In contrast, acute hyperglycemia reduced the infarct volume and neurologic symptoms in lacunar stroke within 4 min after stroke induction, and this effect persisted for up to 24 h post-stroke. In conclusion, acute hyperglycemia aggravated the neurologic outcomes in diffuse infarction, although it significantly reduced the size of the cerebral infarct and improved the neurologic deficits in lacunar stroke. PMID:27226775

Development and validation of clinical prediction models for mortality, functional outcome and cognitive impairment after stroke: a study protocol.

PubMed

Fahey, Marion; Rudd, Anthony; Béjot, Yannick; Wolfe, Charles; Douiri, Abdel

2017-08-18

Stroke is a leading cause of adult disability and death worldwide. The neurological impairments associated with stroke prevent patients from performing basic daily activities and have enormous impact on families and caregivers. Practical and accurate tools to assist in predicting outcome after stroke at patient level can provide significant aid for patient management. Furthermore, prediction models of this kind can be useful for clinical research, health economics, policymaking and clinical decision support. 2869 patients with first-ever stroke from South London Stroke Register (SLSR) (1995-2004) will be included in the development cohort. We will use information captured after baseline to construct multilevel models and a Cox proportional hazard model to predict cognitive impairment, functional outcome and mortality up to 5 years after stroke. Repeated random subsampling validation (Monte Carlo cross-validation) will be evaluated in model development. Data from participants recruited to the stroke register (2005-2014) will be used for temporal validation of the models. Data from participants recruited to the Dijon Stroke Register (1985-2015) will be used for external validation. Discrimination, calibration and clinical utility of the models will be presented. Patients, or for patients who cannot consent their relatives, gave written informed consent to participate in stroke-related studies within the SLSR. The SLSR design was approved by the ethics committees of Guy's and St Thomas' NHS Foundation Trust, Kings College Hospital, Queens Square and Westminster Hospitals (London). The Dijon Stroke Registry was approved by the Comité National des Registres and the InVS and has authorisation of the Commission Nationale de l'Informatique et des Libertés. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Electroacupunctre improves motor impairment via inhibition of microglia-mediated neuroinflammation in the sensorimotor cortex after ischemic stroke.

PubMed

Liu, Weilin; Wang, Xian; Yang, Shanli; Huang, Jia; Xue, Xiehua; Zheng, Yi; Shang, Guanhao; Tao, Jing; Chen, Lidian

2016-04-15

Electroacupuncture (EA) is one of the safety and effective therapies for improving neurological and sensorimotor impairment via blockade of inappropriate inflammatory responses. However, the mechanisms of anti-inflammation involved is far from been fully elucidated. Focal cerebral ischemic stroke was administered by the middle cerebral artery occlusion and reperfusion (MCAO/R) surgery. The MCAO/R rats were accepted EA treatment at the LI 11 and ST 36 acupoints for consecutive 3days. The neurological outcome, animal behaviors test and molecular biology assays were used to evaluate the MCAO/R model and therapeutic effect of EA. EA treatment for MCAO rats showed a significant reduction in the infarct volumes accompanied by functional recovery in mNSS outcomes, motor function performances. The possible mechanisms that EA treatment attenuated the over-activation of Iba-1 and ED1 positive microglia in the peri-infract sensorimotor cortex. Simultaneously, both tissue and serum protein levels of the tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were decreased by EA treatment in MCAO/R injured rats. The levels of inflammatory cytokine tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) were decreased in the peri-infract sensorimotor cortex and blood serum of MCAO/R injured rats after EA treatment. Furthermore, we found that EA treatment prevented from the nucleus translocation of NF-κB p65 and suppressed the expression of p38 mitogen-activated protein kinase (p38 MAPK) and myeloid differentiation factor 88 (MyD88) in the peri-infract sensorimotor cortex. The findings from this study indicated that EA improved the motor impairment via inhibition of microglia-mediated neuroinflammation that invoked NF-κB p65, p38 MAPK and MyD88 produced proinflammatory cytokine in the peri-infract sensorimotor cortex of rats following ischemic stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke

PubMed Central

Yang, Fan; Sumbria, Rachita K.; Xue, Dong; Yu, Chuanhui; He, Dan; Liu, Shuo; Paganini-Hill, Annlia; Fisher, Mark J.

2015-01-01

PURPOSE The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis. PMID:25224348

Explaining poorer stroke outcomes in women: women surviving 3 months have more severe strokes than men despite a lower 3-month case fatality.

PubMed

Olsen, Tom Skyhøj; Andersen, Zorana Jovanovic; Andersen, Klaus Kaae

2012-06-01

Women who survive stroke are more disabled and more often institutionalized than men. We explore this phenomenon by studying case fatality and stroke severity in stroke survivors separately for men and women. A Danish stroke registry (2000-2007) contains information about 26,818 patients with first-ever ischemic stroke, including stroke severity (Scandinavian Stroke Scale, 0 worst to 58 best), computed tomography scan, cardiovascular risk factors, and death 3 months after stroke. We modeled stroke severity by generalized additive linear model and 3-month case fatality with logistic model adjusting for age and cardiovascular risk factors. Male to female ratio was 51.5% to 48.5%. Mean age was 68.8 (SD 12.6) years in men; 73.7 (13.8) years in women. Stroke was more severe in women (mean [SD] Scandinavian Stroke Scale, 42.2 [16.0]) than in men (mean [SD] Scandinavian Stroke Scale, 45.6 [14.2]) also after adjustment for age and cardiovascular risk factors; significant in patients older than 75 years. In survivors at 3 months, stroke was more severe in women than men, given same age and cardiovascular risk factor profile; significant in patients older than 75 years. More women (11.9%) had died within 3 months than men (8.6%). However, adjusting for age, stroke severity, and risk factor profile, 3-month case fatality was lower in women than men; significant in patients older than 78 years. Although 3-month case fatality was lower in women than men, strokes were more severe among survivors at 3 months in women than in men. In addition, strokes were more severe in women. Our data help elucidate why women survive stroke better but have poorer functional outcomes that require more care than men. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Derivation and external validation of a case mix model for the standardized reporting of 30-day stroke mortality rates.

PubMed

Bray, Benjamin D; Campbell, James; Cloud, Geoffrey C; Hoffman, Alex; James, Martin; Tyrrell, Pippa J; Wolfe, Charles D A; Rudd, Anthony G

2014-11-01

Case mix adjustment is required to allow valid comparison of outcomes across care providers. However, there is a lack of externally validated models suitable for use in unselected stroke admissions. We therefore aimed to develop and externally validate prediction models to enable comparison of 30-day post-stroke mortality outcomes using routine clinical data. Models were derived (n=9000 patients) and internally validated (n=18 169 patients) using data from the Sentinel Stroke National Audit Program, the national register of acute stroke in England and Wales. External validation (n=1470 patients) was performed in the South London Stroke Register, a population-based longitudinal study. Models were fitted using general estimating equations. Discrimination and calibration were assessed using receiver operating characteristic curve analysis and correlation plots. Two final models were derived. Model A included age (<60, 60-69, 70-79, 80-89, and ≥90 years), National Institutes of Health Stroke Severity Score (NIHSS) on admission, presence of atrial fibrillation on admission, and stroke type (ischemic versus primary intracerebral hemorrhage). Model B was similar but included only the consciousness component of the NIHSS in place of the full NIHSS. Both models showed excellent discrimination and calibration in internal and external validation. The c-statistics in external validation were 0.87 (95% confidence interval, 0.84-0.89) and 0.86 (95% confidence interval, 0.83-0.89) for models A and B, respectively. We have derived and externally validated 2 models to predict mortality in unselected patients with acute stroke using commonly collected clinical variables. In settings where the ability to record the full NIHSS on admission is limited, the level of consciousness component of the NIHSS provides a good approximation of the full NIHSS for mortality prediction. © 2014 American Heart Association, Inc.

Specialized stroke services: a meta-analysis comparing three models of care.

PubMed

Foley, Norine; Salter, Katherine; Teasell, Robert

2007-01-01

Using previously published data, the purpose of this study was to identify and discriminate between three different forms of inpatient stroke care based on timing and duration of treatment and to compare the results of clinically important outcomes. Randomized controlled trials, including a recent review of inpatient stroke unit/rehabilitation care, were identified and grouped into three models of care as follows: (a) acute stroke unit care (patients admitted within 36 h of stroke onset and remaining for up to 2 weeks; n = 5), (b) units combining acute and rehabilitative care (combined; n = 4), and (c) rehabilitation units where patients were transferred onto the service approximately 2 weeks following stroke (post-acute; n = 5). Pooled analyses for the outcomes of mortality, combined death and dependency and length of hospital stay were calculated for each model of care, compared to conventional care. All three models of care were associated with significant reductions in the odds of combined death and dependency; however, acute stroke units were not associated with significant reductions in mortality when this outcome was analyzed separately (OR 0.80; 95% CI: 0.61-1.03). Post-acute stroke units were associated with the greatest reduction in the odds of mortality (OR 0.60; 95% CI: 0.44-0.81). Significant reductions in length of hospital stay were associated with combined stroke units only (weighted mean difference -14 days; 95% CI: -27 to -2). Overall, specialized stroke services were associated with significant reductions in mortality, death and dependency and length of hospital stay although not every model of care was associated with equal benefit.

Overexpression of Thioredoxin in Transgenic Mice Attenuates Focal Ischemic Brain Damage

NASA Astrophysics Data System (ADS)

Takagi, Yasushi; Mitsui, Akira; Nishiyama, Akira; Nozaki, Kazuhiko; Sono, Hiroshi; Gon, Yasuhiro; Hashimoto, Nobuo; Yodoi, Junji

1999-03-01

Thioredoxin (TRX) plays important biological roles both in intra- and extracellular compartments, including in regulation of various intracellular molecules via thiol redox control. We produced TRX overexpressing mice and confirmed that there were no anatomical and physiological differences between wild-type (WT) mice and TRX transgenic (Tg) mice. In the present study we subjected mice to focal brain ischemia to shed light on the role of TRX in brain ischemic injury. At 24 hr after middle cerebral artery occlusion, infarct areas and volume were significantly smaller in Tg mice than in WT mice. Moreover neurological deficit was ameliorated in Tg mice compared with WT mice. Protein carbonyl content, a marker of cellular protein oxidation, in Tg mice showed less increase than did that of WT mice after the ischemic insult. Furthermore, c-fos expression in Tg mice was stronger than in WT mice 1 hr after ischemia. Our results suggest that transgene expression of TRX decreased ischemic neuronal injury and that TRX and the redox state modified by TRX play a crucial role in brain damage during stroke.

Narrative discourse in children with early focal brain injury.

PubMed

Reilly, J S; Bates, E A; Marchman, V A

1998-02-15

Children with early brain damage, unlike adult stroke victims, often go on to develop nearly normal language. However, the route and extent of their linguistic development are still unclear, as is the relationship between lesion site and patterns of delay and recovery. Here we address these questions by examining narratives from children with early brain damage. Thirty children (ages 3:7-10:10) with pre- or perinatal unilateral focal brain damage and their matched controls participated in a storytelling task. Analyses focused on linguistic proficiency and narrative competence. Overall, children with brain damage scored significantly lower than their age-matched controls on both linguistic (morphological and syntactic) indices and those targeting broader narrative qualities. Rather than indicating that children with brain damage fully catch up, these data suggest that deficits in linguistic abilities reassert themselves as children face new linguistic challenges. Interestingly, after age 5, site of lesion does not appear to be a significant factor and the delays we have witnessed do not map onto the lesion profiles observed in adults with analogous brain injuries.

Risk modelling study for carotid endarterectomy.

PubMed

Kuhan, G; Gardiner, E D; Abidia, A F; Chetter, I C; Renwick, P M; Johnson, B F; Wilkinson, A R; McCollum, P T

2001-12-01

The aims of this study were to identify factors that influence the risk of stroke or death following carotid endarterectomy (CEA) and to develop a model to aid in comparative audit of vascular surgeons and units. A series of 839 CEAs performed by four vascular surgeons between 1992 and 1999 was analysed. Multiple logistic regression analysis was used to model the effect of 15 possible risk factors on the 30-day risk of stroke or death. Outcome was compared for four surgeons and two units after adjustment for the significant risk factors. The overall 30-day stroke or death rate was 3.9 per cent (29 of 741). Heart disease, diabetes and stroke were significant risk factors. The 30-day predicted stroke or death rates increased with increasing risk scores. The observed 30-day stroke or death rate was 3.9 per cent for both vascular units and varied from 3.0 to 4.2 per cent for the four vascular surgeons. Differences in the outcomes between the surgeons and vascular units did not reach statistical significance after risk adjustment. Diabetes, heart disease and stroke are significant risk factors for stroke or death following CEA. The risk score model identified patients at higher risk and aided in comparative audit.

Geographic Modeling to Quantify the Impact of Primary and Comprehensive Stroke Center Destination Policies.

PubMed

Mullen, Michael T; Pajerowski, William; Messé, Steven R; Mechem, C Crawford; Jia, Judy; Abboud, Michael; David, Guy; Carr, Brendan G; Band, Roger

2018-04-01

We evaluated the impact of a primary stroke center (PSC) destination policy in a major metropolitan city and used geographic modeling to evaluate expected changes for a comprehensive stroke center policy. We identified suspected stroke emergency medical services encounters from 1/1/2004 to 12/31/2013 in Philadelphia, PA. Transport times were compared before and after initiation of a PSC destination policy on 10/3/2011. Geographic modeling estimated the impact of bypassing the closest hospital for the closest PSC and for the closest comprehensive stroke center. There were 2 326 943 emergency medical services runs during the study period, of which 15 099 had a provider diagnosis of stroke. Bypassing the closest hospital for a PSC was common before the official policy and increased steadily over time. Geographic modeling suggested that bypassing the closest hospital in favor of the closest PSC adds a median of 3.1 minutes to transport time. Bypassing to the closest comprehensive stroke center would add a median of 8.3 minutes. Within a large metropolitan area, the time cost of routing patients preferentially to PSCs and comprehensive stroke centers is low. © 2018 American Heart Association, Inc.

Factors for short-term outcomes in patients with a minor stroke: results from China National Stroke Registry.

PubMed

Wu, Lingyun; Wang, Anxin; Wang, Xianwei; Zhao, Xingquan; Wang, Chunxue; Liu, Liping; Zheng, Huaguang; Wang, Yongjun; Cao, Yibin; Wang, Yilong

2015-12-09

Stroke recurrence and disability in patients with a minor stroke is one of the most depressing medical situations. In this study, we aimed to identify which factors were associated with adverse outcomes of a minor stroke. The China National Stroke Registry (CNSR) is a nationwide prospective registry for patients presented to hospitals with acute cerebrovascular events between September 2007 and August 2008. The 3-month follow-up was completed in 4669 patients with a minor stroke defined as the initial neurological severity lower than 4 in the National Institutes of Health Stroke Scale (NIHSS). Multivariate model was used to determine the association between risk factors and clinical outcomes. Of 4669 patients with a minor stroke during 3-month follow-up, 459 (9.8 %) patients experienced recurrent stroke, 679 (14.5 %) had stroke disability and 168 (3.6 %) died. Multivariate model identified hypertension, diabetes mellitus, atrial fibrillation, coronary heart disease and previous stroke as independent predictors for the recurrent stroke. Age, diabetes mellitus, atrial fibrillation, previous stroke and time from onset to admission < 24 h were independent predictors for stroke disability. The independent predictors for the all-caused death were age, atrial fibrillation, and coronary heart disease. The short-term risk of poor clinical outcome in Chinese patients with a minor stroke was substantial. Therefore, patients with a minor stroke should be given expeditious assessment and urgent aggressive intervention.

Passive movement improves the learning and memory function of rats with cerebral infarction by inhibiting neuron cell apoptosis.

PubMed

Li, Man; Peng, Jun; Wang, Meng-Die; Song, Yan-Ling; Mei, Yuan-Wu; Fang, Yuan

2014-02-01

Passive movement has been found to improve evidently ischemic stroke patients' impaired capacity of learning and memory, but the optimal time window of initiating the therapy and the underlying mechanism are not fully understood. In this study, the effect of passive movement at different time windows on learning and memory of rats with cerebral infarction was detected. The results showed that the expression of caspase-3 and escape latency in the passive movement group were all considerably lower than those in the model group (P < 0.05), while the expression of Bcl-2 mRNA was significantly higher than those in the model group (P < 0.05). Moreover, we found that there were most significant changes of escape latency and expressions of Bcl-2 mRNA and caspase-3 when the therapy started at 24 h after focal cerebral infarction. These results suggest that passive movement is able to contribute to the recovery of learning and memory of rats with cerebral infarction, which is partially mediated by inhibiting neuron cell apoptosis, and the optimal therapeutic time is at 24 h after cerebral infarction.

A modified method for determining the focal ratio degradation and length properties of optical fibres in astronomy

NASA Astrophysics Data System (ADS)

Yan, Yunxiang; Wang, Gang; Sun, Weimin; Luo, A.-Li; Ma, Zhenyu; Li, Jian; Wang, Shuqing

2017-04-01

Focal ratio degradation (FRD) is a major contributor to throughput and light loss in a fibre spectroscopic telescope system. We combine the guided mode theory in geometric optics and a well-known model, the power distribution model (PDM), to predict and explain the FRD dependence properties. We present a robust method by modifying the energy distribution method with f-intercept to control the input condition. This method provides a way to determine the proper position of the fibre end on the focal plane to improve energy utilization and FRD performance, which lifts the relative throughput up to 95 per cent with variation of output focal ratio less than 2 per cent. This method can also help to optimize the arrangement of the position of focal-plane plate to enhance the coupling efficiency in a telescope. To investigate length properties, we modified the PDM by introducing a new parameter, the focal distance f, into the original model to make it available for a multiposition measurement system. The results show that the modified model is robust and feasible for measuring the key parameter d0 to simulate the transmission characteristics. The output focal ratio in the experiment does not follow the prediction trend but shows an interesting phenomenon: the output focal ratio increases first to the peak, then decreases and remains stable finally with increasing fibre length longer than 15 m. This provides a reference for choosing the appropriate length of fibre to improve the FRD performance for the design of the fibre system in a telescope.

A risk score for in-hospital death in patients admitted with ischemic or hemorrhagic stroke.

PubMed

Smith, Eric E; Shobha, Nandavar; Dai, David; Olson, DaiWai M; Reeves, Mathew J; Saver, Jeffrey L; Hernandez, Adrian F; Peterson, Eric D; Fonarow, Gregg C; Schwamm, Lee H

2013-01-28

We aimed to derive and validate a single risk score for predicting death from ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Data from 333 865 stroke patients (IS, 82.4%; ICH, 11.2%; SAH, 2.6%; uncertain type, 3.8%) in the Get With The Guidelines-Stroke database were used. In-hospital mortality varied greatly according to stroke type (IS, 5.5%; ICH, 27.2%; SAH, 25.1%; unknown type, 6.0%; P<0.001). The patients were randomly divided into derivation (60%) and validation (40%) samples. Logistic regression was used to determine the independent predictors of mortality and to assign point scores for a prediction model in the overall population and in the subset with the National Institutes of Health Stroke Scale (NIHSS) recorded (37.1%). The c statistic, a measure of how well the models discriminate the risk of death, was 0.78 in the overall validation sample and 0.86 in the model including NIHSS. The model with NIHSS performed nearly as well in each stroke type as in the overall model including all types (c statistics for IS alone, 0.85; for ICH alone, 0.83; for SAH alone, 0.83; uncertain type alone, 0.86). The calibration of the model was excellent, as demonstrated by plots of observed versus predicted mortality. A single prediction score for all stroke types can be used to predict risk of in-hospital death following stroke admission. Incorporation of NIHSS information substantially improves this predictive accuracy.

Reversible Cerebral Vasoconstriction Syndrome Without Typical Thunderclap Headache.

PubMed

Wolff, Valérie; Ducros, Anne

2016-04-01

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headache and diffuse segmental intracranial arterial constriction that resolve within three months. Stroke, which is the major complication of RCVS, can result in persistent neurological disability, and rarely causes death. Diagnosis of RCVS early in the clinical course might improve outcomes. Although recurrent thunderclap headache is the clinical hallmark of RCVS, the absence of such a pattern should not lead to discard the diagnosis. Our literature review shows that RCVS can also manifest as an unspecific headache, such as a single severe headache episode, a mild or a progressive headache. Moreover, a subset of patients with severe RCVS presents without any headache, but frequently with seizures, focal neurological deficits, confusion or coma, in the setting of stroke or posterior reversible encephalopathy syndrome. These patients may be aphasic or in comatose state, explaining their inability to give their own medical history. They may have forgotten the headache they had a few days before more dramatic symptoms, or may have a variant of the classical RCVS. By consequence, an RCVS should be suspected in patients with any unusual headache, whether thunderclap or not, and in patients with cryptogenic stroke or convexity subarachnoid hemorrhage, whether the patient also has headache or not. Diagnosis in such cases relies on the demonstration of reversible multifocal intracranial arterial stenosis and the exclusion of other causes. © 2016 American Headache Society.

Stroke-like episodes, peri-episodic seizures, and MELAS mutations.

PubMed

Finsterer, Josef; Wakil, Salma Majid

2016-11-01

Stroke-like episodes (SLEs) are a hallmark of various mitochondrial disorders, in particular MELAS syndrome. SLEs manifest with vasogenic oedema (DWI and ADC hyperintensity) or partial cytotoxic oedema (DWI hyperintensity, ADC hypointensity) in the acute and subacute stage, and with gyriform T1-hyperintensity (cortical necrosis) in the chronic stage. SLEs must be clearly distinguished from ischaemic stroke, since management of these two entities is different. SLEs may go along with or without seizures or epileptiform discharges on EEG. However, in MELAS syndrome seizures may also occur in the absence of SLEs. Focal and generalised seizures have been reported but it is currently unknown if the one or the other prevail. SLEs with and without seizures may respond to NO-precursors l-arginine, succinate, or citrulline. As a supportive measure a ketogenic diet should be initiated. Seizures prior to or during a SLE or paroxysmal EEG-activity during a SLE should be initially treated with antiepileptic drugs (AEDs) with low mitochondrion-toxicity. Only in case these AEDs are ineffective, AEDs with higher mitochondrion-toxicity should be added. All patients with SLEs need to have an EEG recorded irrespective if they have manifesting seizures or not. There are no mtDNA or nDNA mutations which predispose for SLEs with seizures. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

A novel approach for mechanical tissue characterization indicates decreased elastic strength in brain areas affected by experimental thromboembolic stroke.

PubMed

Michalski, Dominik; Härtig, Wolfgang; Krueger, Martin; Hobohm, Carsten; Käs, Josef A; Fuhs, Thomas

2015-07-08

As treatment of ischemic stroke remains a challenge with respect to the failure of numerous neuroprotective attempts, there is an ongoing need for better understanding of pathophysiological mechanisms causing tissue damage. Although ischemic outcomes have been studied extensively at the cellular and molecular level using histological and biochemical methods, properties of ischemia-affected brain tissue with respect to mechanical integrity have not been addressed so far. As a novel approach, this study used fluorescence-based detection of regions affected by experimental thromboembolic stroke in combination with scanning force microscopy to examine mechanical alterations in selected rat brain areas. Twenty-five hours after onset of ischemia, a decreased elastic strength in the striatum as the region primarily affected by ischemia was found compared with the contralateral nonaffected hemisphere. Additional intrahemispheric analyses showed decreased elastic strength in the ischemic border zone compared with the more severely affected striatum. In conclusion, these data strongly indicate a critical alteration in mechanical tissue integrity caused by focal cerebral ischemia. Further, on the basis of data that have been obtained in relation to the ischemic border zone, a shell-like pattern of mechanical tissue damage was found in good accordance with the penumbra concept. These findings might enable the development of specific therapeutic interventions to protect affected areas from critical loss of mechanical integrity.

Visual extinction in relation to visuospatial neglect after right-hemispheric stroke: quantitative assessment and statistical lesion-symptom mapping.

PubMed

Vossel, S; Eschenbeck, P; Weiss, P H; Weidner, R; Saliger, J; Karbe, H; Fink, G R

2011-08-01

Visual neglect and extinction are two common neurological syndromes in patients with right-hemispheric brain damage. Whether and how these two syndromes are associated or share common neural substrates is still a matter of debate. To address these issues, the authors investigated 56 patients with right-hemispheric stroke with a novel diagnostic test to detect extinction and neglect. In this computerised task, subjects had to respond to target stimuli in uni- and bilateral stimulation conditions with detection probabilities being assessed. A cluster-analytical approach identified 18 patients with neglect and 13 patients with extinction. Statistical lesion-symptom mapping analyses with measures for extinction and neglect were performed. Extinction and neglect co-occurred in a subset of patients but were also observed independently from each other, thereby constituting a double dissociation. Lesions within the right inferior parietal cortex were significantly associated with the severity of visual extinction. Visuospatial neglect was related to damage of fronto-parietal brain regions, with parieto-occipital areas affecting line bisection and dorsal fronto-parietal areas affecting cancellation task performance, respectively. Quantifying lesion-induced symptoms with this novel paradigm shows that extinction and neglect are dissociable syndromes in patients with right-hemispheric stroke. Furthermore, extinction and neglect can be related to differential neural substrates, with extinction being related to focal brain damage within the right inferior parietal cortex.

Genetic Variant of Kalirin Gene Is Associated with Ischemic Stroke in a Chinese Han Population.

PubMed

Li, Hong; Yu, Shasha; Wang, Rui; Sun, Zhaoqing; Zhou, Xinghu; Zheng, Liqiang; Yin, Zhihua; Zhang, Xingang; Sun, Yingxian

2017-01-01

Ischemic stroke is a complex disorder resulting from the interplay of genetic and environmental factors. Previous studies showed that kalirin gene variations were associated with cardiovascular disease. However, the association between this gene and ischemic stroke was unknown. We performed this study to confirm if kalirin gene variation was associated with ischemic stroke. We enrolled 385 ischemic stroke patients and 362 controls from China. Three SNPs of kalirin gene were genotyped by means of ligase detection reaction-PCR method. Data was processed with SPSS and SHEsis platform. SNP rs7620580 (dominant model: OR = 1.590, p = 0.002 and adjusted OR = 1.662, p = 0.014; additive model: OR = 1.490, p = 0.002 and adjusted OR = 1.636, p = 0.005; recessive model: OR = 2.686, p = 0.039) and SNP rs1708303 (dominant model: OR = 1.523, p = 0.007 and adjusted OR = 1.604, p = 0.028; additive model: OR = 1.438, p = 0.01 and adjusted OR = 1.476, p = 0.039) were associated with ischemic stroke. The GG genotype and G allele of SNP rs7620580 were associated with a risk for ischemic stroke with an adjusted OR of 3.195 and an OR of 1.446, respectively. Haplotype analysis revealed that A-T-G,G-T-A, and A-T-A haplotypes were associated with ischemic stroke. Our results provide evidence that kalirin gene variations were associated with ischemic stroke in the Chinese Han population.

Arterial Cannulation and Cerebral Perfusion Strategies for Aortic Arch Operations.

PubMed

Foley, Lisa S; Yamanaka, Katsuhiro; Reece, T Brett

2016-12-01

Neurologic injuries following aortic arch operations can be devastating, with stroke occurring in up to 12% of elective operations and significant cerebral dysfunction occurring in up to 25% of cases. The primary challenge unique to aortic arch operations involves interruption of direct perfusion of the brachiocephalic vessels during arch reconstruction. For this reason, neuroprotection is paramount. The 2 main modes of protection are (1) reducing metabolic demand through hypothermia and (2) limiting, or even eliminating, the ischemic period. Preoperative selection of the cerebral perfusion plan for each operation is imperative to maintain maximal diffuse cerebral protection and prevent focal neurologic events. © The Author(s) 2016.

