Non-Invasive Monitoring of CNS MHC-I Molecules in Ischemic Stroke Mice.

PubMed

Xia, Jing; Zhang, Ying; Zhao, Huanhuan; Wang, Jie; Gao, Xueren; Chen, Jinpeng; Fu, Bo; Shen, Yuqing; Miao, Fengqin; Zhang, Jianqiong; Teng, Gaojun

2017-01-01

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. The expression of major histocompatibility complex class I (MHC-I) molecules in the central nervous system, which are silenced under normal physiological conditions, have been reported to be induced by injury stimulation. The purpose of this study was to determine whether MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke and to assess whether a high-affinity peptide specific for MHC-I molecules could be applied in the near-infrared imaging of cerebral ischemic mice. Quantitative real-time PCR and Western blotting were used to detect the expression of MHC-I molecules in two mouse models of cerebral ischemic stroke and an in vitro model of ischemia. The NetMHC 4.0 server was used to screen a high-affinity peptide specific for mouse MHC-I molecules. The Rosetta program was used to identify the specificity and affinity of the screened peptide (histocompatibility-2 binding peptide, H2BP). The results demonstrated that MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke. Cy5.5-H2BP molecular probes could be applied in the near-infrared imaging of cerebral ischemic mice. Research on the expression of MHC-I molecules in the acute phase after ischemia and MHC-I-targeted imaging may not only be helpful for understanding the mechanism of ischemic and hypoxic brain injury and repair but also has potential application value in the imaging of ischemic stroke.

Neuroprotective effects of tanshinone I from Danshen extract in a mouse model of hypoxia-ischemia

PubMed Central

Lee, Jae-Chul; Park, Joon Ha; Park, Ok Kyu; Kim, In Hye; Yan, Bing Chun; Ahn, Ji Hyeon; Kwon, Seung-Hae; Choi, Jung Hoon

2013-01-01

Hypoxia-ischemia leads to serious neuronal damage in some brain regions and is a strong risk factor for stroke. The aim of this study was to investigate the neuroprotective effect of tanshinone I (TsI) derived from Danshen (Radix Salvia miltiorrhiza root extract) against neuronal damage using a mouse model of cerebral hypoxia-ischemia. Brain infarction and neuronal damage were examined using 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin histochemistry, and Fluoro-Jade B histofluorescence. Pre-treatment with TsI (10 mg/kg) was associated with a significant reduction in infarct volume 1 day after hypoxia-ischemia was induced. In addition, TsI protected against hypoxia-ischemia-induced neuronal death in the ipsilateral region. Our present findings suggest that TsI has strong potential for neuroprotection against hypoxic-ischemic damage. These results may be used in research into new anti-stroke medications. PMID:24179693

Novel Regenerative Therapies Based on Regionally Induced Multipotent Stem Cells in Post-Stroke Brains: Their Origin, Characterization, and Perspective.

PubMed

Takagi, Toshinori; Yoshimura, Shinichi; Sakuma, Rika; Nakano-Doi, Akiko; Matsuyama, Tomohiro; Nakagomi, Takayuki

2017-12-01

Brain injuries such as ischemic stroke cause severe neural loss. Until recently, it was believed that post-ischemic areas mainly contain necrotic tissue and inflammatory cells. However, using a mouse model of cerebral infarction, we demonstrated that stem cells develop within ischemic areas. Ischemia-induced stem cells can function as neural progenitors; thus, we initially named them injury/ischemia-induced neural stem/progenitor cells (iNSPCs). However, because they differentiate into more than neural lineages, we now refer to them as ischemia-induced multipotent stem cells (iSCs). Very recently, we showed that putative iNSPCs/iSCs are present within post-stroke areas in human brains. Because iNSPCs/iSCs isolated from mouse and human ischemic tissues can differentiate into neuronal lineages in vitro, it is possible that a clearer understanding of iNSPC/iSC profiles and the molecules that regulate iNSPC/iSC fate (e.g., proliferation, differentiation, and survival) would make it possible to perform neural regeneration/repair in patients following stroke. In this article, we introduce the origin and traits of iNSPCs/iSCs based on our reports and recent viewpoints. We also discuss their possible contribution to neurogenesis through endogenous and exogenous iNSPC/iSC therapies following ischemic stroke.

Severe hypertriglyceridemia does not protect from ischemic brain injury in gene-modified hypertriglyceridemic mice.

PubMed

Chen, Yong; Liu, Ping; Qi, Rong; Wang, Yu-Hui; Liu, George; Wang, Chun

2016-05-15

Hypertriglyceridemia (HTG) is a weak risk factor in primary ischemic stroke prevention. However, clinical studies have found a counterintuitive association between a good prognosis after ischemic stroke and HTG. This "HTG paradox" requires confirmation and further explanation. The aim of this study was to experimentally assess this paradox relationship using the gene-modified mice model of extreme HTG. We first used the human Apolipoprotein CIII transgenic (Tg-ApoCIII) mice and non-transgenic (Non-Tg) littermates to examine the effect of HTG on stroke. To our surprise, infarct size, neurological deficits, brain edema, BBB permeability, neuron density and lipid peroxidation were the same in Tg-ApoCIII mice and Non-Tg mice after temporary middle cerebral artery occlusion (tMCAO). In the late phase (21 days after surgery), no differences were found in brain atrophy, neurological dysfunctions, weight and mortality between the two groups. To confirm the results in Tg-ApoCIII mice, Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1(GPIHBP1) knockout mice, another severe HTG mouse model, were used and yielded similar results. Our study demonstrates for the first time that extreme HTG does not affect ischemic brain injuries in the tMCAO mouse model, indicating that the association between HTG and good outcomes after ischemic stroke probably represents residual unmeasured confounding. Further clinical and prospective population-based studies are needed to explore variables that contribute to the paradox. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimization of behavioural tests for the prediction of outcomes in mouse models of focal middle cerebral artery occlusion.

PubMed

Wen, Zhuoyu; Xu, Xiaomeng; Xu, Lili; Yang, Lian; Xu, Xiaohui; Zhu, Juehua; Wu, Li; Jiang, Yongjun; Liu, Xinfeng

2017-06-15

Intraluminal middle cerebral artery occlusion (MCAO) is the most widely used model of stroke. We aimed to predict the outcome of MCAO using a combination of fine behavioural tests for the prediction of unsuccessful surgery in mice leading to no infarction, haemorrhage and unexpected death. MCAO was performed on adult mice under the guidance of laser-Doppler flowmetry (LDF) to warrant a decrease in regional cerebral blood flow (rCBF) in the MCA territory. Four outcomes of MCAO were defined according to histological analysis: infarction, no infarction, haemorrhage and unexpected death (death within 24h post-surgery). Fine behavioural tests including the rotarod, modified neurological severity score (mNSS), Clark general and Clark focal tests were performed separately at 6h, 12h and 24h post-stroke. A total of 94 mice were included in the analysis. The infarction rate associated with MCAO was 58.5% (55/94). After optimization of the timing and behavioural tests, we found that higher Clark focal (>17.5) or higher mNSS scores (>10) were markedly related to early death, whereas a lower mNSS score (<3.5) was indicative of a tendency to show no infarction at 6h post-stroke. After 24h post-stroke, there was a positive correlation between the infarct volume and Clark focal results. Behavioural tests could help to predict the outcomes in the MCAO mouse model. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

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.

Ventilatory Patterning in a Mouse Model of Stroke

PubMed Central

Koo, Brian B; Strohl, Kingman P; Gillombardo, Carl B; Jacono, Frank J

2010-01-01

Cheyne-Stokes respiration (CSR) is a breathing pattern characterized by waxing and waning of breath volume and frequency, and is often recognized following stroke, when causal pathways are often obscure. We used an animal model to address the hypothesis that cerebral infarction is a mechanism for producing breathing instability. Fourteen male A/J mice underwent either stroke (n=7) or sham (n=7) procedure. Ventilation was measured using whole body plethysmography. Respiratory rate (RR), tidal volume (VT) and minute ventilation (Ve) mean values and coefficient of variation were computed for ventilation and oscillatory behavior. In addition, the ventilatory data were computationally fit to models to quantify autocorrelation, mutual information, sample entropy and a nonlinear complexity index. At the same time post procedure, stroke when compared to sham animal breathing consisted of a lower RR and autocorrelation, higher coefficient of variation for VT and higher coefficient of variation for Ve. Mutual information and the nonlinear complexity index were higher in breathing following stroke which also demonstrated a waxing/waning pattern. The absence of stroke in the sham animals was verified anatomically. We conclude that ventilatory pattern following cerebral infarction demonstrated increased variability with increased nonlinear patterning and a waxing/waning pattern, consistent with CSR. PMID:20472101

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.

Optical-resolution photoacoustic microscopy of ischemic stroke

NASA Astrophysics Data System (ADS)

Hu, Song; Gonzales, Ernie; Soetikno, Brian; Gong, Enhao; Yan, Ping; Maslov, Konstantin; Lee, Jin-Moo; Wang, Lihong V.

2011-03-01

A major obstacle in understanding the mechanism of ischemic stroke is the lack of a tool to noninvasively or minimally invasively monitor cerebral hemodynamics longitudinally. Here, we applied optical-resolution photoacoustic microscopy (OR-PAM) to longitudinally study ischemic stroke induced brain injury in a mouse model with transient middle cerebral artery occlusion (MCAO). OR-PAM showed that, during MCAO, the average hemoglobin oxygen saturation (sO2) values of feeder arteries and draining veins within the stroke core region dropped ~10% and ~34%, respectively. After reperfusion, arterial sO2 recovered back to the baseline; however, the venous sO2 increased above the baseline value by ~7%. Thereafter, venous sO2 values were close to the arterial sO2 values, suggesting eventual brain tissue infarction.

Expression patterns of histone deacetylases in experimental stroke and potential targets for neuroprotection.

PubMed

Chen, Yan-Ting; Zang, Xue-Feng; Pan, Jie; Zhu, Xiao-Lei; Chen, Fei; Chen, Zhi-Bin; Xu, Yun

2012-09-01

1. Histone deacetylase (HDAC) inhibitors exert neuroprotection in both cellular and animal models of ischaemic stroke. However, which HDAC isoform (or isoforms) mediates this beneficial effect has not yet been determined. 2. In the present study, gene levels of the HDAC isoforms were determined in the mouse cortex using reverse transcription-polymerase chain reaction (RT-PCR), whereas changes in the expression of individual zinc-dependent HDAC family members were evaluated by western blotting, 3, 12, 24 and 48 h after cerebral ischaemia induced by transient middle cerebral artery occlusion in male Kunming mice. 3. The HDAC isoforms HDAC1-11 were all expressed in the mouse cortex and differentially affected by cerebral ischaemia. Notably, there was a substantial increase in HDAC3, HDAC6 and HDAC11 expression during the early phases of experimental stroke, indicating their contribution to stroke pathogenesis. Furthermore, induction of HDAC3 and HDAC6 in cortical neurons by ischaemic stroke was confirmed in vivo and in vitro using double-labelled immunostaining and RT-PCR, respectively. Therefore, small hairpin (sh) RNAs were used to selectively knock down HDAC3 or HDAC6. This knockdown appreciably promoted the survival of cortical neurons subjected to oxygen and glucose deprivation. 4. The findings of the present study demonstrate the expression patterns of HDAC isoforms during experimental ischaemic stroke. Furthermore, HDAC3 and HDAC6 were identified as potential mediators in the neurotoxicity of ischaemic stroke, suggesting that specific therapeutic approaches may be considered according to HDAC subtype. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.

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.

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.

Efficacy of Alteplase® in a mouse model of acute ischemic stroke: a retrospective pooled analysis

PubMed Central

Orset, Cyrille; Haelewyn, Benoit; Allan, Stuart M.; Ansar, Saema; Campos, Francesco; Cho, Tae Hee; Durand, Anne; El Amki, Mohamad; Fatar, Marc; Garcia-Yébenes, Isaac; Gauberti, Maxime; Grudzenski, Saskia; Lizasoain, Ignacio; Lo, Eng; Macrez, Richard; Margaill, Isabelle; Maysami, Samaneh; Meairs, Stephen; Nighoghossian, Norbert; Orbe, Josune; Paramo, Jose Antonio; Parienti, Jean-Jacques; Rothwell, Nancy J.; Rubio, Marina; Waeber, Christian; Young, Alan R.

2016-01-01

Background and purpose The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). Methods We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3h) versus late (≥3h) drug administration. Final infarct volumes, assessed by histology or MRI, were compared in each study and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. Results When compared to saline controls, early rt-PA administration was associated with a significant benefit (absolute difference = −6.63 mm3; 95%CI, −9.08 to −4.17; I2=76%) whereas late rt-PA treatment showed a deleterious effect (+5.06 mm3; 95%CI, +2.78 to +7.34; I2=42%, Pint<0.00001). Results remained unchanged following subgroup analyses. Conclusion Our results provide the basis needed for the design of future pre-clinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multi-center trial would require 123 animals per group instead of 40 for a single center trial. PMID:27032444

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model.

PubMed

Low, Pei Ching; Manzanero, Silvia; Mohannak, Nika; Narayana, Vinod K; Nguyen, Tam H; Kvaskoff, David; Brennan, Faith H; Ruitenberg, Marc J; Gelderblom, Mathias; Magnus, Tim; Kim, Hyun Ah; Broughton, Brad R S; Sobey, Christopher G; Vanhaesebroeck, Bart; Stow, Jennifer L; Arumugam, Thiruma V; Meunier, Frédéric A

2014-03-14

Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kδ) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kδ inhibition confers protection in ischaemia/reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kδ inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kδ (p110δ(D910A/D910A)) or wild-type mice pre- or post-treated with the PI3Kδ inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kδ as a potential therapeutic target in ischaemic stroke.

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.

Imaging of the stroke-related changes in the vascular system of the mouse brain with the use of extended focus optical coherence microscopy

NASA Astrophysics Data System (ADS)

Tamborski, Szymon; Lyu, Hong Chou; Bukowska, Danuta; Dolezyczek, Hubert; Wilczynski, Grzegorz; Szlag, Daniel; Lasser, Theo; Wojtkowski, Maciej; Szkulmowski, Maciej

2016-03-01

We used Optical Coherence Microscopy (OCM) to monitor structural and functional changes due to ischemic stroke in small animals brains in vivo. To obtain lateral resolution of 2.2 μm over the range of 600 μm we used extended focus configuration of OCM instrument involving Bessel beam. It provided access to detailed 3D information about the changes in brain vascular system up to the level of capillaries across I and II/III layers of neocortex. We used photothrombotic stroke model involving photoactive application of rose bengal to assure minimal invasiveness of the procedure and precise localization of the clot distribution center. We present the comparative analysis involving structural and angiographic maps of the stroke-affected brain enabling in-depth insight to the process of development of the disorder.

Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis

PubMed Central

Passos, Giselle F; Kilday, Kelley; Gillen, Daniel L; Vasilevko, Vitaly

2015-01-01

Hypertension and cerebral amyloid angiopathy (CAA) are major risk factors for intracerebral hemorrhage (ICH); however the mechanisms of interplay between the two are not fully understood. We investigated the effect of hypertension in a transgenic mouse model with Alzheimer’s-like pathology (Tg2576) treating them with angiontensin II and L-NG-nitroarginine methyl ester. A similar increase in systolic blood pressure was observed in both Tg2576 and control mice; however Tg2576 mice developed signs of stroke with a markedly shorter latency. Cerebral deposition of amyloid beta promotes the hypertension-induced ICH, thus supporting the notion that hypertension is a risk factor for ICH among patients with CAA. PMID:26661173

Histopathology of motor cortex in an experimental focal ischemic stroke in mouse model.

PubMed

de Oliveira, Juçara Loli; Crispin, Pedro di Tárique Barreto; Duarte, Elisa Cristiana Winkelmann; Marloch, Gilberto Domingos; Gargioni, Rogério; Trentin, Andréa Gonçalves; Alvarez-Silva, Marcio

2014-05-01

Experimental ischemia results in cortical brain lesion followed by ischemic stroke. In this study, focal cerebral ischemia was induced in mice by occlusion of the middle cerebral artery. We studied cortical layers I, II/III, V and VI in the caudal forelimb area (CFA) and medial agranular cortex (AGm) from control and C57BL/6 mice induced with ischemic stroke. Based on our analysis of CFA and AGm motor cortex, significant differences were observed in the numbers of neurons, astrocytes and microglia in the superficial II/III and deep V cortical layers. Cellular changes were more prominent in layer V of the CFA with nuclear pyknosis, chromatin fragmentation, necrosis and degeneration, as well as, morphological evidence of apoptosis, mainly in neurons. As result, the CFA was more severely impaired than the AGm in this focal cerebral ischemic model, as evidenced by the proliferation of astrocytes, potentially resulting in neuroinflammation by microglia-like cells. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

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

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

PubMed

Liu, Yu-Cheng; Lee, Yu-Da; Wang, Hwai-Lee; Liao, Kate Hsiurong; Chen, Kuen-Bao; Poon, Kin-Shing; Pan, Yu-Ling; Lai, Ted Weita

2017-01-01

Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison to the inhibitors of the neuronal death signaling cascade; these, in fact, can attenuate the infarct volume measured at 24 h post-ischemia when administered at 6 h in our same stroke model.

B-vitamin and choline supplementation increases neuroplasticity and recovery after stroke.

PubMed

Jadavji, Nafisa M; Emmerson, Joshua T; MacFarlane, Amanda J; Willmore, William G; Smith, Patrice D

2017-07-01

Folates are B-vitamins that play an important role in brain function. Dietary and genetic deficiencies in folate metabolism result in elevated levels of homocysteine which have been linked to increased risk of developing a stroke. Reducing levels of homocysteine before or after a stroke through B-vitamin supplementation has been a focus of many clinical studies, however, the results remain inconsistent. Animal model systems provide a powerful mechanism to study and understand functional impact and mechanisms through which supplementation affects stroke recovery. The aim of this study was to understand the role of B-vitamins in stroke pathology using in vivo and in vitro mouse models. The first objective assessed the impact of folate deficiency prior to ischemic damage followed by B-vitamins and choline supplementation. Ischemic damage targeted the sensorimotor cortex. C57Bl/6 wild-type mice were maintained on a folic acid deficient diet for 4weeks prior to ischemic damage to increased levels of plasma homocysteine, a risk factor for stroke. Post-operatively mice were placed on a B-vitamin and choline supplemented diet for a period of four weeks, after which motor function was assessed in mice using the rotarod, ladder beam and forepaw asymmetry tasks. The second objective was to determine how a genetic deficiency in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism, increases vulnerability to stroke. Primary cortical neurons were isolated from Mthfr +/+ , Mthfr +/- and Mthfr -/- embryos and were exposed to in vitro models of stroke which include hypoxia or oxygen glucose deprivation. Cell viability was measured 24-h after exposure stroke like conditions in vitro. In supplemented diet mice, we report improved motor function after ischemic damage compared to mice fed a control diet after ischemic damage. Within the perilesional cortex, we show enhanced proliferation, neuroplasticity and anti-oxidant activity in mice fed the supplemented diet. A genetic MTHFR deficiency resulted in neurodegeneration after exposure to in vitro models of stroke, by activating apoptosis promoting p53-dependent mechanisms. These results suggest that one-carbon metabolism plays a significant role in recovery after stroke and MTHFR deficiency contributes to poor recovery from stroke. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

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.

Post-ischaemic administration of the murine Canakinumab-surrogate antibody improves outcome in experimental stroke.

PubMed

Liberale, Luca; Diaz-Cañestro, Candela; Bonetti, Nicole R; Paneni, Francesco; Akhmedov, Alexander; Beer, Jürg H; Montecucco, Fabrizio; Lüscher, Thomas F; Camici, Giovanni G

2018-05-16

The CANTOS trial underscored the efficacy of selective antibody-based interleukin (IL)-1β inhibition with Canakinumab in secondary prevention of cardiovascular events. Despite the success of the trial, incidence of stroke was not reduced likely due to the low number of events and the relatively young age of patients enrolled. Given the established role of IL-1β in stroke, we tested the efficacy of the murine Canakinumab-equivalent antibody in a mouse model of ischaemic stroke. To mimic the clinical scenario of modern stroke management, IL-1β inhibition was performed post-ischaemically upon reperfusion as it would be the case in patients presenting to the emergency room and eligible for thrombolytic therapy. Transient middle cerebral artery occlusion (tMCAO) was performed in wild type mice; upon reperfusion, mice were randomly allocated to anti-IL-1β antibody or vehicle treatment. Following tMCAO, cerebral IL-1β levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1β antibody reduced infarct size, cerebral oedema and improved neurological performance as assessed by 2,3,5-triphenyltetrazolium chloride staining, Bederson and RotaRod tests. Antibody-treated animals also exhibited a reduced neutrophil and matrix metalloproteinase (MMP)-2 but not MMP-9, activity in ipsilateral hemispheres as compared to vehicle-treated mice. Noteworthy, tMCAO associated vascular endothelial-cadherin reduction was blunted in IL-1β antibody-treated mice compared to vehicle-treated, likely providing the mechanistic explanation for the improved outcome. Our data for the first time demonstrate the efficacy of selective post-ischaemic IL-1β blockade in improving outcome following experimental ischaemia/reperfusion brain injury in the mouse and encourage further focused clinical studies assessing the potential of the approved IL-1β antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic stroke patients.

Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model.

PubMed

Guzman, Raphael; De Los Angeles, Alejandro; Cheshier, Samuel; Choi, Raymond; Hoang, Stanley; Liauw, Jason; Schaar, Bruce; Steinberg, Gary

2008-04-01

Intravascular delivery of neural stem cells (NSCs) after stroke has been limited by the low efficiency of transendothelial migration. Vascular cell adhesion molecule-1 is an endothelial adhesion molecule known to be upregulated early after stroke and is responsible for the firm adhesion of inflammatory cells expressing the surface integrin, CD49d. We hypothesize that enriching for NSCs that express CD49d and injecting them into the carotid artery would improve targeted cell delivery to the injured brain. Mouse NSCs were analyzed for the expression of CD49d by fluorescence activated cell sorting. A CD49d-enriched (CD49d(+)) (>95%) and -depleted (CD49d(-); <5%) NSC population was obtained by cell sorting. C57/Bl6 mice underwent left-sided hypoxia-ischemia surgery and were assigned to receive 3 x 10(5) CD49d(+), CD49d(-) NSCs, or vehicle injection into the left common carotid artery 48 hours after stroke. Behavioral recovery was measured using a rotarod for 2 weeks after cell injection. Fluorescence activated cell sorting analysis revealed 25% CD49d(+) NSCs. In a static adhesion assay, NSCs adhered to vascular cell adhesion molecule-1 in a dose-dependent manner. Significantly more NSCs were found in the cortex, the hippocampus, and the subventricular zone in the ischemic hemisphere in animals receiving CD49d(+) NSCs as compared with CD49d(-) NSCs (P<0.05). Animals treated with CD49d(+) cells showed a significantly better behavioral recovery as compared with CD49d(-) and vehicle-treated animals. We show that enrichment of NSCs by fluorescence activated cell sorting for the surface integrin, CD49d, and intracarotid delivery promotes cell homing to the area of stroke in mice and improves behavioral recovery.

A Linear Temporal Increase in Thrombin Activity and Loss of Its Receptor in Mouse Brain following Ischemic Stroke.

PubMed

Bushi, Doron; Stein, Efrat Shavit; Golderman, Valery; Feingold, Ekaterina; Gera, Orna; Chapman, Joab; Tanne, David

2017-01-01

Brain thrombin activity is increased following acute ischemic stroke and may play a pathogenic role through the protease-activated receptor 1 (PAR1). In order to better assess these factors, we obtained a novel detailed temporal and spatial profile of thrombin activity in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Thrombin activity was measured by fluorescence spectroscopy on coronal slices taken from the ipsilateral and contralateral hemispheres 2, 5, and 24 h following pMCAo ( n  = 5, 6, 5 mice, respectively). Its spatial distribution was determined by punch samples taken from the ischemic core and penumbra and further confirmed using an enzyme histochemistry technique ( n  = 4). Levels of PAR1 were determined using western blot. Two hours following pMCAo, thrombin activity in the stroke core was already significantly higher than the contralateral area (11 ± 5 vs. 2 ± 1 mU/ml). At 5 and 24 h, thrombin activity continued to rise linearly ( r  = 0.998, p  = 0.001) and to expand in the ischemic hemisphere beyond the ischemic core reaching deleterious levels of 271 ± 117 and 123 ± 14 mU/ml (mean ± SEM) in the basal ganglia and ischemic cortex, respectively. The peak elevation of thrombin activity in the ischemic core that was confirmed by fluorescence histochemistry was in good correlation with the infarcts areas. PAR1 levels in the ischemic core decreased as stroke progressed and thrombin activity increased. In conclusion, there is a time- and space-related increase in brain thrombin activity in acute ischemic stroke that is closely related to the progression of brain damage. These results may be useful in the development of therapeutic strategies for ischemic stroke that involve the thrombin-PAR1 pathway in order to prevent secondary thrombin related brain damage.

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.

Role of eNOS in water exchange index maintenance-MRI studies

NASA Astrophysics Data System (ADS)

Atochin, D.; Litvak, M.; Huang, S.; Kim, Y. R.; Huang, P.

2017-08-01

Stroke studies employ experimental models of cerebral ischemic and reperfusion injury in rodents. MRI provides valuable supravital data of cerebral blood flow and brain tissue damage. This paper presents MRI applications for cerebral blood flow research in mice lines with impaired nitric oxide production by endothelial nitric oxide synthase. Our data demonstrates that specific modifications of MRI methodology in transgenic mouse models help to evaluate the role of eNOS in the brain-blood barrier function.

GDF10 Is a Signal for Axonal Sprouting and Functional Recovery after Stroke

PubMed Central

Li, S; Nie, EH; Yin, Y; Benowitz, LI; Tung, S; Vinters, HV; Bahjat, FR; Stenzel-Poore, MP; Kawaguchi, R; Coppola, G; Carmichael, ST

2016-01-01

Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and Differentiation Factor 10 (GDF10) is induced in peri-infarct neurons in mouse, non-human primate and human. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGFβRI/II signaling. Using pharmacogenetic gain and loss of function studies, GDF10 produces axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocks axonal sprouting and reduces recovery. RNA-seq from peri-infarct cortical neurons indicates that GDF10 downregulates PTEN and upregulates PI3 kinase signaling and induces specific axonal guidance molecules. Unsupervised genome-wide association analysis of the GDF10 transcriptome shows that it is not related to neurodevelopment but may partially overlap with other CNS injury patterns. GDF10 is a stroke-induced signal for axonal sprouting and functional recovery. PMID:26502261

Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesisin a mouse model

PubMed Central

Taguchi, Akihiko; Soma, Toshihiro; Tanaka, Hidekazu; Kanda, Takayoshi; Nishimura, Hiroyuki; Yoshikawa, Hiroo; Tsukamoto, Yoshitane; Iso, Hiroyuki; Fujimori, Yoshihiro; Stern, David M.; Naritomi, Hiroaki; Matsuyama, Tomohiro

2004-01-01

Thrombo-occlusive cerebrovascular disease resulting in stroke and permanent neuronal loss is an important cause of morbidity and mortality. Because of the unique properties of cerebral vasculature and the limited reparative capability of neuronal tissue, it has been difficult to devise effective neuroprotective therapies in cerebral ischemia. Our results demonstrate that systemic administration of human cord blood–derived CD34+ cells to immunocompromised mice subjected to stroke 48 hours earlier induces neovascularization in the ischemic zone and provides a favorable environment for neuronal regeneration. Endogenous neurogenesis, suppressed by an antiangiogenic agent, is accelerated as a result of enhanced migration of neuronal progenitor cells to the damaged area, followed by their maturation and functional recovery. Our data suggest an essential role for CD34+ cells in promoting directly or indirectly an environment conducive to neovascularization of ischemic brain so that neuronal regeneration can proceed. PMID:15286799

Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: Implications for cerebral ischemic stroke.

PubMed

Han, Bing; Zhang, Yuan; Zhang, Yanhong; Bai, Ying; Chen, Xufeng; Huang, Rongrong; Wu, Fangfang; Leng, Shuo; Chao, Jie; Zhang, John H; Hu, Gang; Yao, Honghong

2018-06-25

Circular RNAs (circRNAs) are highly expressed in the central nervous system and are involved in the regulation of physiological and pathophysiological processes. However, the potential role of circRNAs in stroke remains largely unknown. Here, using a circRNA microarray, we showed that circular RNA Hectd1 (circHectd1) levels were significantly increased in ischemic brain tissues in transient middle cerebral artery occlusion (tMCAO) mouse stroke models and further validated this finding in plasma samples from acute ischemic stroke (AIS) patients. Knockdown of circHectd1 expression significantly decreased infarct areas, attenuated neuronal deficits, and ameliorated astrocyte activation in tMCAO mice. Mechanistically, circHECTD1 functions as an endogenous MIR142 (microRNA 142) sponge to inhibit MIR142 activity, resulting in the inhibition of TIPARP (TCDD inducible poly[ADP-ribose] polymerase) expression with subsequent inhibition of astrocyte activation via macroautophagy/autophagy. Taken together, the results of our study indicate that circHECTD1 and its coupling mechanism are involved in cerebral ischemia, thus providing translational evidence that circHECTD1 can serve as a novel biomarker of and therapeutic target for stroke.

Ivabradine and metoprolol differentially affect cardiac glucose metabolism despite similar heart rate reduction in a mouse model of dyslipidemia.

PubMed

Vaillant, Fanny; Lauzier, Benjamin; Ruiz, Matthieu; Shi, Yanfen; Lachance, Dominic; Rivard, Marie-Eve; Bolduc, Virginie; Thorin, Eric; Tardif, Jean-Claude; Des Rosiers, Christine

2016-10-01

While heart rate reduction (HRR) is a target for the management of patients with heart disease, contradictory results were reported using ivabradine, which selectively inhibits the pacemaker I f current, vs. β-blockers like metoprolol. This study aimed at testing whether similar HRR with ivabradine vs. metoprolol differentially modulates cardiac energy substrate metabolism, a factor determinant for cardiac function, in a mouse model of dyslipidemia (hApoB +/+ ;LDLR -/- ). Following a longitudinal study design, we used 3- and 6-mo-old mice, untreated or treated for 3 mo with ivabradine or metoprolol. Cardiac function was evaluated in vivo and ex vivo in working hearts perfused with 13 C-labeled substrates to assess substrate fluxes through energy metabolic pathways. Compared with 3-mo-old, 6-mo-old dyslipidemic mice had similar cardiac hemodynamics in vivo but impaired (P < 0.001) contractile function (aortic flow: -45%; cardiac output: -34%; stroke volume: -35%) and glycolysis (-24%) ex vivo. Despite inducing a similar 10% HRR, ivabradine-treated hearts displayed significantly higher stroke volume values and glycolysis vs. their metoprolol-treated counterparts ex vivo, values for the ivabradine group being often not significantly different from 3-mo-old mice. Further analyses highlighted additional significant cardiac alterations with disease progression, namely in the total tissue level of proteins modified by O-linked N-acetylglucosamine (O-GlcNAc), whose formation is governed by glucose metabolism via the hexosamine biosynthetic pathway, which showed a similar pattern with ivabradine vs. metoprolol treatment. Collectively, our results emphasize the implication of alterations in cardiac glucose metabolism and signaling linked to disease progression in our mouse model. Despite similar HRR, ivabradine, but not metoprolol, preserved cardiac function and glucose metabolism during disease progression. Copyright © 2016 the American Physiological Society.

A protocol for characterizing the impact of collateral flow after distal middle cerebral artery occlusion

PubMed Central

DeFazio, R. Anthony; Levy, Sean; Morales, Carmen L.; Levy, Rebecca V.; Dave, Kunjan R.; Lin, Hung W.; Abaffy, Tatjana; Watson, Brant D.; Perez-Pinzon, Miguel A.; Ohanna, Victoria

2010-01-01

I. SUMMARY In humans and in animal models of stroke, collateral blood flow between territories of the major pial arteries has a profound impact on cortical infarct size. However, there is a gap in our understanding of the genetic determinants of collateral formation and flow, as well as the signaling pathways and neurovascular interactions regulating this flow. Previous studies have demonstrated that collateral flow between branches of the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) can protect mouse cortex from infarction after middle cerebral artery occlusion. Because the number and diameter of collaterals varies among mouse strains and after transgenic manipulations, a combination of methods is required to control for these variations. Here, we report an inexpensive approach to characterizing the cerebrovascular anatomy, and in vivo monitoring of cerebral blood flow as well. Further, we introduce a new, minimally invasive method for the occlusion of distal MCA branches. These methods will permit a new generation of studies on the mechanisms regulating collateral remodeling and cortical blood flow after stroke. PMID:21593993

Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke

PubMed Central

Webb, Robin L.; Kaiser, Erin E.; Jurgielewicz, Brian J.; Spellicy, Samantha; Scoville, Shelley L.; Thompson, Tyler A.; Swetenburg, Raymond L.; Hess, David C.; West, Franklin D.

2018-01-01

Background and Purpose— Recent work from our group suggests that human neural stem cell–derived extracellular vesicle (NSC EV) treatment improves both tissue and sensorimotor function in a preclinical thromboembolic mouse model of stroke. In this study, NSC EVs were evaluated in a pig ischemic stroke model, where clinically relevant end points were used to assess recovery in a more translational large animal model. Methods— Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAO), and either NSC EV or PBS treatment was administered intravenously at 2, 14, and 24 hours post-MCAO. NSC EV effects on tissue level recovery were evaluated via magnetic resonance imaging at 1 and 84 days post-MCAO. Effects on functional recovery were also assessed through longitudinal behavior and gait analysis testing. Results— NSC EV treatment was neuroprotective and led to significant improvements at the tissue and functional levels in stroked pigs. NSC EV treatment eliminated intracranial hemorrhage in ischemic lesions in NSC EV pigs (0 of 7) versus control pigs (7 of 8). NSC EV–treated pigs exhibited a significant decrease in cerebral lesion volume and decreased brain swelling relative to control pigs 1-day post-MCAO. NSC EVs significantly reduced edema in treated pigs relative to control pigs, as assessed by improved diffusivity through apparent diffusion coefficient maps. NSC EVs preserved white matter integrity with increased corpus callosum fractional anisotropy values 84 days post-MCAO. Behavior and mobility improvements paralleled structural changes as NSC EV–treated pigs exhibited improved outcomes, including increased exploratory behavior and faster restoration of spatiotemporal gait parameters. Conclusions— This study demonstrated for the first time that in a large animal model novel NSC EVs significantly improved neural tissue preservation and functional levels post-MCAO, suggesting NSC EVs may be a paradigm changing stroke therapeutic. PMID:29650593

Towards ultrahigh resting-state functional connectivity in the mouse brain using photoacoustic microscopy

NASA Astrophysics Data System (ADS)

Hariri, Ali; Bely, Nicholas; Chen, Chen; Nasiriavanaki, Mohammadreza

2016-03-01

The increasing use of mouse models for human brain disease studies, coupled with the fact that existing high-resolution functional imaging modalities cannot be easily applied to mice, presents an emerging need for a new functional imaging modality. Utilizing both mechanical and optical scanning in the photoacoustic microscopy, we can image spontaneous cerebral hemodynamic fluctuations and their associated functional connections in the mouse brain. The images is going to be acquired noninvasively with a fast frame rate, a large field of view, and a high spatial resolution. We developed an optical resolution photoacoustic microscopy (OR-PAM) with diode laser. Laser light was raster scanned due to XY-stage movement. Images from ultra-high OR-PAM can then be used to study brain disorders such as stroke, Alzheimer's, schizophrenia, multiple sclerosis, autism, and epilepsy.

Generating and measuring photochemical changes inside the brain using optical fibers: exploring stroke.

PubMed

Tsiminis, Georgios; Klarić, Thomas S; Schartner, Erik P; Warren-Smith, Stephen C; Lewis, Martin D; Koblar, Simon A; Monro, Tanya M

2014-11-01

We report here on the development of a method for inducing a stroke in a specific location within a mouse brain through the use of an optical fiber. By capturing the emitted fluorescence signal generated using the same fiber it is possible to monitor photochemical changes within the brain in real-time, and directly measure the concentration of the stroke-inducing dye, Rose Bengal, at the infarct site. This technique reduces the requirement for post-operative histology to determine if a stroke has successfully been induced within the animal, and therefore opens up the opportunity to explore the recovery of the brain after the stroke event.

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.

Novel test of motor and other dysfunctions in mouse neurological disease models.

PubMed

Barth, Albert M I; Mody, Istvan

2014-01-15

Just like human neurological disorders, corresponding mouse models present multiple deficiencies. Estimating disease progression or potential treatment effectiveness in such models necessitates the use of time consuming and multiple tests usually requiring a large number of scarcely available genetically modified animals. Here we present a novel and simple single camera arrangement and analysis software for detailed motor function evaluation in mice walking on a wire mesh that provides complex 3D information (instantaneous position, speed, distance traveled, foot fault depth, duration, location, relationship to speed of movement, etc.). We investigated 3 groups of mice with various neurological deficits: (1) unilateral motor cortical stroke; (2) effects of moderate ethanol doses; and (3) aging (96-99 weeks old). We show that post stroke recovery can be divided into separate stages based on strikingly different characteristics of motor function deficits, some resembling the human motor neglect syndrome. Mice treated with moderate dose of alcohol and aged mice showed specific motor and exploratory deficits. Other tests rely either partially or entirely on manual video analysis introducing a significant subjective component into the analysis, and analyze a single aspect of motor function. Our novel experimental approach provides qualitatively new, complex information about motor impairments and locomotor/exploratory activity. It should be useful for the detailed characterization of a broad range of human neurological disease models in mice, and for the more accurate assessment of disease progression or treatment effectiveness. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

PubMed

Klein, Brian D; Jacobson, Catherine A; Metcalf, Cameron S; Smith, Misty D; Wilcox, Karen S; Hampson, Aidan J; Kehne, John H

2017-07-01

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED 50 164 mg/kg), mouse MES (ED 50 83.5 mg/kg) and rat MES (ED 50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED 50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

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.

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

A protocol to study ex vivo mouse working heart at human-like heart rate.

PubMed

Feng, Han-Zhong; Jin, Jian-Ping

2018-01-01

Genetically modified mice are widely used as experimental models to study human heart function and diseases. However, the fast rate of normal mouse heart at 400-600bpm limits its capacity of assessing kinetic parameters that are important for the physiology and pathophysiology of human heart that beats at a much slower rate (75-180bpm). To extend the value of mouse models, we established a protocol to study ex vivo mouse working hearts at a human-like heart rate. In the presence of 300μM lidocaine to lower pacemaker and conductive activities and prevent arrhythmia, a stable rate of 120-130bpm at 37°C is achieved for ex vivo mouse working hearts. The negative effects of decreased heart rate on force-frequency dependence and lidocaine as a myocardial depressant on intracellular calcium can be compensated by using a higher but still physiological level of calcium (2.75mM) in the perfusion media. Multiple parameters were studied to compare the function at the human-like heart rate with that of ex vivo mouse working hearts at the standard rate of 480bpm. The results showed that the conditions for slower heart rate in the presence of 300μM lidocaine did not have depressing effect on left ventricular pressure development, systolic and diastolic velocities and stroke volume with maintained positive inotropic and lusitropic responses to β-adrenergic stimulation. Compared with that at 480bpm, the human-like heart rate increased ventricular filling and end diastolic volume with enhanced Frank-Starling responses. Coronary perfusion was increased from longer relaxation time and interval between beats whereas cardiac efficiency was significantly improved. Although the intrinsic differences between mouse and human heart remain, this methodology for ex vivo mouse hearts to work at human-like heart rate extends the value of using genetically modified mouse models to study cardiac function and human heart diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Two-color Dye-swap DNA Microarray approach toward confident gene expression profiling in PMCAO mouse model for ischemia-related and PACAP38-influenced genes

PubMed Central

Hori, Motohide; Shibato, Junko; Nakamachi, Tomoya; Rakwal, Randeep; Ogawa, Tetsuo; Shioda, Seiji; Numazawa, Satoshi

2015-01-01

Toward twin goals of identifying molecular factors in brain injured by ischemic stroke, and the effects of neuropeptide pituitary adenylate-cyclase activating polypeptide (PACAP) on the ischemic brain, we have established the permanent middle cerebral artery occlusion (PMCAO) mouse model and utilized the Agilent mouse whole genome 4 × 44 K DNA chip. PACAP38 (1 pmol) injection was given intracerebroventrically in comparison to a control saline (0.9% NaCl) injection, to screen genes responsive to PACAP38. Two sets of tissues were prepared, whole hemispheres (ischemic and non-ischemic) and infract core and penumbra regions at 6 and 24 h. In this study, we have detailed the experimental design and protocol used therein and explained the quality controls for the use of total RNA in the downstream DNA microarray experiment utilizing a two-color dye-swap approach for stringent and confident gene identification published in a series of papers by Hori and coworkers (Hori et al., 2012–2015). PMID:26484166

Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement.