Neurotoxicity Associated With Dimethyl Sulfoxide Used in Allogeneic Stem Cell Transplantation.

PubMed

Ataseven, Eda; Tüfekçi, Özlem; Yilmaz, Şebnem; Güleryüz, Handan; Ören, Hale

2017-07-01

Dimethyl sulfoxide (DMSO) is a cryoprotective agent used in storage of frozen stem cells in stem cell transplantation. Central nervous system side effects of DMSO such as epileptic seizures, stroke, transient global amnesia, and temporary leucoencephalopathy are rarely seen. Here, we report a pediatric patient who developed seizures after DMSO-cryopreserved stem cell infusion and whose magnetic resonance imaging of the brain demonstrated parietal and occipital focal cortical T2-signal intensity increase. DMSO toxicity should be kept in mind in patients who received cryopreserved stem cell infusion and magnetic resonance imaging may be helpful in differential diagnosis of central nervous system involvement.

Enhancing the Alignment of the Preclinical and Clinical Stroke Recovery Research Pipeline: Consensus-Based Core Recommendations From the Stroke Recovery and Rehabilitation Roundtable Translational Working Group.

PubMed

Corbett, Dale; Carmichael, S Thomas; Murphy, Timothy H; Jones, Theresa A; Schwab, Martin E; Jolkkonen, Jukka; Clarkson, Andrew N; Dancause, Numa; Weiloch, Tadeusz; Johansen-Berg, Heidi; Nilsson, Michael; McCullough, Louise D; Joy, Mary T

2017-08-01

Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

Association of RTEL1 gene polymorphisms with stroke risk in a Chinese Han population.

PubMed

Cai, Yi; Zeng, Chaosheng; Su, Qingjie; Zhou, Jingxia; Li, Pengxiang; Dai, Mingming; Wang, Desheng; Long, Faqing

2017-12-29

We investigated the associations between single nucleotide polymorphisms (SNPs) in the regulator of telomere elongation helicase 1 ( RTEL1 ) gene and stroke in the Chinese population. A total of 400 stroke patients and 395 healthy participants were included in this study. Five SNPs in RTEL1 were genotyped and the association with stroke risk was analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used to identify SNPs that correlated with stroke. Rs2297441 was associated with an increased risk of stroke in an allele model (odds ratio [OR] = 1.24, 95% confidence interval [95% CI] = 1.01-1.52, p = 0.043). Rs6089953 was associated with an increased risk of stroke under the genotype model ([OR] = 1.862, [CI] = 1.123-3.085, p = 0.016). Rs2297441 was associated with an increased risk of stroke in an additive model (OR = 1.234, 95% CI = 1.005, p = 0.045, Rs6089953, Rs6010620 and Rs6010621 were associated with an increased risk of stroke in the recessive model (Rs6089953:OR = 1.825, 95% CI = 1.121-2.969, p =0.01546; Rs6010620: OR = 1.64, 95% CI = 1.008-2.669, p =0.04656;Rs6010621:OR = 1.661, 95% CI = 1.014-2.722, p =0.04389). Our findings reveal a possible association between SNPs in the RTEL1 gene and stroke risk in Chinese population.

Stroke trends in an aging population. The Technology Assessment Methods Project Team.

PubMed

Niessen, L W; Barendregt, J J; Bonneux, L; Koudstaal, P J

1993-07-01

Trends in stroke incidence and survival determine changes in stroke morbidity and mortality. This study examines the extent of the incidence decline and survival improvement in the Netherlands from 1979 to 1989. In addition, it projects future changes in stroke morbidity during the period 1985 to 2005, when the country's population will be aging. A state-event transition model is used, which combines Dutch population projections and existing data on stroke epidemiology. Based on the clinical course of stroke, the model describes historical national age- and sex-specific hospital admission and mortality rates for stroke. It extrapolates observed trends and projects future changes in stroke morbidity rates. There is evidence of a continuing incidence decline. The most plausible rate of change is an annual decline of -1.9% (range, -1.7% to -2.1%) for men and -2.4% (range, -2.3% to -2.8%) for women. Projecting a constant mortality decline, the model shows a 35% decrease of the stroke incidence rate for a period of 20 years. Prevalence rates for major stroke will decline among the younger age groups but increase among the oldest because of increased survival in the latter. In absolute numbers this results in an 18% decrease of acute stroke episodes and an 11% increase of major stroke cases. The increase in survival cannot fully explain the observed mortality decline and, therefore, a concomitant incidence decline has to be assumed. Aging of the population partially outweighs the effect of an incidence decline on the total burden of stroke. Increase in cardiovascular survival leads to a further increase in major stroke prevalence among the oldest age groups.

Quality of life after lacunar stroke: the Secondary Prevention of Small Subcortical Strokes study.

PubMed

Dhamoon, Mandip S; McClure, Leslie A; White, Carole L; Lau, Helena; Benavente, Oscar; Elkind, Mitchell S V

2014-01-01

We sought to describe the course and predictors of quality of life (QOL) after lacunar stroke. We hypothesized that there is a decline in QOL after recovery from lacunar stroke. The Secondary Prevention of Small Subcortical Strokes is a clinical trial in lacunar stroke patients with annual assessments of QOL with the stroke-specific QOL score. The overall score was used and analyzed as a continuous variable (range 0-5). We fit linear mixed models to assess the trend in QOL over time, assuming linearity of time, and adjusted for demographics, medical risk factors, cognitive factors, and functional status in univariable and multivariable models. Among 2870 participants, mean age was 63.4 years (SD 10.7), 63% were men, 51% White, 32% Hispanic, 36% had college education, 36% had diabetes, 89% had hypertension, and 10% had prior stroke. Mean poststroke Barthel Index (BI) score was 95.4 (assessed on average 6 months after stroke). In the final multivariable model, there was an average increase in QOL of .6% per year, and factors associated with decline in QOL over time included age (-.0003 per year, P < .0001), any college education (-.0013 per year, .01), prior stroke (-.004 per year, P < .0001), and BI (-.0002 per year, P < .0001). In this clinical trial of lacunar stroke patients, there was a slight annual increase in QOL overall, and age, level of education, and prior stroke were associated with changes in QOL over time. Multiple strokes may cause decline in QOL over time in the absence of recurrent events. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Increased calcineurin expression after pilocarpine-induced status epilepticus is associated with brain focal edema and astrogliosis.

PubMed

Liu, Jinzhi; Li, Xiaolin; Chen, Liguang; Xue, Ping; Yang, Qianqian; Wang, Aihua

2015-07-28

Calcineurin plays an important role in the development of neuronal excitability, modulation of receptor's function and induction of apoptosis in neurons. It has been established in kindling models that status epilepticus induces brain focal edema and astrocyte activation. However, the role of calcineurin in brain focal edema and astrocyte activation in status epilepticus has not been fully understood. In this study, we employed a model of lithium-pilocarpine-induced status epilepticus and detected calcineurin expression in hippocampus by immunoblotting, brain focal edema by non-invasive magnetic resonance imaging (MRI-7T) and astrocyte expression by immunohistochemistry. We found that the brain focal edema was seen at 24 h after status epilepticus, and astrocyte expression was obviously seen at 7 d after status epilepticus. Meanwhile, calcineurin expression was seen at24 h and retained to 7 d after status epilepticus. A FK506, a calcineurin inhibitor, remarkably suppressed the status epilepticus-induced brain focal edema and astrocyte expression. Our data suggested that calcineurin overexpression plays a very important role in brain focal edema and astrocyte expression. Therefore, calcineurin may be a novel candidate for brain focal edema occurring and intracellular trigger of astrogliosis in status epilepticus.

Arctigenin protects focal cerebral ischemia-reperfusion rats through inhibiting neuroinflammation.

PubMed

Fan, Tao; Jiang, Wei Long; Zhu, Jian; Feng Zhang, Yu

2012-01-01

Stroke is the third leading cause of death in industrialized countries and the most important cause of acquired adult disability. Many evidences suggest that inflammation accounts for the progression of cerebral ischemic injury. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignin isolated from certain plants, has shown anti-inflammatory activity against diabetes and Alzheimer's disease. In this study, we tested whether arctigenin can protect middle cerebral artery occluded (MCAO) rats. Male Sprague-Dawley rats were pretreated with arctigenin or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Rats were evaluated at 24 h after MCAO for neurological deficit scoring. Furthermore, the mechanism of the anti-inflammatory effect of arctigenin was investigated with a focus on inflammatory cells, proinflammatory cytokines, and transcriptional factors. Arctigenin significantly reduced cerebral infarction and improved neurological outcome. Arctigenin suppressed the activation of microglia and decreased the expression of interleukin (IL)- 1β and tumor necrosis factor (TNF)-α. These results revealed that arctigenin has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.

ICARUSS, the Integrated Care for the Reduction of Secondary Stroke trial: rationale and design of a randomized controlled trial of a multimodal intervention to prevent recurrent stroke in patients with a recent cerebrovascular event, ACTRN = 12611000264987.

PubMed

Joubert, J; Davis, S M; Hankey, G J; Levi, C; Olver, J; Gonzales, G; Donnan, G A

2015-07-01

The majority of strokes, both ischaemic and haemorrhagic, are attributable to a relatively small number of risk factors which are readily manageable in primary care setting. Implementation of best-practice recommendations for risk factor management is calculated to reduce stroke recurrence by around 80%. However, risk factor management in stroke survivors has generally been poor at primary care level. A model of care that supports long-term effective risk factor management is needed. To determine whether the model of Integrated Care for the Reduction of Recurrent Stroke (ICARUSS) will, through promotion of implementation of best-practice recommendations for risk factor management reduce the combined incidence of stroke, myocardial infarction and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. A prospective, Australian, multicentre, randomized controlled trial. Academic stroke units in Melbourne, Perth and the John Hunter Hospital, New South Wales. 1000 stroke survivors recruited as from March 2007 with a recent (<3 months) stroke (ischaemic or haemorrhagic) or a TIA (brain or eye). Randomization and data collection are performed by means of a central computer generated telephone system (IVRS). Exposure to the ICARUSS model of integrated care or usual care. The composite of stroke, MI or death from any vascular cause, whichever occurs first. Risk factor management in the community, depression, quality of life, disability and dementia. With 1000 patients followed up for a median of one-year, with a recurrence rate of 7-10% per year in patients exposed to usual care, the study will have at least 80% power to detect a significant reduction in primary end-points The ICARUSS study aims to recruit and follow up patients between 2007 and 2013 and demonstrate the effectiveness of exposure to the ICARUSS model in stroke survivors to reduce recurrent stroke or vascular events and promote the implementation of best practice risk factor management at primary care level. © 2015 World Stroke Organization.

Greater stroke severity predominates over all other factors for the worse outcome of cardioembolic stroke.

PubMed

Hong, Keun-Sik; Lee, Juneyoung; Bae, Hee-Joon; Lee, Ji Sung; Kang, Dong-Wha; Yu, Kyung-Ho; Han, Moon-Ku; Cho, Yong-Jin; Song, Pamela; Park, Jong-Moo; Oh, Mi-Sun; Koo, Jaseong; Lee, Byung-Chul

2013-11-01

Cardioembolic (CE) strokes are more disabling and more fatal than non-CE strokes. Multiple prognostic factors have been recognized, but the magnitude of their relative contributions has not been well explored. Using a prospective stroke outcome database, we compared the 3-month outcomes of CE and non-CE strokes. We assessed the relative contribution of each prognostic factor of initial stroke severity, poststroke complications, and baseline characteristics with multivariable analyses and model fitness improvement using -2 log-likelihood and Nagelkerke R2. This study included 1233 patients with acute ischemic stroke: 193 CE strokes and 1040 non-CE strokes. Compared with the non-CE group, CE group had less modified Rankin Scale (mRS) 0-2 outcomes (47.2% versus 68.5%; odds ratio [95% confidence interval], .41 [.30-.56]), less mRS 0-1 outcomes (33.7% versus 53.5%; .44 [.32-.61]), more mRS 5-6 outcomes (32.1% versus 10.9%; 3.88 [2.71-5.56]), and higher mortality (19.2% versus 5.2%; 4.33 [2.76-6.80]) at 3 months. When adjusting either baseline characteristics or poststroke complications, the outcome differences between the 2 groups remained significant. However, adjusting initial National Institute of Health Stroke Scale (NIHSS) score alone abolished all outcome differences except for mortality. For mRS 0-2 outcomes, the decrement of -2 log-likelihood and the Nagelkerke R2 of the model adjusting initial NIHSS score alone approached 70.2% and 76.7% of the fully adjusting model. Greater stroke severity predominates over all other factors for the worse outcome of CE stroke. Primary prevention and more efficient acute therapy for stroke victims should be given top priorities to reduce the burden of CE strokes. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Positive effects of intermittent fasting in ischemic stroke.

PubMed

Fann, David Yang-Wei; Ng, Gavin Yong Quan; Poh, Luting; Arumugam, Thiruma V

2017-03-01

Intermittent fasting (IF) is a dietary protocol where energy restriction is induced by alternate periods of ad libitum feeding and fasting. Prophylactic intermittent fasting has been shown to extend lifespan and attenuate the progress and severity of age-related diseases such as cardiovascular (e.g. stroke and myocardial infarction), neurodegenerative (e.g. Alzheimer's disease and Parkinson's disease) and cancerous diseases in animal models. Stroke is the second leading cause of death, and lifestyle risk factors such as obesity and physical inactivity have been associated with elevated risks of stroke in humans. Recent studies have shown that prophylactic IF may mitigate tissue damage and neurological deficit following ischemic stroke by a mechanism(s) involving suppression of excitotoxicity, oxidative stress, inflammation and cell death pathways in animal stroke models. This review summarizes data supporting the potential hormesis mechanisms of prophylactic IF in animal models, and with a focus on findings from animal studies of prophylactic IF in stroke in our laboratory. Copyright © 2017 Elsevier Inc. All rights reserved.

Coadministration of the Human Umbilical Cord Matrix-Derived Mesenchymal Cells and Aspirin Alters Postischemic Brain Injury in Rats.

PubMed

Shams ara, Ali; Sheibani, Vahid; Esmaeilpour, Khadije; Eslaminejad, Touba; Nematollahi-Mahani, Seyed N

2015-09-01

Ischemic stroke is an acute brain insult that induces dramatic changes in the neurons. Treatment of brain stroke is one of the main therapeutic targets of neuroprotective therapies. The aim of this study was to evaluate the protective potential of implanted human umbilical cord mesenchymal stem (hUCMs) cells with/without aspirin (ASA) against focal cerebral ischemia. We assessed the migration and distribution of PKH26-labeled cells after transplantation. After day 10 of transient occlusion, we evaluated the effect of ASA and hUCMs on the recovery of learning and memory in rats by Morris water maze. Afterward, animals were sacrificed, and the infarct area in the brain was evaluated using 2, 3, 5-triphenyltetrazolium chloride staining and also by hematoxylin and eosin. The recovery of learning and memory in ischemic animals that received ASA and hUCM cells improved significantly compared with the untreated ischemic animals. Coadministration of ASA and hUCM cells did not improve the outcome at a comparable rate with ASA and hUCM cells alone. PKH26-labeled cells were detectable in the ischemic area of the brain tissue sections. 2,3,5-Triphenyltetrazolium chloride staining and histologic examinations showed that treatment with ASA and hUCM cells could significantly alter the ischemic area. The results of the present study suggest that ASA and hUCM cells can withstand degenerative changes induced by artificial stroke in the rat. Also the learning and memory disturbance in the ASA and cell-treated animals is less pronounced than ischemic animals. Coadministration of ASA and hUCM cells did not raise the outcome higher than administration of ASA and hUCM cells alone. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

High ABCD2 Scores and In-Hospital Interventions following Transient Ischemic Attack

PubMed Central

Cutting, Shawna; Regan, Elizabeth; Lee, Vivien H.; Prabhakaran, Shyam

2016-01-01

Background and Purpose Following transient ischemic attack (TIA), there is increased risk for ischemic stroke. The American Heart Association recommends admission of patients with ABCD2 scores ≥3 for observation, rapid performance of diagnostic tests, and potential acute intervention. We aimed to determine if there is a relationship between ABCD2 scores, in-hospital ischemic events, and in-hospital treatments after TIA admission. Methods We reviewed consecutive patients admitted between 2006 and 2011 following a TIA, defined as transient focal neurological symptoms attributed to a specific vascular distribution and lasting <24 h. Three interventions were prespecified: anticoagulation for atrial fibrillation, carotid or intracranial revascularization, and intravenous or intra-arterial reperfusion therapies. We compared rates of in-hospital recurrent TIA or ischemic stroke and the receipt of interventions among patients with low (<3) versus high (≥3) ABCD2 scores. Results Of 249 patients, 11 patients (4.4%) had recurrent TIAs or strokes during their stay (8 TIAs, 3 strokes). All 11 had ABCD2 scores ≥3, and no neurological events occurred in patients with lower scores (5.1 vs. 0%; p = 0.37). Twelve patients (4.8%) underwent revascularization for large artery stenosis, 16 (6.4%) were started on anticoagulants, and no patient received intravenous or intra-arterial reperfusion therapy. The ABCD2 score was not associated with anticoagulation (p = 0.59) or revascularization (p = 0.20). Conclusions Higher ABCD2 scores may predict early ischemic events after TIA but do not predict the need for intervention. Outpatient evaluation for those with scores <3 would potentially have delayed revascularization or anticoagulant treatment in nearly one-fifth of ‘low-risk’ patients. PMID:27721312

By improving regional cortical blood flow, attenuating mitochondrial dysfunction and sequential apoptosis galangin acts as a potential neuroprotective agent after acute ischemic stroke.

PubMed

Li, Shaojing; Wu, Chuanhong; Zhu, Li; Gao, Jian; Fang, Jing; Li, Defeng; Fu, Meihong; Liang, Rixin; Wang, Lan; Cheng, Ming; Yang, Hongjun

2012-11-09

Ischemic stroke is a devastating disease with a complex pathophysiology. Galangin is a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, which has been widely used as an antioxidant agent. However, its effects against ischemic stroke have not been reported and its related neuroprotective mechanism has not really been explored. In this study, neurological behavior, cerebral infarct volumes and the improvement of the regional cortical blood flow (rCBF) were used to evaluate the therapeutic effect of galangin in rats impaired by middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. Furthermore, the determination of mitochondrial function and Western blot of apoptosis-related proteins were performed to interpret the neuroprotective mechanism of galangin. The results showed that galangin alleviated the neurologic impairments, reduced cerebral infarct at 24 h after MCAO and exerted a protective effect on the mitochondria with decreased production of mitochondrial reactive oxygen species (ROS). These effects were consistent with improvements in the membrane potential level (Dym), membrane fluidity, and degree of mitochondrial swelling in a dose-dependent manner. Moreover, galangin significantly improved the reduced rCBF after MCAO. Western blot analysis revealed that galangin also inhibited apoptosis in a dose-dependent manner concomitant with the up-regulation of Bcl-2 expression, down-regulation of Bax expression and the Bax/Bcl-2 ratio, a reduction in cytochrome c release from the mitochondria to the cytosol, the reduced expression of activated caspase-3 and the cleavage of poly(ADP-ribose) polymerase (PARP). All these data in this study demonstrated that galangin might have therapeutic potential for ischemic stroke and play its protective role through the improvement in rCBF, mitochondrial protection and inhibiting caspase-dependent mitochondrial cell death pathway for the first time.

B-type natriuretic peptides help in cardioembolic stroke diagnosis: pooled data meta-analysis.

PubMed

Llombart, Víctor; Antolin-Fontes, Albert; Bustamante, Alejandro; Giralt, Dolors; Rost, Natalia S; Furie, Karen; Shibazaki, Kensaku; Biteker, Murat; Castillo, José; Rodríguez-Yáñez, Manuel; Fonseca, Ana Catarina; Watanabe, Tetsu; Purroy, Francisco; Zhixin, Wu; Etgen, Thorleif; Hosomi, Naohisa; Jafarian Kerman, Scott Reza; Sharma, Jagdish C; Knauer, Carolin; Santamarina, Estevo; Giannakoulas, George; García-Berrocoso, Teresa; Montaner, Joan

2015-05-01

Determining the underlying cause of stroke is important to optimize secondary prevention treatment. Increased blood levels of natriuretic peptides (B-type natriuretic peptide/N-terminal pro-BNP [BNP/NT-proBNP]) have been repeatedly associated with cardioembolic stroke. Here, we evaluate their clinical value as pathogenic biomarkers for stroke through a literature systematic review and individual participants' data meta-analysis. We searched publications in PubMed database until November 2013 that compared BNP and NT-proBNP circulating levels among stroke causes. Standardized individual participants' data were collected to estimate predictive values of BNP/NT-proBNP for cardioembolic stroke. Dichotomized BNP/NT-proBNP levels were included in logistic regression models together with clinical variables to assess the sensitivity and specificity to identify cardioembolic strokes and the additional value of biomarkers using area under the curve and integrated discrimination improvement index. From 23 selected articles, we collected information of 2834 patients with a defined cause. BNP/NT-proBNP levels were significantly elevated in cardioembolic stroke until 72 hours from symptoms onset. Predictive models showed a sensitivity >90% and specificity >80% when BNP/NT-proBNP were added considering the lowest and the highest quartile, respectively. Both peptides also increased significantly the area under the curve and integrated discrimination improvement index compared with clinical models. Sensitivity, specificity, and precision of the models were validated in 197 patients with initially undetermined stroke with final pathogenic diagnosis after ancillary follow-up. Natriuretic peptides are strongly increased in cardioembolic strokes. Future multicentre prospective studies comparing BNP and NT-proBNP might aid in finding the optimal biomarker, the best time point, and the optimal cutoff points for cardioembolic stroke identification. © 2015 American Heart Association, Inc.

DEPDC5 takes a second hit in familial focal epilepsy.

PubMed

Anderson, Matthew P

2018-04-30

Loss-of-function mutations in a single allele of the gene encoding DEP domain-containing 5 protein (DEPDC5) are commonly linked to familial focal epilepsy with variable foci; however, a subset of patients presents with focal cortical dysplasia that is proposed to result from a second-hit somatic mutation. In this issue of the JCI, Ribierre and colleagues provide several lines of evidence to support second-hit DEPDC5 mutations in this disorder. Moreover, the authors use in vivo, in utero electroporation combined with CRISPR-Cas9 technology to generate a murine model of the disease that recapitulates human manifestations, including cortical dysplasia-like changes, focal seizures, and sudden unexpected death. This study provides important insights into familial focal epilepsy and provides a preclinical model for evaluating potential therapies.

Neighborhood Differences in Post-Stroke Mortality

PubMed Central

Osypuk, Theresa L.; Ehntholt, Amy; Moon, J. Robin; Gilsanz, Paola; Glymour, M. Maria

2017-01-01

Background Post-stroke mortality is higher among residents of disadvantaged neighborhoods, but it is not known whether neighborhood inequalities are specific to stroke survival or similar to mortality patterns in the general population. We hypothesized that neighborhood disadvantage would predict higher post-stroke mortality and neighborhood effects would be relatively larger for stroke patients than for individuals with no history of stroke. Methods and Results Health and Retirement Study participants aged 50+ without stroke at baseline (n=15,560) were followed up to 12 years for incident stroke (1,715 events over 159,286 person-years) and mortality (5,325 deaths). Baseline neighborhood characteristics included objective measures based on census tracts (family income, poverty, deprivation, residential stability, and percent white, black or foreign-born) and self-reported neighborhood social ties. Using Cox proportional hazard models, we compared neighborhood mortality effects for people with versus without a history of stroke. Most neighborhood variables predicted mortality for both stroke patients and the general population in demographic-adjusted models. Neighborhood percent white predicted lower mortality for stroke survivors (HR=0.75 for neighborhoods in highest 25th percentile vs. below, 95 % CI: 0.62, 0.91) more strongly than for stroke-free adults (HR=0.92 (0.83, 1.02); p=0.04 for stroke-by-neighborhood interaction). No other neighborhood characteristic had different effects for people with versus without stroke. Neighborhood-mortality associations emerged within three months after stroke, when associations were often stronger than among stroke-free individuals. Conclusions Neighborhood characteristics predict post-stroke mortality, but most effects are similar for individuals without stroke. Eliminating disparities in stroke survival may require addressing pathways that are not specific to traditional post-stroke care. PMID:28228449

Risk Factors and Stroke Characteristic in Patients with Postoperative Strokes.

PubMed

Dong, Yi; Cao, Wenjie; Cheng, Xin; Fang, Kun; Zhang, Xiaolong; Gu, Yuxiang; Leng, Bing; Dong, Qiang

2017-07-01

Intravenous thrombolysis and intra-arterial thrombectomy are now the standard therapies for patients with acute ischemic stroke. In-house strokes have often been overlooked even at stroke centers and there is no consensus on how they should be managed. Perioperative stroke happens rather frequently but treatment protocol is lacking, In China, the issue of in-house strokes has not been explored. The aim of this study is to explore the current management of in-house stroke and identify the common risk factors associated with perioperative strokes. Altogether, 51,841 patients were admitted to a tertiary hospital in Shanghai and the records of those who had a neurological consult for stroke were reviewed. Their demographics, clinical characteristics, in-hospital complications and operations, and management plans were prospectively studied. Routine laboratory test results and risk factors of these patients were analyzed by multiple logistic regression model. From January 1, 2015, to December 31, 2015, over 1800 patients had neurological consultations. Among these patients, 37 had an in-house stroke and 20 had more severe stroke during the postoperative period. Compared to in-house stroke patients without a procedure or operation, leukocytosis and elevated fasting glucose levels were more common in perioperative strokes. In multiple logistic regression model, perioperative strokes were more likely related to large vessel occlusion. Patients with perioperative strokes had different risk factors and severity from other in-house strokes. For these patients, obtaining a neurological consultation prior to surgery may be appropriate in order to evaluate the risk of perioperative stroke. Copyright © 2017. Published by Elsevier Inc.

Interactions between Age, Sex, and Hormones in Experimental Ischemic Stroke

PubMed Central

Liu, Fudong; McCullough, Louise D.

2012-01-01

Age, sex, and gonadal hormones have profound effects on ischemic stroke outcomes, although how these factors impact basic stroke pathophysiology remains unclear. There is a plethora of inconsistent data reported throughout the literature, primarily due to differences in the species examined, the timing and methods used to evaluate injury, the models used, and confusion regarding differences in stroke incidence as seen in clinical populations versus effects on acute neuroprotection or neurorepair in experimental stroke models. Sex and gonadal hormone exposure have considerable independent impact on stroke outcome, but these factors also interact with each other, and the contribution of each differs throughout the lifespan. The contribution of sex and hormones to experimental stroke will be the focus of this review. Recent advances and our current understanding of age, sex, and hormone interactions in ischemic stroke with a focus on inflammation will be discussed. PMID:23068990

The consequences of ignoring measurement invariance for path coefficients in structural equation models

PubMed Central

Guenole, Nigel; Brown, Anna

2014-01-01

We report a Monte Carlo study examining the effects of two strategies for handling measurement non-invariance – modeling and ignoring non-invariant items – on structural regression coefficients between latent variables measured with item response theory models for categorical indicators. These strategies were examined across four levels and three types of non-invariance – non-invariant loadings, non-invariant thresholds, and combined non-invariance on loadings and thresholds – in simple, partial, mediated and moderated regression models where the non-invariant latent variable occupied predictor, mediator, and criterion positions in the structural regression models. When non-invariance is ignored in the latent predictor, the focal group regression parameters are biased in the opposite direction to the difference in loadings and thresholds relative to the referent group (i.e., lower loadings and thresholds for the focal group lead to overestimated regression parameters). With criterion non-invariance, the focal group regression parameters are biased in the same direction as the difference in loadings and thresholds relative to the referent group. While unacceptable levels of parameter bias were confined to the focal group, bias occurred at considerably lower levels of ignored non-invariance than was previously recognized in referent and focal groups. PMID:25278911

Computed Tomography Perfusion Improves Diagnostic Accuracy in Acute Posterior Circulation Stroke.