PubMed

Manwani, Bharti; Bentivegna, Kathryn; Benashski, Sharon E; Venna, Venugopal Reddy; Xu, Yan; Arnold, Arthur P; McCullough, Louise D

2015-02-01

Epidemiologic studies have shown sex differences in ischemic stroke. The four core genotype (FCG) mouse model, in which the testes determining gene, Sry, has been moved from Y chromosome to an autosome, was used to dissociate the effects of sex hormones from sex chromosome in ischemic stroke outcome. Middle cerebral artery occlusion (MCAO) in gonad intact FCG mice revealed that gonadal males (XXM and XYM) had significantly higher infarct volumes as compared with gonadal females (XXF and XYF). Serum testosterone levels were equivalent in adult XXM and XYM, as was serum estrogen in XXF and XYF mice. To remove the effects of gonadal hormones, gonadectomized FCG mice were subjected to MCAO. Gonadectomy significantly increased infarct volumes in females, while no change was seen in gonadectomized males, indicating that estrogen loss increases ischemic sensitivity. Estradiol supplementation in gonadectomized FCG mice rescued this phenotype. Interestingly, FCG male mice were less sensitive to effects of hormones. This may be due to enhanced expression of the transgene Sry in brains of FCG male mice. Sex differences in ischemic stroke sensitivity appear to be shaped by organizational and activational effects of sex hormones, rather than sex chromosomal complement.

A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action

PubMed Central

Chakravarty, Sumana; Maitra, Swati; Reddy, R Gajendra; Das, Tapatee; Jhelum, Priya; Kootar, Scherazad; Rajan, Wenson D.; Samanta, Anumita; Samineni, Ramesh; Pabbaraja, Srihari; Kernie, Steven G.; Mehta, Goverdhan; Kumar, Arvind

2015-01-01

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds. PMID:26388493

The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.

PubMed

Rutten, Julie W; Klever, Roselin R; Hegeman, Ingrid M; Poole, Dana S; Dauwerse, Hans G; Broos, Ludo A M; Breukel, Cor; Aartsma-Rus, Annemieke M; Verbeek, J Sjef; van der Weerd, Louise; van Duinen, Sjoerd G; van den Maagdenberg, Arn M J M; Lesnik Oberstein, Saskia A J

2015-12-29

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.

Lack of TAFI increases brain damage and microparticle generation after thrombolytic therapy in ischemic stroke.

PubMed

Orbe, J; Alexandru, N; Roncal, C; Belzunce, M; Bibiot, P; Rodriguez, J A; Meijers, J C M; Georgescu, A; Paramo, J A

2015-08-01

Thrombin-activatable fibrinolysis inhibitor (TAFI) plays an important role in coagulation and fibrinolysis. Whereas TAFI deficiency may lead to a haemorrhagic tendency, data from TAFI knockout mice (TAFI-/-) are controversial and no differences have been reported in these animals after ischemic stroke. There are also no data regarding the role of circulating microparticles (MPs) in TAFI-/-. to examine the effect of tPA on the rate of intracranial haemorrhage (ICH) and on MPs generated in a model of ischemic stroke in TAFI-/- mice. Thrombin was injected into the middle cerebral artery (MCA) to analyse the effect of tPA (10mg/Kg) on the infarct size and haemorrhage in the absence of TAFI. Immunofluorescence for Fluoro-Jade C was performed on frozen brain slides to analyse neuronal degeneration after ischemia. MPs were isolated from mouse blood and their concentrations calculated by flow cytometry. Compared with saline, tPA significantly increased the infarct size in TAFI-/- mice (p<0.05). Although plasma fibrinolytic activity (fibrin plate assay) was higher in these animals, no macroscopic or microscopic ICH was detected. A positive signal for apoptosis and degenerating neurons was observed in the infarct area, being significantly higher in tPA treated TAFI-/- mice (p<0.05). Interestingly, higher numbers of MPs were found in TAFI-/- plasma as compared to wild type, after stroke (p<0.05). TAFI deficiency results in increased brain damage in a model of thrombolysis after ischemic stroke, which was not associated with bleeding but with neuronal degeneration and MP production. Copyright © 2015 Elsevier Ltd. All rights reserved.

Model mice for mild-form glycine encephalopathy: behavioral and biochemical characterizations and efficacy of antagonists for the glycine binding site of N-methyl D-aspartate receptor.

PubMed

Kojima-ishii, Kanako; Kure, Shigeo; Ichinohe, Akiko; Shinka, Toshikatsu; Narisawa, Ayumi; Komatsuzaki, Shoko; Kanno, Junnko; Kamada, Fumiaki; Aoki, Yoko; Yokoyama, Hiroyuki; Oda, Masaya; Sugawara, Taku; Mizoi, Kazuo; Nakahara, Daiichiro; Matsubara, Yoichi

2008-09-01

Glycine encephalopathy (GE) is caused by an inherited deficiency of the glycine cleavage system (GCS) and characterized by accumulation of glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.

Glial scars are permeable to the neurotoxic environment of chronic stroke infarcts

PubMed Central

Zbesko, Jacob C.; Nguyen, Thuy-Vi V.; Yang, Tao; Frye, Jennifer Beischel; Hussain, Omar; Hayes, Megan; Chung, Amanda; Day, W. Anthony; Stepanovic, Kristina; Krumberger, Maj; Mona, Justine; Longo, Frank M.; Doyle, Kristian P.

2018-01-01

Following stroke, the damaged tissue undergoes liquefactive necrosis, a stage of infarct resolution that lasts for months although the exact length of time is currently unknown. One method of repair involves reactive astrocytes and microglia forming a glial scar to compartmentalize the area of liquefactive necrosis from the rest of the brain. The formation of the glial scar is a critical component of the healing response to stroke, as well as other central nervous system (CNS) injuries. The goal of this study was to evaluate the toxicity of the extracellular fluid present in areas of liquefactive necrosis and determine how effectively it is segregated from the remainder of the brain. To accomplish this goal, we used a mouse model of stroke in conjunction with an extracellular fluid toxicity assay, fluorescent and electron microscopy, immunostaining, tracer injections into the infarct, and multiplex immunoassays. We confirmed that the extracellular fluid present in areas of liquefactive necrosis following stroke is toxic to primary cortical and hippocampal neurons for at least 7 weeks following stroke, and discovered that although glial scars are robust physical and endocytic barriers, they are nevertheless permeable. We found that molecules present in the area of liquefactive necrosis can leak across the glial scar and are removed by a combination of paravascular clearance and microglial endocytosis in the adjacent tissue. Despite these mechanisms, there is delayed atrophy, cytotoxic edema, and neuron loss in regions adjacent to the infarct for weeks following stroke. These findings suggest that one mechanism of neurodegeneration following stroke is the failure of glial scars to impermeably segregate areas of liquefactive necrosis from surviving brain tissue. PMID:29331263

Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke

PubMed Central

Kim, Eunhee; Woo, Moon-Sook; Qin, Luye; Ma, Thong; Beltran, Cesar D.; Bao, Yi; Bailey, Jason A.; Corbett, Dale; Ratan, Rajiv R.; Lahiri, Debomoy K.

2015-01-01

Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect. SIGNIFICANCE STATEMENT There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients. PMID:26558782

Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.

PubMed

Kim, Eunhee; Woo, Moon-Sook; Qin, Luye; Ma, Thong; Beltran, Cesar D; Bao, Yi; Bailey, Jason A; Corbett, Dale; Ratan, Rajiv R; Lahiri, Debomoy K; Cho, Sunghee

2015-11-11

Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect. There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients. Copyright © 2015 the authors 0270-6474/15/3515113-14$15.00/0.

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.

[Post-ischemic innate immunity and its application for novel therapeutic strategy targeting brain inflammation].

PubMed

Ito, Minako; Kondo, Taisuke; Shichita, Takashi; Yoshimura, Akihiko

2013-07-01

Stroke or brain ischemia is one of the major causes of death and disability worldwide. Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In a mouse stroke model, we have reported that IL-23 produced from infiltrating macrophages induces IL-17 producing T cells. IL-17 is mainly produced from gammadeltaT cells and promotes delayed (day 3-4) ischemic brain damage. We also demonstrated that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including IL-23 in macrophages through activation of Toll-like receptor 2(TLR2) and TLR4, thereby promoting neural cell death. We thus propose that regulation of the IL-23-IL-17 axis including gammadeltaT cells, macrophages, and extracellular Prxs could be a potent neuroprotective tool.

Cardiac function and perfusion dynamics measured on a beat-by-beat basis in the live mouse using ultra-fast 4D optoacoustic imaging

NASA Astrophysics Data System (ADS)

Ford, Steven J.; Deán-Ben, Xosé L.; Razansky, Daniel

2015-03-01

The fast heart rate (~7 Hz) of the mouse makes cardiac imaging and functional analysis difficult when studying mouse models of cardiovascular disease, and cannot be done truly in real-time and 3D using established imaging modalities. Optoacoustic imaging, on the other hand, provides ultra-fast imaging at up to 50 volumetric frames per second, allowing for acquisition of several frames per mouse cardiac cycle. In this study, we combined a recently-developed 3D optoacoustic imaging array with novel analytical techniques to assess cardiac function and perfusion dynamics of the mouse heart at high, 4D spatiotemporal resolution. In brief, the heart of an anesthetized mouse was imaged over a series of multiple volumetric frames. In another experiment, an intravenous bolus of indocyanine green (ICG) was injected and its distribution was subsequently imaged in the heart. Unique temporal features of the cardiac cycle and ICG distribution profiles were used to segment the heart from background and to assess cardiac function. The 3D nature of the experimental data allowed for determination of cardiac volumes at ~7-8 frames per mouse cardiac cycle, providing important cardiac function parameters (e.g., stroke volume, ejection fraction) on a beat-by-beat basis, which has been previously unachieved by any other cardiac imaging modality. Furthermore, ICG distribution dynamics allowed for the determination of pulmonary transit time and thus additional quantitative measures of cardiovascular function. This work demonstrates the potential for optoacoustic cardiac imaging and is expected to have a major contribution toward future preclinical studies of animal models of cardiovascular health and disease.

Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury

NASA Astrophysics Data System (ADS)

Gaudin, Alice; Yemisci, Müge; Eroglu, Hakan; Lepetre-Mouelhi, Sinda; Turkoglu, Omer Faruk; Dönmez-Demir, Buket; Caban, Seçil; Sargon, Mustafa Fevzi; Garcia-Argote, Sébastien; Pieters, Grégory; Loreau, Olivier; Rousseau, Bernard; Tagit, Oya; Hildebrandt, Niko; Le Dantec, Yannick; Mougin, Julie; Valetti, Sabrina; Chacun, Hélène; Nicolas, Valérie; Desmaële, Didier; Andrieux, Karine; Capan, Yilmaz; Dalkara, Turgay; Couvreur, Patrick

2014-12-01

There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This Article shows, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

A selective cannabinoid CB2 agonist attenuates damage and improves memory retention following stroke in mice.

PubMed

Ronca, Richard D; Myers, Alyssa M; Ganea, Doina; Tuma, Ronald F; Walker, Ellen A; Ward, Sara Jane

2015-10-01

We have recently demonstrated that treatment with a cannabinoid CB2 agonist was protective in a mouse middle cerebral artery occlusion model of cerebral ischemia/reperfusion injury. The present study aimed to determine whether these protective effects of CB2 agonism would extend to a mouse photoinjury model of permanent ischemia and determine associated alterations in cognition and infarct size. Mice received three injections of the CB2 selective agonist O-1966 or vehicle 1h prior to and 2 and 5days following induction of stroke. Infarct size was assessed at 1, 3, or 7days post-injury and learning and memory effects of injury and O-1966 treatment were assessed on days 6 and 7 using a novel object recognition task and an operant acquisition and retention procedure. O-1966 treated mice had significantly smaller infarct volumes compared with vehicle treated mice. Photoinjury was also associated with a significant memory impairment on day 7 post-injury, and this deficit was reversed with O-1966 treatment. Surprisingly, sham-operated mice receiving O-1966 treatment showed a significant learning deficit in both the recognition and operant tasks compared with vehicle treated sham mice. We conclude that CB2 activation is protective against cognitive deficits and tissue damage following permanent ischemia, but may dysregulate glial or neuronal function of learning and memory circuits in the absence of injury and/or inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

Label-free NIR reflectance imaging as a complimentary tool for two-photon fluorescence microscopy: multimodal investigation of stroke (Conference Presentation)

NASA Astrophysics Data System (ADS)

Allegra Mascaro, Anna Letizia; Costantini, Irene; Margoni, Emilia; Iannello, Giulio; Bria, Alessandro; Sacconi, Leonardo; Pavone, Francesco S.

2016-03-01

Two-photon imaging combined with targeted fluorescent indicators is extensively used for visualizing critical features of brain functionality and structural plasticity. Back-scattered photons from the NIR laser provide complimentary information without introducing any exogenous labelling. Here, we describe a versatile approach that, by collecting the reflected NIR light, provides structural details on the myelinated axons and blood vessels in the brain, both in fixed samples and in live animals. Indeed, by combining NIR reflectance and two-photon imaging of a slice of hippocampus from Thy1-GFPm mice, we show the presence of randomly oriented axons intermingled with sparsely fluorescent neuronal processes. The back-scattered photons guide the contextualization of the fluorescence structure within brain atlas thanks to the recognition of characteristic hippocampal structures. Label-free detection of axonal elongations over the layer 2/3 of mouse cortex under a cranial window was also possible in live brain. Finally, blood flow could be measured in vivo, thus validating label free NIR reflectance as a tool for monitoring hemodynamic fluctuations. The prospective versatility of this label-free technique complimentary to two-photon fluorescence microscopy is demonstrated in a mouse model of photothrombotic stroke in which the axonal degeneration and blood flow remodeling can be investigated simultaneously.

The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice

PubMed Central

Gelderblom, Mathias; Leypoldt, Frank; Lewerenz, Jan; Birkenmayer, Gabriel; Orozco, Denise; Ludewig, Peter; Thundyil, John; Arumugam, Thiruma V; Gerloff, Christian; Tolosa, Eva; Maher, Pamela; Magnus, Tim

2012-01-01

The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia. PMID:22234339

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.

Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke.

PubMed

Pu, Hongjian; Jiang, Xiaoyan; Hu, Xiaoming; Xia, Jinchao; Hong, Dandan; Zhang, Wenting; Gao, Yanqin; Chen, Jun; Shi, Yejie

2016-12-01

Prophylactic dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been shown to remarkably ameliorate ischemic brain injury. However, the therapeutic efficacy of n-3 PUFA administration post-stroke, especially its impact on neurovascular remodeling and long-term neurological recovery, has not been fully characterized thus far. In this study, we investigated the effect of n-3 PUFA supplementation, as well as in combination with docosahexaenoic acid (DHA) injections, on long-term stroke outcomes. Mice were subjected to transient middle cerebral artery occlusion (MCAO) before randomly assigned to four groups to receive the following: (1) low dose of n-3 PUFAs as the vehicle control, (2) intraperitoneal DHA injections, (3) n-3 PUFA dietary supplement, or (4) combined treatment of (2) and (3). Neurological deficits and brain atrophy, neurogenesis, angiogenesis, and glial scar formation were assessed up to 28 days after MCAO. Results revealed that groups 2 and 3 showed only marginal reduction in post-stroke tissue loss and attenuation of cognitive deficits. Interestingly, group 4 exhibited significantly reduced tissue atrophy and improved cognitive functions compared to groups 2 and 3 with just a single treatment. Mechanistically, the combined treatment promoted post-stroke neurogenesis and angiogenesis, as well as reduced glial scar formation, all of which significantly correlated with the improved spatial memory in the Morris water maze. These results demonstrate an effective therapeutic regimen to enhance neurovascular restoration and long-term cognitive recovery in the mouse model of MCAO. Combined post-stroke DHA treatment and n-3 PUFA dietary supplementation thus may be a potential clinically translatable therapy for stroke or related brain disorders.

Impact of microRNA-134 on neural cell survival against ischemic injury in primary cultured neuronal cells and mouse brain with ischemic stroke by targeting HSPA12B.

PubMed

Chi, Wenying; Meng, Fanjun; Li, Yan; Li, Peilong; Wang, Guizhi; Cheng, Hong; Han, Song; Li, Junfa

2014-12-10

As a newly discovered member of the HSP70 family, heat shock protein A12B (HSPA12B) is involved in brain ischemic injury. According to our previous study, microRNA-134 (miR-134) could target HSPA12B by binding to its 3'-untranslated region (UTR). However, the regulation of miR-134 on HSPA12B and their role in protecting neuronal cells from ischemic injury are unclear. In this study, the miR-134 expression level was manipulated, and the HSPA12B protein levels were also determined in oxygen-glucose deprivation (OGD)-treated primary cultured neuronal cells in vitro and mouse brain after middle cerebral artery occlusion (MCAO)-induced ischemic stroke in vivo. The results showed that miR-134 expression levels increased in primary cultured neuronal cells and mouse brain from 12h to 7 day reoxygenation/reperfusion after 1h OGD or 1h MCAO treatment. miR-134 overexpression promoted neuronal cell death and apoptosis by decreasing HSPA12B protein levels. Conversely, downregulating miR-134 reduced neuronal cell death and apoptosis by enhancing HSPA12B protein levels. Also, HSPA12B siRNA could block miR-134 inhibitor-mediated neuroprotection against OGD-induced neuronal cell injury in vitro. Taken together, miR-134 might influence neuronal cell survival against ischemic injury in primary cultured neuronal cells and mouse brain with ischemic stroke by negatively modulating HSPA12B protein expression in a posttranscriptional manner. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

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.

Functional connectivity in the mouse brain imaged by B-mode photoacoustic microscopy

NASA Astrophysics Data System (ADS)

Nasiriavanaki, Mohammadreza; Xing, Wenxin; Xia, Jun; Wang, Lihong V.

2014-03-01

The increasing use of mouse models for human brain disease studies, coupled with the fact that existing functional imaging modalities cannot be easily applied to mice, presents an emerging need for a new functional imaging modality. Utilizing acoustic-resolution photoacoustic microscopy (AR-PAM), we imaged spontaneous cerebral hemodynamic fluctuations and their associated functional connections in the mouse brain. The images were acquired noninvasively in B-scan mode with a fast frame rate, a large field of view, and a high spatial resolution. At a location relative to the bregma 0, correlations were investigated inter-hemispherically between bilaterally homologous regions, as well as intra-hemispherically within the same functional regions. The functional connectivity in different functional regions was studied. The locations of these regions agreed well with the Paxinos mouse brain atlas. The functional connectivity map obtained in this study can then be used in the investigation of brain disorders such as stroke, Alzheimer's, schizophrenia, multiple sclerosis, autism, and epilepsy. Our experiments show that photoacoustic microscopy is capable to detect connectivities between different functional regions in B-scan mode, promising a powerful functional imaging modality for future brain research.

Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke

PubMed Central

Srinivasan, Vivek J.; Mandeville, Emiri T.; Can, Anil; Blasi, Francesco; Climov, Mihail; Daneshmand, Ali; Lee, Jeong Hyun; Yu, Esther; Radhakrishnan, Harsha; Lo, Eng H.; Sakadžić, Sava; Eikermann-Haerter, Katharina; Ayata, Cenk

2013-01-01

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties. PMID:23940761

Limb remote ischemic post-conditioning mitigates brain recovery in a mouse model of ischemic stroke by regulating reactive astrocytic plasticity.

PubMed

Cheng, Xue; Zhao, Haiping; Yan, Feng; Tao, Zhen; Wang, Rongliang; Han, Ziping; Li, Guangwen; Luo, Yumin; Ji, Xunming

2018-05-01

Maladaptive alterations of astrocytic plasticity may cause brain edema in the acute stage of stroke and glial scar formation in the recovery stage. The present study was designed to investigate the potential regulation of limb remote ischemic post-conditioning (RIPC) on astrocytic plasticity in experimental cerebral ischemia-reperfusion injury. Cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h in C57BL/6 mice, who were treated with RIPC immediately after reperfusion. The results showed that RIPC decreased hemispheric swelling, infarct volume and brain atrophy, and increased neurological function recovery and survival rates of ischemic mice at 3 and 14 d after cerebral ischemia-reperfusion, respectively. Moreover, the proportion of astrocyte subtypes was adjusted by RIPC treatment, demonstrated by decreased expression of the fibrous type (glial fibrillary acidic protein, GFAP) and increased expression of the protoplasmic type (glutamine synthetase, GS) in the ipsilateral side of the mouse brain at 14 d after cerebral ischemia-reperfusion. RIPC treatment adjusted the proportion of GFAP subtypes by downregulating the protein level of GFAPα, as well as upregulating the GFAPδ/GFAPα ratio in the ipsilateral side at 3 and 14 d after reperfusion. Notably, RIPC inhibited the phosphorylation of signal transducer and activators of transcriptions 3 (p-STAT3) in the ipsilateral side at 3 and 14 d after cerebral ischemia-reperfusion. Taken together, the results show that RIPC treatment could regulate reactive astrocytic plasticity and inhibition of STAT3 phosphorylation to promote neurological function recovery following ischemic stroke. Copyright © 2018 Elsevier B.V. All rights reserved.

Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation

PubMed Central

Bernardo, Bianca C.; Sapra, Geeta; Patterson, Natalie L.; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A.; McMullen, Julie R.

2015-01-01

Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions. PMID:26660322

Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation.

PubMed

Bernardo, Bianca C; Sapra, Geeta; Patterson, Natalie L; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A; McMullen, Julie R

2015-01-01

Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions.

An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease.

PubMed

Rodríguez Cruz, Yamila; Strehaiano, Manon; Rodríguez Obaya, Teresita; García Rodríguez, Julío César; Maurice, Tangui

2017-01-01

Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.

Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke.

PubMed

Mao, Leilei; Li, Peiying; Zhu, Wen; Cai, Wei; Liu, Zongjian; Wang, Yanling; Luo, Wenli; Stetler, Ruth A; Leak, Rehana K; Yu, Weifeng; Gao, Yanqin; Chen, Jun; Chen, Gang; Hu, Xiaoming

2017-07-01

Delayed thrombolytic treatment with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier breakdown after ischaemic stroke and lead to lethal haemorrhagic transformation. The immune system is a dynamic modulator of stroke response, and excessive immune cell accumulation in the cerebral vasculature is associated with compromised integrity of the blood-brain barrier. We previously reported that regulatory T cells, which function to suppress excessive immune responses, ameliorated blood-brain barrier damage after cerebral ischaemia. This study assessed the impact of regulatory T cells in the context of tPA-induced brain haemorrhage and investigated the underlying mechanisms of action. The number of circulating regulatory T cells in stroke patients was dramatically reduced soon after stroke onset (84 acute ischaemic stroke patients with or without intravenous tPA treatment, compared to 115 age and gender-matched healthy controls). Although stroke patients without tPA treatment gradually repopulated the numbers of circulating regulatory T cells within the first 7 days after stroke, post-ischaemic tPA treatment led to sustained suppression of regulatory T cells in the blood. We then used the murine suture and embolic middle cerebral artery occlusion models of stroke to investigate the therapeutic potential of adoptive regulatory T cell transfer against tPA-induced haemorrhagic transformation. Delayed administration of tPA (10 mg/kg) resulted in haemorrhagic transformation in the ischaemic territory 1 day after ischaemia. When regulatory T cells (2 × 106/mouse) were intravenously administered immediately after delayed tPA treatment in ischaemic mice, haemorrhagic transformation was significantly decreased, and this was associated with improved sensorimotor functions. Blood-brain barrier disruption and tight junction damages were observed in the presence of delayed tPA after stroke, but were mitigated by regulatory T cell transfer. Mechanistic studies demonstrated that regulatory T cells completely abolished the tPA-induced elevation of MMP9 and CCL2 after stroke. Using MMP9 and CCL2 knockout mice, we discovered that both molecules partially contributed to the protective actions of regulatory T cells. In an in vitro endothelial cell-based model of the blood-brain barrier, we confirmed that regulatory T cells inhibited tPA-induced endothelial expression of CCL2 and preserved blood-brain barrier integrity after an ischaemic challenge. Lentivirus-mediated CCL2 knockdown in endothelial cells completely abolished the blood-brain barrier protective effect of regulatory T cells in vitro. Altogether, our studies suggest that regulatory T cell adoptive transfer may alleviate thrombolytic treatment-induced haemorrhage in stroke victims. Furthermore, regulatory T cell-afforded protection in the tPA-treated stroke model is mediated by two inhibitory mechanisms involving CCL2 and MMP9. Thus, regulatory T cell adoptive transfer may be useful as a cell-based therapy to improve the efficacy and safety of thrombolytic treatment for ischaemic stroke. © 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.

Altered steering strategies for goal-directed locomotion in stroke

PubMed Central

2013-01-01

Background Individuals who have sustained a stroke can manifest altered locomotor steering behaviors when exposed to optic flows expanding from different locations. Whether these alterations persist in the presence of a visible goal and whether they can be explained by the presence of a perceptuo-motor disorder remain unknown. The purpose of this study was to compare stroke participants and healthy participants on their ability to control heading while exposed to changing optic flows and target locations. Methods Ten participants with stroke (55.6 ± 9.3 yrs) and ten healthy controls (57.0 ± 11.5 yrs) participated in a mouse-driven steering task (perceptuo-motor task) while seated and in a walking steering task. In the seated steering task, participants were instructed to head or ‘walk’ toward a target in the virtual environment by using a mouse while wearing a helmet-mounted display (HMD). In the walking task, participants performed a similar steering task in the same virtual environment while walking overground at their comfortable speed. For both experiments, the target and/or the focus of expansion (FOE) of the optic flow shifted to the side (±20°) or remained centered. The main outcome measure was net heading errors (NHE). Secondary outcomes included mediolateral displacement, horizontal head orientation, and onsets of heading and head reorientation. Results In the walking steering task, the presence of FOE shifts modulated the extent and timing of mediolateral displacement and head rotation changes, as well as NHE magnitudes. Participants overshot and undershot their net heading, respectively, in response to ipsilateral and contralateral FOE and target shifts. Stroke participants made larger NHEs, especially when the FOE was shifted towards the non-paretic side. In the seated steering task, similar NHEs were observed between stroke and healthy participants. Conclusions The findings highlight the fine coordination between rotational and translational steering mechanisms in presence of targets and FOE shifts. The altered performance of stroke participants in walking but not in the seated steering task suggests that an altered perceptuo-motor processing of optic flow is not a main contributing factor and that other stroke-related sensorimotor deficits are involved. PMID:23875969

Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

PubMed

Jeanne, Marion; Jorgensen, Jeff; Gould, Douglas B

2015-05-05

Collagen type IV alpha1 (COL4A1) and alpha2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases, including cerebral microbleeds, porencephaly, and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown, and there is a lack of effective treatment. Using Col4a1 and Col4a2 mutant mouse models, we investigated the genetic complexity and cellular mechanisms underlying the disease. We found that Col4a1 mutations cause abnormal vascular development, which triggers small-vessel disease, recurrent hemorrhagic strokes, and age-related macroangiopathy. We showed that allelic heterogeneity, genetic context, and environmental factors such as intense exercise or anticoagulant medication modulated disease severity and contributed to phenotypic heterogeneity. We found that intracellular accumulation of mutant collagen in vascular endothelial cells and pericytes was a key triggering factor of ICH. Finally, we showed that treatment of mutant mice with a US Food and Drug Administration-approved chemical chaperone resulted in a decreased collagen intracellular accumulation and a significant reduction in ICH severity. Our data are the first to show therapeutic prevention in vivo of ICH resulting from Col4a1 mutation and imply that a mechanism-based therapy promoting protein folding might also prevent ICH in patients with COL4A1 and COL4A2 mutations. © 2015 American Heart Association, Inc.

Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain

PubMed Central

Rink, Cameron; Gnyawali, Surya; Stewart, Richard; Teplitsky, Seth; Harris, Hallie; Roy, Sashwati; Sen, Chandan K.; Khanna, Savita

2017-01-01

Ischemic stroke results in excessive release of glutamate, which contributes to neuronal cell death. Here, we test the hypothesis that otherwise neurotoxic glutamate can be productively metabolized by glutamate oxaloacetate transaminase (GOT) to maintain cellular energetics and protect the brain from ischemic stroke injury. The GOT-dependent metabolism of glutamate was studied in primary neural cells and in stroke-affected C57-BL6 mice using magnetic resonance spectroscopy and GC-MS. Extracellular Glu sustained cell viability under hypoglycemic conditions and increased GOT-mediated metabolism in vitro. Correction of stroke-induced hypoxia using supplemental oxygen in vivo lowered Glu levels as measured by 1H magnetic resonance spectroscopy. GOT knockdown abrogated this effect and caused ATP loss in the stroke-affected brain. GOT overexpression increased anaplerotic refilling of tricarboxylic acid cycle intermediates in mouse brain during ischemic stroke. Furthermore, GOT overexpression not only reduced ischemic stroke lesion volume but also attenuated neurodegeneration and improved poststroke sensorimotor function. Taken together, our results show that GOT enables metabolism of otherwise neurotoxic extracellular Glu through a truncated tricarboxylic acid cycle under hypoglycemic conditions.—Rink, C., Gnyawali, S., Stewart, R., Teplitsky, S., Harris, H., Roy, S., Sen, C. K., Khanna, S. Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain. PMID:28096234

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.

Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling.

PubMed

He, Yating; Ma, Xiaofeng; Li, Daojing; Hao, Junwei

2017-08-01

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1 + cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

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

p53-dependent programmed necrosis controls germ cell homeostasis during spermatogenesis.

PubMed

Napoletano, Francesco; Gibert, Benjamin; Yacobi-Sharon, Keren; Vincent, Stéphane; Favrot, Clémentine; Mehlen, Patrick; Girard, Victor; Teil, Margaux; Chatelain, Gilles; Walter, Ludivine; Arama, Eli; Mollereau, Bertrand

2017-09-01

The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis.

Nop2 is expressed during proliferation of neural stem cells and in adult mouse and human brain.

PubMed

Kosi, Nina; Alić, Ivan; Kolačević, Matea; Vrsaljko, Nina; Jovanov Milošević, Nataša; Sobol, Margarita; Philimonenko, Anatoly; Hozák, Pavel; Gajović, Srećko; Pochet, Roland; Mitrečić, Dinko

2015-02-09

The nucleolar protein 2 gene encodes a protein specific for the nucleolus. It is assumed that it plays a role in the synthesis of ribosomes and regulation of the cell cycle. Due to its link to cell proliferation, higher expression of Nop2 indicates a worse tumor prognosis. In this work we used Nop2(gt1gaj) gene trap mouse strain. While lethality of homozygous animals suggested a vital role of this gene, heterozygous animals allowed the detection of expression of Nop2 in various tissues, including mouse brain. Histochemistry, immunohistochemistry and immunoelectron microscopy techniques, applied to a mature mouse brain, human brain and on mouse neural stem cells revealed expression of Nop2 in differentiating cells, including astrocytes, as well as in mature neurons. Nop2 was detected in various regions of mouse and human brain, mostly in large pyramidal neurons. In the human, Nop2 was strongly expressed in supragranular and infragranular layers of the somatosensory cortex and in layer III of the cingulate cortex. Also, Nop2 was detected in CA1 and the subiculum of the hippocampus. Subcellular analyses revealed predominant location of Nop2 within the dense fibrillar component of the nucleolus. To test if Nop2 expression correlates to cell proliferation occurring during tissue regeneration, we induced strokes in mice by middle cerebral artery occlusion. Two weeks after stroke, the number of Nop2/nestin double positive cells in the region affected by ischemia and the periventricular zone substantially increased. Our findings suggest a newly discovered role of Nop2 in both mature neurons and in cells possibly involved in the regeneration of nervous tissue. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Polyamines and Their Metabolites as Diagnostic Markers of Human Diseases

PubMed Central

Park, Myung Hee; Igarashi, Kazuei

2013-01-01

Polyamines, putrescine, spermidine and spermine, are ubiquitous in living cells and are essential for eukaryotic cell growth. These polycations interact with negatively charged molecules such as DNA, RNA, acidic proteins and phospholipids and modulate various cellular functions including macromolecular synthesis. Dysregulation of the polyamine pathway leads to pathological conditions including cancer, inflammation, stroke, renal failure and diabetes. Increase in polyamines and polyamine synthesis enzymes is often associated with tumor growth, and urinary and plasma contents of polyamines and their metabolites have been investigated as diagnostic markers for cancers. Of these, diacetylated derivatives of spermidine and spermine are elevated in the urine of cancer patients and present potential markers for early detection. Enhanced catabolism of cellular polyamines by polyamine oxidases (PAO), spermine oxidase (SMO) or acetylpolyamine oxidase (AcPAO), increases cellular oxidative stress and generates hydrogen peroxide and a reactive toxic metabolite, acrolein, which covalently incorporates into lysine residues of cellular proteins. Levels of protein-conjuagated acrolein (PC-Acro) and polyamine oxidizing enzymes were increased in the locus of brain infarction and in plasma in a mouse model of stroke and also in the plasma of stroke patients. When the combined measurements of PC-Acro, interleukin 6 (IL-6), and C-reactive protein (CRP) were evaluated, even silent brain infarction (SBI) was detected with high sensitivity and specificity. Considering that there are no reliable biochemical markers for early stage of stroke, PC-Acro and PAOs present promising markers. Thus the polyamine metabolites in plasma or urine provide useful tools in early diagnosis of cancer and stroke. PMID:24009852

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.

Differential subnetwork of chemokines/cytokines in human, mouse, and rat brain cells after oxygen-glucose deprivation.

PubMed

Du, Yang; Deng, Wenjun; Wang, Zixing; Ning, MingMing; Zhang, Wei; Zhou, Yiming; Lo, Eng H; Xing, Changhong

2017-04-01

Mice and rats are the most commonly used animals for preclinical stroke studies, but it is unclear whether targets and mechanisms are always the same across different species. Here, we mapped the baseline expression of a chemokine/cytokine subnetwork and compared responses after oxygen-glucose deprivation in primary neurons, astrocytes, and microglia from mouse, rat, and human. Baseline profiles of chemokines (CX3CL1, CXCL12, CCL2, CCL3, and CXCL10) and cytokines (IL-1α, IL-1β, IL-6, IL-10, and TNFα) showed significant differences between human and rodents. The response of chemokines/cytokines to oxygen-glucose deprivation was also significantly different between species. After 4 h oxygen-glucose deprivation and 4 h reoxygenation, human and rat neurons showed similar changes with a downregulation in many chemokines, whereas mouse neurons showed a mixed response with up- and down-regulated genes. For astrocytes, subnetwork response patterns were more similar in rats and mice compared to humans. For microglia, rat cells showed an upregulation in all chemokines/cytokines, mouse cells had many down-regulated genes, and human cells showed a mixed response with up- and down-regulated genes. This study provides proof-of-concept that species differences exist in chemokine/cytokine subnetworks in brain cells that may be relevant to stroke pathophysiology. Further investigation of differential gene pathways across species is warranted.

CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.

PubMed

Choe, Chi-un; Lardong, Kerstin; Gelderblom, Mathias; Ludewig, Peter; Leypoldt, Frank; Koch-Nolte, Friedrich; Gerloff, Christian; Magnus, Tim

2011-01-01

Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion. We show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8(+) cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO) model. CD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke.

Brain Ischemia Induces Diversified Neuroantigen-Specific T-Cell Responses That Exacerbate Brain Injury.

PubMed

Jin, Wei-Na; Gonzales, Rayna; Feng, Yan; Wood, Kristofer; Chai, Zhi; Dong, Jing-Fei; La Cava, Antonio; Shi, Fu-Dong; Liu, Qiang

2018-06-01

Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG 35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigen-presenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. By coupling transfer of labeled MOG 35-55 -specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG 91-108 and MOG 103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury. © 2018 The Authors.

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.

Poloxamer-188 and citicoline provide neuronal membrane integrity and protect membrane stability in cortical spreading depression.

PubMed

Yıldırım, Timur; Eylen, Alpaslan; Lule, Sevda; Erdener, Sefik Evren; Vural, Atay; Karatas, Hulya; Ozveren, Mehmet Faik; Dalkara, Turgay; Gursoy-Ozdemir, Yasemin

2015-01-01

Under pathological conditions such as brain trauma, subarachnoid hemorrhage and stroke, cortical spreading depression (CSD) or peri-infarct depolarizations contribute to brain damage in animal models of neurological disorders as well as in human neurological diseases. CSD causes transient megachannel opening on the neuronal membrane, which may compromise neuronal survival under pathological conditions. Poloxamer-188 (P-188) and citicoline are neuroprotectants with membrane sealing properties. The aim of this study is to investigate the effect of P-188 and citicoline on the neuronal megachannel opening induced by CSD in the mouse brain. We have monitored megachannel opening with propidium iodide, a membrane impermeable fluorescent dye and, demonstrate that P-188 and citicoline strikingly decreased CSD-induced neuronal PI influx in cortex and hippocampal dentate gyrus. Therefore, these agents may be providing neuroprotection by blocking megachannel opening, which may be related to their membrane sealing action and warrant further investigation for treatment of traumatic brain injury and ischemic stroke.

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

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

A novel indication of platonin, a therapeutic immunomodulating medicine, on neuroprotection against ischemic stroke in mice

PubMed Central

Sheu, Joen-Rong; Chen, Zhih-Cherng; Jayakumar, Thanasekaran; Chou, Duen-Suey; Yen, Ting-Lin; Lee, Hsing-Ni; Pan, Szu-Han; Hsia, Chih-Hsuan; Yang, Chih-Hao; Hsieh, Cheng-Ying

2017-01-01

Thrombosis and stroke are major causes of disability and death worldwide. However, the regular antithrombotic drugs may have unsatisfactory results and side effects. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers and some acute inflammation. Here, we explored the neuroprotective effects of platonin against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in mice. Platonin(200 μg/kg) substantially reduced cerebral infarct volume, brain edema, neuronal cell death and neurological deficit scores, and improved the MCAO-reduced locomotor activity and rotarod performance. Platonin(5–10 μM) potently inhibited platelet aggregation and c-Jun NH2-terminal kinase (JNK) phosphorylation in collagen-activated platelets. The antiaggregation effect did not affect bleeding time but increased occlusion time in platonin(100 and 200 μg/kg)-treated mice. Platonin(2–10 μM) was potent in diminishing collagen- and Fenton reaction-induced ∙OH formation. Platonin(5–10 μM) also suppressed the expression of nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1β, and JNK phosphorylation in lipopolysaccharide-stimulated macrophages. MCAO-induced expression of 3-nitrotyrosine and Iba1 was apparently attenuated in platonin(200 μg/kg)-treated mice. In conclusion, platonin exhibited remarkable neuroprotective properties against MCAO-induced ischemia in a mouse model through its antiaggregation, antiinflammatory and antiradical properties. The observed therapeutic efficacy of platonin may consider being a novel medcine against ischemic stroke. PMID:28165057

Targeted mini-strokes produce changes in interhemispheric sensory signal processing that are indicative of disinhibition within minutes.

PubMed

Mohajerani, Majid H; Aminoltejari, Khatereh; Murphy, Timothy H

2011-05-31

Most processing of sensation involves the cortical hemisphere opposite (contralateral) to the stimulated limb. Stroke patients can exhibit changes in the interhemispheric balance of sensory signal processing. It is unclear whether these changes are the result of poststroke rewiring and experience, or whether they could result from the immediate effect of circuit loss. We evaluated the effect of mini-strokes over short timescales (<2 h) where cortical rewiring is unlikely by monitoring sensory-evoked activity throughout much of both cortical hemispheres using voltage-sensitive dye imaging. Blockade of a single pial arteriole within the C57BL6J mouse forelimb somatosensory cortex reduced the response evoked by stimulation of the limb contralateral to the stroke. However, after stroke, the ipsilateral (uncrossed) forelimb response within the unaffected hemisphere was spared and became independent of the contralateral forelimb cortex. Within the unaffected hemisphere, mini-strokes in the opposite hemisphere significantly enhanced sensory responses produced by stimulation of either contralateral or ipsilateral pathways within 30-50 min of stroke onset. Stroke-induced enhancement of responses within the spared hemisphere was not reproduced by inhibition of either cortex or thalamus using pharmacological agents in nonischemic animals. I/LnJ acallosal mice showed similar rapid interhemispheric redistribution of sensory processing after stroke, suggesting that subcortical connections and not transcallosal projections were mediating the novel activation patterns. Thalamic inactivation before stroke prevented the bilateral rearrangement of sensory responses. These findings suggest that acute stroke, and not merely loss of activity, activates unique pathways that can rapidly redistribute function within the spared cortical hemisphere.

Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia.

PubMed

Matsuura, Wataru; Harada, Shinichi; Tokuyama, Shogo

2016-01-01

Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.

TREATMENT OF STROKE WITH DETA-NONOATE AND BONE MARROW STROMAL CELLS UPREGULATES ANGIOPOIETIN-1/TIE2 AND ENHANCES NEOVASCULARIZATION

PubMed Central

CUI, X.; CHEN, J.; ZACHAREK, A.; ROBERTS, C.; SAVANT-BHONSALE, S.; CHOPP, M.

2008-01-01

Neovascularization may contribute to functional recovery after neural injury. Combination treatment of stroke with a nitric oxide donor, DETA-NONOate and bone marrow stromal cells promote functional recovery. However, the mechanisms underlying functional improvement have not been elucidated. In this study, we tested the hypothesis that combination treatment upregulates Angiopoietin1 and its receptor Tie2 in the ischemic brain and bone marrow stromal cells, thereby enhances cerebral neovascularization after stroke. Adult wild type male C57BL/6 mice were intravenously administered PBS, bone marrow stromal cells 5×105, DETA-NONOate 0.4 mg/kg or combination DETA-NONOate with bone marrow stromal cells (n=12/group) after middle cerebral artery occlusion. Combination treatment significantly upregulated Angiopoietin-1/Tie2 and tight junction protein (occludin) expression, and increased the number, diameter and perimeter of blood vessels in the ischemic brain compared with vehicle control (mean ± SE, p<0.05). In vitro, DETA-NONOate significantly increased Angiopoietin-1/Tie2 protein (n=6/group) and Tie2 mRNA (n=3/group) expression in bone marrow stromal cells. DETA-NONOate also significantly increased Angiopoietin-1 protein (n=6/group) and mRNA (n=3/group) expression in mouse brain endothelial cells (p<0.05). Angiopoietin-1 mRNA (n=3/group) was significantly increased in mouse brain endothelial cells treated with DETA-NONOate in combination with bone marrow stromal cells conditioned medium compared with cells treated with bone marrow stromal cells conditioned medium or DETA-NONOate alone. Mouse brain endothelial cell capillary tube-like formation assays (n=6/group) showed that Angiopoietin-1 peptide, the supernatant of bone marrow stromal cells and DETA-NONOate significantly increased capillary tube formation compared to vehicle control. Combination treatment significantly increased capillary tube formation compared with DETA-NONOate treatment alone. Inhibition of Angiopoietin-1 significantly attenuated combination treatment-induced tube formation. Our data indicated that combination treatment of stroke with DETA-NONOate and bone marrow stromal cells promotes neovascularization, which is at least partially mediated by upregulation of the Angiopoietin-1/Tie2 axis. PMID:18691637

p53-dependent programmed necrosis controls germ cell homeostasis during spermatogenesis

PubMed Central

Napoletano, Francesco; Vincent, Stéphane; Favrot, Clémentine; Mehlen, Patrick; Girard, Victor; Chatelain, Gilles; Walter, Ludivine; Arama, Eli

2017-01-01

The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis. PMID:28945745

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

Animal models of ischemic stroke and their application in clinical research.

PubMed

Fluri, Felix; Schuhmann, Michael K; Kleinschnitz, Christoph

2015-01-01

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.

Animal models of ischemic stroke and their application in clinical research

PubMed Central

Fluri, Felix; Schuhmann, Michael K; Kleinschnitz, Christoph

2015-01-01

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models. PMID:26170628

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.

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

Detection of different states of sleep in the rodents by the means of artificial neural networks

NASA Astrophysics Data System (ADS)

Musatov, Viacheslav; Dykin, Viacheslav; Pitsik, Elena; Pisarchik, Alexander

2018-04-01

This paper considers the possibility of classification of electroencephalogram (EEG) and electromyogram (EMG) signals corresponding to different phases of sleep and wakefulness of mice by the means of artificial neural networks. A feed-forward artificial neural network based on multilayer perceptron was created and trained on the data of one of the rodents. The trained network was used to read and classify the EEG and EMG data corresponding to different phases of sleep and wakefulness of the same mouse and other mouse. The results show a good recognition quality of all phases for the rodent on which the training was conducted (80-99%) and acceptable recognition quality for the data collected from the same mouse after a stroke.

A Bayesian Approach for Image Segmentation with Shape Priors

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

Chang, Hang; Yang, Qing; Parvin, Bahram

2008-06-20

Color and texture have been widely used in image segmentation; however, their performance is often hindered by scene ambiguities, overlapping objects, or missingparts. In this paper, we propose an interactive image segmentation approach with shape prior models within a Bayesian framework. Interactive features, through mouse strokes, reduce ambiguities, and the incorporation of shape priors enhances quality of the segmentation where color and/or texture are not solely adequate. The novelties of our approach are in (i) formulating the segmentation problem in a well-de?ned Bayesian framework with multiple shape priors, (ii) ef?ciently estimating parameters of the Bayesian model, and (iii) multi-object segmentationmore » through user-speci?ed priors. We demonstrate the effectiveness of our method on a set of natural and synthetic images.« less

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.

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.

X-Chromosome Dosage and the Response to Cerebral Ischemia

PubMed Central

Turtzo, L. Christine; Siegel, Chad; McCullough, Louise D.

2011-01-01

Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and EdaTa). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes, nor the parent of origin of the remaining X chromosome, had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice. PMID:21917808

X chromosome dosage and the response to cerebral ischemia.

PubMed

Turtzo, L Christine; Siegel, Chad; McCullough, Louise D

2011-09-14

Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and Eda(Ta)). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes nor the parent of origin of the remaining X chromosome had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice.

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.

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.

PubMed

Kleinschnitz, Christoph; Kraft, Peter; Dreykluft, Angela; Hagedorn, Ina; Göbel, Kerstin; Schuhmann, Michael K; Langhauser, Friederike; Helluy, Xavier; Schwarz, Tobias; Bittner, Stefan; Mayer, Christian T; Brede, Marc; Varallyay, Csanad; Pham, Mirko; Bendszus, Martin; Jakob, Peter; Magnus, Tim; Meuth, Sven G; Iwakura, Yoichiro; Zernecke, Alma; Sparwasser, Tim; Nieswandt, Bernhard; Stoll, Guido; Wiendl, Heinz

2013-01-24

We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.

Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia

PubMed Central

Choy, Fong Chan; Klarić, Thomas S; Leong, Wai Khay; Koblar, Simon A

2015-01-01

Stroke is the second leading cause of death and the most frequent cause of adult disability. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischaemia. Although previous studies have demonstrated that Npas4 plays a critical role in protecting neurons against neurodegenerative insults, the neuroprotective effect of Npas4 in response to ischaemic brain injury remains unknown. In this study, we used a loss-of-function approach to examine the neuroprotective potential of Npas4 in the context of ischaemic damage. Using oxygen and glucose deprivation, we demonstrated that the knockdown of Npas4 in mouse cortical neurons resulted in increased susceptibility to cell death. The protective effect of Npas4 was further investigated in vivo using a photochemically-induced stroke model in mice. We found a significantly larger lesion size and increased neurodegeneration in Npas4 knockout mice as compared to wild-type mice. Moreover, we also showed that ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death. Taken together, these data suggest that Npas4 plays a neuroprotective role in ischaemic stroke by limiting progressive neurodegeneration and neuroinflammation. PMID:26661154

Production and characterization of immortal human neural stem cell line with multipotent differentiation property.

PubMed

Kim, Seung U; Nagai, Atsushi; Nakagawa, Eiji; Choi, Hyun B; Bang, Jung H; Lee, Hong J; Lee, Myung A; Lee, Yong B; Park, In H

2008-01-01

We document the protocols and methods for the production of immortalized cell lines of human neural stem cells from the human fetal central nervous system (CNS) cells by using a retroviral vector encoding v-myc oncogene. One of the human neural stem cell lines (HB1.F3) was found to express nestin and other specific markers for human neural stem cells, giving rise to three fundamental cell types of the CNS: neurons, astrocytes, and oligodendrocytes. After transplantation into the brain of mouse model of stroke, implanted human neural stem cells were observed to migrate extensively from the site of implantation into other anatomical sites and to differentiate into neurons and glial cells.

Resting-state functional connectivity imaging of the mouse brain using photoacoustic tomography

NASA Astrophysics Data System (ADS)

Nasiriavanaki, Mohammadreza; Xia, Jun; Wan, Hanlin; Bauer, Adam Q.; Culver, Joseph P.; Wang, Lihong V.

2014-03-01

Resting-state functional connectivity (RSFC) imaging is an emerging neuroimaging approach that aims to identify spontaneous cerebral hemodynamic fluctuations and their associated functional connections. Clinical studies have demonstrated that RSFC is altered in brain disorders such as stroke, Alzheimer's, autism, and epilepsy. However, conventional neuroimaging modalities cannot easily be applied to mice, the most widely used model species for human brain disease studies. For instance, functional magnetic resonance imaging (fMRI) of mice requires a very high magnetic field to obtain a sufficient signal-to-noise ratio and spatial resolution. Functional connectivity mapping with optical intrinsic signal imaging (fcOIS) is an alternative method. Due to the diffusion of light in tissue, the spatial resolution of fcOIS is limited, and experiments have been performed using an exposed skull preparation. In this study, we show for the first time, the use of photoacoustic computed tomography (PACT) to noninvasively image resting-state functional connectivity in the mouse brain, with a large field of view and a high spatial resolution. Bilateral correlations were observed in eight regions, as well as several subregions. These findings agreed well with the Paxinos mouse brain atlas. This study showed that PACT is a promising, non-invasive modality for small-animal functional brain imaging.

A Systematic Review and Meta-Analysis of the Haemodynamic Effects of Cannabidiol

PubMed Central

Sultan, Salahaden R.; Millar, Sophie A.; England, Timothy J.; O'Sullivan, Saoirse E.

2017-01-01

Despite cannabidiol (CBD) having numerous cardiovascular effects in vitro, its haemodynamic effects in vivo are unclear. Nonetheless, the clinical use of CBD (Epidiolex) is becoming more widespread. The aim of this systematic review was to establish whether CBD is associated with changes in haemodynamics in vivo. Twenty-five studies that assessed the haemodynamic effects of CBD (from PubMed, Medline and EMBASE) were systematically reviewed and meta-analyzed. Data on blood pressure (BP), heart rate (HR), and blood flow (BF) were extracted and analyzed using random effects models. Twenty-two publications assessed BP and HR among 6 species (BP n = 344 and HR n = 395), and 5 publications assessed BF in 3 species (n = 56) after acute dosing of CBD. Chronic dosing was assessed in 4 publications in 3 species (total subjects BP, n = 6; HR, n = 27; BF, n = 3). Acute CBD dosing had no effect on BP or HR under control conditions. Similarly, chronic dosing with CBD had no effect on HR. In models of stress, acute CBD administration significantly reduced the increase in BP and HR induced by stress (BP, mean difference (MD) −3.54, 95% CI −5.19, −1.9, p < 0.0001; HR, MD −16.23, 95% CI −26.44, −6.02, p = 0.002). In mouse models of stroke, CBD significantly increased cerebral blood flow (CBF, standardized mean difference (SMD) 1.62, 95% CI 0.41, 2.83, p = 0.009). Heterogeneity among the studies was present, there was no publication bias except in HR of control and stressful conditions after acute CBD dosing, and median study quality was 5 out of 9 (ranging from 1 to 8). From the limited data available, we conclude that acute and chronic administration of CBD had no effect on BP or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral blood flow (CBF) in mouse models of stroke. Further studies are required to fully understand the potential haemodynamic effects of CBD in humans under normal and pathological conditions. PMID:28286481

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.

PubMed

Cahill, Lindsay S; Gazdzinski, Lisa M; Tsui, Albert Ky; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory Mt; Kassner, Andrea; Sled, John G

2017-03-01

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

PubMed Central

Gazdzinski, Lisa M; Tsui, Albert KY; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory MT; Kassner, Andrea; Sled, John G

2016-01-01

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia. PMID:27165012

Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy.

PubMed

Rahn, J J; Bestman, J E; Josey, B J; Inks, E S; Stackley, K D; Rogers, C E; Chou, C J; Chan, S S L

2014-02-14

Epilepsy is a debilitating disease affecting 1-2% of the world's population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a critical need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit histone deacetylases (HDACs) using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compound pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously determined to be a measurable manifestation of seizures. In our first screen, we tested a number of different HDAC inhibitors and found that one, 2-benzamido-1 4-naphthoquinone (NQN1), significantly decreased swim activity to levels equal to that of valproic acid, 2-n-propylpentanoic acid (VPA). We continued to screen structurally related compounds including Vitamin K3 (VK3) and a number of novel Vitamin K (VK) analogs. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compounds. Three of these compounds were subsequently tested on mouse seizure models at the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compound 2h reduced seizures particularly well in the minimal clonic seizure (6Hz) and corneal-kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compounds on mitochondrial respiration and ATP production in a mouse hippocampal cell line. We demonstrate that these compounds affect ATP metabolism and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogs for the prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compounds to affect energy production. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Real-time optoacoustic monitoring of stroke

NASA Astrophysics Data System (ADS)

Kneipp, Moritz; Turner, Jake; Hambauer, Sebastian; Krieg, Sandro M.; Lehmberg, Jens; Lindauer, Ute; Razansky, Daniel

2014-03-01

Characterizing disease progression and identifying possible therapeutic interventions in stroke is greatly aided by the use of longitudinal function imaging studies. In this study, we investigate the applicability of real-time multispectral optoacoustic tomography (MSOT) as a tool for non-invasive monitoring of the progression of stroke in the whole brain. The middle cerebral artery occlusion (MCAO) method was used to induce stroke. Mice were imaged under isoflurane anesthesia preoperatively and at several time points during and after the 60-minute occlusion. The animals were sacrificed after 24 hours and their excised brains frozen at -80°C for sectioning. The cryosection were stained using H&E staining to identify the ischemic lesion. Major vessels are readily identifiable in the whole mouse head in the in vivo optoacoustic scans. During ischemia, a reduction in cerebral blood volume is detectable in the cortex. Post ischemia, spectral unmixing of the optoacoustic signals shows an asymmetry of the deoxygenated hemoglobin in the hemisphere affected by MCAO. This hypoxic area was mainly located around the boundary of the ischemic lesion and was therefore identified as the ischemic penumbra. Non-invasive functional MSOT imaging is able to visualize the hypoxic penumbra in brains affected by stroke. Stopping the spread of the infarct area and revitalizing the penumbra is central in stroke research, this new imaging technique may therefore prove to be a valuable tool in the monitoring and developing new treatments.

Treatment of stroke with (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1, 2-diolate and bone marrow stromal cells upregulates angiopoietin-1/Tie2 and enhances neovascularization.

PubMed

Cui, X; Chen, J; Zacharek, A; Roberts, C; Savant-Bhonsale, S; Chopp, M

2008-09-22

Neovascularization may contribute to functional recovery after neural injury. Combination treatment of stroke with a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1, 2-diolate (DETA-NONOate) and bone marrow stromal cells promotes functional recovery. However, the mechanisms underlying functional improvement have not been elucidated. In this study, we tested the hypothesis that combination treatment upregulates angiopoietin-1 and its receptor Tie2 in the ischemic brain and bone marrow stromal cells, thereby enhancing cerebral neovascularization after stroke. Adult wild type male C57BL/6 mice were i.v. administered PBS, bone marrow stromal cells 5x10(5), DETA-NONOate 0.4 mg/kg or combination DETA-NONOate with bone marrow stromal cells (n=12/group) after middle cerebral artery occlusion. Combination treatment significantly upregulated angiopoietin-1/Tie2 and tight junction protein (occludin) expression, and increased the number, diameter and perimeter of blood vessels in the ischemic brain compared with vehicle control (mean+ or -S.E., P<0.05). In vitro, DETA-NONOate significantly increased angiopoietin-1/Tie2 protein (n=6/group) and Tie2 mRNA (n=3/group) expression in bone marrow stromal cells. DETA-NONOate also significantly increased angiopoietin-1 protein (n=6/group) and mRNA (n=3/group) expression in mouse brain endothelial cells (P<0.05). Angiopoietin-1 mRNA (n=3/group) was significantly increased in mouse brain endothelial cells treated with DETA-NONOate in combination with bone marrow stromal cell-conditioned medium compared with cells treated with bone marrow stromal cell-conditioned medium or DETA-NONOate alone. Mouse brain endothelial cell capillary tube-like formation assays (n=6/group) showed that angiopoietin-1 peptide, the supernatant of bone marrow stromal cells and DETA-NONOate significantly increased capillary tube formation compared with vehicle control. Combination treatment significantly increased capillary tube formation compared with DETA-NONOate treatment alone. Inhibition of angiopoietin-1 significantly attenuated combination treatment-induced tube formation. Our data indicated that combination treatment of stroke with DETA-NONOate and bone marrow stromal cells promotes neovascularization, which is at least partially mediated by upregulation of the angiopoietin-1/Tie2 axis.

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.

In vivo near-infrared imaging of fibrin deposition in thromboembolic stroke in mice.

PubMed

Zhang, Yi; Fan, Shufeng; Yao, Yuyu; Ding, Jie; Wang, Yu; Zhao, Zhen; Liao, Lei; Li, Peicheng; Zang, Fengchao; Teng, Gao-Jun

2012-01-01

Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa-targeted near-infrared fluorescence (NIRF) imaging. The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia. In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume. Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke.