PubMed

Sporns, Peter; Schmidt, Rene; Minnerup, Jens; Dziewas, Rainer; Kemmling, André; Dittrich, Ralf; Zoubi, Tarek; Heermann, Philipp; Cnyrim, Christian; Schwindt, Wolfram; Heindel, Walter; Niederstadt, Thomas; Hanning, Uta

2016-01-01

Computed tomography perfusion (CTP) has a high diagnostic value in the detection of acute ischemic stroke in the anterior circulation. However, the diagnostic value in suspected posterior circulation (PC) stroke is uncertain, and whole brain volume perfusion is not yet in widespread use. We therefore studied the additional value of whole brain volume perfusion to non-contrast CT (NCCT) and CT angiography source images (CTA-SI) for infarct detection in patients with suspected acute ischemic PC stroke. This is a retrospective review of patients with suspected stroke in the PC in a database of our stroke center (n = 3,011) who underwent NCCT, CTA and CTP within 9 h after stroke onset and CT or MRI on follow-up. Images were evaluated for signs and pc-ASPECTS locations of ischemia. Three imaging models - A (NCCT), B (NCCT + CTA-SI) and C (NCCT + CTA-SI + CTP) - were compared with regard to the misclassification rate relative to gold standard (infarction in follow-up imaging) using the McNemar's test. Of 3,011 stroke patients, 267 patients had a suspected stroke in the PC and 188 patients (70.4%) evidenced a PC infarct on follow-up imaging. The sensitivity of Model C (76.6%) was higher compared with that of Model A (21.3%) and Model B (43.6%). CTP detected significantly more ischemic lesions, especially in the cerebellum, posterior cerebral artery territory and thalami. Our findings in a large cohort of consecutive patients show that CTP detects significantly more ischemic strokes in the PC than CTA and NCCT alone. © 2016 S. Karger AG, Basel.

Association of RTEL1 gene polymorphisms with stroke risk in a Chinese Han population

PubMed Central

Cai, Yi; Zeng, Chaosheng; Su, Qingjie; Zhou, Jingxia; Li, Pengxiang; Dai, Mingming; Wang, Desheng; Long, Faqing

2017-01-01

We investigated the associations between single nucleotide polymorphisms (SNPs) in the regulator of telomere elongation helicase 1 (RTEL1) gene and stroke in the Chinese population. A total of 400 stroke patients and 395 healthy participants were included in this study. Five SNPs in RTEL1 were genotyped and the association with stroke risk was analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used to identify SNPs that correlated with stroke. Rs2297441 was associated with an increased risk of stroke in an allele model (odds ratio [OR] = 1.24, 95% confidence interval [95% CI] = 1.01–1.52, p = 0.043). Rs6089953 was associated with an increased risk of stroke under the genotype model ([OR] = 1.862, [CI] = 1.123–3.085, p = 0.016). Rs2297441 was associated with an increased risk of stroke in an additive model (OR = 1.234, 95% CI = 1.005, p = 0.045, Rs6089953, Rs6010620 and Rs6010621 were associated with an increased risk of stroke in the recessive model (Rs6089953:OR = 1.825, 95% CI = 1.121–2.969, p =0.01546; Rs6010620: OR = 1.64, 95% CI = 1.008–2.669, p =0.04656;Rs6010621:OR = 1.661, 95% CI = 1.014–2.722, p =0.04389). Our findings reveal a possible association between SNPs in the RTEL1 gene and stroke risk in Chinese population. PMID:29383136

Mild Contralesional Hypothermia Reduces Use of the Unimpaired Forelimb in a Skilled Reaching Task After Motor Cortex Injury in Rats.

PubMed

Klahr, Ana C; Fagan, Kelly; Aziz, Jasmine R; John, Roseleen; Colbourne, Frederick

2018-06-01

Therapeutic hypothermia (TH) mitigates neuronal injury in models of ischemic stroke. Although this therapy is meant for injured tissue, most protocols cool the whole body, including the contralesional hemisphere. Neuroplasticity responses within this hemisphere can affect functional outcome. Thus, cooling the contralesional hemisphere serves no clear neuroprotective function and may instead be detrimental. In this study, we cooled the contralesional hemisphere to determine whether this harms behavioral recovery after cortical injury in rats. All rats were trained on skilled reaching and walking tasks. Rats then received a motor cortex insult contralateral to their dominant paw after which they were randomly assigned to focal contralesional TH (∼33°C) for 1-48, 1-97, or 48-96 hours postinjury, or to a normothermic control group. Contralesional cooling did not impact lesion volume (p = 0.371) and had minimal impact on neurological outcome of the impaired limb. However, rats cooled early were significantly less likely to shift paw preference to the unimpaired paw (p ≤ 0.043), suggesting that cooling reduced learned nonuse. In a second experiment, we tested whether cooling impaired learning of the skilled reaching task in naive rats. Localized TH applied to the hemisphere contralateral or ipsilateral to the preferred paw did not impair learning (p ≥ 0.677) or dendritic branching/length in the motor cortex (p ≥ 0.105). In conclusion, localized TH did not impair learning or plasticity in the absence of neural injury, but contralesional TH may reduce unwanted shifts in limb preference after stroke.

Association of multiple ischemic strokes with mortality in incident hemodialysis patients: an application of multistate model to determine transition probabilities in a retrospective observational cohort.

PubMed

Wetmore, James B; Mahnken, Jonathan D; Phadnis, Milind A

2016-09-21

Little is known about the effect of multiple, or subsequent, ischemic strokes in patients receiving hemodialysis. We undertook a retrospective cohort study of incident hemodialysis patients with Medicare coverage who had experienced a first ischemic stroke. Factors associated with either a subsequent ischemic stroke or death following a first new stroke were modeled. A multistate model with Cox proportional hazards was used to predict transition probabilities from first ischemic stroke to either subsequent stroke or to death, and the demographic and clinical factors associated with the respective transition probabilities were determined. Effect of a subsequent ischemic stroke on survival was quantified. Overall, 12,054 individuals (mean age 69.7 years, 41.3 % male, 53.0 % Caucasian and 34.0 % African-American) experienced a first new ischemic stroke. Female sex was associated with an increased risk of having a subsequent ischemic stroke (adjusted hazard ratio 1.37, 95 % confidence intervals 1.20 - 1.56, P < 0.0001); African-Americans, as compared to Caucasians, had lower likelihood of dying after a first new ischemic stroke (0.81, 0.77 - 0.85, P < 0.0001). A subsequent stroke trended towards having a higher likelihood of transitioning to death compared to a first new ischemic stroke on dialysis (1.72, 0.96 - 3.09, P = 0.071). When a subsequent ischemic stroke occurs at 24 months, probability of survival dropped >15 %, in absolute terms, from 0.254 to 0.096, with substantial drops observed at subsequent time points such that the probability of survival was more than halved. Likelihood of subsequent ischemic stroke and of survival in hemodialysis patients appears to vary by sex and race: females are more likely than males to experience a subsequent ischemic stroke, and Caucasians are more likely than African-Americans to die after a first new ischemic stroke. The risk of a transitioning to a subsequent stroke (after having had a first) increases until about 1 year, then decreases. Subsequent strokes are associated with decreased probability of survival, an effect which increases as time since first stroke elapses. This information may be of assistance to clinicians when counseling hemodialysis patients about the implications of recurrent ischemic stroke.

Multiple therapeutic effects of progranulin on experimental acute ischaemic stroke.

PubMed

Kanazawa, Masato; Kawamura, Kunio; Takahashi, Tetsuya; Miura, Minami; Tanaka, Yoshinori; Koyama, Misaki; Toriyabe, Masafumi; Igarashi, Hironaka; Nakada, Tsutomu; Nishihara, Masugi; Nishizawa, Masatoyo; Shimohata, Takayoshi

2015-07-01

In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which progranulin exerts protective effects on ischaemic brain injury remains unknown. Furthermore, the therapeutic potential of progranulin against acute focal cerebral ischaemia, including combination treatment with tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of progranulin after ischaemia as well as the therapeutic effects of progranulin on ischaemic brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in progranulin expression in ischaemic Sprague-Dawley rats, including increased levels of progranulin expression in microglia within the ischaemic core, and increased levels of progranulin expression in viable neurons as well as induction of progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory isoform of progranulin (∼88 kDa) decreased, whereas the glycosylated immature isoform of progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature isoform was secreted only from the microglia. Second, we demonstrated that progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. We found that progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischaemia via anti-inflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43 as demonstrated in progranulin knockout mice (C57BL/6 background). Finally, we demonstrated the therapeutic potential of progranulin against acute focal cerebral ischaemia using a rat autologous thrombo-embolic model with delayed tissue plasminogen activator treatment. Intravenously administered recombinant progranulin reduced cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes (P = 0.007, 0.038, 0.007 and 0.004, respectively). In conclusion, progranulin may be a novel therapeutic target that provides vascular protection, anti-neuroinflammation, and neuroprotection related in part to vascular endothelial growth factor, interleukin 10, and TAR DNA-binding protein-43, respectively. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Stroke mortality variations in South-East Asia: empirical evidence from the field.

PubMed

Hoy, Damian G; Rao, Chalapati; Hoa, Nguyen Phuong; Suhardi, S; Lwin, Aye Moe Moe

2013-10-01

Stroke is a leading cause of death in Asia; however, many estimates of stroke mortality are based on epidemiological models rather than empirical data. Since 2005, initiatives have been undertaken in a number of Asian countries to strengthen and analyse vital registration data. This has increased the availability of empirical data on stroke mortality. The aim of this paper is to present estimates of stroke mortality for Indonesia, Myanmar, Viet Nam, Thailand, and Malaysia, which have been derived using these empirical data. Age-specific stroke mortality rates were calculated in each of the five countries, and adjusted for data completeness or misclassification where feasible. All data were age-standardized and the resulting rates were compared with World Health Organization estimates, which are largely based on epidemiological models. Using empirical data, stroke ranked as the leading cause of death in all countries except Malaysia, where it ranked as the second leading cause. Age-standardized rates for males ranged from 94 per 100,000 in Thailand, to over 300 per 100,000 in Indonesia. In all countries, rates were higher for males than for females, and those compiled from empirical data were generally higher than modelled estimates published by World Health Organization. This study highlights the extent of stroke mortality in selected Asian countries, and provides important baseline information to investigate the aetiology of stroke in Asia and design appropriate public health strategies to address the rapidly growing burden from stroke. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Genetic polymorphisms and the risk of stroke after cardiac surgery.

PubMed

Grocott, Hilary P; White, William D; Morris, Richard W; Podgoreanu, Mihai V; Mathew, Joseph P; Nielsen, Dahlia M; Schwinn, Debra A; Newman, Mark F

2005-09-01

Stroke represents a significant cause of morbidity and mortality after cardiac surgery. Although the risk of stroke varies according to both patient and procedural factors, the impact of genetic variants on stroke risk is not well understood. Therefore, we tested the hypothesis that specific genetic polymorphisms are associated with an increased risk of stroke after cardiac surgery. Patients undergoing cardiac surgery utilizing cardiopulmonary bypass surgery were studied. DNA was isolated from preoperative blood and analyzed for 26 different single-nucleotide polymorphisms. Multivariable logistic regression modeling was used to determine the association of clinical and genetic characteristics with stroke. Permutation analysis was used to adjust for multiple comparisons inherent in genetic association studies. A total of 1635 patients experiencing 28 strokes (1.7%) were included in the final genetic model. The combination of the 2 minor alleles of C-reactive protein (CRP; 3'UTR 1846C/T) and interleukin-6 (IL-6; -174G/C) polymorphisms, occurring in 583 (35.7%) patients, was significantly associated with stroke (odds ratio, 3.3; 95% CI, 1.4 to 8.1; P=0.0023). In a multivariable logistic model adjusting for age, the CRP and IL-6 single-nucleotide polymorphism combination remained significantly associated with stroke (P=0.0020). We demonstrate that common genetic variants of CRP (3'UTR 1846C/T) and IL-6 (-174G/C) are significantly associated with the risk of stroke after cardiac surgery, suggesting a pivotal role of inflammation in post-cardiac surgery stroke.

The Therapeutic Potential of Induced Pluripotent Stem Cells After Stroke: Evidence from Rodent Models.

PubMed

Zents, Karlijn; Copray, Sjef

2016-01-01

Stroke is the second most common cause of death and the leading cause of disability in the world. About 30% of the people that are affected by stroke die within a year; 25% of the patients that survive stroke remain in need of care after a year. Therefore, stroke is a major burden for health care costs. The most common subtype is ischemic stroke. This type is characterized by a reduced and insufficient blood supply to a certain part of the brain. Despite the high prevalence of stroke, the currently used therapeutic interventions are limited. No therapies that aim to restore damaged neuronal tissue or to promote recovery are available nowadays. Transplantation of stem cell-derived cells has been investigated as a potential regenerative and protective treatment. Embryonic stem cell (ESC)-based cell therapy in rodent models of stroke has been shown to improve functional outcome. However, the clinical use of ESCs still raises ethical questions and implantation of ESC-derived cells requires continuous immunosuppression. The groundbreaking detection of induced pluripotent stem cells (iPSCs) has provided a most promising alternative. This mini-review summarizes current literature in which the potential use of iPSC-derived cells has been tested in rodent models of stroke. iPSC-based cell therapy has been demonstrated to improve motor function, decrease stroke volume, promote neurogenesis and angiogenesis and to exert immunomodulatory, anti-inflammatory effects in the brain of stroke-affected rodents.

Measures of adiposity and risk of stroke in China: a result from the Kailuan study.

PubMed

Wang, Anxin; Wu, Jianwei; Zhou, Yong; Guo, Xiuhua; Luo, Yanxia; Wu, Shouling; Zhao, Xingquan

2013-01-01

The objective of this study was to explore the association between adiposity and risk of incident stroke among men and women. We studied the relationship between adiposity and stroke among 94,744 participants (18-98 years old) in the Kailuan study. During a follow-up of 4 years, 1,547 ischemic or hemorrhagic strokes were recorded. Measurements of adiposity included body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated from Cox regression models and each model fit was assessed using -2log-likelihood. Every measurement of adiposity was associated with the risk for total stroke and ischemic stroke, but not for hemorrhagic stroke. After adjusting for confounders and intermediates, the HR (comparing the mean of the highest quintile with that of the lowest quintile) for total stroke was 1.34(1.13-1.60) for BMI, 1.26(1.06-1.52) for WC, 1.29(1.08-1.56) for WHpR, and 1.38(1.15-1.66) for WHtR. The HR for ischemic stroke was 1.52(1.24-1.88) for BMI, 1.46(1.17-1.81) for WC, 1.40(1.12-1.74) for WHpR, and 1.62(1.29-2.04) for WHtR. The model fit for each of the indices was similar. Adiposity increases the total risk of stroke and ischemic stroke, but not of hemorrhagic stroke. No clinically meaningful differences among the associations between BMI, WC, WHpR, and WHtR and stroke incidence were identified in this study.

Lost Productivity in Stroke Survivors: An Econometrics Analysis.

PubMed

Vyas, Manav V; Hackam, Daniel G; Silver, Frank L; Laporte, Audrey; Kapral, Moira K

2016-01-01

Stroke leads to a substantial societal economic burden. Loss of productivity among stroke survivors is a significant contributor to the indirect costs associated with stroke. We aimed to characterize productivity and factors associated with employability in stroke survivors. We used the Canadian Community Health Survey 2011-2012 to identify stroke survivors and employment status. We used multivariable logistic models to determine the impact of stroke on employment and on factors associated with employability, and used Heckman models to estimate the effect of stroke on productivity (number of hours worked/week and hourly wages). We included data from 91,633 respondents between 18 and 70 years and identified 923 (1%) stroke survivors. Stroke survivors were less likely to be employed (adjusted OR 0.39, 95% CI 0.33-0.46) and had hourly wages 17.5% (95% CI 7.7-23.7) lower compared to the general population, although there was no association between work hours and being a stroke survivor. We found that factors like older age, not being married, and having medical comorbidities were associated with lower odds of employment in stroke survivors in our sample. Stroke survivors are less likely to be employed and they earn a lower hourly wage than the general population. Interventions such as dedicated vocational rehabilitation and policies targeting return to work could be considered to address this lost productivity among stroke survivors. © 2016 S. Karger AG, Basel.

Antibody Levels to Persistent Pathogens and Incident Stroke in Mexican Americans

PubMed Central

Sealy-Jefferson, Shawnita; Gillespie, Brenda W.; Aiello, Allison E.; Haan, Mary N.; Morgenstern, Lewis B.; Lisabeth, Lynda D.

2013-01-01

Background Persistent pathogens have been proposed as risk factors for stroke; however, the evidence remains inconclusive. Mexican Americans have an increased risk of stroke especially at younger ages, as well as a higher prevalence of infections caused by several persistent pathogens. Methodology/Principal Findings Using data from the Sacramento Area Latino Study on Aging (n = 1621), the authors used discrete-time regression to examine associations between stroke risk and (1) immunoglobulin G antibody levels to Helicobacter pylori (H. pylori), Cytomegalovirus, Varicella Zoster Virus, Toxoplasma gondii and Herpes simplex virus 1, and (2) concurrent exposure to several pathogens (pathogen burden), defined as: (a) summed sero-positivity, (b) number of pathogens eliciting high antibody levels, and (c) average antibody level. Models were adjusted for socio-demographics and stroke risk factors. Antibody levels to H. pylori predicted incident stroke in fully adjusted models (Odds Ratio: 1.58; 95% Confidence Interval: 1.09, 2.28). No significant associations were found between stroke risk and antibody levels to the other four pathogens. No associations were found for pathogen burden and incident stroke in fully adjusted models. Conclusions/Significance Our results suggest that exposure to H. pylori may be a stroke risk factor in Mexican Americans and may contribute to ethnic differences in stroke risk given the increased prevalence of exposure to H. pylori in this population. Future studies are needed to confirm this association. PMID:23799066

40 CFR 90.107 - Application for certification.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., manufacturers of two-stroke lawnmower engines must submit with their application for a certificate of conformity: (i) For model year 1997, information establishing the highest number of two-stroke lawnmower engines... production and projected production for the current year. (2) In model year 1997, two-stroke lawnmower engine...

40 CFR 90.107 - Application for certification.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., manufacturers of two-stroke lawnmower engines must submit with their application for a certificate of conformity: (i) For model year 1997, information establishing the highest number of two-stroke lawnmower engines... production and projected production for the current year. (2) In model year 1997, two-stroke lawnmower engine...

40 CFR 90.107 - Application for certification.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., manufacturers of two-stroke lawnmower engines must submit with their application for a certificate of conformity: (i) For model year 1997, information establishing the highest number of two-stroke lawnmower engines... production and projected production for the current year. (2) In model year 1997, two-stroke lawnmower engine...

40 CFR 90.107 - Application for certification.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., manufacturers of two-stroke lawnmower engines must submit with their application for a certificate of conformity: (i) For model year 1997, information establishing the highest number of two-stroke lawnmower engines... production and projected production for the current year. (2) In model year 1997, two-stroke lawnmower engine...

Modulation of brain plasticity in stroke: a novel model for neurorehabilitation.

PubMed

Di Pino, Giovanni; Pellegrino, Giovanni; Assenza, Giovanni; Capone, Fioravante; Ferreri, Florinda; Formica, Domenico; Ranieri, Federico; Tombini, Mario; Ziemann, Ulf; Rothwell, John C; Di Lazzaro, Vincenzo

2014-10-01

Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model--which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies--is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance-recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.

Numerical Cerebrospinal System Modeling in Fluid-Structure Interaction.

PubMed

Garnotel, Simon; Salmon, Stéphanie; Balédent, Olivier

2018-01-01

Cerebrospinal fluid (CSF) stroke volume in the aqueduct is widely used to evaluate CSF dynamics disorders. In a healthy population, aqueduct stroke volume represents around 10% of the spinal stroke volume while intracranial subarachnoid space stroke volume represents 90%. The amplitude of the CSF oscillations through the different compartments of the cerebrospinal system is a function of the geometry and the compliances of each compartment, but we suspect that it could also be impacted be the cardiac cycle frequency. To study this CSF distribution, we have developed a numerical model of the cerebrospinal system taking into account cerebral ventricles, intracranial subarachnoid spaces, spinal canal and brain tissue in fluid-structure interactions. A numerical fluid-structure interaction model is implemented using a finite-element method library to model the cerebrospinal system and its interaction with the brain based on fluid mechanics equations and linear elasticity equations coupled in a monolithic formulation. The model geometry, simplified in a first approach, is designed in accordance with realistic volume ratios of the different compartments: a thin tube is used to mimic the high flow resistance of the aqueduct. CSF velocity and pressure and brain displacements are obtained as simulation results, and CSF flow and stroke volume are calculated from these results. Simulation results show a significant variability of aqueduct stroke volume and intracranial subarachnoid space stroke volume in the physiological range of cardiac frequencies. Fluid-structure interactions are numerous in the cerebrospinal system and difficult to understand in the rigid skull. The presented model highlights significant variations of stroke volumes under cardiac frequency variations only.

Constant speed control of four-stroke micro internal combustion swing engine

NASA Astrophysics Data System (ADS)

Gao, Dedong; Lei, Yong; Zhu, Honghai; Ni, Jun

2015-09-01

The increasing demands on safety, emission and fuel consumption require more accurate control models of micro internal combustion swing engine (MICSE). The objective of this paper is to investigate the constant speed control models of four-stroke MICSE. The operation principle of the four-stroke MICSE is presented based on the description of MICSE prototype. A two-level Petri net based hybrid model is proposed to model the four-stroke MICSE engine cycle. The Petri net subsystem at the upper level controls and synchronizes the four Petri net subsystems at the lower level. The continuous sub-models, including breathing dynamics of intake manifold, thermodynamics of the chamber and dynamics of the torque generation, are investigated and integrated with the discrete model in MATLAB Simulink. Through the comparison of experimental data and simulated DC voltage output, it is demonstrated that the hybrid model is valid for the four-stroke MICSE system. A nonlinear model is obtained from the cycle average data via the regression method, and it is linearized around a given nominal equilibrium point for the controller design. The feedback controller of the spark timing and valve duration timing is designed with a sequential loop closing design approach. The simulation of the sequential loop closure control design applied to the hybrid model is implemented in MATLAB. The simulation results show that the system is able to reach its desired operating point within 0.2 s, and the designed controller shows good MICSE engine performance with a constant speed. This paper presents the constant speed control models of four-stroke MICSE and carries out the simulation tests, the models and the simulation results can be used for further study on the precision control of four-stroke MICSE.

The Virtual Brain: Modeling Biological Correlates of Recovery after Chronic Stroke

PubMed Central

Falcon, Maria Inez; Riley, Jeffrey D.; Jirsa, Viktor; McIntosh, Anthony R.; Shereen, Ahmed D.; Chen, E. Elinor; Solodkin, Ana

2015-01-01

There currently remains considerable variability in stroke survivor recovery. To address this, developing individualized treatment has become an important goal in stroke treatment. As a first step, it is necessary to determine brain dynamics associated with stroke and recovery. While recent methods have made strides in this direction, we still lack physiological biomarkers. The Virtual Brain (TVB) is a novel application for modeling brain dynamics that simulates an individual’s brain activity by integrating their own neuroimaging data with local biophysical models. Here, we give a detailed description of the TVB modeling process and explore model parameters associated with stroke. In order to establish a parallel between this new type of modeling and those currently in use, in this work we establish an association between a specific TVB parameter (long-range coupling) that increases after stroke with metrics derived from graph analysis. We used TVB to simulate the individual BOLD signals for 20 patients with stroke and 10 healthy controls. We performed graph analysis on their structural connectivity matrices calculating degree centrality, betweenness centrality, and global efficiency. Linear regression analysis demonstrated that long-range coupling is negatively correlated with global efficiency (P = 0.038), but is not correlated with degree centrality or betweenness centrality. Our results suggest that the larger influence of local dynamics seen through the long-range coupling parameter is closely associated with a decreased efficiency of the system. We thus propose that the increase in the long-range parameter in TVB (indicating a bias toward local over global dynamics) is deleterious because it reduces communication as suggested by the decrease in efficiency. The new model platform TVB hence provides a novel perspective to understanding biophysical parameters responsible for global brain dynamics after stroke, allowing the design of focused therapeutic interventions. PMID:26579071

The Impacts of Peptic Ulcer on Stroke Recurrence.

PubMed

Xu, Zongliang; Wang, Ling; Lin, Ying; Wang, Zhaojun; Zhang, Yun; Li, Junrong; Li, Shenghua; Ye, Zusen; Yuan, Kunxiong; Shan, Wanying; Liu, Xinfeng; Fan, Xinying; Xu, Gelin

2018-04-10

Peptic ulcer has been associated with an increased risk of stroke. This study aimed to evaluate the impacts of peptic ulcer on stroke recurrence and mortality. Patients with first-ever ischemic stroke were retrospectively confirmed with or without a history of peptic ulcer. The primary end point was defined as fatal and nonfatal stroke recurrence. Risks of 1-year fatal and nonfatal stroke recurrence were analyzed with the Kaplan-Meier method. Predictors of fatal and nonfatal stroke recurrence were evaluated with the Cox proportional hazards model. Among the 2577 enrolled patients with ischemic stroke, 129 (5.0%) had a history of peptic ulcer. The fatal and nonfatal stroke recurrence within 1 year of the index stroke was higher in patients with peptic ulcer than in patients without peptic ulcer (12.4% versus 7.2%, P = .030). Cox proportional hazards model detected that age (hazard ratio [HR] = 1.018, 95% confidence interval [CI] 1.005-1.031, P = .008), hypertension (HR = 1.397, 95% CI 1.017-1.918, P = .039), and history of peptic ulcer (HR = 1.853, 95% CI 1.111-3.091, P = .018) were associated with stroke recurrence. Ischemic stroke patients with peptic ulcer may have an increased risk of stroke recurrence. The results emphasize the importance of appropriate prevention and management of peptic ulcer for secondary stroke prevention. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Estimating the cost-effectiveness of stroke units in France compared with conventional care.

PubMed

Launois, R; Giroud, M; Mégnigbêto, A C; Le Lay, K; Présenté, G; Mahagne, M H; Durand, I; Gaudin, A F

2004-03-01

The incidence of stroke in France is estimated at between 120 000 and 150 000 cases per year. This modeling study assessed the clinical and economic benefits of establishing specialized stroke units compared with conventional care. Data from the Dijon stroke registry were used to determine healthcare trajectories according to the degree of autonomy and organization of patient care. The relative risks of death or institutionalization or death or dependence after passage through a stroke unit were compared with conventional care. These risks were then inserted with the costing data into a Markov model to estimate the cost-effectiveness of stroke units. Patients cared for in a stroke unit survive more trimesters without sequelae in the 5 years after hospitalization than those cared for conventionally (11.6 versus 8.28 trimesters). The mean cost per patient at 5 years was estimated at 30 983 for conventional care and 34 638 in a stroke unit. An incremental cost-effectiveness ratio for stroke units of 1359 per year of life gained without disability was estimated. The cost-effectiveness ratio for stroke units is much lower than the threshold (53 400 ) of acceptability recognized by the international scientific community. This finding justifies organizational changes in the management of stroke patients and the establishment of stroke units in France.

OPLS statistical model versus linear regression to assess sonographic predictors of stroke prognosis.