In Vivo Near-Infrared Imaging of Fibrin Deposition in Thromboembolic Stroke in Mice

PubMed Central

Zhang, Yi; Fan, Shufeng; Yao, Yuyu; Ding, Jie; Wang, Yu; Zhao, Zhen; Liao, Lei; Li, Peicheng; Zang, Fengchao; Teng, Gao-Jun

2012-01-01

Objectives Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa–targeted near-infrared fluorescence (NIRF) imaging. Materials and Methods The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia. Results In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume. Conclusion Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke. PMID:22272319

Norepinephrine Modulates Pyramidal Cell Synaptic Properties in the Anterior Piriform Cortex of Mice: Age-Dependent Effects of β-adrenoceptors

PubMed Central

Ghosh, Abhinaba; Purchase, Nicole C.; Chen, Xihua; Yuan, Qi

2015-01-01

Early odor preference learning in rodents occurs within a sensitive period [≤postnatal day (P)10–12], during which pups show a heightened ability to form an odor preference when a novel odor is paired with a tactile stimulation (e.g., stroking). Norepinephrine (NE) release from the locus coeruleus during stroking mediates this learning. However, in older pups, stroking loses its ability to induce learning. The cellular and circuitry mechanisms underpinning the sensitive period for odor preference learning is not well understood. We first established the sensitive period learning model in mice – odor paired with stroking induced odor preference in P8 but not P14 mice. This learning was dependent on NE-β-adrenoceptors as it was prevented by propranolol injection prior to training. We then tested whether there are developmental changes in pyramidal cell excitability and NE responsiveness in the anterior piriform cortex (aPC) in mouse pups. Although significant differences of pyramidal cell intrinsic properties were found in two age groups (P8–11 and P14+), NE at two concentrations (0.1 and 10 μM) did not alter intrinsic properties in either group. In contrast, in P8–11 pups, NE at 0.1 μM presynaptically decreased miniature IPSC and increased miniature EPSC frequencies. These effects were reversed with a higher dose of NE (10 μM), suggesting involvement of different adrenoceptor subtypes. In P14+ pups, NE at higher doses (1 and 10 μM) acted both pre- and postsynaptically to promote inhibition. These results suggest that enhanced synaptic excitation and reduced inhibition by NE in the aPC network may underlie the sensitive period. PMID:26635530

Fluoxetine protects against IL-1β-induced neuronal apoptosis via downregulation of p53.

PubMed

Shan, Han; Bian, Yaqi; Shu, Zhaoma; Zhang, Linxia; Zhu, Jialei; Ding, Jianhua; Lu, Ming; Xiao, Ming; Hu, Gang

2016-08-01

Fluoxetine, a selective serotonin reuptake inhibitor, exerts neuroprotective effects in a variety of neurological diseases including stroke, but the underlying mechanism remains obscure. In the present study, we addressed the molecular events in fluoxetine against ischemia/reperfusion-induced acute neuronal injury and inflammation-induced neuronal apoptosis. We showed that treatment of fluoxetine (40 mg/kg, i.p.) with twice injections at 1 h and 12 h after transient middle cerebral artery occlusion (tMCAO) respectively alleviated neurological deficits and neuronal apoptosis in a mouse ischemic stroke model, accompanied by inhibiting interleukin-1β (IL-1β), Bax and p53 expression and upregulating anti-apoptotic protein Bcl-2 level. We next mimicked neuroinflammation in ischemic stroke with IL-1β in primary cultured cortical neurons and found that pretreatment with fluoxetine (1 μM) prevented IL-1β-induced neuronal apoptosis and upregulation of p53 expression. Furthermore, we demonstrated that p53 overexpression in N2a cell line abolished the anti-apoptotic effect of fluoxetine, indicating that p53 downregulation is required for the protective role of fluoxetine in IL-1β-induced neuronal apoptosis. Fluoxetine downregulating p53 expression could be mimicked by SB203580, a specific inhibitor of p38, but blocked by anisomycin, a p38 activator. Collectively, our findings have revealed that fluoxetine protects against IL-1β-induced neuronal apoptosis via p38-p53 dependent pathway, which give us an insight into the potential of fluoxetine in terms of opening up novel therapeutic avenues for neurological diseases including stroke. Copyright © 2016 Elsevier Ltd. All rights reserved.

Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model.

PubMed

Lee, Hong J; Kim, Kwang S; Kim, Eun J; Choi, Hyun B; Lee, Kwang H; Park, In H; Ko, Yong; Jeong, Sang W; Kim, Seung U

2007-05-01

We have generated stable, immortalized cell lines of human NSCs from primary human fetal telencephalon cultures via a retroviral vector encoding v-myc. HB1.F3, one of the human NSC lines, expresses a normal human karyotype of 46, XX, and nestin, a cell type-specific marker for NSCs. F3 has the ability to proliferate continuously and differentiate into cells of neuronal and glial lineage. The HB1.F3 human NSC line was used for cell therapy in a mouse model of intracerebral hemorrhage (ICH) stroke. Experimental ICH was induced in adult mice by intrastriatal administration of bacterial collagenase; 1 week after surgery, the rats were randomly divided into two groups so as to receive intracerebrally either human NSCs labeled with beta-galactosidase (n = 31) or phosphate-buffered saline (PBS) (n = 30). Transplanted NSCs were detected by 5-bromo-4-chloro-3-indolyl-beta-d-galactoside histochemistry or double labeling with beta-galactosidase (beta-gal) and mitogen-activated protein (MAP)2, neurofilaments (both for neurons), or glial fibrillary acidic protein (GFAP) (for astrocytes). Behavior of the animals was evaluated for period up to 8 weeks using modified Rotarod tests and a limb placing test. Transplanted human NSCs were identified in the perihematomal areas and differentiated into neurons (beta-gal/MAP2(+) and beta-gal/NF(+)) or astrocytes (beta-gal/GFAP(+)). The NSC-transplanted group showed markedly improved functional performance on the Rotarod test and limb placing after 2-8 weeks compared with the control PBS group (p < .001). These results indicate that the stable immortalized human NSCs are a valuable source of cells for cell replacement and gene transfer for the treatment of ICH and other human neurological disorders. Disclosure of potential conflicts of interest is found at the end of this article.

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.

PubMed

Chang, Junlei; Mancuso, Michael R; Maier, Carolina; Liang, Xibin; Yuki, Kanako; Yang, Lu; Kwong, Jeffrey W; Wang, Jing; Rao, Varsha; Vallon, Mario; Kosinski, Cynthia; Zhang, J J Haijing; Mah, Amanda T; Xu, Lijun; Li, Le; Gholamin, Sharareh; Reyes, Teresa F; Li, Rui; Kuhnert, Frank; Han, Xiaoyuan; Yuan, Jenny; Chiou, Shin-Heng; Brettman, Ari D; Daly, Lauren; Corney, David C; Cheshier, Samuel H; Shortliffe, Linda D; Wu, Xiwei; Snyder, Michael; Chan, Pak; Giffard, Rona G; Chang, Howard Y; Andreasson, Katrin; Kuo, Calvin J

2017-04-01

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

Automated Morphological Analysis of Microglia After Stroke.

PubMed

Heindl, Steffanie; Gesierich, Benno; Benakis, Corinne; Llovera, Gemma; Duering, Marco; Liesz, Arthur

2018-01-01

Microglia are the resident immune cells of the brain and react quickly to changes in their environment with transcriptional regulation and morphological changes. Brain tissue injury such as ischemic stroke induces a local inflammatory response encompassing microglial activation. The change in activation status of a microglia is reflected in its gradual morphological transformation from a highly ramified into a less ramified or amoeboid cell shape. For this reason, the morphological changes of microglia are widely utilized to quantify microglial activation and studying their involvement in virtually all brain diseases. However, the currently available methods, which are mainly based on manual rating of immunofluorescent microscopic images, are often inaccurate, rater biased, and highly time consuming. To address these issues, we created a fully automated image analysis tool, which enables the analysis of microglia morphology from a confocal Z-stack and providing up to 59 morphological features. We developed the algorithm on an exploratory dataset of microglial cells from a stroke mouse model and validated the findings on an independent data set. In both datasets, we could demonstrate the ability of the algorithm to sensitively discriminate between the microglia morphology in the peri-infarct and the contralateral, unaffected cortex. Dimensionality reduction by principal component analysis allowed to generate a highly sensitive compound score for microglial shape analysis. Finally, we tested for concordance of results between the novel automated analysis tool and the conventional manual analysis and found a high degree of correlation. In conclusion, our novel method for the fully automatized analysis of microglia morphology shows excellent accuracy and time efficacy compared to traditional analysis methods. This tool, which we make openly available, could find application to study microglia morphology using fluorescence imaging in a wide range of brain disease models.

The Use of Animal Models for Stroke Research: A Review

PubMed Central

Casals, Juliana B; Pieri, Naira CG; Feitosa, Matheus LT; Ercolin, Anna CM; Roballo, Kelly CS; Barreto, Rodrigo SN; Bressan, Fabiana F; Martins, Daniele S; Miglino, Maria A; Ambrósio, Carlos E

2011-01-01

Stroke has been identified as the second leading cause of death worldwide. Stroke is a focal neurologic deficit caused by a change in cerebral circulation. The use of animal models in recent years has improved our understanding of the physiopathology of this disease. Rats and mice are the most commonly used stroke models, but the demand for larger models, such as rabbits and even nonhuman primates, is increasing so as to better understand the disease and its treatment. Although the basic mechanisms of stroke are nearly identical among mammals, we here discuss the differences between the human encephalon and various animals. In addition, we compare common surgical techniques used to induce animal models of stroke. A more complete anatomic knowledge of the cerebral vessels of various model species is needed to develop more reliable models for objective results that improve knowledge of the pathology of stroke in both human and veterinary medicine. PMID:22330245

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

Sensorimotor Functional and Structural Networks after Intracerebral Stem Cell Grafts in the Ischemic Mouse Brain.

PubMed

Green, Claudia; Minassian, Anuka; Vogel, Stefanie; Diedenhofen, Michael; Beyrau, Andreas; Wiedermann, Dirk; Hoehn, Mathias

2018-02-14

Past investigations on stem cell-mediated recovery after stroke have limited their focus on the extent and morphological development of the ischemic lesion itself over time or on the integration capacity of the stem cell graft ex vivo However, an assessment of the long-term functional and structural improvement in vivo is essential to reliably quantify the regenerative capacity of cell implantation after stroke. We induced ischemic stroke in nude mice and implanted human neural stem cells (H9 derived) into the ipsilateral cortex in the acute phase. Functional and structural connectivity changes of the sensorimotor network were noninvasively monitored using magnetic resonance imaging for 3 months after stem cell implantation. A sharp decrease of the functional sensorimotor network extended even to the contralateral hemisphere, persisting for the whole 12 weeks of observation. In mice with stem cell implantation, functional networks were stabilized early on, pointing to a paracrine effect as an early supportive mechanism of the graft. This stabilization required the persistent vitality of the stem cells, monitored by bioluminescence imaging. Thus, we also observed deterioration of the early network stabilization upon vitality loss of the graft after a few weeks. Structural connectivity analysis showed fiber-density increases between the cortex and white matter regions occurring predominantly on the ischemic hemisphere. These fiber-density changes were nearly the same for both study groups. This motivated us to hypothesize that the stem cells can influence, via early paracrine effect, the functional networks, while observed structural changes are mainly stimulated by the ischemic event. SIGNIFICANCE STATEMENT In recent years, research on strokes has made a shift away from a focus on immediate ischemic effects and towards an emphasis on the long-range effects of the lesion on the whole brain. Outcome improvements in stem cell therapies also require the understanding of their influence on the whole-brain networks. Here, we have longitudinally and noninvasively monitored the structural and functional network alterations in the mouse model of focal cerebral ischemia. Structural changes of fiber-density increases are stimulated in the endogenous tissue without further modulation by the stem cells, while functional networks are stabilized by the stem cells via a paracrine effect. These results will help decipher the underlying networks of brain plasticity in response to cerebral lesions and offer clues to unravelling the mystery of how stem cells mediate regeneration. Copyright © 2018 the authors 0270-6474/18/381648-14$15.00/0.

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.

Arterial Spin Labeling - Fast Imaging with Steady-State Free Precession (ASL-FISP): A Rapid and Quantitative Perfusion Technique for High Field MRI

PubMed Central

Gao, Ying; Goodnough, Candida L.; Erokwu, Bernadette O.; Farr, George W.; Darrah, Rebecca; Lu, Lan; Dell, Katherine M.; Yu, Xin; Flask, Chris A.

2014-01-01

Arterial Spin Labeling (ASL) is a valuable non-contrast perfusion MRI technique with numerous clinical applications. Many previous ASL MRI studies have utilized either Echo-Planar Imaging (EPI) or True Fast Imaging with Steady-State Free Precession (True FISP) readouts that are prone to off-resonance artifacts on high field MRI scanners. We have developed a rapid ASL-FISP MRI acquisition for high field preclinical MRI scanners providing perfusion-weighted images with little or no artifacts in less than 2 seconds. In this initial implementation, a FAIR (Flow-Sensitive Alternating Inversion Recovery) ASL preparation was combined with a rapid, centrically-encoded FISP readout. Validation studies on healthy C57/BL6 mice provided consistent estimation of in vivo mouse brain perfusion at 7 T and 9.4 T (249±38 ml/min/100g and 241±17 ml/min/100g, respectively). The utility of this method was further demonstrated in detecting significant perfusion deficits in a C57/BL6 mouse model of ischemic stroke. Reasonable kidney perfusion estimates were also obtained for a healthy C57/BL6 mouse exhibiting differential perfusion in the renal cortex and medulla. Overall, the ASL-FISP technique provides a rapid and quantitative in vivo assessment of tissue perfusion for high field MRI scanners with minimal image artifacts. PMID:24891124

Usability of a Low-Cost Head Tracking Computer Access Method following Stroke.

PubMed

Mah, Jasmine; Jutai, Jeffrey W; Finestone, Hillel; Mckee, Hilary; Carter, Melanie

2015-01-01

Assistive technology devices for computer access can facilitate social reintegration and promote independence for people who have had a stroke. This work describes the exploration of the usefulness and acceptability of a new computer access device called the Nouse™ (Nose-as-mouse). The device uses standard webcam and video recognition algorithms to map the movement of the user's nose to a computer cursor, thereby allowing hands-free computer operation. Ten participants receiving in- or outpatient stroke rehabilitation completed a series of standardized and everyday computer tasks using the Nouse™ and then completed a device usability questionnaire. Task completion rates were high (90%) for computer activities only in the absence of time constraints. Most of the participants were satisfied with ease of use (70%) and liked using the Nouse™ (60%), indicating they could resume most of their usual computer activities apart from word-processing using the device. The findings suggest that hands-free computer access devices like the Nouse™ may be an option for people who experience upper motor impairment caused by stroke and are highly motivated to resume personal computing. More research is necessary to further evaluate the effectiveness of this technology, especially in relation to other computer access assistive technology devices.

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

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.

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

Changes in motor function, cognition, and emotion-related behavior after right hemispheric intracerebral hemorrhage in various brain regions of mouse.

PubMed

Zhu, Wei; Gao, Yufeng; Wan, Jieru; Lan, Xi; Han, Xiaoning; Zhu, Shanshan; Zang, Weidong; Chen, Xuemei; Ziai, Wendy; Hanley, Daniel F; Russo, Scott J; Jorge, Ricardo E; Wang, Jian

2018-03-01

Intracerebral hemorrhage (ICH) is a detrimental type of stroke. Mouse models of ICH, induced by collagenase or blood infusion, commonly target striatum, but not other brain sites such as ventricular system, cortex, and hippocampus. Few studies have systemically investigated brain damage and neurobehavioral deficits that develop in animal models of ICH in these areas of the right hemisphere. Therefore, we evaluated the brain damage and neurobehavioral dysfunction associated with right hemispheric ICH in ventricle, cortex, hippocampus, and striatum. The ICH model was induced by autologous whole blood or collagenase VII-S (0.075 units in 0.5 µl saline) injection. At different time points after ICH induction, mice were assessed for brain tissue damage and neurobehavioral deficits. Sham control mice were used for comparison. We found that ICH location influenced features of brain damage, microglia/macrophage activation, and behavioral deficits. Furthermore, the 24-point neurologic deficit scoring system was most sensitive for evaluating locomotor abnormalities in all four models, especially on days 1, 3, and 7 post-ICH. The wire-hanging test was useful for evaluating locomotor abnormalities in models of striatal, intraventricular, and cortical ICH. The cylinder test identified locomotor abnormalities only in the striatal ICH model. The novel object recognition test was effective for evaluating recognition memory dysfunction in all models except for striatal ICH. The tail suspension test, forced swim test, and sucrose preference test were effective for evaluating emotional abnormality in all four models but did not correlate with severity of brain damage. These results will help to inform future preclinical studies of ICH outcomes. Copyright © 2018 Elsevier Inc. All rights reserved.

Mice lacking Faim2 show increased cell death in the MPTP mouse model of Parkinson disease.

PubMed

Komnig, Daniel; Schulz, Jörg B; Reich, Arno; Falkenburger, Björn H

2016-12-01

The death receptor Fas/CD95 mediates apoptotic cell death in response to external stimuli. In neurons, Fas-induced apoptosis is prevented by Fas-apoptotic inhibitory molecule 2 (Faim2). Mice lacking Faim2 showed increased neurodegeneration in animal models of stroke and bacterial meningitis. We therefore tested the relevance of Faim2 in a classical animal model of Parkinson disease and determined the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Faim2-deficient mice. Without MPTP treatment, there was no difference in the dopaminergic system between Faim2-deficient mice and control mice. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. Fourteen days after the last MPTP injection, the number of dopaminergic neurons in the lateral substantia nigra, assayed by stereological counting, was reduced by 39% in control mice and 53% in Faim2-deficient mice. The density of dopaminergic fibers in the dorsal striatum was reduced by 36% in control mice and 69% in Faim2-deficient mice, in the ventral striatum 44% in control mice and 76% in Faim2-deficient mice. Fiber density recovered at 90 days after MPTP with similar density in both groups. Striatal catecholamine levels were reduced by 81-84% in both groups and recovered at 90 days. Faim2 expression was documented in mouse midbrain using quantitative reverse transcription-PCR (qRT-PCR) and found decreased after MPTP administration. Taken together, our findings demonstrate increased degeneration of dopaminergic neurons with Faim2 deficiency, indicating that Fas-induced apoptosis contributes to cell death in the MPTP mouse model. Along with the decreased expression of Faim2 after MPTP, this finding indicates that boosting Faim2 function might represent a therapeutic strategy for Parkinson disease. © 2016 International Society for Neurochemistry.

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.

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

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.

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.

RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury.

PubMed

Newton, K; Dugger, D L; Maltzman, A; Greve, J M; Hedehus, M; Martin-McNulty, B; Carano, R A D; Cao, T C; van Bruggen, N; Bernstein, L; Lee, W P; Wu, X; DeVoss, J; Zhang, J; Jeet, S; Peng, I; McKenzie, B S; Roose-Girma, M; Caplazi, P; Diehl, L; Webster, J D; Vucic, D

2016-09-01

Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.

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

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.

Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

PubMed Central

Tanaka, Emi; Ogawa, Yuko; Mukai, Takeo; Sato, Yoshiaki; Hamazaki, Takashi; Nagamura-Inoue, Tokiko; Harada-Shiba, Mariko; Shintaku, Haruo; Tsuji, Masahiro

2018-01-01

Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating the microglial reaction in the peri-infarct cortex. PMID:29568282

Ocular Dominance Plasticity after Stroke Was Preserved in PSD-95 Knockout Mice.

PubMed

Greifzu, Franziska; Parthier, Daniel; Goetze, Bianka; Schlüter, Oliver M; Löwel, Siegrid

2016-01-01

Neuronal plasticity is essential to enable rehabilitation when the brain suffers from injury, such as following a stroke. One of the most established models to study cortical plasticity is ocular dominance (OD) plasticity in the primary visual cortex (V1) of the mammalian brain induced by monocular deprivation (MD). We have previously shown that OD-plasticity in adult mouse V1 is absent after a photothrombotic (PT) stroke lesion in the adjacent primary somatosensory cortex (S1). Exposing lesioned mice to conditions which reduce the inhibitory tone in V1, such as raising animals in an enriched environment or short-term dark exposure, preserved OD-plasticity after an S1-lesion. Here we tested whether modification of excitatory circuits can also be beneficial for preserving V1-plasticity after stroke. Mice lacking postsynaptic density protein-95 (PSD-95), a signaling scaffold present at mature excitatory synapses, have lifelong juvenile-like OD-plasticity caused by an increased number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) -silent synapses in V1 but unaltered inhibitory tone. In fact, using intrinsic signal optical imaging, we show here that OD-plasticity was preserved in V1 of adult PSD-95 KO mice after an S1-lesion but not in PSD-95 wildtype (WT)-mice. In addition, experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both lesioned PSD-95 KO and PSD-95 WT mice. Basic V1-activation and retinotopic map quality were, however, not different between lesioned PSD-95 KO mice and their WT littermates. The preserved OD-plasticity in the PSD-95 KO mice indicates that V1-plasticity after a distant stroke can be promoted by either changes in excitatory circuitry or by lowering the inhibitory tone in V1 as previously shown. Furthermore, the present data indicate that an increased number of AMPA-silent synapses preserves OD-plasticity not only in the healthy brain, but also in another experimental paradigm of cortical plasticity, namely the long-range influence on V1-plasticity after an S1-lesion.

Ocular Dominance Plasticity after Stroke Was Preserved in PSD-95 Knockout Mice

PubMed Central

Greifzu, Franziska; Parthier, Daniel; Goetze, Bianka; Schlüter, Oliver M.; Löwel, Siegrid

2016-01-01

Neuronal plasticity is essential to enable rehabilitation when the brain suffers from injury, such as following a stroke. One of the most established models to study cortical plasticity is ocular dominance (OD) plasticity in the primary visual cortex (V1) of the mammalian brain induced by monocular deprivation (MD). We have previously shown that OD-plasticity in adult mouse V1 is absent after a photothrombotic (PT) stroke lesion in the adjacent primary somatosensory cortex (S1). Exposing lesioned mice to conditions which reduce the inhibitory tone in V1, such as raising animals in an enriched environment or short-term dark exposure, preserved OD-plasticity after an S1-lesion. Here we tested whether modification of excitatory circuits can also be beneficial for preserving V1-plasticity after stroke. Mice lacking postsynaptic density protein-95 (PSD-95), a signaling scaffold present at mature excitatory synapses, have lifelong juvenile-like OD-plasticity caused by an increased number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) -silent synapses in V1 but unaltered inhibitory tone. In fact, using intrinsic signal optical imaging, we show here that OD-plasticity was preserved in V1 of adult PSD-95 KO mice after an S1-lesion but not in PSD-95 wildtype (WT)-mice. In addition, experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both lesioned PSD-95 KO and PSD-95 WT mice. Basic V1-activation and retinotopic map quality were, however, not different between lesioned PSD-95 KO mice and their WT littermates. The preserved OD-plasticity in the PSD-95 KO mice indicates that V1-plasticity after a distant stroke can be promoted by either changes in excitatory circuitry or by lowering the inhibitory tone in V1 as previously shown. Furthermore, the present data indicate that an increased number of AMPA-silent synapses preserves OD-plasticity not only in the healthy brain, but also in another experimental paradigm of cortical plasticity, namely the long-range influence on V1-plasticity after an S1-lesion. PMID:26930616

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.

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

Sonification as a possible stroke rehabilitation strategy

PubMed Central

Scholz, Daniel S.; Wu, Liming; Pirzer, Jonas; Schneider, Johann; Rollnik, Jens D.; Großbach, Michael; Altenmüller, Eckart O.

2014-01-01

Despite cerebral stroke being one of the main causes of acquired impairments of motor skills worldwide, well-established therapies to improve motor functions are sparse. Recently, attempts have been made to improve gross motor rehabilitation by mapping patient movements to sound, termed sonification. Sonification provides additional sensory input, supplementing impaired proprioception. However, to date no established sonification-supported rehabilitation protocol strategy exists. In order to examine and validate the effectiveness of sonification in stroke rehabilitation, we developed a computer program, termed “SonicPointer”: Participants' computer mouse movements were sonified in real-time with complex tones. Tone characteristics were derived from an invisible parameter mapping, overlaid on the computer screen. The parameters were: tone pitch and tone brightness. One parameter varied along the x, the other along the y axis. The order of parameter assignment to axes was balanced in two blocks between subjects so that each participant performed under both conditions. Subjects were naive to the overlaid parameter mappings and its change between blocks. In each trial a target tone was presented and subjects were instructed to indicate its origin with respect to the overlaid parameter mappings on the screen as quickly and accurately as possible with a mouse click. Twenty-six elderly healthy participants were tested. Required time and two-dimensional accuracy were recorded. Trial duration times and learning curves were derived. We hypothesized that subjects performed in one of the two parameter-to-axis–mappings better, indicating the most natural sonification. Generally, subjects' localizing performance was better on the pitch axis as compared to the brightness axis. Furthermore, the learning curves were steepest when pitch was mapped onto the vertical and brightness onto the horizontal axis. This seems to be the optimal constellation for this two-dimensional sonification. PMID:25368548

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.

The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage

PubMed Central

Yoo, Seung-Jun; Cho, Bongki; Lee, Deokho; Son, Gowoon; Lee, Yeong-Bae; Soo Han, Hyung; Kim, Eunjoo; Moon, Chanil; Moon, Cheil

2017-01-01

Erythropoietin (EPO) has been well known as a hematopoietic cytokine over the past decades. However, recent reports have demonstrated that EPO plays a neuroprotective role in the central nervous system, and EPO has been considered as a therapeutic target in neurodegenerative diseases such as ischemic stroke. Despite the neuroprotective effect of EPO, clinical trials have shown its unexpected side effects, including undesirable proliferative effects such as erythropoiesis and tumor growth. Therefore, the development of EPO analogs that would confer neuroprotection without adverse effects has been attempted. In this study, we examined the potential of a novel EPO-based short peptide, MK-X, as a novel drug for stroke treatment in comparison with EPO. We found that MK-X administration with reperfusion dramatically reduced brain injury in an in vivo mouse model of ischemic stroke induced by middle cerebral artery occlusion, whereas EPO had little effect. Similar to EPO, MK-X efficiently ameliorated mitochondrial dysfunction followed by neuronal death caused by glutamate-induced oxidative stress in cultured neurons. Consistent with this effect, MK-X significantly decreased caspase-3 cleavage and nuclear translocation of apoptosis-inducing factor induced by glutamate. MK-X completely mimicked the effect of EPO on multiple activation of JAK2 and its downstream PI3K/AKT and ERK1/2 signaling pathways, and this signaling process was involved in the neuroprotective effect of MK-X. Furthermore, MK-X and EPO induced similar changes in the gene expression patterns under glutamate-induced excitotoxicity. Interestingly, the most significant difference between MK-X and EPO was that MK-X better penetrated into the brain across the brain–blood barrier than did EPO. In conclusion, we suggest that MK-X might be used as a novel drug for protection from brain injury caused by ischemic stroke, which penetrates into the brain faster in comparison with EPO, even though MK-X and EPO have similar protective effects against excitotoxicity. PMID:28817120

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.

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.

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

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and CNS Homeostasis

PubMed Central

Tran, Khiem A.; Zhang, Xianming; Predescu, Dan; Huang, Xiaojia; Machado, Roberto F.; Göthert, Joachim R.; Malik, Asrar B.; Valyi-Nagy, Tibor; Zhao, You-Yang

2015-01-01

Background The blood-brain barrier (BBB) formed by brain endothelial cells (ECs) interconnected by tight junctions (TJs) is essential for the homeostasis of the central nervous system (CNS). Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results Using a mouse model with tamoxifen-inducible EC-restricted disruption of ctnnb1 (iCKO), here we show that endothelial β-catenin signaling is essential for maintaining BBB integrity and CNS homeostasis in adult. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and CNS inflammation, and all died postictal. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of specific TJ proteins Claudin-1 and -3 in adult brain ECs. The clinical relevance of the data is indicated by the observation of decreased expression of Claudin-1 and nuclear β-catenin in brain ECs of hemorrhagic lesions of hemorrhagic stroke patients. Conclusion These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity and CNS inflammation. PMID:26538583

Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection

PubMed Central

Gunnarson, Eli; Song, Yutong; Kowalewski, Jacob M.; Brismar, Hjalmar; Brines, Michael; Cerami, Anthony; Andersson, Ulf; Zelenina, Marina; Aperia, Anita

2009-01-01

Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water uptake. Here we report that erythropoietin (EPO), which in recent years has emerged as a potent neuro-protective agent, antagonizes the effect of a group I mGluR agonist on astrocyte water permeability. Activation of group I mGluRs triggers fast and highly regular intracellular calcium oscillations and we show that EPO interferes with this signaling event by altering the frequency of the oscillations. These effects of EPO are immediate, in contrast to the neuroprotective effects of EPO that are known to depend upon gene activation. Our findings indicate that EPO may directly reduce the risk of astrocyte swelling in stroke and other brain insults. In support of this conclusion we found that EPO reduced the neurological symptoms in a mouse model of primary brain edema known to depend upon AQP4 water transport. PMID:19164545

A TIGAR-regulated metabolic pathway is critical for protection of brain ischemia.

PubMed

Li, Mei; Sun, Meiling; Cao, Lijuan; Gu, Jin-hua; Ge, Jianbin; Chen, Jieyu; Han, Rong; Qin, Yuan-Yuan; Zhou, Zhi-Peng; Ding, Yuqiang; Qin, Zheng-Hong

2014-05-28

TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and increases the flow of pentose phosphate pathway (PPP), which generates NADPH and pentose. We hypothesized that TIGAR plays a neuroprotective role in brain ischemia as neurons do not rely on glycolysis but are vulnerable to oxidative stress. We found that TIGAR was highly expressed in brain neurons and was rapidly upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. Overexpression of TIGAR in normal mice with lentivirus reduced ischemic neuronal injury, whereas lentivirus-mediated TIGAR knockdown aggravated it. In cultured primary neurons, increasing TIGAR expression reduced oxygen and glucose deprivation (OGD)/reoxygenation-induced injury, whereas decreasing its expression worsened the injury. The glucose 6-phosphate dehydrogenase was upregulated in mouse and cellular models of stroke, and its upregulation was further enhanced by overexpression of TIGAR. Supplementation of NADPH also reduced ischemia/reperfusion brain injury and alleviated TIGAR knockdown-induced aggravation of ischemic injury. In animal and cellular stroke models, ischemia/reperfusion increased mitochondrial localization of TIGAR. OGD/reoxygenation-induced elevation of ROS, reduction of GSH, dysfunction of mitochondria, and activation of caspase-3 were rescued by overexpression of TIGAR or supplementation of NADPH, while knockdown of TIGAR aggravated these changes. Together, our results show that TIGAR protects ischemic brain injury via enhancing PPP flux and preserving mitochondria function, and thus may be a valuable therapeutic target for ischemic brain injury. Copyright © 2014 the authors 0270-6474/14/347458-14$15.00/0.

The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains.

PubMed

Chen, Li; Zhu, Yan-Mei; Li, Yu-Nong; Li, Peng-Yan; Wang, Di; Liu, Yu; Qu, You-Yang; Zhu, Da-Ling; Zhu, Yu-Lan

2017-09-01

Angiogenesis promotes neurobehavioral recovery after cerebral ischemic stroke. 15(S)-hydroxyeicosatetraenoic acid (15-HETE) is one of the major metabolites of arachidonic acid by 15-lipoxygenase (15-LO) and stimulates the production of vascular endothelial growth factor (VEGF), thus, inducing autocrine-mediated angiogenesis. The present study aimed to investigate the role of 15-LO/15-HETE system on VEGF expression and angiogenesis in brain ischemia. Rat cerebral arterial vascular endothelial cells were used to set up a cell injury model of oxygen-glucose deprivation and reoxygenation (OGD/R), mimicking a condition of brain ischemia. A mouse model of middle cerebral artery occlusion (MCAO) was established. Oxygen-glucose deprivation increased cellular expression of 15-LO-1 and VEGF. Transfection of 15-LO-1 siRNA depleted cells of 15-LO-1, and sequentially induced downregulation of VEGF expression; while, incubation of 15-HETE increased the expression of VEGF. Incubation of 15-HETE attenuated the reduction in cell viability induced by oxygen-glucose deprivation, and promoted cell migration, while transfection of 15-LO-1 siRNA showed an opposite effect. In animal experiments, the density of microvessels in hypoxic regions of brains was significantly increased after MCAO, while intracerebroventricular delivery of 15-LO-1 siRNA significantly reduced the density of microvessels, and downregulates VEGF expression. The results indicate that the 15-LO-1/15-HETE system promotes angiogenesis in ischemic brains by upregulation of VEGF, representing a potential target for improving neurobehavioral recovery after cerebral ischemic stroke.

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.

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.

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.

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.

Animal models of ischaemic stroke and characterisation of the ischaemic penumbra.

PubMed

McCabe, Christopher; Arroja, Mariana M; Reid, Emma; Macrae, I Mhairi

2018-05-15

Over the past forty years, animal models of focal cerebral ischaemia have allowed us to identify the critical cerebral blood flow thresholds responsible for irreversible cell death, electrical failure, inhibition of protein synthesis, energy depletion and thereby the lifespan of the potentially salvageable penumbra. They have allowed us to understand the intricate biochemical and molecular mechanisms within the 'ischaemic cascade' that initiate cell death in the first minutes, hours and days following stroke. Models of permanent, transient middle cerebral artery occlusion and embolic stroke have been developed each with advantages and limitations when trying to model the complex heterogeneous nature of stroke in humans. Yet despite these advances in understanding the pathophysiological mechanisms of stroke-induced cell death with numerous targets identified and drugs tested, a lack of translation to the clinic has hampered pre-clinical stroke research. With recent positive clinical trials of endovascular thrombectomy in acute ischaemic stroke the stroke community has been reinvigorated, opening up the potential for future translation of adjunctive treatments that can be given alongside thrombectomy/thrombolysis. This review discusses the major animal models of focal cerebral ischaemia highlighting their advantages and limitations. Acute imaging is crucial in longitudinal pre-clinical stroke studies in order to identify the influence of acute therapies on tissue salvage over time. Therefore, the methods of identifying potentially salvageable ischaemic penumbra are discussed. This article is part of the Special Issue entitled 'Cerebral Ischemia'. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Innate immune memory in the brain shapes neurological disease hallmarks.

PubMed

Wendeln, Ann-Christin; Degenhardt, Karoline; Kaurani, Lalit; Gertig, Michael; Ulas, Thomas; Jain, Gaurav; Wagner, Jessica; Häsler, Lisa M; Wild, Katleen; Skodras, Angelos; Blank, Thomas; Staszewski, Ori; Datta, Moumita; Centeno, Tonatiuh Pena; Capece, Vincenzo; Islam, Md Rezaul; Kerimoglu, Cemil; Staufenbiel, Matthias; Schultze, Joachim L; Beyer, Marc; Prinz, Marco; Jucker, Mathias; Fischer, André; Neher, Jonas J

2018-04-01

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

Leveraging business intelligence to make better decisions: Part III.

PubMed

Reimers, Mona

2014-01-01

Accounts receivable and scheduling datasets have been available to medical practices since the 1990s, and discrete medical records data have become available over the past few years. But the frustrations that arose from the difficulties in reporting data grew with each keyboard stroke and mouse click. With reporting mandated to meet changing payment models, measuring quality of care and medical outcomes, practice managers must find more efficient and effective methods of extracting and compiling the data they have in their systems. Taming the reporting beast and learning to effectively apply business intelligence (BI) tools will become an expected managerial proficiency in the next few years. Practice managers' roles are changing quickly, and they will be required to understand the meaning of their practice's data and craft ways to leverage that data toward a strategic advantage.

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.

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.

Post-Stroke Depression Modulation and in Vivo Antioxidant Activity of Gallic Acid and Its Synthetic Derivatives in a Murine Model System.

PubMed

Nabavi, Seyed Fazel; Habtemariam, Solomon; Di Lorenzo, Arianna; Sureda, Antoni; Khanjani, Sedigheh; Nabavi, Seyed Mohammad; Daglia, Maria

2016-04-28

Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is a plant secondary metabolite, which shows antioxidant activity and is commonly found in many plant-based foods and beverages. Recent evidence suggests that oxidative stress contributes to the development of many human chronic diseases, including cardiovascular and neurodegenerative pathologies, metabolic syndrome, type 2 diabetes and cancer. GA and its derivative, methyl-3-O-methyl gallate (M3OMG), possess physiological and pharmacological activities closely related to their antioxidant properties. This paper describes the antidepressive-like effects of intraperitoneal administration of GA and two synthetic analogues, M3OMG and P3OMG (propyl-3-O-methylgallate), in balb/c mice with post-stroke depression, a secondary form of depression that could be due to oxidative stress occurring during cerebral ischemia and the following reperfusion. Moreover, this study determined the in vivo antioxidant activity of these compounds through the evaluation of superoxide dismutase (SOD) and catalase (Cat) activity, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH) levels in mouse brain. GA and its synthetic analogues were found to be active (at doses of 25 and 50 mg/kg) in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior and, at least in part, antioxidant endogenous defenses, with M3OMG being the most active of these compounds. SOD, TBARS, and GSH all showed strong correlation with behavioral parameters, suggesting that oxidative stress is tightly linked to the pathological processes involved in stroke and PSD. As a whole, the obtained results show that the administration of GA, M3OMG and P3OMG induce a reduction in depressive symptoms and oxidative stress.

Post-Stroke Depression Modulation and in Vivo Antioxidant Activity of Gallic Acid and Its Synthetic Derivatives in a Murine Model System

PubMed Central

Nabavi, Seyed Fazel; Habtemariam, Solomon; Di Lorenzo, Arianna; Sureda, Antoni; Khanjani, Sedigheh; Nabavi, Seyed Mohammad; Daglia, Maria

2016-01-01

Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is a plant secondary metabolite, which shows antioxidant activity and is commonly found in many plant-based foods and beverages. Recent evidence suggests that oxidative stress contributes to the development of many human chronic diseases, including cardiovascular and neurodegenerative pathologies, metabolic syndrome, type 2 diabetes and cancer. GA and its derivative, methyl-3-O-methyl gallate (M3OMG), possess physiological and pharmacological activities closely related to their antioxidant properties. This paper describes the antidepressive-like effects of intraperitoneal administration of GA and two synthetic analogues, M3OMG and P3OMG (propyl-3-O-methylgallate), in balb/c mice with post-stroke depression, a secondary form of depression that could be due to oxidative stress occurring during cerebral ischemia and the following reperfusion. Moreover, this study determined the in vivo antioxidant activity of these compounds through the evaluation of superoxide dismutase (SOD) and catalase (Cat) activity, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH) levels in mouse brain. GA and its synthetic analogues were found to be active (at doses of 25 and 50 mg/kg) in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior and, at least in part, antioxidant endogenous defenses, with M3OMG being the most active of these compounds. SOD, TBARS, and GSH all showed strong correlation with behavioral parameters, suggesting that oxidative stress is tightly linked to the pathological processes involved in stroke and PSD. As a whole, the obtained results show that the administration of GA, M3OMG and P3OMG induce a reduction in depressive symptoms and oxidative stress. PMID:27136579

Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment.

PubMed

Tan, Xing-Lin; Xue, Yue-Qiang; Ma, Tao; Wang, Xiaofang; Li, Jing Jing; Lan, Lubin; Malik, Kafait U; McDonald, Michael P; Dopico, Alejandro M; Liao, Francesca-Fang

2015-06-24

Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer's disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS(+/-) mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels. Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS(+/-) mice as early as 3-6 months of age but not in eNOS(+/+) mice at any age. Remarkably, vascular occlusions in eNOS(+/-) mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS(+/-) mice. These data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS(+/-) mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD.

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.

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.

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

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

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

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.

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.

Down-regulation of MIF by NFκB under hypoxia accelerated neuronal loss during stroke

PubMed Central

Zhang, Si; Zis, Odysseus; Ly, Philip T. T.; Wu, Yili; Zhang, Shuting; Zhang, Mingming; Cai, Fang; Bucala, Richard; Shyu, Woei-Cherng; Song, Weihong

2014-01-01

Neuronal apoptosis is one of the major causes of poststroke neurological deficits. Inflammation during the acute phase of stroke results in nuclear translocation of NFκB in affected cells in the infarct area. Macrophage migration inhibitory factor (MIF) promotes cardiomyocyte survival in mice following heart ischemia. However, the role of MIF during stroke remains limited. In this study, we showed that MIF expression is down-regulated by 0.75 ± 0.10-fold of the control in the infarct area in the mouse brains. Two functional cis-acing NFκB response elements were identified in the human MIF promoter. Dual activation of hypoxia and NFκB signaling resulted in significant reduction of MIF promoter activity to 0.86 ± 0.01-fold of the control. Furthermore, MIF reduced caspase-3 activation and protected neurons from oxidative stress- and in vitro ischemia/reperfusion-induced apoptosis. H2O2 significantly induced cell death with 12.81 ± 0.58-fold increase of TUNEL-positive cells, and overexpression of MIF blocked the H2O2-induced cell death. Disruption of the MIF gene in MIF-knockout mice resulted in caspase-3 activation, neuronal loss, and increased infarct development during stroke in vivo. The infarct volume was increased from 6.51 ± 0.74% in the wild-type mice to 9.07 ± 0.66% in the MIF-knockout mice. Our study demonstrates that MIF exerts a neuronal protective effect and that down-regulation of MIF by NFκB-mediated signaling under hypoxia accelerates neuronal loss during stroke. Our results suggest that MIF is an important molecule for preserving a longer time window for stroke treatment, and strategies to maintain MIF expression at physiological level could have beneficial effects for stroke patients.—Zhang, S., Zis, O., Ly, P. T. T., Wu, Y., Zhang, S., Zhang, M., Cai, F., Bucala, R., Shyu, W.-C., Song, W. Down-regulation of MIF by NFκB under hypoxia accelerated neuronal loss during stroke. PMID:24970391

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity.