PubMed

Vajargah, Kianoush Fathi; Sadeghi-Bazargani, Homayoun; Mehdizadeh-Esfanjani, Robab; Savadi-Oskouei, Daryoush; Farhoudi, Mehdi

2012-01-01

The objective of the present study was to assess the comparable applicability of orthogonal projections to latent structures (OPLS) statistical model vs traditional linear regression in order to investigate the role of trans cranial doppler (TCD) sonography in predicting ischemic stroke prognosis. The study was conducted on 116 ischemic stroke patients admitted to a specialty neurology ward. The Unified Neurological Stroke Scale was used once for clinical evaluation on the first week of admission and again six months later. All data was primarily analyzed using simple linear regression and later considered for multivariate analysis using PLS/OPLS models through the SIMCA P+12 statistical software package. The linear regression analysis results used for the identification of TCD predictors of stroke prognosis were confirmed through the OPLS modeling technique. Moreover, in comparison to linear regression, the OPLS model appeared to have higher sensitivity in detecting the predictors of ischemic stroke prognosis and detected several more predictors. Applying the OPLS model made it possible to use both single TCD measures/indicators and arbitrarily dichotomized measures of TCD single vessel involvement as well as the overall TCD result. In conclusion, the authors recommend PLS/OPLS methods as complementary rather than alternative to the available classical regression models such as linear regression.

Psychosocial distress and stroke risk in older adults.

PubMed

Henderson, Kimberly M; Clark, Cari J; Lewis, Tené T; Aggarwal, Neelum T; Beck, Todd; Guo, Hongfei; Lunos, Scott; Brearley, Ann; Mendes de Leon, Carlos F; Evans, Denis A; Everson-Rose, Susan A

2013-02-01

To investigate the association of psychosocial distress with risk of stroke mortality and incident stroke in older adults. Data were from the Chicago Health and Aging Project, a longitudinal population-based study conducted in 3 contiguous neighborhoods on the south side of Chicago, IL. Participants were community-dwelling black and non-Hispanic white adults, aged 65 years and older (n=4120 for stroke mortality; n=2649 for incident stroke). Psychosocial distress was an analytically derived composite measure of depressive symptoms, perceived stress, neuroticism, and life dissatisfaction. Cox proportional hazards models examined the association of distress with stroke mortality and incident stroke over 6 years of follow-up. Stroke deaths (151) and 452 incident strokes were identified. Adjusting for age, race, and sex, the hazard ratio (HR) for each 1-SD increase in distress was 1.47 (95% confidence interval [CI]=1.28-1.70) for stroke mortality and 1.18 (95% CI=1.07-1.30) for incident stroke. Associations were reduced after adjustment for stroke risk factors and remained significant for stroke mortality (HR=1.29; 95% CI=1.10-1.52) but not for incident stroke (HR=1.09; 95% CI=0.98-1.21). Secondary analyses of stroke subtypes showed that distress was strongly related to incident hemorrhagic strokes (HR=1.70; 95% CI=1.28-2.25) but not ischemic strokes (HR=1.02; 95% CI=0.91-1.15) in fully adjusted models. Increasing levels of psychosocial distress are related to excess risk of both fatal and nonfatal stroke in older black and white adults. Additional research is needed to examine pathways linking psychosocial distress to cerebrovascular disease risk.

5-year survival and rehospitalization due to stroke recurrence among patients with hemorrhagic or ischemic strokes in Singapore.

PubMed

Sun, Yan; Lee, Sze Haur; Heng, Bee Hoon; Chin, Vivien S

2013-10-03

Stroke is the 4th leading cause of death and 1st leading cause of disability in Singapore. However the information on long-term post stroke outcomes for Singaporean patients was limited. This study aimed to investigate the post stroke outcomes of 5-year survival and rehospitalization due to stroke recurrence for hemorrhagic and ischemic stroke patients in Singapore. The outcomes were stratified by age, ethnic group, gender and stroke types. The causes of death and stroke recurrence were also explored in the study. A multi-site retrospective cohort study. Patients admitted for stroke at any of the three hospitals in the National Healthcare Group of Singapore were included in the study. All study patients were followed up to 5 years. Kaplan-Meier was applied to study the time to first event, death or rehospitalization due to stroke recurrence. Cox proportional hazard model was applied to study the time to death with adjustment for stroke type, age, sex, ethnic group, and admission year. Cumulative incidence model with competing risk was applied for comparing the risks of rehospitalization due to stroke recurrence with death as the competing risk. Totally 12,559 stroke patients were included in the study. Among them, 59.3% survived for 5 years; 18.4% were rehospitalized due to stroke recurrence in 5 years. The risk of stroke recurrence and mortality increased with age in all stroke types. Gender, ethnic group and admitting year were not significantly associated with the risk of mortality or stroke recurrence in hemorrhagic stroke. Male or Malay patient had higher risk of stroke recurrence and mortality in ischemic stroke. Hemorrhagic stroke had higher early mortality while ischemic stroke had higher recurrence and late mortality. The top cause of death among died stroke patients was cerebrovascular diseases, followed by pneumonia and ischemic heart diseases. The recurrent stroke was most likely to be the same type as the initial stroke among rehospitalized stroke patients. Five year post-stroke survival and rehospitalization due to stroke recurrence as well as their associations with patient demographics were studied for different stroke types in Singapore. Specific preventive strategies are needed to target the high risk groups to improve their long-term outcomes after acute stroke.

Development of a decision analytic model to support decision making and risk communication about thrombolytic treatment.

PubMed

McMeekin, Peter; Flynn, Darren; Ford, Gary A; Rodgers, Helen; Gray, Jo; Thomson, Richard G

2015-11-11

Individualised prediction of outcomes can support clinical and shared decision making. This paper describes the building of such a model to predict outcomes with and without intravenous thrombolysis treatment following ischaemic stroke. A decision analytic model (DAM) was constructed to establish the likely balance of benefits and risks of treating acute ischaemic stroke with thrombolysis. Probability of independence, (modified Rankin score mRS ≤ 2), dependence (mRS 3 to 5) and death at three months post-stroke was based on a calibrated version of the Stroke-Thrombolytic Predictive Instrument using data from routinely treated stroke patients in the Safe Implementation of Treatments in Stroke (SITS-UK) registry. Predictions in untreated patients were validated using data from the Virtual International Stroke Trials Archive (VISTA). The probability of symptomatic intracerebral haemorrhage in treated patients was incorporated using a scoring model from Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) data. The model predicts probabilities of haemorrhage, death, independence and dependence at 3-months, with and without thrombolysis, as a function of 13 patient characteristics. Calibration (and inclusion of additional predictors) of the Stroke-Thrombolytic Predictive Instrument (S-TPI) addressed issues of under and over prediction. Validation with VISTA data confirmed that assumptions about treatment effect were just. The C-statistics for independence and death in treated patients in the DAM were 0.793 and 0.771 respectively, and 0.776 for independence in untreated patients from VISTA. We have produced a DAM that provides an estimation of the likely benefits and risks of thrombolysis for individual patients, which has subsequently been embedded in a computerised decision aid to support better decision-making and informed consent.

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

PubMed

Ibrahim-Verbaas, Carla A; Fornage, Myriam; Bis, Joshua C; Choi, Seung Hoan; Psaty, Bruce M; Meigs, James B; Rao, Madhu; Nalls, Mike; Fontes, Joao D; O'Donnell, Christopher J; Kathiresan, Sekar; Ehret, Georg B; Fox, Caroline S; Malik, Rainer; Dichgans, Martin; Schmidt, Helena; Lahti, Jari; Heckbert, Susan R; Lumley, Thomas; Rice, Kenneth; Rotter, Jerome I; Taylor, Kent D; Folsom, Aaron R; Boerwinkle, Eric; Rosamond, Wayne D; Shahar, Eyal; Gottesman, Rebecca F; Koudstaal, Peter J; Amin, Najaf; Wieberdink, Renske G; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G; Destefano, Anita L; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A; Decarli, Charles; Ikram, M Arfan; Seshadri, Sudha; Mosley, Thomas H; Longstreth, W T; van Duijn, Cornelia M; Launer, Lenore J

2014-02-01

Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity

PubMed Central

Hu, Heng; Doll, Danielle N.; Sun, Jiahong; Lewis, Sara E.; Wimsatt, Jeffrey H.; Kessler, Matthew J.; Simpkins, James W.; Ren, Xuefang

2016-01-01

Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy. PMID:26816660

Quantifying links between stroke and risk factors: a study on individual health risk appraisal of stroke in a community of Chongqing.

PubMed

Wu, Yazhou; Zhang, Ling; Yuan, Xiaoyan; Wu, Yamin; Yi, Dong

2011-04-01

The objective of this study is to investigate the risk factors of stroke in a community in Chongqing by setting quantitative criteria for determining the risk factors of stroke. Thus, high-risk individuals can be identified and laid a foundation for predicting individual risk of stroke. 1,034 cases with 1:2 matched controls (2,068) were chosen from five communities in Chongqing including Shapingba, Xiaolongkan, Tianxingqiao, Yubei Road and Ciqikou. Participants were interviewed with a uniform questionnaire. The risk factors of stroke and the odds ratios of risk factors were analyzed with a logistic regression model, and risk exposure factors of different levels were converted into risk scores using statistical models. For men, ten risk factors including hypertension (5.728), family history of stroke (4.599), and coronary heart disease (5.404), among others, were entered into the main effect model. For women, 11 risk factors included hypertension (5.270), family history of stroke (4.866), hyperlipidemia (4.346), among others. The related risk scores were added to obtain a combined risk score to predict the individual's risk of stoke in the future. An individual health risk appraisal model of stroke, which was applicable to individuals of different gender, age, health behavior, disease and family history, was established. In conclusion, personal diseases including hypertension, diabetes mellitus, etc., were very important to the prevalence of stoke. The prevalence of stroke can be effectively reduced by changing unhealthy lifestyles and curing the positive individual disease. The study lays a foundation for health education to persuade people to change their unhealthy lifestyles or behaviors, and could be used in community health services.

PRospective Observational POLIsh Study on post-stroke delirium (PROPOLIS): methodology of hospital-based cohort study on delirium prevalence, predictors and diagnostic tools.

PubMed

Klimiec, Elzbieta; Dziedzic, Tomasz; Kowalska, Katarzyna; Szyper, Aleksandra; Pera, Joanna; Potoczek, Paulina; Slowik, Agnieszka; Klimkowicz-Mrowiec, Aleksandra

2015-06-19

Between 10 % to 48 % of patients develop delirium in acute phase of stroke. Delirium determinants and its association with other neuropsychiatric disturbances in stroke are poorly understood. The wildly accepted predictive model of post-stroke delirium is still lacking. This is a prospective, observational, single-center study in patients with acute phase of stroke. We aim to include 750 patients ≥18 years with acute stroke or transient ischemic attack admitted to the stroke unit within 48 hours after stroke onset. The goals of the study are: 1) to determine frequency of delirium and subsyndromal delirium in Polish stroke patients within 7 days after admission to the hospital; 2) to determine factors associated with incidence, severity and duration of delirium and subsyndromal delirium and to create a predictive model for post-stroke delirium; 3) to determine the association between delirium and its cognitive, psychiatric, behavioral and functional short and long-term consequences; 4) to validate scales used for delirium diagnosis in stroke population. Patients will be screened for delirium on daily basis. The diagnosis of delirium will be based on DSM-V criteria. Abbreviated version of Confusion Assessment Method and Confusion Assessment Method for the Intensive Care Unit will be used for delirium and sub-delirium screening. Severity of delirium symptoms will be assessed by Delirium Rating Scale Revised 98 and Cognitive Test for Delirium. Patients who survive will undergo extensive neuropsychological, neuropsychiatric and functional assessment 3 and 12 months after the stroke. This study is designed to provide information on clinical manifestation, diagnostic methods and determinants of delirium spectrum disorders in acute stroke phase and their short and long-term consequences. Collected information allow us to create a predictive model for post-stroke delirium.

Electromagnetic field radiation model for lightning strokes to tall structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Motoyama, H.; Janischewskyj, W.; Hussein, A.M.

1996-07-01

This paper describes observation and analysis of electromagnetic field radiation from lightning strokes to tall structures. Electromagnetic field waveforms and current waveforms of lightning strokes to the CN Tower have been simultaneously measured since 1991. A new calculation model of electromagnetic field radiation is proposed. The proposed model consists of the lightning current propagation and distribution model and the electromagnetic field radiation model. Electromagnetic fields calculated by the proposed model, based on the observed lightning current at the CN Tower, agree well with the observed fields at 2km north of the tower.

Quality Improvement in Acute Ischemic Stroke Care in Taiwan: The Breakthrough Collaborative in Stroke

PubMed Central

Chern, Chang-Ming; Lee, Tsong-Hai; Tang, Sung-Chun; Tsai, Li-Kai; Liao, Hsun-Hsiang; Chang, Hang; LaBresh, Kenneth A.; Lin, Hung-Jung; Chiou, Hung-Yi; Chiu, Hou-Chang; Lien, Li-Ming

2016-01-01

In the management of acute ischemic stroke, guideline adherence is often suboptimal, particularly for intravenous thrombolysis or anticoagulation for atrial fibrillation. We sought to improve stroke care quality via a collaborative model, the Breakthrough Series (BTS)-Stroke activity, in a nationwide, multi-center activity in Taiwan. A BTS Collaborative, a short-term learning system for a large number of multidisciplinary teams from hospitals, was applied to enhance acute ischemic stroke care quality. Twenty-four hospitals participated in and submitted data for this stroke quality improvement campaign in 2010–2011. Totally, 14 stroke quality measures, adopted from the Get With The Guideline (GWTG)-Stroke program, were used to evaluate the performance and outcome of the ischemic stroke patients. Data for a one-year period from 24 hospitals with 13,181 acute ischemic stroke patients were analyzed. In 14 hospitals, most stroke quality measures improved significantly during the BTS-activity compared with a pre-BTS-Stroke activity period (2006–08). The rate of intravenous thrombolysis increased from 1.2% to 4.6%, door-to-needle time ≤60 minutes improved from 7.1% to 50.8%, symptomatic hemorrhage after intravenous thrombolysis decreased from 11.0% to 5.6%, and anticoagulation therapy for atrial fibrillation increased from 32.1% to 64.1%. The yearly composite measures of five stroke quality measures revealed significant improvements from 2006 to 2011 (75% to 86.3%, p<0.001). The quarterly composite measures also improved significantly during the BTS-Stroke activity. In conclusion, a BTS collaborative model is associated with improved guideline adherence for patients with acute ischemic stroke. GWTG-Stroke recommendations can be successfully applied in countries besides the United States. PMID:27487190

Quality Improvement in Acute Ischemic Stroke Care in Taiwan: The Breakthrough Collaborative in Stroke.

PubMed

Hsieh, Fang-I; Jeng, Jiann-Shing; Chern, Chang-Ming; Lee, Tsong-Hai; Tang, Sung-Chun; Tsai, Li-Kai; Liao, Hsun-Hsiang; Chang, Hang; LaBresh, Kenneth A; Lin, Hung-Jung; Chiou, Hung-Yi; Chiu, Hou-Chang; Lien, Li-Ming

2016-01-01

In the management of acute ischemic stroke, guideline adherence is often suboptimal, particularly for intravenous thrombolysis or anticoagulation for atrial fibrillation. We sought to improve stroke care quality via a collaborative model, the Breakthrough Series (BTS)-Stroke activity, in a nationwide, multi-center activity in Taiwan. A BTS Collaborative, a short-term learning system for a large number of multidisciplinary teams from hospitals, was applied to enhance acute ischemic stroke care quality. Twenty-four hospitals participated in and submitted data for this stroke quality improvement campaign in 2010-2011. Totally, 14 stroke quality measures, adopted from the Get With The Guideline (GWTG)-Stroke program, were used to evaluate the performance and outcome of the ischemic stroke patients. Data for a one-year period from 24 hospitals with 13,181 acute ischemic stroke patients were analyzed. In 14 hospitals, most stroke quality measures improved significantly during the BTS-activity compared with a pre-BTS-Stroke activity period (2006-08). The rate of intravenous thrombolysis increased from 1.2% to 4.6%, door-to-needle time ≤60 minutes improved from 7.1% to 50.8%, symptomatic hemorrhage after intravenous thrombolysis decreased from 11.0% to 5.6%, and anticoagulation therapy for atrial fibrillation increased from 32.1% to 64.1%. The yearly composite measures of five stroke quality measures revealed significant improvements from 2006 to 2011 (75% to 86.3%, p<0.001). The quarterly composite measures also improved significantly during the BTS-Stroke activity. In conclusion, a BTS collaborative model is associated with improved guideline adherence for patients with acute ischemic stroke. GWTG-Stroke recommendations can be successfully applied in countries besides the United States.

Hovering and targeting flight simulations of a dragonfly-like flapping wing-body model by the immersed boundary-lattice Boltzmann method

NASA Astrophysics Data System (ADS)

Hirohashi, Kensuke; Inamuro, Takaji

2017-08-01

Hovering and targeting flights of the dragonfly-like flapping wing-body model are numerically investigated by using the immersed boundary-lattice Boltzmann method. The governing parameters of the problem are the Reynolds number Re, the Froude number Fr, and the non-dimensional mass m. We set the parameters at Re = 200, Fr = 15 and m = 51. First, we simulate free flights of the model for various values of the phase difference angle ϕ between the forewing and the hindwing motions and for various values of the stroke angle β between the stroke plane and the horizontal plane. We find that the vertical motion of the model depends on the phase difference angle ϕ, and the horizontal motion of the model depends on the stroke angle β. Secondly, using the above results we try to simulate the hovering flight by dynamically changing the phase difference angle ϕ and the stroke angle β. The hovering flight can be successfully simulated by a simple proportional controller of the phase difference angle and the stroke angle. Finally, we simulate a targeting flight by dynamically changing the stroke angle β.

A novel neuroimaging model to predict early neurological deterioration after acute ischemic stroke.

PubMed

Huang, Yen-Chu; Tsai, Yuan-Hsiung; Lee, Jiann-Der; Yang, Jen-Tsung; Pan, Yi-Ting

2018-05-16

In acute ischemic stroke, early neurological deterioration (END) may occur in up to one-third of patients. However, there is still no satisfying or comprehensive predictive model for all the stroke subtypes. We propose a practical model to predict END using magnetic resonance imaging (MRI). Patients with anterior circulation infarct were recruited and they underwent an MRI within 24 hours of stroke onset. END was defined as an elevation of ≥2 points on the National Institute of Health Stroke Scale (NIHSS) within 72 hours of stroke onset. We examined the relationships of END to individual END models, including: A, infarct swelling; B, small subcortical infarct; C, mismatch; and D, recurrence. There were 163 patients recruited and 43 (26.4%) of them had END. The END models A, B and C significantly predicted END respectively after adjusting for confounding factors (p=0.022, p=0.007 and p<0.001 respectively). In END model D, we examined all imaging predictors of Recurrence Risk Estimator (RRE) individually and only the "multiple acute infarcts" pattern was significantly associated with END (p=0.032). When applying END models A, B, C and D, they successfully predicted END (p<0.001; odds ratio: 17.5[95% confidence interval: 5.1-60.8]), with 93.0% sensitivity, 60.0% specificity, 45.5% positive predictive value and 96.0% negative predictive value. The results demonstrate that the proposed model could predict END in all stroke subtypes of anterior circulation infarction. It provides a practical model for clinical physicians to select high-risk patients for more aggressive treatment to prevent END. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A unified engineering model of the first stroke in downward negative lightning

NASA Astrophysics Data System (ADS)

Nag, Amitabh; Rakov, Vladimir A.

2016-03-01

Each stroke in a negative cloud-to-ground lightning flash is composed of downward leader and upward return stroke processes, which are usually modeled individually. The first stroke leader is stepped and starts with preliminary breakdown (PB) which is often viewed as a separate process. We present the first unified engineering model for computing the electric field produced by a sequence of PB, stepped leader, and return stroke processes, serving to transport negative charge to ground. We assume that a negatively charged channel extends downward in a stepped fashion during both the PB and leader stages. Each step involves a current wave that propagates upward along the newly formed channel section. Once the leader attaches to ground, an upward propagating return stroke neutralizes the charge deposited along the channel. Model-predicted electric fields are in reasonably good agreement with simultaneous measurements at both near (hundreds of meters, electrostatic field component is dominant) and far (tens of kilometers, radiation field component is dominant) distances from the lightning channel. Relations between the features of computed electric field waveforms and model input parameters are examined. It appears that peak currents associated with PB pulses are similar to return stroke peak currents, and the observed variation of electric radiation field peaks produced by leader steps at different heights above ground is influenced by the ground corona space charge.

Development and Validation of a Predictive Model for Functional Outcome After Stroke Rehabilitation: The Maugeri Model.

PubMed

Scrutinio, Domenico; Lanzillo, Bernardo; Guida, Pietro; Mastropasqua, Filippo; Monitillo, Vincenzo; Pusineri, Monica; Formica, Roberto; Russo, Giovanna; Guarnaschelli, Caterina; Ferretti, Chiara; Calabrese, Gianluigi

2017-12-01

Prediction of outcome after stroke rehabilitation may help clinicians in decision-making and planning rehabilitation care. We developed and validated a predictive tool to estimate the probability of achieving improvement in physical functioning (model 1) and a level of independence requiring no more than supervision (model 2) after stroke rehabilitation. The models were derived from 717 patients admitted for stroke rehabilitation. We used multivariable logistic regression analysis to build each model. Then, each model was prospectively validated in 875 patients. Model 1 included age, time from stroke occurrence to rehabilitation admission, admission motor and cognitive Functional Independence Measure scores, and neglect. Model 2 included age, male gender, time since stroke onset, and admission motor and cognitive Functional Independence Measure score. Both models demonstrated excellent discrimination. In the derivation cohort, the area under the curve was 0.883 (95% confidence intervals, 0.858-0.910) for model 1 and 0.913 (95% confidence intervals, 0.884-0.942) for model 2. The Hosmer-Lemeshow χ 2 was 4.12 ( P =0.249) and 1.20 ( P =0.754), respectively. In the validation cohort, the area under the curve was 0.866 (95% confidence intervals, 0.840-0.892) for model 1 and 0.850 (95% confidence intervals, 0.815-0.885) for model 2. The Hosmer-Lemeshow χ 2 was 8.86 ( P =0.115) and 34.50 ( P =0.001), respectively. Both improvement in physical functioning (hazard ratios, 0.43; 0.25-0.71; P =0.001) and a level of independence requiring no more than supervision (hazard ratios, 0.32; 0.14-0.68; P =0.004) were independently associated with improved 4-year survival. A calculator is freely available for download at https://goo.gl/fEAp81. This study provides researchers and clinicians with an easy-to-use, accurate, and validated predictive tool for potential application in rehabilitation research and stroke management. © 2017 American Heart Association, Inc.

A modeling approach to predict acoustic nonlinear field generated by a transmitter with an aluminum lens.

PubMed

Fan, Tingbo; Liu, Zhenbo; Chen, Tao; Li, Faqi; Zhang, Dong

2011-09-01

In this work, the authors propose a modeling approach to compute the nonlinear acoustic field generated by a flat piston transmitter with an attached aluminum lens. In this approach, the geometrical parameters (radius and focal length) of a virtual source are initially determined by Snell's refraction law and then adjusted based on the Rayleigh integral result in the linear case. Then, this virtual source is used with the nonlinear spheroidal beam equation (SBE) model to predict the nonlinear acoustic field in the focal region. To examine the validity of this approach, the calculated nonlinear result is compared with those from the Westervelt and (Khokhlov-Zabolotskaya-Kuznetsov) KZK equations for a focal intensity of 7 kW/cm(2). Results indicate that this approach could accurately describe the nonlinear acoustic field in the focal region with less computation time. The proposed modeling approach is shown to accurately describe the nonlinear acoustic field in the focal region. Compared with the Westervelt equation, the computation time of this approach is significantly reduced. It might also be applicable for the widely used concave focused transmitter with a large aperture angle.

Atorvastatin treatment is associated with increased BDNF level and improved functional recovery after atherothrombotic stroke.

PubMed

Zhang, Jingmiao; Mu, Xiali; Breker, Dane A; Li, Ying; Gao, Zongliang; Huang, Yonglu

2017-01-01

Statins have a positive impact on ischemic stroke outcome. It has been reported that statin have neuroprotective function after ischemic stroke in addition to lipid-lowering effect in animal model. However, the neuroprotective function of statin after stroke has not been confirmed in clinical studies. The aim of this study was to evaluate in a clinical model if statins induce neuroprotection after stroke. We, therefore, assessed serum brain-derived neurotrophic factor (BDNF) levels and functional recovery in atherothrombotic stroke patients and investigated their relationship with atorvastatin treatment. Seventy-eight patients with atherothrombotic stroke were enrolled and randomly assigned to atorvastatin treatment group or placebo control group. Neurological function after stroke was assessed with the National Institutes of Health Stroke Scale, modified Rankin Scale (mRS) and Barthel Index (BI). The serum BDNF levels were both measured at 1 day and 6 weeks after stroke. Linear regression was used to assess the association between BDNF levels and neurological function scores. The mRS and BI were markedly improved in the atorvastatin group when compared to placebo at 6 weeks after stroke. The serum BDNF levels in atorvastatin group were significantly elevated by 6 weeks after stroke and higher than the BDNF levels in controls. In addition, the serum BDNF levels significantly correlated with mRS and BI after stroke. Our results demonstrated that atorvastatin treatment was associated with the increased BDNF level and improved functional recovery after atherothrombotic stroke. This study indicates that atorvastatin-related elevation in the BDNF level may promote functional recovery in stroke patients.

Ultrasonic vocalization changes and FOXP2 expression after experimental stroke.

PubMed

Doran, Sarah J; Trammel, Cassandra; Benashaski, Sharon E; Venna, Venugopal Reddy; McCullough, Louise D

2015-04-15

Speech impairments affect one in four stroke survivors. However, animal models of post-ischemic vocalization deficits are limited. Male mice vocalize at ultrasonic frequencies when exposed to an estrous female mouse. In this study we assessed vocalization patterns and quantity in male mice after cerebral ischemia. FOXP2, a gene associated with verbal dyspraxia in humans, with known roles in neurogenesis and synaptic plasticity, was also examined after injury. Using a transient middle cerebral artery occlusion (MCAO) model, we assessed correlates of vocal impairment at several time-points after stroke. Further, to identify possible lateralization of vocalization deficits induced by left and right hemispheric strokes were compared. Significant differences in vocalization quantity were observed between stroke and sham animals that persisted for a month after injury. Injury to the left hemisphere reduced early vocalizations more profoundly than those to the right hemisphere. Nuclear expression of Foxp2 was elevated early after stroke (at 6h), but significantly decreased 24h after injury in both the nucleus and the cytoplasm. Neuronal Foxp2 expression increased in stroke mice compared to sham animals 4 weeks after injury. This study demonstrates that quantifiable deficits in ultrasonic vocalizations (USVs) are seen after stroke. USV may be a useful tool to assess chronic behavioral recovery in murine models of stroke. Copyright © 2015 Elsevier B.V. All rights reserved.

Clinical Prediction of Functional Outcome after Ischemic Stroke: The Surprising Importance of Periventricular White Matter Disease and Race

PubMed Central

Kissela, Brett; Lindsell, Christopher J.; Kleindorfer, Dawn; Alwell, Kathleen; Moomaw, Charles J.; Woo, Daniel; Flaherty, Matthew L.; Air, Ellen; Broderick, Joseph; Tsevat, Joel

2009-01-01

Background We sought 0074o build models that address questions of interest to patients and families by predicting short- and long-term mortality and functional outcome after ischemic stroke, while allowing for risk re-stratification as comorbid events accumulate. Methods A cohort of 451 ischemic stroke subjects in 1999 were interviewed during hospitalization, at 3 months, and at approximately 4 years. Medical records from the acute hospitalization were abstracted. All hospitalizations for 3 months post-stroke were reviewed to ascertain medical and psychiatric comorbidities, which were categorized for analysis. Multivariable models were derived to predict mortality and functional outcome (modified Rankin Scale) at 3 months and 4 years. Comorbidities were included as modifiers of the 3 month models, and included in 4-year predictions. Results Post-stroke medical and psychiatric comorbidities significantly increased short term post-stroke mortality and morbidity. Severe periventricular white matter disease (PVWMD) was significantly associated with poor functional outcome at 3 months, independent of other factors, such as diabetes and age; inclusion of this imaging variable eliminated other traditional risk factors often found in stroke outcomes models. Outcome at 3 months was a significant predictor of long-term mortality and functional outcome. Black race was a predictor of 4-year mortality. Conclusions We propose that predictive models for stroke outcome, as well as analysis of clinical trials, should include adjustment for comorbid conditions. The effects of PVWMD on short-term functional outcomes and black race on long-term mortality are findings that require confirmation. PMID:19109548

Thrombectomy for ischemic stroke: meta-analyses of recurrent strokes, vasospasms, and subarachnoid hemorrhages.

PubMed

Emprechtinger, Robert; Piso, Brigitte; Ringleb, Peter A

2017-03-01

Mechanical thrombectomy with stent retrievers is an effective treatment for patients with ischemic stroke. Results of recent meta-analyses report that the treatment is safe. However, the endpoints recurrent stroke, vasospasms, and subarachnoid hemorrhage have not been evaluated sufficiently. Hence, we extracted data on these outcomes from the five recent thrombectomy trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA published in 2015). Subsequently, we conducted meta-analyses for each outcome. We report the results of the fixed, as well as the random effects model. Three studies reported data on recurrent strokes. While the results did not reach statistical significance in the random effects model (despite a three times elevated risk), the fixed effects model revealed a significantly higher rate of recurrent strokes after thrombectomy. Four studies reported data on subarachnoid hemorrhage. The higher pooled rates in the intervention groups were statistically significant in both, the fixed and the random effects model. One study reported on vasospasms. We recorded 14 events in the intervention group and none in the control group. The efficacy of mechanical thrombectomy is not questioned, yet our results indicate an increased risk for recurrent strokes, subarachnoid hemorrhage, and vasospasms post-treatment. Therefore, we strongly recommend a thoroughly surveillance, concerning these adverse events in future clinical trials and routine registries.

Big strokes in small persons.

PubMed

Adams, Robert J

2007-11-01

Sickle cell disease (SCD) is understood on a genetic and a molecular level better than most diseases. Young children with SCD are at a very high risk of stroke. The molecular pathologic abnormalities of SCD lead to microvascular occlusion and intravascular hemolytic anemia. Microvascular occlusion is related to painful episodes and probably causes microcirculatory problems in the brain. The most commonly recognized stroke syndrome in children with SCD is large-artery infarction. These "big strokes" are the result of a vascular process involving the large arteries of the circle of Willis leading to territorial infarctions from perfusion failure or possibly artery-to-artery embolism. We can detect children who are developing cerebral vasculopathy using transcranial Doppler ultrasonography (TCD) and can provide effective intervention. Transcranial Doppler ultrasonography measures blood flow velocity in the large arteries of the circle of Willis. Velocity is generally increased by the severe anemia in these patients, and it becomes elevated in a focal manner when stenosis reduces the arterial diameter. Children with SCD who are developing high stroke risk can be detected months to years before the stroke using TCD. Healthy adults have a middle cerebral artery velocity of approximately 60 cm/s, whereas children without anemia have velocities of approximately 90 cm/s. In SCD, the mean is approximately 130 cm/s. Two independent studies have demonstrated that the risk of stroke in children with SCD increases with TCD velocity. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) (1995-2000) was halted prematurely when it became evident that regular blood transfusions produced a marked (90%) reduction in first stroke. Children were selected for STOP if they had 2 TCD studies with velocities of 200 cm/s or greater. Children not undergoing transfusion had a stroke risk of 10% per year, which was reduced to less than 1% per year by regular blood transfusions. Stroke risk in all children with SCD is approximately 0.5% to 1.0% per year. On the basis of STOP, if the patient meets the high-risk TCD criteria, regular blood transfusions are recommended. A second study was performed (2000-2005) to attempt withdrawal of transfusion in selected children in a randomized controlled study. Children with initially abnormal TCD velocities (> or =200 cm/s) treated with regular blood transfusion for 30 months or more, which resulted in reduction of the TCD to less than 170 cm/s, were eligible for randomization into STOP II. Half continued transfusion and half had cessation of transfusion. This trial was halted early for safety reasons. There was an unacceptably high rate of TCD reversion back to high risk (> or =200 cm/s), as well as 2 strokes in children who discontinued transfusion. There are no evidence-based guidelines for the discontinuation of transfusion in children once they have been identified as having high risk based on TCD. The current situation is undesirable because of the long-term effects of transfusion, including iron overload. Iron overload has recently become easier to manage with the introduction of an oral iron chelator. The inflammatory environment known to exist in SCD and the known effect of plasma free hemoglobin, released by hemolysis, of reducing available nitric oxide may contribute to the development of cerebrovascular disease. Further research may lead to more targeted therapies. We can reduce many of the big strokes that occur in these small persons by aggressively screening patients at a young age (and periodically throughout the childhood risk period) and interrupting the process with regular blood transfusions.

Left Atrial Enlargement and Stroke Recurrence: The Northern Manhattan Stroke Study

PubMed Central

Yaghi, Shadi; Moon, Yeseon P.; Mora-McLaughlin, Consuelo; Willey, Joshua Z.; Cheung, Ken; Tullio, Marco R. Di; Homma, Shunichi; Kamel, Hooman; Sacco, Ralph L.; Elkind, Mitchell S. V.

2015-01-01

Background and purpose While left atrial enlargement (LAE) increases incident stroke risk, the association with recurrent stroke is less clear. Our aim was to determine the association of LAE with recurrent stroke most likely related to embolism (cryptogenic and cardioembolic), and all ischemic stroke recurrences. Methods We followed 655 first ischemic stroke patients in the Northern Manhattan Stroke Study for up to 5 years. LA size from 2-D echocardiography was categorized as normal (52.7%), mild LAE (31.6%), and moderate-severe LAE (15.7%). We used Cox proportional hazard models to calculate the hazard ratios and 95% confidence intervals (HR, 95%CI) for the association of LA size and LAE with recurrent cryptogenic/cardioembolic and total recurrent ischemic stroke. Results LA size was available in 529 (81%) patients. Mean age at enrollment was 69±13 years; 45.8% were male, 54.0% Hispanic, and 18.5% had atrial fibrillation. Over a median of 4 years there were 65 recurrent ischemic strokes (29 were cardioembolic or cryptogenic). In multivariable models adjusted for confounders including atrial fibrillation and heart failure, moderate-severe LAE compared to normal LA size was associated with greater risk of recurrent cardioembolic/cryptogenic stroke (adjusted HR 2.83, 95% CI 1.03-7.81), but not total ischemic stroke (adjusted HR 1.06, 95% CI, 0.48-2.30). Mild LAE was not associated with recurrent stroke. Conclusion Moderate to severe LAE was an independent marker of recurrent cardioembolic or cryptogenic stroke in a multiethnic cohort of ischemic stroke patients. Further research is needed to determine whether anticoagulant use may reduce risk of recurrence in ischemic stroke patients with moderate to severe LAE. PMID:25908460

Comment on “Models of stochastic, spatially varying stress in the crust compatible with focal‐mechanism data, and how stress inversions can be biased toward the stress rate” by Deborah Elaine Smith and Thomas H. Heaton

USGS Publications Warehouse

Hardebeck, Jeanne L.

2015-01-01

This model makes specific predictions about the orientations and heterogeneity of earthquake focal mechanisms. Smith and Heaton (2011) attempt to validate this heterogeneous stress model using observations of earthquake focal‐mechanism variability from Hardebeck (2006). They then demonstrate that the model predicts a bias in the orientations of earthquake focal mechanisms, which are biased away from the background stress and toward the stressing rate. They suggest the focal‐mechanism bias in this model invalidates the large body of work over the last several decades, that has inferred stress orientations from the inversion of earthquake focal mechanisms. The question of whether or not the Smith and Heaton (2011) model is applicable to the real Earth is therefore important not only for understanding spatial stress variability but also for evaluating the numerous studies that have inferred crustal stress orientations from earthquake focal mechanisms (e.g., as compiled by Heidbach et al., 2008).

Assimilation of Web-Based Urgent Stroke Evaluation: A Qualitative Study of Two Networks

PubMed Central

Mathiassen, Lars; Switzer, Jeffrey A; Adams, Robert J

2014-01-01

Background Stroke is a leading cause of death and serious, long-term disability across the world. Urgent stroke care treatment is time-sensitive and requires a stroke-trained neurologist for clinical diagnosis. Rural areas, where neurologists and stroke specialists are lacking, have a high incidence of stroke-related death and disability. By virtually connecting emergency department physicians in rural hospitals to regional medical centers for consultations, specialized Web-based stroke evaluation systems (telestroke) have helped address the challenge of urgent stroke care in underserved communities. However, many rural hospitals that have deployed telestroke have not fully assimilated this technology. Objective The objective of this study was to explore potential sources of variations in the utilization of a Web-based telestroke system for urgent stroke evaluation and propose a telestroke assimilation model to improve stroke care performance. Methods An exploratory, qualitative case study of two telestroke networks, each comprising an academic stroke center (hub) and connected rural hospitals (spokes), was conducted. Data were collected from 50 semistructured interviews with 40 stakeholders, telestroke usage logs from 32 spokes, site visits, published papers, and reports. Results The two networks used identical technology (called Remote Evaluation of Acute isCHemic stroke, REACH) and were of similar size and complexity, but showed large variations in telestroke assimilation across spokes. Several observed hub- and spoke-related characteristics can explain these variations. The hub-related characteristics included telestroke institutionalization into stroke care, resources for the telestroke program, ongoing support for stroke readiness of spokes, telestroke performance monitoring, and continuous telestroke process improvement. The spoke-related characteristics included managerial telestroke championship, stroke center certification, dedicated telestroke coordinator, stroke committee of key stakeholders, local neurological expertise, and continuous telestroke process improvement. Conclusions Rural hospitals can improve their stroke readiness with use of telestroke systems. However, they need to integrate the technology into their stroke delivery processes. A telestroke assimilation model may improve stroke care performance. PMID:25601232

Focal surfaces of hyperbolic cylinders

NASA Astrophysics Data System (ADS)

Georgiev, Georgi Hristov; Pavlov, Milen Dimov

2017-12-01

Cylindrical surfaces have many applications in geometric modeling, architecture and other branches of engineering. In this paper, we describe two cylindrical surfaces associated to a given hyperbolic cylinder. The first one is a focal surface which is determined by reciprocal principle curvature of the hyperbolic cylinder. The second one is a generalized focal surface obtained by reciprocal mean curvature of the same hyperbolic cylinder. In particular, we show that each of these surfaces admits three different parametric representations. As consequence, it is proved that the focal and generalized focal surfaces of the hyperbolic cylinder are rational surfaces. An illustrative example is included.

Compensatory Limb Use and Behavioral Assessment of Motor Skill Learning Following Sensorimotor Cortex Injury in a Mouse Model of Ischemic Stroke

PubMed Central

Kerr, Abigail L.; Tennant, Kelly A.

2014-01-01

Mouse models have become increasingly popular in the field of behavioral neuroscience, and specifically in studies of experimental stroke. As models advance, it is important to develop sensitive behavioral measures specific to the mouse. The present protocol describes a skilled motor task for use in mouse models of stroke. The Pasta Matrix Reaching Task functions as a versatile and sensitive behavioral assay that permits experimenters to collect accurate outcome data and manipulate limb use to mimic human clinical phenomena including compensatory strategies (i.e., learned non-use) and focused rehabilitative training. When combined with neuroanatomical tools, this task also permits researchers to explore the mechanisms that support behavioral recovery of function (or lack thereof) following stroke. The task is both simple and affordable to set up and conduct, offering a variety of training and testing options for numerous research questions concerning functional outcome following injury. Though the task has been applied to mouse models of stroke, it may also be beneficial in studies of functional outcome in other upper extremity injury models. PMID:25045916

Serum magnesium but not calcium was associated with hemorrhagic transformation in stroke overall and stroke subtypes: a case-control study in China.

PubMed

Tan, Ge; Yuan, Ruozhen; Wei, ChenChen; Xu, Mangmang; Liu, Ming

2018-05-26

Association between serum calcium and magnesium versus hemorrhagic transformation (HT) remains to be identified. A total of 1212 non-thrombolysis patients with serum calcium and magnesium collected within 24 h from stroke onset were enrolled. Backward stepwise multivariate logistic regression analysis was conducted to investigate association between calcium and magnesium versus HT. Calcium and magnesium were entered into logistic regression analysis in two models, separately: model 1, as continuous variable (per 1-mmol/L increase), and model 2, as four-categorized variable (being collapsed into quartiles). HT occurred in 140 patients (11.6%). Serum calcium was slightly lower in patients with HT than in patient without HT (P = 0.273). But serum magnesium was significantly lower in patients with HT than in patients without HT (P = 0.007). In logistic regression analysis, calcium displayed no association with HT. Magnesium, as either continuous or four-categorized variable, was independently and inversely associated with HT in stroke overall and stroke of large-artery atherosclerosis (LAA). The results demonstrated that serum calcium had no association with HT in patients without thrombolysis after acute ischemic stroke. Serum magnesium in low level was independently associated with increasing HT in stroke overall and particularly in stroke of LAA.

Prehospital factors determining regional variation in thrombolytic therapy in acute ischemic stroke.

PubMed

Lahr, Maarten M H; Vroomen, Patrick C A J; Luijckx, Gert-Jan; van der Zee, Durk-Jouke; de Vos, Ronald; Buskens, Erik

2014-10-01

Treatment rates with intravenous tissue plasminogen activator vary by region, which can be partially explained by organizational models of stroke care. A recent study demonstrated that prehospital factors determine a higher thrombolysis rate in a centralized vs. decentralized model in the north of the Netherlands. To investigate prehospital factors that may explain variation in thrombolytic therapy between a centralized and a decentralized model. A consecutive case observational study was conducted in the north of the Netherlands comparing patients arriving within 4·5 h in a centralized vs. decentralized stroke care model. Factors investigated were transportation mode, prehospital diagnostic accuracy, and preferential referral of thrombolysis candidates. Potential confounders were adjusted using logistic regression analysis. A total of 172 and 299 arriving within 4·5 h were enrolled in centralized and decentralized settings, respectively. The rate of transportation by emergency medical services was greater in the centralized model (adjusted odds ratio 3·11; 95% confidence interval, 1·59-6·06). Also, more misdiagnoses of stroke occurred in the central model (P = 0·05). In postal code areas with and without potential preferential referral of thrombolysis candidates due to overlapping catchment areas, the odds of hospital arrival within 4·5 h in the central vs. decentral model were 2·15 (95% confidence interval, 1·39-3·32) and 1·44 (95% confidence interval, 1·04-2·00), respectively. These results suggest that the larger proportion of patients arriving within 4·5 h in the centralized model might be related to a lower threshold to use emergency services to transport stroke patients and partly to preferential referral of thrombolysis candidates. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.

Effect of antihypertensive treatment on focal cerebral infarction.

PubMed

Fujii, K; Weno, B L; Baumbach, G L; Heistad, D D

1992-06-01

The goal of the current study was to determine whether treatment of hypertension reduces cerebral infarction after occlusion of the middle cerebral artery in stroke-prone spontaneously hypertensive rats (SHRSPs). Three-month-old SHRSPs received untreated drinking water or drinking water containing cilazapril, an angiotensin converting enzyme inhibitor, or hydralazine and hydrochlorothiazide. After 3 months of treatment, the left middle cerebral artery was occluded and neurological deficit was evaluated. Infarct volume was measured 3 days after occlusion using computer imaging techniques from brain slices. Cilazapril and hydralazine with hydrochlorothiazide were equally effective in reducing systolic blood pressure in SHRSPs. One day after occlusion of the middle cerebral artery, neurological deficit was decreased by both cilazapril and hydralazine with hydrochlorothiazide compared with untreated SHRSPs, and the deficit 3 days after occlusion was decreased significantly only by cilazapril. Infarct volume was 178 +/- 7 mm3 (mean +/- SEM) in untreated SHRSPs, and it was significantly reduced to 117 +/- 15 mm3 by hydralazine with hydrochlorothiazide and to 101 +/- 17 mm3 by cilazapril. Infarct volume in Wistar-Kyoto rats was 27 +/- 16 mm3. Thus, reduction in arterial pressure by hydralazine with hydrochlorothiazide or an angiotensin converting enzyme inhibitor is protective against focal cerebral ischemia in SHRSPs.

Disentangling interoception: insights from focal strokes affecting the perception of external and internal milieus

PubMed Central

Couto, Blas; Adolfi, Federico; Sedeño, Lucas; Salles, Alejo; Canales-Johnson, Andrés; Alvarez-Abut, Pablo; Garcia-Cordero, Indira; Pietto, Marcos; Bekinschtein, Tristan; Sigman, Mariano; Manes, Facundo; Ibanez, Agustin

2015-01-01

Interoception is the moment-to-moment sensing of the physiological condition of the body. The multimodal sources of interoception can be classified into two different streams of afferents: an internal pathway of signals arising from core structures (i.e., heart, blood vessels, and bronchi) and an external pathway of body-mapped sensations (i.e., chemosensation and pain) arising from peripersonal space. This study examines differential processing along these streams within the insular cortex (IC) and their subcortical tracts connecting frontotemporal networks. Two rare patients presenting focal lesions of the IC (insular lesion, IL) or its subcortical tracts (subcortical lesion, SL) were tested. Internally generated interoceptive streams were assessed through a heartbeat detection (HBD) task, while those externally triggered were tapped via taste, smell, and pain recognition tasks. A differential pattern was observed. The IC patient showed impaired internal signal processing while the SL patient exhibited external perception deficits. Such selective deficits remained even when comparing each patient with a group of healthy controls and a group of brain-damaged patients. These outcomes suggest the existence of distinguishable interoceptive streams. Results are discussed in relation with neuroanatomical substrates, involving a fronto-insulo-temporal network for interoceptive and cognitive contextual integration. PMID:25983697

White matter injury in term newborns with neonatal encephalopathy.

PubMed

Li, Amanda M; Chau, Vann; Poskitt, Kenneth J; Sargent, Michael A; Lupton, Brian A; Hill, Alan; Roland, Elke; Miller, Steven P

2009-01-01

White matter injury (WMI) is the characteristic pattern of brain injury detected on magnetic resonance imaging in the premature newborn. Focal noncystic WMI is increasingly recognized in populations of term newborns. The aim of this study was to describe the occurrence of focal noncystic WMI in a cohort of 48 term newborns with encephalopathy studied with magnetic resonance imaging at 72 +/- 12 h of life, and to identify clinical risk factors for this pattern of injury. Eleven newborns (23%; 95% CI 11-35) were found to have WMI (four minimal, three moderate, and four severe). In 10 of the 11 newborns, the WMI was associated with restricted diffusion on apparent diffusion coefficient maps. An increasing severity of WMI was associated with lower gestational age at birth (p = 0.05), but not lower birth weight. Newborns with WMI had milder encephalopathy and fewer clinical seizures relative to other newborns in the cohort. Other brain injuries were seen in three of the 11 newborns: basal nuclei predominant pattern of injury in one and cortical strokes in two. These findings suggest that WMI in the term newborn is acquired near birth and that the state of brain maturation is an important determinant of this pattern of brain injury.

Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature.

PubMed

Seidowsky, Alexandre; Hoffmann, Maxime; Glowacki, François; Dhaenens, Claire-Marie; Devaux, Jean-Philippe; de Sainte Foy, Celia Lessore; Provot, François; Gheerbrant, Jean-Dominique; Hummel, Aurelie; Hazzan, Marc; Dracon, Michel; Dieux-Coeslier, Anne; Copin, Marie-Christine; Noël, Christian; Buob, David

2013-12-01

Renal dysfunction is increasingly recognized as a potential clinical feature of mitochondrial cytopathies such as mitochondrial encephalomyopathy, lacticacidosis and stroke-like episodes (MELAS) syndrome. Five cases of MELAS syndrome with renal involvement from 4 unrelated families are presented in this case series. Three of the 5 patients had a history of maternally-inherited diabetes and/or deafness. Focal and segmental glomerulosclerosis and arteriolar hyaline thickening were the most striking findings on renal biopsy. In addition to clinical presentation with the typical symptoms of MELAS syndrome, genetic testing in these patients identified the A3243G point mutation in the tRNALeu gene of the mitochondrial DNA (mtDNA). The diagnosis of MELAS syndrome was thus considered to be unequivocal. The incidence of kidney disease in MELAS syndrome may be underestimated although a study is required to investigate this hypothesis. As the A3243G mtDNA mutation leads to a progressive adult-onset form of focal segmental glomerulosclerosis (FSGS), screening for the MELAS A3243G mtDNA mutation should therefore be performed especially in patients with maternally-inherited diabetes or hearing loss presenting with FSGS.

What Happens after Inbreeding Avoidance? Inbreeding by Rejected Relatives and the Inclusive Fitness Benefit of Inbreeding Avoidance

PubMed Central

Duthie, A. Bradley; Reid, Jane M.

2015-01-01

Avoiding inbreeding, and therefore avoiding inbreeding depression in offspring fitness, is widely assumed to be adaptive in systems with biparental reproduction. However, inbreeding can also confer an inclusive fitness benefit stemming from increased relatedness between parents and inbred offspring. Whether or not inbreeding or avoiding inbreeding is adaptive therefore depends on a balance between inbreeding depression and increased parent-offspring relatedness. Existing models of biparental inbreeding predict threshold values of inbreeding depression above which males and females should avoid inbreeding, and predict sexual conflict over inbreeding because these thresholds diverge. However, these models implicitly assume that if a focal individual avoids inbreeding, then both it and its rejected relative will subsequently outbreed. We show that relaxing this assumption of reciprocal outbreeding, and the assumption that focal individuals are themselves outbred, can substantially alter the predicted thresholds for inbreeding avoidance for focal males. Specifically, the magnitude of inbreeding depression below which inbreeding increases a focal male’s inclusive fitness increases with increasing depression in the offspring of a focal female and her alternative mate, and it decreases with increasing relatedness between a focal male and a focal female’s alternative mate, thereby altering the predicted zone of sexual conflict. Furthermore, a focal male’s inclusive fitness gain from avoiding inbreeding is reduced by indirect opportunity costs if his rejected relative breeds with another relative of his. By demonstrating that variation in relatedness and inbreeding can affect intra- and inter-sexual conflict over inbreeding, our models lead to novel predictions for family dynamics. Specifically, parent-offspring conflict over inbreeding might depend on the alternative mates of rejected relatives, and male-male competition over inbreeding might lead to mixed inbreeding strategies. Making testable quantitative predictions regarding inbreeding strategies occurring in nature will therefore require new models that explicitly capture variation in relatedness and inbreeding among interacting population members. PMID:25909185

Air pollution and the incidence of ischaemic and haemorrhagic stroke in the South London Stroke Register: a case-cross-over analysis.

PubMed

Butland, B K; Atkinson, R W; Crichton, S; Barratt, B; Beevers, S; Spiridou, A; Hoang, U; Kelly, F J; Wolfe, C D

2017-07-01

Few European studies investigating associations between short-term exposure to air pollution and incident stroke have considered stroke subtypes. Using information from the South London Stroke Register for 2005-2012, we investigated associations between daily concentrations of gaseous and particulate air pollutants and incident stroke subtypes in an ethnically diverse area of London, UK. Modelled daily pollutant concentrations based on a combination of measurements and dispersion modelling were linked at postcode level to incident stroke events stratified by haemorrhagic and ischaemic subtypes. The data were analysed using a time-stratified case-cross-over approach. Conditional logistic regression models included natural cubic splines for daily mean temperature and daily mean relative humidity, a binary term for public holidays and a sine-cosine annual cycle. Of primary interest were same day mean concentrations of particulate matter <2.5 and <10 µm in diameter (PM 2.5 , PM 10 ), ozone (O 3 ), nitrogen dioxide (NO 2 ) and NO 2 +nitrogen oxide (NO X ). Our analysis was based on 1758 incident strokes (1311 were ischaemic and 256 were haemorrhagic). We found no evidence of an association between all stroke or ischaemic stroke and same day exposure to PM 2.5 , PM 10 , O 3 , NO 2 or NO X . For haemorrhagic stroke, we found a negative association with PM 10 suggestive of a 14.6% (95% CI 0.7% to 26.5%) fall in risk per 10 µg/m 3 increase in pollutant. Using data from the South London Stroke Register, we found no evidence of a positive association between outdoor air pollution and incident stroke or its subtypes. These results, though in contrast to recent meta-analyses, are not inconsistent with the mixed findings of other UK studies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Dietary patterns are associated with incident stroke and contribute to excess risk of stroke in black Americans.

PubMed

Judd, Suzanne E; Gutiérrez, Orlando M; Newby, P K; Howard, George; Howard, Virginia J; Locher, Julie L; Kissela, Brett M; Shikany, James M

2013-12-01

Black Americans and residents of the Southeastern United States are at increased risk of stroke. Diet is one of many potential factors proposed that might explain these racial and regional disparities. Between 2003 and 2007, the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study enrolled 30 239 black and white Americans aged≥45 years. Dietary patterns were derived using factor analysis and foods from food frequency data. Incident strokes were adjudicated using medical records by a team of physicians. Cox-proportional hazards models were used to examine risk of stroke. During 5.7 years, 490 incident strokes were observed. In a multivariable-adjusted analysis, greater adherence to the plant-based pattern was associated with lower stroke risk (hazard ratio, 0.71; 95% confidence interval, 0.56-0.91; Ptrend=0.005). This association was attenuated after addition of income, education, total energy intake, smoking, and sedentary behavior. Participants with a higher adherence to the Southern pattern experienced a 39% increased risk of stroke (hazard ratio, 1.39; 95% confidence interval, 1.05, 1.84), with a significant (P=0.009) trend across quartiles. Including Southern pattern in the model mediated the black-white risk of stroke by 63%. These data suggest that adherence to a Southern style diet may increase the risk of stroke, whereas adherence to a more plant-based diet may reduce stroke risk. Given the consistency of finding a dietary effect on stroke risk across studies, discussing nutrition patterns during risk screening may be an important step in reducing stroke.

Hemoglobin Concentration and Risk of Incident Stroke in Community-Living Adults.

PubMed

Panwar, Bhupesh; Judd, Suzanne E; Warnock, David G; McClellan, William M; Booth, John N; Muntner, Paul; Gutiérrez, Orlando M

2016-08-01

In previous observational studies, hemoglobin concentrations have been associated with an increased risk of stroke. However, these studies were limited by a relatively low number of stroke events, making it difficult to determine whether the association of hemoglobin and stroke differed by demographic or clinical factors. Using Cox proportional hazards analysis and Kaplan-Meier plots, we examined the association of baseline hemoglobin concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults aged ≥45 years. A total of 518 participants developed stroke over a mean 7±2 years of follow-up. There was a statistically significant interaction between hemoglobin and sex (P=0.05) on the risk of incident stroke. In Cox regression models adjusted for demographic and clinical variables, there was no association of baseline hemoglobin concentration with incident stroke in men, whereas in women, the lowest (<12.4 g/dL) and highest (>14.0 g/dL) quartiles of hemoglobin were associated with higher risk of stroke when compared with the second quartile (12.4-13.2 g/dL; quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.09-2.31; quartile 2: referent; quartile 3: hazard ratio, 0.91; 95% confidence interval, 0.59-1.38; quartile 4: hazard ratio, 1.59; 95% confidence interval, 1.08-2.35). Similar results were observed in models stratified by hemoglobin and sex and when hemoglobin was modeled as a continuous variable using restricted quadratic spline regression. Lower and higher hemoglobin concentrations were associated with a higher risk of incident stroke in women. No such associations were found in men. © 2016 American Heart Association, Inc.

A New Approach of Short Wave Protection against Middle Cerebral Artery Occlusion/Reperfusion Injury via Attenuation of Golgi Apparatus Stress by Inhibition of Downregulation of Secretory Pathway Ca(2+)-ATPase Isoform 1 in Rats.

PubMed

Fan, Yongmei; Zhang, Changjie; Li, Ting; Peng, Wenna; Yin, Jing; Li, Xiaofao; Kong, Ying; Lan, Chunna; Wang, Rumi; Hu, Zhiping

2016-07-01

Short wave (SW), a pattern of electromagnetic therapy, achieves an oscillating electromagnetic field. It has been reported that it may have a potential effect on cerebral injury. The present study was designed to investigate the potential role and possible mechanism of SW in focal cerebral ischemia/reperfusion (I/R) injury in rats. Secretory pathway Ca(2+)/Mn(2+) ATPase isoform 1 is a major component of Golgi apparatus stress. It has been reported as representative of Golgi apparatus stress. Up to 120 minutes of middle cerebral artery occlusion (MCAO) and reperfusion injury was induced in male Sprague-Dawley rats. Different sessions of SW daily were administered over head after reperfusion from day 1 to day 7. Functional recovery scores, survival rates, infarct volume analysis, electron microscope test, and western blotting studies were used to analyze the therapy. SW protected against neuronal death and apoptosis in cornu ammon 1 region of hippocampus by reducing neuronal deficit, infarct volume, and ultrastructure. SW partly inhibited upregulation of caspase3. In addition, the expression of secretory pathway Ca(2+)-ATPase isoform 1 (SPCA1) was upregulated by SW. Our data indicate that SW can be protected against focal cerebral I/R injury, and the influence on Golgi apparatus stress might provide us a new perspective in further study. To the authors' knowledge, this is the first report using SW to increase expression of SPCA1 indicating modulate Golgi apparatus stress in MCAO and reperfusion model. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

The impact of stroke unit care on outcome in a Scottish stroke population, taking into account case mix and selection bias.

PubMed

Turner, Melanie; Barber, Mark; Dodds, Hazel; Dennis, Martin; Langhorne, Peter; Macleod, Mary Joan

2015-03-01

Randomised trials indicate that stroke unit care reduces morbidity and mortality after stroke. Similar results have been seen in observational studies but many have not corrected for selection bias or independent predictors of outcome. We evaluated the effect of stroke unit compared with general ward care on outcomes after stroke in Scotland, adjusting for case mix by incorporating the six simple variables (SSV) model, also taking into account selection bias and stroke subtype. We used routine data from National Scottish datasets for acute stroke patients admitted between 2005 and 2011. Patients who died within 3 days of admission were excluded from analysis. The main outcome measures were survival and discharge home. Multivariable logistic regression was used to estimate the OR for survival, and adjustment was made for the effect of the SSV model and for early mortality. Cox proportional hazards model was used to estimate the hazard of death within 365 days. There were 41 692 index stroke events; 79% were admitted to a stroke unit at some point during their hospital stay and 21% were cared for in a general ward. Using the SSV model, we obtained a receiver operated curve of 0.82 (SE 0.002) for mortality at 6 months. The adjusted OR for survival at 7 days was 3.11 (95% CI 2.71 to 3.56) and at 1 year 1.43 (95% CI 1.34 to 1.54) while the adjusted OR for being discharged home was 1.19 (95% CI 1.11 to 1.28) for stroke unit care. In routine practice, stroke unit admission is associated with a greater likelihood of discharge home and with lower mortality up to 1 year, after correcting for known independent predictors of outcome, and excluding early non-modifiable mortality. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

High-Value Care in the Evaluation of Stroke.

PubMed

Urja, Prakrity; Nippoldt, Eric H; Barak, Virginia; Valenta, Carrie

2017-08-01

Value-based care emphasizes achieving the greatest overall health benefit for every dollar spent. We present an interesting case of stroke, which made us consider how frequently health care providers are utilizing value-based care. A 73-year-old Caucasian, who was initially admitted for a hypertensive emergency, was transferred to our facility for worsening slurring of speech and left-sided weakness. The patient had an extensive chronic cerebrovascular disease, including multiple embolic type strokes, mainly in the distribution of the right temporal-occipital cerebral artery and transient ischemic attacks (TIAs). The patient had a known history of patent foramen ovale (PFO) and occlusion of the right internal carotid artery. He was complicated by intracranial hemorrhage while on anticoagulation for pulmonary embolism. He was chronically on dual antiplatelet therapy (aspirin and clopidogrel) and statin.  Following the transfer, stroke protocol, including the activation of the stroke team, a computed tomography (CT) imaging study, and the rapid stabilization of the patient was initiated. His vitals were stable, and the physical examination was significant for the drooping of the left angle of the mouth, a nonreactive right pupil consistent with the previous stroke, a decreased strength in the left upper and lower extremities, and a faint systolic murmur. His previous stroke was shown to be embolic, involving both the right temporal and occipital regions, which was re-demonstrated in a CT scan. A magnetic resonance imaging (MRI) scan of the brain showed a new, restricted diffusion in the right pons that was compatible with an acute stroke as well as diffusely atherosclerotic vessels with a focal stenosis of the branch vessels. A transthoracic echocardiogram demonstrated no new thrombus in the heart. A transesophageal echocardiogram (TEE) showed known PFO, and repeat hypercoagulation evaluation was negative, as it was in his previous cerebrovascular accident (CVA) evaluation.  Appropriate medical treatment with antiplatelets, as indicated by the acute stroke guidelines, was started. The patient was not eligible for thrombolysis. Value-based care emphasizes the decreased usage in investigations or health care of options that do not contribute to the overall health and well-being of the patient. Given our patient's past medical history and the results of previous investigations, we questioned the value of ordering a hypercoagulable evaluation and TEE in our patient. The need for an evaluation of the hypercoagulable state in an elderly patient with ischemic stroke or TIA remains unknown. Our patient had a complete hypercoagulable evaluation done six years earlier. Repeating the hypercoagulable evaluation would not contribute to the treatment decisions and, as a result, would not satisfy the basic criteria for value-based care.The importance of a repeat TEE is uncertain in the evaluation of embolism for a known cause of stroke. Additionally, no change in management was anticipated regardless of the TEE findings, therefore, repeating TEE in our patient was an inappropriate use of resources. Being mindful of value-based care can reduce overall health care costs, maintain our role of being responsible stewards of our limited resources, and continue to provide high-value care for our patients.

Symptoms of Insomnia and Sleep Duration and Their Association with Incident Strokes: Findings from the Population-Based MONICA/KORA Augsburg Cohort Study.

PubMed

Helbig, A Katharina; Stöckl, Doris; Heier, Margit; Ladwig, Karl-Heinz; Meisinger, Christa

2015-01-01

To examine the relationship between symptoms of insomnia and sleep duration and incident total (non-fatal plus fatal) strokes, non-fatal strokes, and fatal strokes in a large cohort of men and women from the general population in Germany. In four population-based MONICA (monitoring trends and determinants in cardiovascular disease)/KORA (Cooperative Health Research in the Region of Augsburg) surveys conducted between 1984 and 2001, 17,604 men and women (aged 25 to 74 years) were asked about issues like sleep, health behavior, and medical history. In subsequent surveys and mortality follow-ups, incident stroke cases (cerebral hemorrhage, ischemic stroke, transient ischemic attack, unknown stroke type) were gathered prospectively until 2009. Sex-specific hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using sequential Cox proportional hazards regression models. During a mean follow-up of 14 years, 917 strokes (710 non-fatal strokes and 207 fatal strokes) were observed. Trouble falling asleep and difficulty staying asleep were not significantly related to any incident stroke outcome in either sex in the multivariable models. Among men, the HR for the association between short (≤5 hours) and long (≥10 hours) daily sleep duration and total strokes were 1.44 (95% CI: 1.01-2.06) and 1.63 (95% CI: 1.16-2.29), after adjustment for basic confounding variables. As for non-fatal strokes and fatal strokes, in the analyses adjusted for age, survey, education, physical activity, alcohol consumption, smoking habits, body mass index, hypertension, diabetes, and dyslipidemia, the increased risks persisted, albeit somewhat attenuated, but no longer remained significant. Among women, in the multivariable analyses the quantity of sleep was also not related to any stroke outcome. In the present study, symptoms of insomnia and exceptional sleep duration were not significantly predictive of incident total strokes, non-fatal strokes, and fatal strokes in either sex.

Symptoms of Insomnia and Sleep Duration and Their Association with Incident Strokes: Findings from the Population-Based MONICA/KORA Augsburg Cohort Study

PubMed Central

Helbig, A. Katharina; Stöckl, Doris; Heier, Margit; Ladwig, Karl-Heinz; Meisinger, Christa

2015-01-01

Objective To examine the relationship between symptoms of insomnia and sleep duration and incident total (non-fatal plus fatal) strokes, non-fatal strokes, and fatal strokes in a large cohort of men and women from the general population in Germany. Methods In four population-based MONICA (monitoring trends and determinants in cardiovascular disease)/KORA (Cooperative Health Research in the Region of Augsburg) surveys conducted between 1984 and 2001, 17,604 men and women (aged 25 to 74 years) were asked about issues like sleep, health behavior, and medical history. In subsequent surveys and mortality follow-ups, incident stroke cases (cerebral hemorrhage, ischemic stroke, transient ischemic attack, unknown stroke type) were gathered prospectively until 2009. Sex-specific hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using sequential Cox proportional hazards regression models. Results During a mean follow-up of 14 years, 917 strokes (710 non-fatal strokes and 207 fatal strokes) were observed. Trouble falling asleep and difficulty staying asleep were not significantly related to any incident stroke outcome in either sex in the multivariable models. Among men, the HR for the association between short (≤5 hours) and long (≥10 hours) daily sleep duration and total strokes were 1.44 (95% CI: 1.01–2.06) and 1.63 (95% CI: 1.16–2.29), after adjustment for basic confounding variables. As for non-fatal strokes and fatal strokes, in the analyses adjusted for age, survey, education, physical activity, alcohol consumption, smoking habits, body mass index, hypertension, diabetes, and dyslipidemia, the increased risks persisted, albeit somewhat attenuated, but no longer remained significant. Among women, in the multivariable analyses the quantity of sleep was also not related to any stroke outcome. Conclusion In the present study, symptoms of insomnia and exceptional sleep duration were not significantly predictive of incident total strokes, non-fatal strokes, and fatal strokes in either sex. PMID:26230576

Validation of the Neurological Fatigue Index for stroke (NFI-Stroke)

PubMed Central

2012-01-01

Background Fatigue is a common symptom in Stroke. Several self-report scales are available to measure this debilitating symptom but concern has been expressed about their construct validity. Objective To examine the reliability and validity of a recently developed scale for multiple sclerosis (MS) fatigue, the Neurological Fatigue Index (NFI-MS), in a sample of stroke patients. Method Six patients with stroke participated in qualitative interviews which were analysed and the themes compared for equivalence to those derived from existing data on MS fatigue. 999 questionnaire packs were sent to those with a stroke within the past four years. Data from the four subscales, and the Summary scale of the NFI-MS were fitted to the Rasch measurement model. Results Themes identified by stroke patients were consistent with those identified by those with MS. 282 questionnaires were returned and respondents had a mean age of 67.3 years; 62% were male, and were on average 17.2 (SD 11.4, range 2–50) months post stroke. The Physical, Cognitive and Summary scales all showed good fit to the model, were unidimensional, and free of differential item functioning by age, sex and time. The sleep scales failed to show adequate fit in their current format. Conclusion Post stroke fatigue appears to be represented by a combination of physical and cognitive components, confirmed by both qualitative and quantitative processes. The NFI-Stroke, comprising a Physical and Cognitive subscale, and a 10-item Summary scale, meets the strictest measurement requirements. Fit to the Rasch model allows conversion of ordinal raw scores to a linear metric. PMID:22587411

A three-item scale for the early prediction of stroke recovery.

PubMed

Baird, A E; Dambrosia, J; Janket, S; Eichbaum, Q; Chaves, C; Silver, B; Barber, P A; Parsons, M; Darby, D; Davis, S; Caplan, L R; Edelman, R E; Warach, S

2001-06-30

Accurate assessment of prognosis in the first hours of stroke is desirable for best patient management. We aimed to assess whether the extent of ischaemic brain injury on magnetic reasonance diffusion-weighted imaging (MR DWI) could provide additional prognostic information to clinical factors. In a three-phase study we studied 66 patients from a North American teaching hospital who had: MR DWI within 36 h of stroke onset; the National Institutes of Health Stroke Scale (NIHSS) score measured at the time of scanning; and the Barthel Index measured no later than 3 months after stroke. We used logistic regression to derive a predictive model for good recovery. This logistic regression model was applied to an independent series of 63 patients from an Australian teaching hospital, and we then developed a three-item scale for the early prediction of stroke recovery. Combined measurements of the NIHSS score (p=0.01), time in hours from stroke onset to MR DWI (p=0.02), and the volume of ischaemic brain tissue on MR DWI (p=0.04) gave the best prediction of stroke recovery. The model was externally validated on the Australian sample with 0.77 sensitivity and 0.88 specificity. Three likelihood levels for stroke recovery-low (0-2), medium (3-4), and high (5-7)-were identified on the three-item scale. The combination of clinical and MR DWI factors provided better prediction of stroke recovery than any factor alone, shortly after admission to hospital. This information was incorporated into a three-item scale for clinical use.

Mathematical Formulation of the Remote Electric and Magnetic Emissions of the Lightning Dart Leader and Return Stroke

NASA Astrophysics Data System (ADS)

Thiemann, Edward M. B.

Lightning detection and geolocation networks have found widespread use by the utility, air traffic control and forestry industries as a means of locating strikes and predicting imminent recurrence. Accurate lightning geolocation requires detecting VLF radio emissions at multiple sites using a distributed sensor network with typical baselines exceeding 150 km, along with precision time of arrival estimation to triangulate the origin of a strike. The trend has been towards increasing network accuracy without increasing sensor density by incorporating precision GPS synchronized clocks and faster front-end signal processing. Because lightning radio waveforms evolve as they propagate over a finitely conducting earth, and that measurements for a given strike may have disparate propagation path lengths, accurate models are required to determine waveform fiducials for precise strike location. The transition between the leader phase and return stroke phase may offer such a fiducial and warrants quantitative modeling to improve strike location accuracy. The VLF spectrum of the ubiquitous downward negative lightning strike is able to be modeled by the transfer of several Coulombs of negative charge from cloud to ground in a two-step process. The lightning stepped leader ionizes a plasma channel downward from the cloud at a velocity of approximately 0.05c, leaving a column of charge in its path. Upon connection with a streamer, the subsequent return stroke initiates at or near ground level and travels upward at an average but variable velocity of 0.3c. The return stroke neutralizes any negative charge along its path. Subsequent dart leader and return strokes often travel smoothly down the heated channel left by a preceding stroke, lacking the halting motion of the preceding initial stepped leader and initial return stroke. Existing lightning models often neglect the leader current and rely on approximations when solving for the return stroke. In this thesis, I present an analytic solution to Maxwell's Equations for the lightning leader followed by a novel return stroke model. I model the leader as a downward propagating boxcar function of uniform charge density and constant velocity, and the subsequent return stroke is modeled as an upward propagating boxcar with a time dependent velocity. Charge conservation is applied to ensure self-consistency of the driving current and charge sources, and physical observations are used to support model development. The resulting transient electric and magnetic fields are presented at various distances and delay times and compared with measured waveforms and previously published models.

Economic burden of informal care attributable to stroke among those aged 65 years or older in China.

PubMed

Joo, Heesoo; Liang, Di

2017-02-01

Stroke is a leading cause of disability in China, frequently resulting in the need for informal care. No information, however, is available on costs of informal care associated with stroke, required to understand the true cost of stroke in China. Using the 2011 China Health and Retirement Longitudinal Study, we identified 4447 respondents aged ≥65 years suitable for analyses, including 184 stroke survivors. We estimated the economic burden of informal care associated with stroke using a two-part model. The monthly number of hours of informal caregiving associated with stroke was 29.2 h/stroke survivor, and the average annual cost of informal care associated with stroke was 10,612 RMB per stroke survivor. The findings stress the necessity of proper interventions to prevent stroke and will be useful for estimating the economic burden of stroke.

A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice.

PubMed

Atochin, Dmitriy N; Schepetkin, Igor A; Khlebnikov, Andrei I; Seledtsov, Victor I; Swanson, Helen; Quinn, Mark T; Huang, Paul L

2016-04-08

The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30min) with subsequent reperfusion (48h). Mice were treated with IQ-1S (25mg/kg) suspended in 10% solutol or with vehicle alone 30min before and 24h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30min of MCAO provoked by a filament and during the first 30min of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48h of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Three Variations in Rabbit Angiographic Stroke Models

PubMed Central

Culp, William C.; Woods, Sean D.; Brown, Aliza T.; Lowery, John D.; Hennings, Leah J.; Skinner, Robert D.; Borrelli, Michael J.; Roberson, Paula K.

2012-01-01

Purpose To develop angiographic models of embolic stroke in the rabbit using pre-formed clot or microspheres to model clinical situations ranging from transient ischemic events to severe ischemic stroke. Materials and Methods New Zealand White rabbits (N=151) received angiographic access to the internal carotid artery (ICA) from a femoral approach. Variations of emboli type and quantity of emboli were tested by injection into the ICA. These included fresh clots (1.0-mm length, 3–6 h), larger aged clots (4.0-mm length, 3 days), and 2 or 3 insoluble microspheres (700–900 μm). Neurological assessment scores (NAS) were based on motor, sensory, balance, and reflex measures. Rabbits were euthanized at 4, 7, or 24 hours after embolization, and infarct volume was measured as a percent of total brain volume using 2,3,5-triphenyltetrazolium chloride (TTC). Results Infarct volume percent at 24 hours after stroke was lower for rabbits embolized with fresh clot (0.45% ± 0.14%), compared with aged clot (3.52% ± 1.31%) and insoluble microspheres (3.39% ± 1.04%). Overall NAS (including posterior vessel occlusions) were positively correlated to infarct volume percent measurements in the fresh clot (r=0.50), aged clot (r=0.65) and microsphere (r=0.62) models (p<0.001). Conclusion The three basic angiographic stroke models may be similar to human transient ischemic attacks (TIA) (fresh clot), major strokes that can be thrombolysed (aged clot), or major strokes with insoluble emboli such as atheromata (microspheres). Model selection can be tailored to specific research needs. PMID:23142182

Quantifying Selection Bias in National Institute of Health Stroke Scale Data Documented in an Acute Stroke Registry.

PubMed

Thompson, Michael P; Luo, Zhehui; Gardiner, Joseph; Burke, James F; Nickles, Adrienne; Reeves, Mathew J

2016-05-01

As a measure of stroke severity, the National Institutes of Health Stroke Scale (NIHSS) is an important predictor of patient- and hospital-level outcomes, yet is often undocumented. The purpose of this study is to quantify and correct for potential selection bias in observed NIHSS data. Data were obtained from the Michigan Stroke Registry and included 10 262 patients with ischemic stroke aged ≥65 years discharged from 23 hospitals from 2009 to 2012, of which 74.6% of patients had documented NIHSS. We estimated models predicting NIHSS documentation and NIHSS score and used the Heckman selection model to estimate a correlation coefficient (ρ) between the 2 model error terms, which quantifies the degree of selection bias in the documentation of NIHSS. The Heckman model found modest, but significant, selection bias (ρ=0.19; 95% confidence interval: 0.09, 0.29; P<0.001), indicating that because NIHSS score increased (ie, strokes were more severe), the probability of documentation also increased. We also estimated a selection bias-corrected population mean NIHSS score of 4.8, which was substantially lower than the observed mean NIHSS score of 7.4. Evidence of selection bias was also identified using hospital-level analysis, where increased NIHSS documentation was correlated with lower mean NIHSS scores (r=-0.39; P<0.001). We demonstrate modest, but important, selection bias in documented NIHSS data, which are missing more often in patients with less severe stroke. The population mean NIHSS score was overestimated by >2 points, which could significantly alter the risk profile of hospitals treating patients with ischemic stroke and subsequent hospital risk-adjusted outcomes. © 2016 American Heart Association, Inc.

Combined effects of road traffic noise and ambient air pollution in relation to risk for stroke?

PubMed

Sørensen, Mette; Lühdorf, Pernille; Ketzel, Matthias; Andersen, Zorana J; Tjønneland, Anne; Overvad, Kim; Raaschou-Nielsen, Ole

2014-08-01

Exposure to road traffic noise and air pollution have both been associated with risk for stroke. The few studies including both exposures show inconsistent results. We aimed to investigate potential mutual confounding and combined effects between road traffic noise and air pollution in association with risk for stroke. In a population-based cohort of 57,053 people aged 50-64 years at enrollment, we identified 1999 incident stroke cases in national registries, followed by validation through medical records. Mean follow-up time was 11.2 years. Present and historical residential addresses from 1987 to 2009 were identified in national registers and road traffic noise and air pollution were modeled for all addresses. Analyses were done using Cox regression. A higher mean annual exposure at time of diagnosis of 10 µg/m(3) nitrogen dioxide (NO2) and 10 dB road traffic noise at the residential address was associated with ischemic stroke with incidence rate ratios (IRR) of 1.11 (95% CI: 1.03, 1.20) and 1.16 (95% CI: 1.07, 1.24), respectively, in single exposure models. In two-exposure models road traffic noise (IRR: 1.15) and not NO2 (IRR: 1.02) was associated with ischemic stroke. The strongest association was found for combination of high noise and high NO2 (IRR=1.28; 95% CI=1.09-1.52). Fatal stroke was positively associated with air pollution and not with traffic noise. In conclusion, in mutually adjusted models road traffic noise and not air pollution was associated ischemic stroke, while only air pollution affected risk for fatal strokes. There were indications of combined effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Contralesional motor deficits after unilateral stroke reflect hemisphere-specific control mechanisms

PubMed Central

Mani, Saandeep; Mutha, Pratik K.; Przybyla, Andrzej; Haaland, Kathleen Y.; Good, David C.

2013-01-01

We have proposed a model of motor lateralization, in which the left and right hemispheres are specialized for different aspects of motor control: the left hemisphere for predicting and accounting for limb dynamics and the right hemisphere for stabilizing limb position through impedance control mechanisms. Our previous studies, demonstrating different motor deficits in the ipsilesional arm of stroke patients with left or right hemisphere damage, provided a critical test of our model. However, motor deficits after stroke are most prominent on the contralesional side. Post-stroke rehabilitation has also, naturally, focused on improving contralesional arm impairment and function. Understanding whether contralesional motor deficits differ depending on the hemisphere of damage is, therefore, of vital importance for assessing the impact of brain damage on function and also for designing rehabilitation interventions specific to laterality of damage. We, therefore, asked whether motor deficits in the contralesional arm of unilateral stroke patients reflect hemisphere-dependent control mechanisms. Because our model of lateralization predicts that contralesional deficits will differ depending on the hemisphere of damage, this study also served as an essential assessment of our model. Stroke patients with mild to moderate hemiparesis in either the left or right arm because of contralateral stroke and healthy control subjects performed targeted multi-joint reaching movements in different directions. As predicted, our results indicated a double dissociation; although left hemisphere damage was associated with greater errors in trajectory curvature and movement direction, errors in movement extent were greatest after right hemisphere damage. Thus, our results provide the first demonstration of hemisphere specific motor control deficits in the contralesional arm of stroke patients. Our results also suggest that it is critical to consider the differential deficits induced by right or left hemisphere lesions to enhance post-stroke rehabilitation interventions. PMID:23358602

Brain repair after stroke—a novel neurological model

PubMed Central

Small, Steven L.; Buccino, Giovanni; Solodkin, Ana

2017-01-01

Following stroke, patients are commonly left with debilitating motor and speech impairments. This article reviews the state of the art in neurological repair for stroke and proposes a new model for the future. We suggest that stroke treatment—from the time of the ictus itself to living with the consequences—must be fundamentally neurological, from limiting the extent of injury at the outset, to repairing the consequent damage. Our model links brain and behaviour by targeting brain circuits, and we illustrate the model though action observation treatment, which aims to enhance brain network connectivity. The model is based on the assumptions that the mechanisms of neural repair inherently involve cellular and circuit plasticity, that brain plasticity is a synaptic phenomenon that is largely stimulus-dependent, and that brain repair required both physical and behavioural interventions that are tailored to reorganize specific brain circuits. We review current approaches to brain repair after stroke and present our new model, and discuss the biological foundations, rationales, and data to support our novel approach to upper-extremity and language rehabilitation. We believe that by enhancing plasticity at the level of brain network interactions, this neurological model for brain repair could ultimately lead to a cure for stroke. PMID:24217509

Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage.

PubMed

Glushakova, Olena Y; Johnson, Danny; Hayes, Ronald L

2014-07-01

Traumatic brain injury (TBI) is a significant risk factor for chronic traumatic encephalopathy (CTE), Alzheimer's disease (AD), and Parkinson's disease (PD). Cerebral microbleeds, focal inflammation, and white matter damage are associated with many neurological and neurodegenerative disorders including CTE, AD, PD, vascular dementia, stroke, and TBI. This study evaluates microvascular abnormalities observed at acute and chronic stages following TBI in rats, and examines pathological processes associated with these abnormalities. TBI in adult rats was induced by controlled cortical impact (CCI) of two magnitudes. Brain pathology was assessed in white matter of the corpus callosum for 24 h to 3 months following injury using immunohistochemistry (IHC). TBI resulted in focal microbleeds that were related to the magnitude of injury. At the lower magnitude of injury, microbleeds gradually increased over the 3 month duration of the study. IHC revealed TBI-induced focal abnormalities including blood-brain barrier (BBB) damage (IgG), endothelial damage (intercellular adhesion molecule 1 [ICAM-1]), activation of reactive microglia (ionized calcium binding adaptor molecule 1 [Iba1]), gliosis (glial fibrillary acidic protein [GFAP]) and macrophage-mediated inflammation (cluster of differentiation 68 [CD68]), all showing different temporal profiles. At chronic stages (up to 3 months), apparent myelin loss (Luxol fast blue) and scattered deposition of microbleeds were observed. Microbleeds were surrounded by glial scars and co-localized with CD68 and IgG puncta stainings, suggesting that localized BBB breakdown and inflammation were associated with vascular damage. Our results indicate that evolving white matter degeneration following experimental TBI is associated with significantly delayed microvascular damage and focal microbleeds that are temporally and regionally associated with development of punctate BBB breakdown and progressive inflammatory responses. Increased understanding of mechanisms underlying delayed microvascular damage following TBI could provide novel insights into chronic pathological responses to TBI and potential common mechanisms underlying TBI and neurodegenerative diseases.

Early functional MRI activation predicts motor outcome after ischemic stroke: a longitudinal, multimodal study.

PubMed

Du, Juan; Yang, Fang; Zhang, Zhiqiang; Hu, Jingze; Xu, Qiang; Hu, Jianping; Zeng, Fanyong; Lu, Guangming; Liu, Xinfeng

2018-05-15

An accurate prediction of long term outcome after stroke is urgently required to provide early individualized neurorehabilitation. This study aimed to examine the added value of early neuroimaging measures and identify the best approaches for predicting motor outcome after stroke. This prospective study involved 34 first-ever ischemic stroke patients (time since stroke: 1-14 days) with upper limb impairment. All patients underwent baseline multimodal assessments that included clinical (age, motor impairment), neurophysiological (motor-evoked potentials, MEP) and neuroimaging (diffusion tensor imaging and motor task-based fMRI) measures, and also underwent reassessment 3 months after stroke. Bivariate analysis and multivariate linear regression models were used to predict the motor scores (Fugl-Meyer assessment, FMA) at 3 months post-stroke. With bivariate analysis, better motor outcome significantly correlated with (1) less initial motor impairment and disability, (2) less corticospinal tract injury, (3) the initial presence of MEPs, (4) stronger baseline motor fMRI activations. In multivariate analysis, incorporating neuroimaging data improved the predictive accuracy relative to only clinical and neurophysiological assessments. Baseline fMRI activation in SMA was an independent predictor of motor outcome after stroke. A multimodal model incorporating fMRI and clinical measures best predicted the motor outcome following stroke. fMRI measures obtained early after stroke provided independent prediction of long-term motor outcome.

Synergism of Short-Term Air Pollution Exposures and Neighborhood Disadvantage on Initial Stroke Severity.

PubMed

Wing, Jeffrey J; Sánchez, Brisa N; Adar, Sara D; Meurer, William J; Morgenstern, Lewis B; Smith, Melinda A; Lisabeth, Lynda D

2017-11-01

Little is known about the relation between environment and stroke severity. We investigated associations between environmental exposures, including neighborhood socioeconomic disadvantage and short-term exposure to airborne particulate matter <2.5 μm and ozone, and their interactions with initial stroke severity. First-ever ischemic stroke cases were identified from the Brain Attack Surveillance in Corpus Christi project (2000-2012). Associations between pollutants, disadvantage, and National Institutes of Health Stroke Scale were modeled using linear and logistic regression with adjustment for demographics and risk factors. Pollutants and disadvantage were modeled individually, jointly, and with interactions. Higher disadvantage scores and previous-day ozone concentrations were associated with higher odds of severe stroke. Higher levels of particulate matter <2.5 μm were associated with higher odds of severe stroke among those in higher disadvantage areas (odds ratio, 1.24; 95% confidence interval, 1.00-1.55) but not in lower disadvantage areas (odds ratio, 0.82; 95% confidence interval, 0.56-1.22; P interaction =0.097). Air pollution exposures and neighborhood socioeconomic status may be important in understanding stroke severity. Future work should consider the multiple levels of influence on this important stroke outcome. © 2017 American Heart Association, Inc.

Neurochemical changes underpinning the development of adjunct therapies in recovery after stroke: A role for GABA?

PubMed

Johnstone, Ainslie; Levenstein, Jacob M; Hinson, Emily L; Stagg, Charlotte J

2017-01-01

Stroke is a leading cause of long-term disability, with around three-quarters of stroke survivors experiencing motor problems. Intensive physiotherapy is currently the most effective treatment for post-stroke motor deficits, but much recent research has been targeted at increasing the effects of the intervention by pairing it with a wide variety of adjunct therapies, all of which aim to increase cortical plasticity, and thereby hope to maximize functional outcome. Here, we review the literature describing neurochemical changes underlying plasticity induction following stroke. We discuss methods of assessing neurochemicals in humans, and how these measurements change post-stroke. Motor learning in healthy individuals has been suggested as a model for stroke plasticity, and we discuss the support for this model, and what evidence it provides for neurochemical changes. One converging hypothesis from animal, healthy and stroke studies is the importance of the regulation of the inhibitory neurotransmitter GABA for the induction of cortical plasticity. We discuss the evidence supporting this hypothesis, before finally summarizing the literature surrounding the use of adjunct therapies such as non-invasive brain stimulation and SSRIs in post-stroke motor recovery, both of which have been show to influence the GABAergic system.

Assessing Mobile Health Capacity and Task Shifting Strategies to Improve Hypertension Among Ghanaian Stroke Survivors.

PubMed

Nichols, Michelle; Sarfo, Fred Stephen; Singh, Arti; Qanungo, Suparna; Treiber, Frank; Ovbiagele, Bruce; Saulson, Raelle; Patel, Sachin; Jenkins, Carolyn

2017-12-01

There has been a tremendous surge in stroke prevalence in sub-Saharan Africa. Hypertension (HTN), the most potent, modifiable risk factor for stroke, is a particular challenge in sub-Saharan Africa. Culturally sensitive, efficacious HTN control programs that are timely and sustainable are needed, especially among stroke survivors. Mobile health (mHealth) technology and task-shifting offer promising approaches to address this need. Using a concurrent triangulation design, we collected data from stroke survivors, caregivers, community leaders, clinicians and hospital personnel to explore the barriers, facilitators and perceptions toward mHealth related to HTN management among poststroke survivors in Ghana. Exploration included perceptions of a nurse-led navigational model to facilitate care delivery and willingness of stroke survivors and caregivers to use mHealth technology. Two hundred stroke survivors completed study surveys while focus groups (n = 4) were conducted with stroke survivors, caregivers and community leaders (n = 28). Key informant interviews were completed with clinicians and hospital personnel (n = 10). A total of 93% of survey respondents had HTN (60% uncontrolled). Findings support mHealth strategies for poststroke care delivery and HTN management and for task-shifting through a nurse-led model. Of survey and focus group participants, 76% and 78.6%, respectively, have access to mobile phones and 90% express comfort in using mobile phones and conveyed assurance that task-shifting through a nurse-led model could facilitate management of HTN. Findings also identified barriers to care delivery and medication adherence across all levels of the social ecological model. Participants strongly supported enhanced care delivery through mobile health and were receptive toward a nurse-led navigational model. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Oxotremorine-induced cerebral hyperemia does not predict infarction volume in spontaneously hypertensive or stroke-prone rats.

PubMed

Harukuni, I; Takahashi, H; Traystman, R J; Bhardwaj, A; Kirsch, J R

2000-01-01

We tested the following hypotheses: a) spontaneously hypertensive stroke-prone rats (SHR-SP) have more brain injury than spontaneously hypertensive rats (SHR) and normotensive controls (Wistar-Kyoto rats [WKY]) when exposed to transient focal ischemia; b) infarction size is not correlated with baseline blood pressure; and c) infarction size is inversely related to the cerebral hyperemic response to oxotremorine, a muscarinic agonist that increases cerebral blood flow (CBF) by stimulating endothelial nitric oxide synthase. In vivo study. Animal laboratory in a university teaching hospital. Adult age-matched male WKY, SHR, and SHR-SP. Rats were instrumented under halothane anesthesia. Transient focal cerebral ischemia was produced for 2 hrs with the intravascular suture technique. Cerebral perfusion, estimated with laser Doppler flowmetry (LD-CBF), in response to intravenous oxotremorine, was measured in one cohort of rats to estimate endothelial nitric oxide synthase function. Infarction volume was measured at 22 hrs of reperfusion with 2,3,5-triphenyltetrazolium chloride staining. Infarction volume in the striatum of SHR-SP (42+/-4 mm3) was greater than in SHR (29+/-6 mm3) or WKY (1+/-1 mm3) (n = 9 rats/strain). Resting (unanesthetized) mean arterial blood pressure was similar in SHR-SP (177+/-5 mm Hg) and SHR (170+/-5 mm Hg) despite a greater infarction volume in SHR-SP (n = 4) compared with SHR (n = 5). The percentage increase in LD-CBF signal in response to oxotremorine was similar for both groups (SHR, 64%+/-22% [n = 10]; SHR-SP, 69%+/-22% [n = 8]). However, in this cohort, cortical infarction volume was less in SHR (30%+/-4% of ipsilateral cortex) than in SHR-SP (49%+/-2% of ipsilateral cortex). Although SHR-SP have greater infarction volume than SHR, the mechanism of injury does not appear to be related to a difference in unanesthetized baseline mean arterial blood pressure or to an alteration in endothelium-produced nitric oxide.

Quantitative EEG and functional outcome following acute ischemic stroke.

PubMed

Bentes, Carla; Peralta, Ana Rita; Viana, Pedro; Martins, Hugo; Morgado, Carlos; Casimiro, Carlos; Franco, Ana Catarina; Fonseca, Ana Catarina; Geraldes, Ruth; Canhão, Patrícia; Pinho E Melo, Teresa; Paiva, Teresa; Ferro, José M

2018-06-18

To identify the most accurate quantitative electroencephalographic (qEEG) predictor(s) of unfavorable post-ischemic stroke outcome, and its discriminative capacity compared to already known demographic, clinical and imaging prognostic markers. Prospective cohort of 151 consecutive anterior circulation ischemic stroke patients followed for 12 months. EEG was recorded within 72 h and at discharge or 7 days post-stroke. QEEG (global band power, symmetry, affected/unaffected hemisphere and time changes) indices were calculated from mean Fast Fourier Transform and analyzed as predictors of unfavorable outcome (mRS ≥ 3), at discharge and 12 months poststroke, before and after adjustment for age, admission NIHSS and ASPECTS. Higher delta, lower alpha and beta relative powers (RP) predicted outcome. Indices with higher discriminative capacity were delta-theta to alpha-beta ratio (DTABR) and alpha RP. Outcome models including either of these and other clinical/imaging stroke outcome predictors were superior to models without qEEG data. In models with qEEG indices, infarct size was not a significant outcome predictor. DTAABR and alpha RP are the best qEEG indices and superior to ASPECTS in post-stroke outcome prediction. They improve the discriminative capacity of already known clinical and imaging stroke outcome predictors, both at discharge and 12 months after stroke. qEEG indices are independent predictors of stroke outcome. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Recognizing Chinese characters in digital ink from non-native language writers using hierarchical models

NASA Astrophysics Data System (ADS)

Bai, Hao; Zhang, Xi-wen

2017-06-01

While Chinese is learned as a second language, its characters are taught step by step from their strokes to components, radicals to components, and their complex relations. Chinese Characters in digital ink from non-native language writers are deformed seriously, thus the global recognition approaches are poorer. So a progressive approach from bottom to top is presented based on hierarchical models. Hierarchical information includes strokes and hierarchical components. Each Chinese character is modeled as a hierarchical tree. Strokes in one Chinese characters in digital ink are classified with Hidden Markov Models and concatenated to the stroke symbol sequence. And then the structure of components in one ink character is extracted. According to the extraction result and the stroke symbol sequence, candidate characters are traversed and scored. Finally, the recognition candidate results are listed by descending. The method of this paper is validated by testing 19815 copies of the handwriting Chinese characters written by foreign students.

The influence of the breakdown electric field in the configuration of lightning corona sheath on charge distribution in the channel

NASA Astrophysics Data System (ADS)

Ignjatovic, Milan; Cvetic, Jovan; Heidler, Fridolin; Markovic, Slavoljub; Djuric, Radivoje

2014-11-01

A model of corona sheath that surrounds the thin core of the lightning channel has been investigated by using a generalized traveling current source return stroke model. The lightning channel is modeled by a charged corona sheath that stretches around a highly conductive central core through which the main current flows. The channel core with the negatively charged outer channel sheath forms a strong electric field, with an overall radial orientation. The return stroke process is modeled as the negative leader charge in the corona sheath being discharged by the positive charge coming from the channel core. Expressions that describe how the corona sheath radius evolves during the return stroke are obtained from the corona sheath model, which predicts charge motion within the sheath. The corona sheath model, set forth by Maslowski and Rakov (2006), Tausanovic et al. (2010), Marjanovic and Cvetic (2009), Cvetic et al. (2011) and Cvetic et al. (2012), divides the sheath onto three zones: zone 1 (surrounding the channel core with net positive charge), zone 2 (surrounding zone 1 with negative charge) and zone 3 (the outer zone, representing uncharged virgin air). In the present study, we have assumed a constant electric field inside zone 1, as suggested by experimental research of corona discharges in coaxial geometry conducted by Cooray (2000). The present investigation builds upon previous studies by Tausanovic et al. (2010) and Cvetic et al. (2012) in several ways. The value of the breakdown electric field has been varied for probing its effect on channel charge distribution prior and during the return stroke. With the aim of investigating initial space charge distribution along the channel, total electric field at the outer surface of the channel corona sheath, just before the return stroke, is calculated and compared for various return stroke models. A self-consistent algorithm is applied to the generalized traveling current source return stroke model, so that the boundary condition for total electric field is fulfilled. The new density of space charge and the new radius of channel corona envelope, immediately before the return stroke stage, are calculated. The obtained results indicate a strong dependence of channel charge distribution on the breakdown electric field value. Among the compared return stroke models, transmission-line-type models have exhibited a good agreement with the predictions of the Gauss' law regarding total breakdown electric field on the corona sheath's outer surface. The generalized lightning traveling current source return stroke model gives similar results if the adjustment of the space charge density inside the corona sheath is performed.

Balance Confidence: A Predictor of Perceived Physical Function, Perceived Mobility, and Perceived Recovery 1 Year After Inpatient Stroke Rehabilitation.

PubMed

Torkia, Caryne; Best, Krista L; Miller, William C; Eng, Janice J

2016-07-01

To estimate the effect of balance confidence measured at 1 month poststroke rehabilitation on perceived physical function, mobility, and stroke recovery 12 months later. Longitudinal study (secondary analysis). Multisite, community-based. Community-dwelling individuals (N=69) with stroke living in a home setting. Not applicable. Activities-specific Balance Confidence scale; physical function and mobility subscales of the Stroke Impact Scale 3.0; and a single item from the Stroke Impact Scale for perceived recovery. Balance confidence at 1 month postdischarge from inpatient rehabilitation predicts perceived physical function (model 1), mobility (model 2), and recovery (model 3) 12 months later after adjusting for important covariates. The covariates included in model 1 were age, sex, basic mobility, and depression. The covariates selected for model 2 were age, sex, balance capacity, and anxiety, and the covariates in model 3 were age, sex, walking capacity, and social support. The amount of variance in perceived physical function, perceived mobility, and perceived recovery that balance confidence accounted for was 12%, 9%, and 10%, respectively. After discharge from inpatient rehabilitation poststroke, balance confidence predicts individuals' perceived physical function, mobility, and recovery 12 months later. There is a need to address balance confidence at discharge from inpatient stroke rehabilitation. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Age at stroke: temporal trends in stroke incidence in a large, biracial population.

PubMed

Kissela, Brett M; Khoury, Jane C; Alwell, Kathleen; Moomaw, Charles J; Woo, Daniel; Adeoye, Opeolu; Flaherty, Matthew L; Khatri, Pooja; Ferioli, Simona; De Los Rios La Rosa, Felipe; Broderick, Joseph P; Kleindorfer, Dawn O

2012-10-23

We describe temporal trends in stroke incidence stratified by age from our population-based stroke epidemiology study. We hypothesized that stroke incidence in younger adults (age 20-54) increased over time, most notably between 1999 and 2005. The Greater Cincinnati/Northern Kentucky region includes an estimated population of 1.3 million. Strokes were ascertained in the population between July 1, 1993, and June 30, 1994, and in calendar years 1999 and 2005. Age-, race-, and gender-specific incidence rates with 95 confidence intervals were calculated assuming a Poisson distribution. We tested for differences in age trends over time using a mixed-model approach, with appropriate link functions. The mean age at stroke significantly decreased from 71.2 years in 1993/1994 to 69.2 years in 2005 (p < 0.0001). The proportion of all strokes under age 55 increased from 12.9% in 1993/1994 to 18.6% in 2005. Regression modeling showed a significant change over time (p = 0.002), characterized as a shift to younger strokes in 2005 compared with earlier study periods. Stroke incidence rates in those 20-54 years of age were significantly increased in both black and white patients in 2005 compared to earlier periods. We found trends toward increasing stroke incidence at younger ages. This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable.

Therapeutic dormancy to delay postsurgical glioma recurrence: the past, present and promise of focal hypothermia.

PubMed

Wion, Didier

2017-07-01

Surgery precedes both radiotherapy and chemotherapy as the first-line therapy for glioma. However, despite multimodal treatment, most glioma patients die from local recurrence in the resection margin. Glioma surgery is inherently lesional, and the response of brain tissue to surgery includes hemostasis, angiogenesis, reactive gliosis and inflammation. Unfortunately, these processes are also associated with tumorigenic side-effects. An increasing amount of evidence indicates that the response to a surgery-related brain injury is hijacked by residual glioma cells and participates in the local regeneration of tumor tissues at the resection margin. Inducing therapeutic hypothermia in the brain has long been used to treat the secondary damage, such as neuroinflammation and edema, that are caused by accidental traumatic brain injuries. There is compelling evidence to suggest that inducing therapeutic hypothermia at the resection margin would delay the local recurrence of glioma by (i) limiting cell proliferation, (ii) disrupting the pathological connection between inflammation and glioma recurrence, and (iii) limiting the consequences of the functional heterogeneity and complexity inherent to the tumor ecosystem. While the global whole-body cooling methods that are currently used to treat stroke in clinical practice may not adequately treat the resection margin, the future lies in implantable focal microcooling devices similar to those under development for the treatment of epilepsy. Preclinical and clinical strategies to evaluate focal hypothermia must be implemented to prevent glioma recurrence in the resection margin. Placing the resection margin in a state of hibernation may potentially provide such a long-awaited therapeutic breakthrough.

Role of Hydrogen Sulfide in Early Blood-Brain Barrier Disruption following Transient Focal Cerebral Ischemia

PubMed Central

Jiang, Zheng; Li, Chun; Manuel, Morganne L.; Yuan, Shuai; Kevil, Christopher G.; McCarter, Kimberly D.; Lu, Wei; Sun, Hong

2015-01-01

We determined the role of endogenous hydrogen sulfide (H₂S) in cerebral vasodilation/hyperemia and early BBB disruption following ischemic stroke. A cranial window was prepared over the left frontal, parietal and temporal cortex in mice. Transient focal cerebral Ischemia was induced by directly ligating the middle cerebral artery (MCA) for two hours. Regional vascular response and cerebral blood flow (CBF) during ischemia and reperfusion were measured in real time. Early BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. Topical treatment with DL-propargylglycine (PAG, an inhibitor for cystathionine γ-lyase (CSE)) and aspartate (ASP, inhibitor for cysteine aminotransferase/3-mercaptopyruvate sulfurtransferase (CAT/3-MST)), but not O-(Carboxymethyl)hydroxylamine hemihydrochloride (CHH, an inhibitor for cystathionine β-synthase (CBS)), abolished postischemic cerebral vasodilation/hyperemia and prevented EB and Na-F extravasation. CSE knockout (CSE-/-) reduced postischemic cerebral vasodilation/hyperemia but only inhibited Na-F extravasation. An upregulated CBS was found in cerebral cortex of CSE-/- mice. Topical treatment with CHH didn’t further alter postischemic cerebral vasodilation/hyperemia, but prevented EB extravasation in CSE-/- mice. In addition, L-cysteine-induced hydrogen sulfide (H2S) production similarly increased in ischemic side cerebral cortex of control and CSE-/- mice. Our findings suggest that endogenous production of H2S by CSE and CAT/3-MST during reperfusion may be involved in postischemic cerebral vasodilation/hyperemia and play an important role in early BBB disruption following transient focal cerebral ischemia. PMID:25695633

Heart Performance Determination by Visualization in Larval Fishes: Influence of Alternative Models for Heart Shape and Volume

PubMed Central

Perrichon, Prescilla; Grosell, Martin; Burggren, Warren W.

2017-01-01

Understanding cardiac function in developing larval fishes is crucial for assessing their physiological condition and overall health. Cardiac output measurements in transparent fish larvae and other vertebrates have long been made by analyzing videos of the beating heart, and modeling this structure using a conventional simple prolate spheroid shape model. However, the larval fish heart changes shape during early development and subsequent maturation, but no consideration has been made of the effect of different heart geometries on cardiac output estimation. The present study assessed the validity of three different heart models (the “standard” prolate spheroid model as well as a cylinder and cone tip + cylinder model) applied to digital images of complete cardiac cycles in larval mahi-mahi and red drum. The inherent error of each model was determined to allow for more precise calculation of stroke volume and cardiac output. The conventional prolate spheroid and cone tip + cylinder models yielded significantly different stroke volume values at 56 hpf in red drum and from 56 to 104 hpf in mahi. End-diastolic and stroke volumes modeled by just a simple cylinder shape were 30–50% higher compared to the conventional prolate spheroid. However, when these values of stroke volume multiplied by heart rate to calculate cardiac output, no significant differences between models emerged because of considerable variability in heart rate. Essentially, the conventional prolate spheroid shape model provides the simplest measurement with lowest variability of stroke volume and cardiac output. However, assessment of heart function—especially if stroke volume is the focus of the study—should consider larval heart shape, with different models being applied on a species-by-species and developmental stage-by-stage basis for best estimation of cardiac output. PMID:28725199

Interleukin-6 (IL-6) rs1800796 and cyclin dependent kinase inhibitor (CDKN2A/CDKN2B) rs2383207 are associated with ischemic stroke in indigenous West African Men.

PubMed

Akinyemi, Rufus; Arnett, Donna K; Tiwari, Hemant K; Ovbiagele, Bruce; Sarfo, Fred; Srinivasasainagendra, Vinodh; Irvin, Marguerite Ryan; Adeoye, Abiodun; Perry, Rodney T; Akpalu, Albert; Jenkins, Carolyn; Owolabi, Lukman; Obiako, Reginald; Wahab, Kolawole; Sanya, Emmanuel; Komolafe, Morenikeji; Fawale, Michael; Adebayo, Philip; Osaigbovo, Godwin; Sunmonu, Taofiki; Olowoyo, Paul; Chukwuonye, Innocent; Obiabo, Yahaya; Akpa, Onoja; Melikam, Sylvia; Saulson, Raelle; Kalaria, Raj; Ogunniyi, Adesola; Owolabi, Mayowa

2017-08-15

Inherited genetic variations offer a possible explanation for the observed peculiarities of stroke in sub - Saharan African populations. Interleukin-6 polymorphisms have been previously associated with ischemic stroke in some non-African populations. Herein we investigated, for the first time, the association of genetic polymorphisms of IL-6, CDKN2A- CDKN2B and other genes with ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study. Twenty-three previously identified single nucleotide polymorphisms (SNPs) in 14 genes of relevance to the neurobiology of ischemic stroke were investigated. Logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of the 23 SNPs in rigorously phenotyped cases (N=429) of ischemic stroke (Men=198; Women=231) and stroke- free (N=483) controls (Men=236; Women=247). Interleukin-6 (IL6) rs1800796 (C minor allele; frequency: West Africans=8.6%) was significantly associated with ischemic stroke in men (OR=2.006, 95% CI=[1.065, 3.777], p=0.031) with hypertension in the model but not in women. In addition, rs2383207 in CDKN2A/CDKN2B (minor allele A with frequency: West Africans=1.7%) was also associated with ischemic stroke in men (OR=2.550, 95% CI=[1.027, 6.331], p=0.044) with primary covariates in the model, but not in women. Polymorphisms in other genes did not show significant association with ischemic stroke. Polymorphisms rs1800796 in IL6 gene and rs2383207 in CDKN2A/CDKN2B gene have significant associations with ischemic stroke in indigenous West African men. CDKN2A/CDKN2B SNP rs2383207 is independently associated with ischemic stroke in indigenous West African men. Further research should focus on the contributions of inflammatory genes and other genetic polymorphisms, as well as the influence of sex on the neurobiology of stroke in people of African ancestry. Copyright © 2017 Elsevier B.V. All rights reserved.

Isolated insular strokes and plasma MR-proANP levels are associated with newly diagnosed atrial fibrillation: a pilot study.

PubMed

Frontzek, Karl; Fluri, Felix; Siemerkus, Jakob; Müller, Beat; Gass, Achim; Christ-Crain, Mirjam; Katan, Mira

2014-01-01

In this study, we assessed the relationship of insular strokes and plasma MR-proANP levels with newly diagnosed atrial fibrillation (NDAF). This study is based on a prospective acute stroke cohort (http://www.clinicaltrials.gov, NCT00390962). Patient eligibility was dependent on the diagnosis of acute ischemic stroke, absence of previous stroke based on past medical history and MRI, no history of AF and congestive heart failure (cohort A) and, additionally, no stroke lesion size ≥ 20 mL (sub-cohort A*). AF, the primary endpoint, was detected on 24-hour electrocardiography and/or echocardiography. Involvement of the insula was assessed by two experienced readers on MRI blinded to clinical data. MR-proANP levels were obtained through a novel sandwich immunoassay. Logistic-regression-models were fitted to estimate odds ratios for the association of insular strokes and MR-proANP with NDAF. The discriminatory accuracy of insular strokes and MR-proANP was assessed by a model-wise comparison of the area under the receiver-operating-characteristics-curve (AUC) with known predictors of AF. 104 (cohort A) and 83 (cohort A*) patients fulfilled above-mentioned criteria. Patients with isolated insular strokes had a 10.7-fold higher odds of NDAF than patients with a small ischemic stroke at any other location. The AUC of multivariate logistic regression models for the prediction of NDAF improved significantly when adding stroke location and MR-proANP levels. Moreover, MR-proANP levels remained significantly elevated throughout the acute hospitalization period in patients with NDAF compared to those without. Isolated insular strokes and plasma MR-proANP levels on admission are independent predictors of NDAF and significantly improve the prediction accuracy of identifying patients with NDAF compared to known predictors including age, the NIHSS and lesion size. To accelerate accurate diagnosis and enhance secondary prevention in acute stroke, higher levels of MR-proANP and insular strokes may represent easily accessible indicators of AF if confirmed in an independent validation cohort.

Modelling the potential impact of a sugar-sweetened beverage tax on stroke mortality, costs and health-adjusted life years in South Africa.

PubMed

Manyema, Mercy; Veerman, Lennert J; Tugendhaft, Aviva; Labadarios, Demetre; Hofman, Karen J

2016-05-31

Stroke poses a growing human and economic burden in South Africa. Excess sugar consumption, especially from sugar-sweetened beverages (SSBs), has been associated with increased obesity and stroke risk. Research shows that price increases for SSBs can influence consumption and modelling evidence suggests that taxing SSBs has the potential to reduce obesity and related diseases. This study estimates the potential impact of an SSB tax on stroke-related mortality, costs and health-adjusted life years in South Africa. A proportional multi-state life table-based model was constructed in Microsoft Excel (2010). We used consumption data from the 2012 South African National Health and Nutrition Examination Survey, previously published own and cross price elasticities of SSBs and energy balance equations to estimate changes in daily energy intake and BMI arising from increased SSB prices. Stroke relative risk, and prevalent years lived with disability estimates from the Global Burden of Disease Study and modelled disease epidemiology estimates from a previous study, were used to estimate the effect of the BMI changes on the burden of stroke. Our model predicts that an SSB tax may avert approximately 72 000 deaths, 550 000 stroke-related health-adjusted life years and over ZAR5 billion, (USD400 million) in health care costs over 20 years (USD296-576 million). Over 20 years, the number of incident stroke cases may be reduced by approximately 85 000 and prevalent cases by about 13 000. Fiscal policy has the potential, as part of a multi-faceted approach, to mitigate the growing burden of stroke in South Africa and contribute to the achievement of the target set by the Department of Health to reduce relative premature mortality (less than 60 years) from non-communicable diseases by the year 2020.

C-reactive protein in the detection of post-stroke infections: systematic review and individual participant data analysis.

PubMed

Bustamante, Alejandro; Vilar-Bergua, Andrea; Guettier, Sophie; Sánchez-Poblet, Josep; García-Berrocoso, Teresa; Giralt, Dolors; Fluri, Felix; Topakian, Raffi; Worthmann, Hans; Hug, Andreas; Molnar, Tihamer; Waje-Andreassen, Ulrike; Katan, Mira; Smith, Craig J; Montaner, Joan

2017-04-01

We conducted a systematic review and individual participant data meta-analysis to explore the role of C-reactive protein (CRP) in early detection or prediction of post-stroke infections. CRP, an acute-phase reactant binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria, thereby activating complement and promoting phagocytosis by macrophages. We searched PubMed up to May-2015 for studies measuring CRP in stroke and evaluating post-stroke infections. Individual participants' data were merged into a single database. CRP levels were standardized and divided into quartiles. Factors independently associated with post-stroke infections were determined by logistic regression analysis and the additional predictive value of CRP was assessed by comparing areas under receiver operating characteristic curves and integrated discrimination improvement index. Data from seven studies including 699 patients were obtained. Standardized CRP levels were higher in patients with post-stroke infections beyond 24 h. Standardized CRP levels in the fourth quartile were independently associated with infection in two different logistic regression models, model 1 [stroke severity and dysphagia, odds ratio = 9.70 (3.10-30.41)] and model 2 [age, sex, and stroke severity, odds ratio = 3.21 (1.93-5.32)]. Addition of CRP improved discrimination in both models [integrated discrimination improvement = 9.83% (0.89-18.77) and 5.31% (2.83-7.79), respectively], but accuracy was only improved for model 1 (area under the curve 0.806-0.874, p = 0.036). In this study, CRP was independently associated with development of post-stroke infections, with the optimal time-window for measurement at 24-48 h. However, its additional predictive value is moderate over clinical information. Combination with other biomarkers in a panel seems a promising strategy for future studies. © 2017 International Society for Neurochemistry.

The Additional Contribution of White Matter Hyperintensity Location to Post-stroke Cognitive Impairment: Insights From a Multiple-Lesion Symptom Mapping Study.

PubMed

Zhao, Lei; Wong, Adrian; Luo, Yishan; Liu, Wenyan; Chu, Winnie W C; Abrigo, Jill M; Lee, Ryan K L; Mok, Vincent; Shi, Lin

2018-01-01

White matter hyperintensities (WMH) are common in acute ischemic stroke patients. Although WMH volume has been reported to influence post-stroke cognition, it is still not clear whether WMH location, independent of acute ischemic lesion (AIL) volume and location, contributes to cognitive impairment after stroke. Here, we proposed a multiple-lesion symptom mapping model that considers both the presence of WMH and AIL to measure the additional contribution of WMH locations to post-stroke cognitive impairment. Seventy-six first-ever stroke patients with AILs in the left hemisphere were examined by Montreal Cognitive Assessment (MoCA) at baseline and 1 year after stroke. The association between the location of AIL and WMH and global cognition was investigated by a multiple-lesion symptom mapping (MLSM) model based on support vector regression (SVR). To explore the relative merits of MLSM over the existing lesion-symptom mapping approaches with only AIL considered (mass-univariate VLSM and SVR-LSM), we measured the contribution of the significant AIL and/or WMH clusters from these models to post-stroke cognitive impairment. In addition, we compared the significant WMH locations identified by the optimal SVR-MLSM model for cognitive impairment at baseline and 1 year post stroke. The identified strategic locations of WMH significantly contributed to the prediction of MoCA at baseline (short-term) and 1 year (long-term) after stroke independent of the strategic locations of AIL. The significant clusters of WMH for short-term and long-term post-stroke cognitive impairment were mainly in the corpus callosum, corona radiata, and posterior thalamic radiation. We noted that in some regions, the AIL clusters that were significant for short-term outcome were no longer significant for long-term outcome, and interestingly more WMH clusters in these regions became significant for long-term outcome compared to short-term outcome. This indicated that there are some regions where local WMH burden has larger impact than AIL burden on the long-term post-stroke cognitive impairment. In consequence, SVR-MLSM was effective in identifying the WMH locations that have additional impact on post-stroke cognition on top of AIL locations. Such a method can also be applied to other lesion-behavior studies where multiple types of lesions may have potential contributions to a specific behavior.

Stroke Location Is an Independent Predictor of Cognitive Outcome.

PubMed

Munsch, Fanny; Sagnier, Sharmila; Asselineau, Julien; Bigourdan, Antoine; Guttmann, Charles R; Debruxelles, Sabrina; Poli, Mathilde; Renou, Pauline; Perez, Paul; Dousset, Vincent; Sibon, Igor; Tourdias, Thomas

2016-01-01

On top of functional outcome, accurate prediction of cognitive outcome for stroke patients is an unmet need with major implications for clinical management. We investigated whether stroke location may contribute independent prognostic value to multifactorial predictive models of functional and cognitive outcomes. Four hundred twenty-eight consecutive patients with ischemic stroke were prospectively assessed with magnetic resonance imaging at 24 to 72 hours and at 3 months for functional outcome using the modified Rankin Scale and cognitive outcome using the Montreal Cognitive Assessment (MoCA). Statistical maps of functional and cognitive eloquent regions were derived from the first 215 patients (development sample) using voxel-based lesion-symptom mapping. We used multivariate logistic regression models to study the influence of stroke location (number of eloquent voxels from voxel-based lesion-symptom mapping maps), age, initial National Institutes of Health Stroke Scale and stroke volume on modified Rankin Scale and MoCA. The second part of our cohort was used as an independent replication sample. In univariate analyses, stroke location, age, initial National Institutes of Health Stroke Scale, and stroke volume were all predictive of poor modified Rankin Scale and MoCA. In multivariable analyses, stroke location remained the strongest independent predictor of MoCA and significantly improved the prediction compared with using only age, initial National Institutes of Health Stroke Scale, and stroke volume (area under the curve increased from 0.697-0.771; difference=0.073; 95% confidence interval, 0.008-0.155). In contrast, stroke location did not persist as independent predictor of modified Rankin Scale that was mainly driven by initial National Institutes of Health Stroke Scale (area under the curve going from 0.840 to 0.835). Similar results were obtained in the replication sample. Stroke location is an independent predictor of cognitive outcome (MoCA) at 3 months post stroke. © 2015 American Heart Association, Inc.

Lesion segmentation from multimodal MRI using random forest following ischemic stroke.

PubMed

Mitra, Jhimli; Bourgeat, Pierrick; Fripp, Jurgen; Ghose, Soumya; Rose, Stephen; Salvado, Olivier; Connelly, Alan; Campbell, Bruce; Palmer, Susan; Sharma, Gagan; Christensen, Soren; Carey, Leeanne

2014-09-01

Understanding structure-function relationships in the brain after stroke is reliant not only on the accurate anatomical delineation of the focal ischemic lesion, but also on previous infarcts, remote changes and the presence of white matter hyperintensities. The robust definition of primary stroke boundaries and secondary brain lesions will have significant impact on investigation of brain-behavior relationships and lesion volume correlations with clinical measures after stroke. Here we present an automated approach to identify chronic ischemic infarcts in addition to other white matter pathologies, that may be used to aid the development of post-stroke management strategies. Our approach uses Bayesian-Markov Random Field (MRF) classification to segment probable lesion volumes present on fluid attenuated inversion recovery (FLAIR) MRI. Thereafter, a random forest classification of the information from multimodal (T1-weighted, T2-weighted, FLAIR, and apparent diffusion coefficient (ADC)) MRI images and other context-aware features (within the probable lesion areas) was used to extract areas with high likelihood of being classified as lesions. The final segmentation of the lesion was obtained by thresholding the random forest probabilistic maps. The accuracy of the automated lesion delineation method was assessed in a total of 36 patients (24 male, 12 female, mean age: 64.57±14.23yrs) at 3months after stroke onset and compared with manually segmented lesion volumes by an expert. Accuracy assessment of the automated lesion identification method was performed using the commonly used evaluation metrics. The mean sensitivity of segmentation was measured to be 0.53±0.13 with a mean positive predictive value of 0.75±0.18. The mean lesion volume difference was observed to be 32.32%±21.643% with a high Pearson's correlation of r=0.76 (p<0.0001). The lesion overlap accuracy was measured in terms of Dice similarity coefficient with a mean of 0.60±0.12, while the contour accuracy was observed with a mean surface distance of 3.06mm±3.17mm. The results signify that our method was successful in identifying most of the lesion areas in FLAIR with a low false positive rate. Copyright © 2014 Elsevier Inc. All rights reserved.

Novel Screening Tool for Stroke Using Artificial Neural Network.

PubMed

Abedi, Vida; Goyal, Nitin; Tsivgoulis, Georgios; Hosseinichimeh, Niyousha; Hontecillas, Raquel; Bassaganya-Riera, Josep; Elijovich, Lucas; Metter, Jeffrey E; Alexandrov, Anne W; Liebeskind, David S; Alexandrov, Andrei V; Zand, Ramin

2017-06-01

The timely diagnosis of stroke at the initial examination is extremely important given the disease morbidity and narrow time window for intervention. The goal of this study was to develop a supervised learning method to recognize acute cerebral ischemia (ACI) and differentiate that from stroke mimics in an emergency setting. Consecutive patients presenting to the emergency department with stroke-like symptoms, within 4.5 hours of symptoms onset, in 2 tertiary care stroke centers were randomized for inclusion in the model. We developed an artificial neural network (ANN) model. The learning algorithm was based on backpropagation. To validate the model, we used a 10-fold cross-validation method. A total of 260 patients (equal number of stroke mimics and ACIs) were enrolled for the development and validation of our ANN model. Our analysis indicated that the average sensitivity and specificity of ANN for the diagnosis of ACI based on the 10-fold cross-validation analysis was 80.0% (95% confidence interval, 71.8-86.3) and 86.2% (95% confidence interval, 78.7-91.4), respectively. The median precision of ANN for the diagnosis of ACI was 92% (95% confidence interval, 88.7-95.3). Our results show that ANN can be an effective tool for the recognition of ACI and differentiation of ACI from stroke mimics at the initial examination. © 2017 American Heart Association, Inc.

Environmental pollution and deaths due to stroke in a city with low levels of air pollution: ecological time series study.

PubMed

Amancio, Camila Trolez; Nascimento, Luiz Fernando

2014-12-01

Little has been discussed about the increased risk of stroke after exposure to air pollutants, particularly in Brazil. The mechanisms through which air pollution can influence occurrences of vascular events such as stroke are still poorly understood. The aim of this study was to estimate the association between exposure to some air pollutants and risk of death due to stroke. Ecological time series study with data from São José dos Campos, Brazil. Data on deaths due to stroke among individuals of all ages living in São José dos Campos and on particulate matter, sulfur dioxide and ozone were used. Statistical analysis was performed using a generalized additive model of Poisson regression with the Statistica software, in unipollutant and multipollutant models. The percentage increase in the risk of increased interquartile difference was calculated. There were 1,032 deaths due to stroke, ranging from 0 to 5 per day. The statistical significance of the exposure to particulate matter was ascertained in the unipollutant model and the importance of particulate matter and sulfur dioxide, in the multipollutant model. The increases in risk were 10% and 7%, for particulate matter and sulfur dioxide, respectively. It was possible to identify exposure to air pollutants as a risk factor for death due to stroke, even in a city with low levels of air pollution.

Intensive language training enhances brain plasticity in chronic aphasia

PubMed Central

Meinzer, Marcus; Elbert, Thomas; Wienbruch, Christian; Djundja, Daniela; Barthel, Gabriela; Rockstroh, Brigitte

2004-01-01

Background Focal clusters of slow wave activity in the delta frequency range (1–4 Hz), as measured by magnetencephalography (MEG), are usually located in the vicinity of structural damage in the brain. Such oscillations are usually considered pathological and indicative of areas incapable of normal functioning owing to deafferentation from relevant input sources. In the present study we investigated the change in Delta Dipole Density in 28 patients with chronic aphasia (>12 months post onset) following cerebrovascular stroke of the left hemisphere before and after intensive speech and language therapy (3 hours/day over 2 weeks). Results Neuropsychologically assessed language functions improved significantly after training. Perilesional delta activity decreased after therapy in 16 of the 28 patients, while an increase was evident in 12 patients. The magnitude of change of delta activity in these areas correlated with the amount of change in language functions as measured by standardized language tests. Conclusions These results emphasize the significance of perilesional areas in the rehabilitation of aphasia even years after the stroke, and might reflect reorganisation of the language network that provides the basis for improved language functions after intensive training. PMID:15331014

Dissociations among functional subsystems governing melody recognition after right-hemisphere damage.

PubMed

Steinke, W R; Cuddy, L L; Jakobson, L S

2001-07-01

This study describes an amateur musician, KB, who became amusic following a right-hemisphere stroke. A series of assessments conducted post-stroke revealed that KB functioned in the normal range for most verbal skills. However, compared with controls matched in age and music training, KB showed severe loss of pitch and rhythmic processing abilities. His ability to recognise and identify familiar instrumental melodies was also lost. Despite these deficits, KB performed remarkably well when asked to recognise and identify familiar song melodies presented without accompanying lyrics. This dissociation between the ability to recognise/identify song vs. instrumental melodies was replicated across different sets of musical materials, including newly learned melodies. Analyses of the acoustical and musical features of song and instrumental melodies discounted an explanation of the dissociation based on these features alone. Rather, the results suggest a functional dissociation resulting from a focal brain lesion. We propose that, in the case of song melodies, there remains sufficient activation in KB's melody analysis system to coactivate an intact representation of both associative information and the lyrics in the speech lexicon, making recognition and identification possible. In the case of instrumental melodies, no such associative processes exist; thus recognition and identification do not occur.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis.

PubMed

Graham, Catriona; Lewis, Steff; Forbes, John; Mead, Gillian; Hackett, Maree L; Hankey, Graeme J; Gommans, John; Nguyen, Huy Thang; Lundström, Erik; Isaksson, Eva; Näsman, Per; Rudberg, Ann-Sofie; Dennis, Martin

2017-12-28

Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients' functional outcome. The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2-15 days after stroke onset. Patients are randomised centrally via each trials' web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020. FOCUS: ISRCTN , ISRCTN83290762 . Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012. Australian New Zealand Clinical Trials Registry, ACTRN12611000774921 . Registered on 22 July 2011. ISRCTN , ISRCTN13020412 . Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213 . Registered on 2 February 2016. EudraCT, 2011-006130-16 . Registered on 8 August 2014.

Predicting stroke through genetic risk functions: The CHARGE risk score project

PubMed Central

Ibrahim-Verbaas, Carla A; Fornage, Myriam; Bis, Joshua C; Choi, Seung Hoan; Psaty, Bruce M; Meigs, James B; Rao, Madhu; Nalls, Mike; Fontes, Joao D; O’Donnell, Christopher J.; Kathiresan, Sekar; Ehret, Georg B.; Fox, Caroline S; Malik, Rainer; Dichgans, Martin; Schmidt, Helena; Lahti, Jari; Heckbert, Susan R; Lumley, Thomas; Rice, Kenneth; Rotter, Jerome I; Taylor, Kent D; Folsom, Aaron R; Boerwinkle, Eric; Rosamond, Wayne D; Shahar, Eyal; Gottesman, Rebecca F.; Koudstaal, Peter J; Amin, Najaf; Wieberdink, Renske G.; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G; DeStefano, Anita L.; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A.; DeCarli, Charles; Ikram, M. Arfan; Seshadri, Sudha; Mosley, Thomas H; Longstreth, WT; van Duijn, Cornelia M; Launer, Lenore J

2014-01-01

Background and Purpose Beyond the Framingham Stroke Risk Score (FSRS), prediction of future stroke may improve with a genetic risk score (GRS) based on Single nucleotide polymorphisms (SNPs) associated with stroke and its risk factors. Methods The study includes four population-based cohorts with 2,047 first incident strokes from 22,720 initially stroke-free European origin participants aged 55 years and older, who were followed for up to 20 years. GRS were constructed with 324 SNPs implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with Area under the curve (AUC) statistics comparing the GRS to age sex, and FSRS models, and with reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke (IS). Results In the meta-analysis, adding the GRS to the FSRS, age and sex model resulted in a significant improvement in discrimination (All stroke: Δjoint AUC =0.016, p-value=2.3*10-6; IS: Δ joint AUC =0.021, p-value=3.7*10−7), although the overall AUC remained low. In all studies there was a highly significantly improved net reclassification index (p-values <10−4). Conclusions The SNPs associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared to the classical epidemiological risk factors for stroke. PMID:24436238

Heart rate as a predictor of stroke in high-risk, hypertensive patients with previous stroke or transient ischemic attack.

PubMed

Sandset, Else Charlotte; Berge, Eivind; Kjeldsen, Sverre E; Julius, Stevo; Holzhauer, Björn; Krarup, Lars-Henrik; Hua, Tsushung A

2014-01-01

Risk factors for first stroke are well established, but less is known about risk factors for recurrent stroke. In the present analysis, we aimed to assess the effect of heart rate and other possible predictors of stroke in a hypertensive population with previous stroke or transient ischemic attack (TIA). The Valsartan Antihypertensive Long-Term Use Evaluation trial was a multicentre, double-masked, randomized controlled, parallel group trial comparing the effects of an angiotensin receptor blocker (valsartan) and a calcium channel blocker (amlodipine) in patients with hypertension and high cardiovascular risk. We used Cox proportional hazard models to investigate the effect of baseline variables on the risk of stroke. Quadratic terms of the continuous variables were entered in the models to test for linearity. Of 15,245 patients included in the trial, 3014 had a previous stroke or TIA at baseline and were included in the present analysis. Stroke recurrence occurred in 239 patients (7.9%) during a median of 4.5 years of follow-up. Resting heart rate (per 10 beats per minute; hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.18-6.58) and diabetes mellitus at baseline (HR, 1.47; 95% CI, 1.03-2.10) were significantly associated with an increased risk of stroke recurrence in the multivariable analysis. In high-risk, hypertensive patients with previous stroke or TIA, resting heart rate was the strongest predictor of recurrent stroke. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Patients living in impoverished areas have more severe ischemic strokes.

PubMed

Kleindorfer, Dawn; Lindsell, Christopher; Alwell, Kathleen A; Moomaw, Charles J; Woo, Daniel; Flaherty, Matthew L; Khatri, Pooja; Adeoye, Opeolu; Ferioli, Simona; Kissela, Brett M

2012-08-01

Initial stroke severity is one of the strongest predictors of eventual stroke outcome. However, predictors of initial stroke severity have not been well-described within a population. We hypothesized that poorer patients would have a higher initial stroke severity on presentation to medical attention. We identified all cases of hospital-ascertained ischemic stroke occurring in 2005 within a biracial population of 1.3 million. "Community" socioecomic status was determined for each patient based on the percentage below poverty in the census tract in which the patient resided. Linear regression was used to model the effect of socioeconomic status on stroke severity. Models were adjusted for race, gender, age, prestroke disability, and history of medical comorbidities. There were 1895 ischemic stroke events detected in 2005 included in this analysis; 22% were black, 52% were female, and the mean age was 71 years (range, 19-104). The median National Institutes of Health Stroke Scale was 3 (range, 0-40). The poorest community socioeconomic status was associated with a significantly increased initial National Institutes of Health Stroke Scale by 1.5 points (95% confidence interval, 0.5-2.6; P<0.001) compared with the richest category in the univariate analysis, which increased to 2.2 points after adjustment for demographics and comorbidities. We found that increasing community poverty was associated with worse stroke severity at presentation, independent of other known factors associated with stroke outcomes. Socioeconomic status may impact stroke severity via medication compliance, access to care, and cultural factors, or may be a proxy measure for undiagnosed disease states.

Determinants of Health-Related Quality of Life in Taiwanese Middle-Aged Women Stroke Survivors.

PubMed

Pai, Hsiang-Chu; Wu, Ming-Hsiu; Chang, Mei-Yueh

Female stroke victims have a higher survival rate and experience a greater loss of quality of life than do male stroke victims. The aim of this study was to evaluate the determinants of health-related quality of life in middle-aged women stroke survivors. This study is a cross-sectional design. This cross-sectional research uses a descriptive, prospective, and correlational study design to investigate the associations between latent variables. Participants included women stroke survivors, aged 45-65 years, who were patients at a medical center in Taiwan. Participants completed an interview and a six-part questionnaire comprising the Short-Form Health Survey (SF-36), National Institutes of Health Stroke Scale, Modified Rankin Scale, Burden Scale, Chinese Health Questionnaire, and five items that pertain to the survivor's cognitive appraisal of coping. Structural equation modeling (SEM), with the use of the partial least squares (PLS) method, was used to examine the proposed conceptual model. A total of 48 dyad samples (48 female stroke survivors, mean age = 55.29; 48 caregivers, mean age = 42.71) participated in the study. Overall, women's physical functioning (PF; stroke severity), cognitive appraisal of coping, and caregiver's psychosocial functioning were the predictors, explaining 43.3% of the variance in women's health-related quality of life. We found that female stroke survivors' level of stroke severity and negative appraisal-impact of stroke are significant predictors of the stroke survivor's quality of life. In addition to assisting women in their PF rehabilitation, rehabilitation nurses also should help to develop survivors' self-care confidence as a means to avoid the recurrence of stroke.

Long-term projections of temperature-related mortality risks for ischemic stroke, hemorrhagic stroke, and acute ischemic heart disease under changing climate in Beijing, China.

PubMed

Li, Tiantian; Horton, Radley M; Bader, Daniel A; Liu, Fangchao; Sun, Qinghua; Kinney, Patrick L

2018-03-01

Changing climates have been causing variations in the number of global ischemic heart disease and stroke incidences, and will continue to affect disease occurrence in the future. To project temperature-related mortality for acute ischemic heart disease, and ischemic and hemorrhagic stroke with concomitant climate warming. We estimated the exposure-response relationship between daily cause-specific mortality and daily mean temperature in Beijing. We utilized outputs from 31 downscaled climate models and two representative concentration pathways (RCPs) for the 2020s, 2050s, and 2080s. This strategy was used to estimate future net temperature along with heat- and cold-related deaths. The results for predicted temperature-related deaths were subsequently contrasted with the baseline period. In the 2080s, using the RCP8.5 and no population variation scenarios, the net total number of annual temperature-related deaths exhibited a median value of 637 (with a range across models of 434-874) for ischemic stroke; this is an increase of approximately 100% compared with the 1980s. The median number of projected annual temperature-related deaths was 660 (with a range across models of 580-745) for hemorrhagic stroke (virtually no change compared with the 1980s), and 1683 (with a range across models of 1351-2002) for acute ischemic heart disease (a slight increase of approximately 20% compared with the 1980s). In the 2080s, the monthly death projection for hemorrhagic stroke and acute ischemic heart disease showed that the largest absolute changes occurred in summer and winter while the largest absolute changes for ischemic stroke occurred in summer. We projected that the temperature-related mortality associated with ischemic stroke will increase dramatically due to climate warming. However, projected temperature-related mortality pertaining to acute ischemic heart disease and hemorrhagic stroke should remain relatively stable over time. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tissue hypoxia during ischemic stroke: adaptive clues from hypoxia-tolerant animal models.

PubMed

Nathaniel, Thomas I; Williams-Hernandez, Ashley; Hunter, Anan L; Liddy, Caroline; Peffley, Dennis M; Umesiri, Francis E; Imeh-Nathaniel, Adebobola

2015-05-01

The treatment and prevention of hypoxic/ischemic brain injury in stroke patients remain a severe and global medical issue. Numerous clinical studies have resulted in a failure to develop chemical neuroprotection for acute, ischemic stroke. Over 150 estimated clinical trials of ischemic stroke treatments have been done, and more than 200 drugs and combinations of drugs for ischemic and hemorrhagic strokes have been developed. Billions of dollars have been invested for new scientific breakthroughs with only limited success. The revascularization of occluded cerebral arteries such as anti-clot treatments of thrombolysis has proven effective, but it can only be used in a 3-4.5h time frame after the onset of a stroke, and not for every patient. This review is about novel insights on how to resist tissue hypoxia from unconventional animal models. Ability to resist tissue hypoxia is an extraordinary ability that is not common in many laboratory animals such as rat and mouse models. For example, we can learn from a naked mole-rat, Chrysemys picta, how to actively regulate brain metabolic activity to defend the brain against fluctuating oxygen tension and acute bouts of oxidative stress following the onset of a stroke. Additionally, a euthermic arctic ground squirrel can teach us how the brain of a stroke patient can remain well oxygenated during tissue hypoxia with no evidence of cellular stress. In this review, we discuss how these animals provide us with a system to gain insight into the possible mechanisms of tissue hypoxia/ischemia. This issue is of clinical significance to stroke patients. We describe specific physiological and molecular adaptations employed by different animals' models of hypoxia tolerance in aquatic and terrestrial environments. We highlight how these adaptations might provide potential clues on strategies to adapt for the clinical management of tissue hypoxia during conditions such as stroke where oxygen demand fails to match the supply. Copyright © 2015 Elsevier Inc. All rights reserved.

Analysis of spontaneous oscillations for a three-state power-stroke model.

PubMed

Washio, Takumi; Hisada, Toshiaki; Shintani, Seine A; Higuchi, Hideo

2017-02-01

Our study considers the mechanism of the spontaneous oscillations of molecular motors that are driven by the power stroke principle by applying linear stability analysis around the stationary solution. By representing the coupling equation of microscopic molecular motor dynamics and mesoscopic sarcomeric dynamics by a rank-1 updated matrix system, we derived the analytical representations of the eigenmodes of the Jacobian matrix that cause the oscillation. Based on these analytical representations, we successfully derived the essential conditions for the oscillation in terms of the rate constants of the power stroke and the reversal stroke transitions of the molecular motor. Unlike the two-state model, in which the dependence of the detachment rates on the motor coordinates or the applied forces on the motors plays a key role for the oscillation, our three-state power stroke model demonstrates that the dependence of the rate constants of the power and reversal strokes on the strains in the elastic elements in the motor molecules plays a key role, where these rate constants are rationally determined from the free energy available for the power stroke, the stiffness of the elastic element in the molecular motor, and the working stroke size. By applying the experimentally confirmed values to the free energy, the stiffness, and the working stroke size, our numerical model reproduces well the experimentally observed oscillatory behavior. Furthermore, our analysis shows that two eigenmodes with real positive eigenvalues characterize the oscillatory behavior, where the eigenmode with the larger eigenvalue indicates the transient of the system of the quick sarcomeric lengthening induced by the collective reversal strokes, and the smaller eigenvalue correlates with the speed of sarcomeric shortening, which is much slower than lengthening. Applying the perturbation analyses with primal physical parameters, we find that these two real eigenvalues occur on two branches derived from a merge point of a pair of complex-conjugate eigenvalues generated by Hopf bifurcation.

Design and testing of a novel multi-stroke micropositioning system with variable resolutions.

PubMed

Xu, Qingsong

2014-02-01

Multi-stroke stages are demanded in micro-/nanopositioning applications which require smaller and larger motion strokes with fine and coarse resolutions, respectively. This paper presents the conceptual design of a novel multi-stroke, multi-resolution micropositioning stage driven by a single actuator for each working axis. It eliminates the issue of the interference among different drives, which resides in conventional multi-actuation stages. The stage is devised based on a fully compliant variable stiffness mechanism, which exhibits unequal stiffnesses in different strokes. Resistive strain sensors are employed to offer variable position resolutions in the different strokes. To quantify the design of the motion strokes and coarse/fine resolution ratio, analytical models are established. These models are verified through finite-element analysis simulations. A proof-of-concept prototype XY stage is designed, fabricated, and tested to demonstrate the feasibility of the presented ideas. Experimental results of static and dynamic testing validate the effectiveness of the proposed design.