PubMed

Li, Minshu; Li, Zhiguo; Yao, Yang; Jin, Wei-Na; Wood, Kristofer; Liu, Qiang; Shi, Fu-Dong; Hao, Junwei

2017-01-17

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15-expressing transgenic mouse (GFAP-IL-15 tg ) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8 + T and natural killer (NK) cells was augmented in these GFAP-IL-15 tg mice after brain ischemia. Of note, depletion of CD8 + T or NK cells attenuated ischemic brain injury in GFAP-IL-15 tg mice. Furthermore, knockdown of the IL-15 receptor α or blockade of cell-to-cell contact diminished the activation and effector function of CD8 + T and NK cells in GFAP-IL-15 tg mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8 + T and NK cell-mediated immunity.

Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness

PubMed Central

Halabi, Carmen M.; Broekelmann, Thomas J.; Knutsen, Russell H.; Ye, Li; Mecham, Robert P.

2015-01-01

Increased arterial stiffness is a common characteristic of humans with Williams-Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4–6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency. PMID:26232234

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.

Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models.

PubMed

Cristofaro, Brunella; Shi, Yu; Faria, Marcella; Suchting, Steven; Leroyer, Aurelie S; Trindade, Alexandre; Duarte, Antonio; Zovein, Ann C; Iruela-Arispe, M Luisa; Nih, Lina R; Kubis, Nathalie; Henrion, Daniel; Loufrani, Laurent; Todiras, Mihail; Schleifenbaum, Johanna; Gollasch, Maik; Zhuang, Zhen W; Simons, Michael; Eichmann, Anne; le Noble, Ferdinand

2013-04-01

Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4(+/-) mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4(+/-) mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality.

Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models

PubMed Central

Cristofaro, Brunella; Shi, Yu; Faria, Marcella; Suchting, Steven; Leroyer, Aurelie S.; Trindade, Alexandre; Duarte, Antonio; Zovein, Ann C.; Iruela-Arispe, M. Luisa; Nih, Lina R.; Kubis, Nathalie; Henrion, Daniel; Loufrani, Laurent; Todiras, Mihail; Schleifenbaum, Johanna; Gollasch, Maik; Zhuang, Zhen W.; Simons, Michael; Eichmann, Anne; le Noble, Ferdinand

2013-01-01

Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4+/- mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4+/- mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality. PMID:23533173

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.

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.

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.

Magnetic resonance imaging of post-ischemic blood-brain barrier damage with PEGylated iron oxide nanoparticles

NASA Astrophysics Data System (ADS)

Liu, Dong-Fang; Qian, Cheng; An, Yan-Li; Chang, Di; Ju, Sheng-Hong; Teng, Gao-Jun

2014-11-01

Blood-brain barrier (BBB) damage during ischemia may induce devastating consequences like cerebral edema and hemorrhagic transformation. This study presents a novel strategy for dynamically imaging of BBB damage with PEGylated supermagnetic iron oxide nanoparticles (SPIONs) as contrast agents. The employment of SPIONs as contrast agents made it possible to dynamically image the BBB permeability alterations and ischemic lesions simultaneously with T2-weighted MRI, and the monitoring could last up to 24 h with a single administration of PEGylated SPIONs in vivo. The ability of the PEGylated SPIONs to highlight BBB damage by MRI was demonstrated by the colocalization of PEGylated SPIONs with Gd-DTPA after intravenous injection of SPION-PEG/Gd-DTPA into a mouse. The immunohistochemical staining also confirmed the leakage of SPION-PEG from cerebral vessels into parenchyma. This study provides a novel and convenient route for imaging BBB alteration in the experimental ischemic stroke model.

Compensatory Hypertrophy Induced by Ventricular Cardiomyocyte Specific COX-2 Expression in Mice

PubMed Central

Streicher, John M.; Kamei, Kenichiro; Ishikawa, Tomo-o; Herschman, Harvey; Wang, Yibin

2010-01-01

Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases, due to the finding that highly specific COX-2 inhibitors (i.e. Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact heart remains to be determined. We report here the development of a transgenic mouse model, using a loxP-Cre approach, that displays robust COX-2 overexpression and subsequent prostaglandin synthesis specifically in ventricular myocytes. Histological, functional and molecular analyses showed that ventricular myocyte specific COX-2 overexpression led to cardiac hypertrophy and fetal gene marker activation, but with preserved cardiac function. Therefore, specific induction of COX-2 and prostaglandin in vivo is sufficient to induce compensated hypertrophy and molecular remodeling. PMID:20170663

Mast Cells: Pivotal Players in Cardiovascular Diseases

PubMed Central

Bot, Ilze; van Berkel, Theo J.C; Biessen, Erik A.L

2008-01-01

The clinical outcome of cardiovascular diseases as myocardial infarction and stroke are generally caused by rupture of an atherosclerotic plaque. However, the actual cause of a plaque to rupture is not yet established. Interestingly, pathology studies have shown an increased presence of the mast cell, an important inflammatory effector cell in allergy and host defense, in (peri)vascular tissue during plaque progression, which may point towards a causal role for mast cells. Very recent data in mouse models show that mast cells and derived mediators indeed can profoundly impact plaque progression, plaque stability and acute cardiovascular syndromes such as vascular aneurysm or myocardial infarction. In this review, we discuss recent evidence on the role of mast cells in the progression of cardiovascular disorders and give insight in the therapeutic potential of modulation of mast cell function in these processes to improve the resilience of a plaque to rupture. PMID:19936193

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.

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis.

PubMed

Tran, Khiem A; Zhang, Xianming; Predescu, Dan; Huang, Xiaojia; Machado, Roberto F; Göthert, Joachim R; Malik, Asrar B; Valyi-Nagy, Tibor; Zhao, You-Yang

2016-01-12

The blood-brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Using a mouse model with tamoxifen-inducible endothelial cell-restricted disruption of ctnnb1 (iCKO), we show here that endothelial β-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear β-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients. These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation. © 2015 American Heart Association, Inc.

Photoacoustic monitoring of clot formation during surgery and tumor surgery

NASA Astrophysics Data System (ADS)

Juratli, Mazen A.; Galanzha, Ekaterina I.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Suen, James Y.; Zharov, Vladimir P.

2013-03-01

When a blood vessel is injured, the normal physiological response of the body is to form a clot (thrombus) to prevent blood loss. Alternatively, even without injury to the blood vessel, the pathological condition called thromboembolism may lead to the formation of circulating blood clots (CBCs), also called emboli, which can clog blood vessels throughout the body. Veins of the extremities (venous thromboembolism), lungs (pulmonary embolism ), brain (embolic stroke), heart (myocardial infarction), kidneys, and gastrointestinal tract are often affected. Emboli are also common complications of infection, inflammation, cancer, surgery, radiation and coronary artery bypass grafts. Despite the clear medical significance of CBCs, however, little progress has been made in the development of methods for real-time detection and identification of CBCs. To overcome these limitations, we developed a new modification of in vivo photoacoustic (PA) flow cytometry (PAFC) for real-time detection of white, red, and mixed clots through a transient decrease, increase or fluctuation of PA signal amplitude, respectively. In this work, using PAFC and mouse models, we present for the first time direct evidence that some medical procedures, such as conventional or cancer surgery may initiate the formation of CBCs. In conclusion, the PA diagnostic platform can be used in real-time to define risk factors for cardiovascular diseases, assist in the prognosis and potential prevention of stroke by using a well-timed therapy or as a clot count as a marker of therapy efficacy.

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.

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.

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

OCT-based in vivo tissue injury mapping

NASA Astrophysics Data System (ADS)

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

2016-03-01

Tissue injury mapping (TIM) is developed by using a non-invasive in vivo optical coherence tomography to generate optical attenuation coefficient and microvascular map of the injured tissue. Using TIM, the infarct region development in mouse cerebral cortex during stroke is visualized. Moreover, we demonstrate the in vivo human facial skin structure and microvasculature during an acne lesion development. The results indicate that TIM may help in the study and the treatment of various diseases by providing high resolution images of tissue structural and microvascular changes.

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

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.

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/.

CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice.

PubMed

Wang, Jianping; Liu, Xi; Lu, Hong; Jiang, Chao; Cui, Xiaobing; Yu, Lie; Fu, Xiaojie; Li, Qian; Wang, Jian

2015-03-01

Cell-based therapy is considered to be a promising therapeutic strategy for stroke treatment. Although unfractionated bone marrow mononuclear cells (BMMNCs) have been tried in both preclinical and clinical trials, the effective subpopulations need to be identified. In this study, we used fluorescence-activated cell sorting to harvest the CXCR4(+)CD45(+) and CXCR4(+)CD45(-) BMMNC subpopulations from transgenic mice that express enhanced green fluorescent protein. We then allogeneically grafted unfractionated BMMNCs or a subpopulation into mice subjected to transient middle cerebral artery occlusion (tMCAO) and compared the effects on stroke outcomes. We found that CXCR4(+)CD45(-) BMMNCs, but not CXCR4(+)CD45(+) BMMNCs, more effectively reduced infarction volume and neurologic deficits than did unfractionated BMMNCs. Brain tissue from the ischemic hemisphere of mice treated with CXCR4(+)CD45(-) BMMNCs had higher levels of vascular endothelial growth factor and lower levels of TNF-α than did tissue from mice treated with unfractionated BMMNCs. In contrast, CXCR4(+)CD45(+) BMMNCs showed an increase in TNF-α. Additionally, CXCR4(+)CD45(+) and CXCR4(+)CD45(-) populations exhibited more robust migration into the lesion areas and were better able to express cell-specific markers of different linages than were the unfractionated BMMNCs. Endothelial and astrocyte cell markers did not colocalize with eGFP(+) cells in the brains of tMCAO mice that received CXCR4(+)CD45(+) BMMNCs. In vitro, the CXCR4(+)CD45(-) BMMNCs expressed significantly more Oct-4 and Nanog mRNA than did the unfractionated BMMNCs. However, we did not detect gene expression of these two pluripotent markers in CXCR4(+)CD45(+) BMMNCs. Taken together, our study shows for the first time that the CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs in ameliorating cerebral damage in a mouse model of tMCAO and could represent a new therapeutic approach for stroke treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

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.

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.

Hyperforin promotes post-stroke functional recovery through interleukin (IL)-17A-mediated angiogenesis.

PubMed

Zhang, Jiancheng; Yao, Chengye; Chen, Jiayi; Zhang, Yujing; Yuan, Shiying; Lin, Yun

2016-09-01

Hyperforin, the main active ingredient of the medicinal plant Hypericum perforatum, has been shown to be neuroprotective against acute ischemic stroke. However, the long-term actions of hyperforin on the post-stroke functional recovery and underlying mechanisms have not been investigated. C57BL/6 wild-type mice or interleukin (IL)-17A knock-out mice underwent middle cerebral artery occlusion (60min) followed by reperfusion for 28 days. Here, we found that delayed treatment with hyperforin significantly promoted functional recovery and increased IL-17A expression in the ischemic hemisphere at 28 days post-ischemia (dpi). IL-17A knock-out or anti-IL-17A monoclonal antibody (mAb) treatment significantly attenuated the promoting effects of hyperforin on functional recovery. After screening for neurotrophic factors, we revealed that blocking IL-17A significantly decreased, whereas recombinant mouse IL-17A (rIL-17A) treatment significantly increased vascular endothelial growth factor (VEGF) expression. Our data also showed that rIL-17A treatment significantly increased CD34 expression and promoted functional recovery at 28dpi, and the promoting effects were attenuated by VEGF neutralizing antibody treatment. Furthermore, hyperforin treatment significantly increased the expression of VEGF and CD34 in the ischemic hemisphere at 28dpi, and the effects were attenuated by blocking IL-17A. Furthermore, VEGF neutralizing antibody significantly attenuated the promoting role of hyperforin on the cerebral CD34 expression. Thus, our results suggest that, in addition to the acute neuroprotection when delivered immediately after ischemic stroke, hyperforin could also promote functional recovery when delivered in the later phases of stroke recovery. Our results also reveal a previously uncharacterized property of IL-17A/VEGF signaling-induced angiogenesis in hyperforin-mediated functional recovery. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Ischemic Brain Injury Leads to Brain Edema via Hyperthermia-Induced TRPV4 Activation.

PubMed

Hoshi, Yutaka; Okabe, Kohki; Shibasaki, Koji; Funatsu, Takashi; Matsuki, Norio; Ikegaya, Yuji; Koyama, Ryuta

2018-06-20

Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain largely unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which male mouse brain slices were treated with oxygen-glucose deprivation (OGD) to mimic ischemia. We continuously measured the cross-sectional area of the brain slice for 150 min under macroscopic microscopy, finding that OGD induces swelling of brain slices. OGD-induced swelling was prevented by pharmacologically blocking or genetically knocking out the transient receptor potential vanilloid 4 (TRPV4), a member of the thermosensitive TRP channel family. Because TRPV4 is activated at around body temperature and its activation is enhanced by heating, we next elevated the temperature of the perfusate in the recording chamber, finding that hyperthermia induces swelling via TRPV4 activation. Furthermore, using the temperature-dependent fluorescence lifetime of a fluorescent-thermosensitive probe, we confirmed that OGD treatment increases the temperature of brain slices through the activation of glutamate receptors. Finally, we found that brain edema following traumatic brain injury was suppressed in TRPV4-deficient male mice in vivo Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia. SIGNIFICANCE STATEMENT Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which mouse brain slices were treated with oxygen-glucose deprivation. Using this system, we showed that the increase in brain temperature and the following activation of the thermosensitive cation channel TRPV4 (transient receptor potential vanilloid 4) are involved in the pathology of edema. Finally, we confirmed that TRPV4 is involved in brain edema in vivo using TRPV4-deficient mice, concluding that hyperthermia activates TRPV4 and induces brain edema after ischemia. Copyright © 2018 the authors 0270-6474/18/385700-10$15.00/0.

Post-Stroke Longitudinal Alterations of Inter-Hemispheric Correlation and Hemispheric Dominance in Mouse Pre-Motor Cortex

PubMed Central

Panarese, Alessandro; Alia, Claudia; Micera, Silvestro; Caleo, Matteo; Di Garbo, Angelo

2016-01-01

Purpose Limited restoration of function is known to occur spontaneously after an ischemic injury to the primary motor cortex. Evidence suggests that Pre-Motor Areas (PMAs) may “take over” control of the disrupted functions. However, little is known about functional reorganizations in PMAs. Forelimb movements in mice can be driven by two cortical regions, Caudal and Rostral Forelimb Areas (CFA and RFA), generally accepted as primary motor and pre-motor cortex, respectively. Here, we examined longitudinal changes in functional coupling between the two RFAs following unilateral photothrombotic stroke in CFA (mm from Bregma: +0.5 anterior, +1.25 lateral). Methods Local field potentials (LFPs) were recorded from the RFAs of both hemispheres in freely moving injured and naïve mice. Neural signals were acquired at 9, 16 and 23 days after surgery (sub-acute period in stroke animals) through one bipolar electrode per hemisphere placed in the center of RFA, with a ground screw over the occipital bone. LFPs were pre-processed through an efficient method of artifact removal and analysed through: spectral,cross-correlation, mutual information and Granger causality analysis. Results Spectral analysis demonstrated an early decrease (day 9) in the alpha band power in both the RFAs. In the late sub-acute period (days 16 and 23), inter-hemispheric functional coupling was reduced in ischemic animals, as shown by a decrease in the cross-correlation and mutual information measures. Within the gamma and delta bands, correlation measures were already reduced at day 9. Granger analysis, used as a measure of the symmetry of the inter-hemispheric causal connectivity, showed a less balanced activity in the two RFAs after stroke, with more frequent oscillations of hemispheric dominance. Conclusions These results indicate robust electrophysiological changes in PMAs after stroke. Specifically, we found alterations in transcallosal connectivity, with reduced inter-hemispheric functional coupling and a fluctuating dominance pattern. These reorganizations may underlie vicariation of lost functions following stroke. PMID:26752066

Post-Stroke Longitudinal Alterations of Inter-Hemispheric Correlation and Hemispheric Dominance in Mouse Pre-Motor Cortex.

PubMed

Vallone, Fabio; Lai, Stefano; Spalletti, Cristina; Panarese, Alessandro; Alia, Claudia; Micera, Silvestro; Caleo, Matteo; Di Garbo, Angelo

2016-01-01

Limited restoration of function is known to occur spontaneously after an ischemic injury to the primary motor cortex. Evidence suggests that Pre-Motor Areas (PMAs) may "take over" control of the disrupted functions. However, little is known about functional reorganizations in PMAs. Forelimb movements in mice can be driven by two cortical regions, Caudal and Rostral Forelimb Areas (CFA and RFA), generally accepted as primary motor and pre-motor cortex, respectively. Here, we examined longitudinal changes in functional coupling between the two RFAs following unilateral photothrombotic stroke in CFA (mm from Bregma: +0.5 anterior, +1.25 lateral). Local field potentials (LFPs) were recorded from the RFAs of both hemispheres in freely moving injured and naïve mice. Neural signals were acquired at 9, 16 and 23 days after surgery (sub-acute period in stroke animals) through one bipolar electrode per hemisphere placed in the center of RFA, with a ground screw over the occipital bone. LFPs were pre-processed through an efficient method of artifact removal and analysed through: spectral,cross-correlation, mutual information and Granger causality analysis. Spectral analysis demonstrated an early decrease (day 9) in the alpha band power in both the RFAs. In the late sub-acute period (days 16 and 23), inter-hemispheric functional coupling was reduced in ischemic animals, as shown by a decrease in the cross-correlation and mutual information measures. Within the gamma and delta bands, correlation measures were already reduced at day 9. Granger analysis, used as a measure of the symmetry of the inter-hemispheric causal connectivity, showed a less balanced activity in the two RFAs after stroke, with more frequent oscillations of hemispheric dominance. These results indicate robust electrophysiological changes in PMAs after stroke. Specifically, we found alterations in transcallosal connectivity, with reduced inter-hemispheric functional coupling and a fluctuating dominance pattern. These reorganizations may underlie vicariation of lost functions following stroke.

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

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.

Gravity-supported exercise with computer gaming improves arm function in chronic stroke.

PubMed

Jordan, Kimberlee; Sampson, Michael; King, Marcus

2014-08-01

To investigate the effect of 4 to 6 weeks of exergaming with a computer mouse embedded within an arm skate on upper limb function in survivors of chronic stroke. Intervention study with a 4-week postintervention follow-up. In home. Survivors (N=13) of chronic (≥6 mo) stroke with hemiparesis of the upper limb with stable baseline Fugl-Meyer assessment scores received the intervention. One participant withdrew, and 2 participants were not reassessed at the 4-week follow-up. No participants withdrew as a result of adverse effects. Four to 6 weeks of exergaming using the arm skate where participants received either 9 (n=5) or 16 (n=7) hours of game play. Upper limb component of the Fugl-Meyer assessment. There was an average increase in the Fugl-Meyer upper limb assessment score from the beginning to end of the intervention of 4.9 points. At the end of the 4-week period after the intervention, the increase was 4.4 points. A 4- to 6-week intervention using the arm skate significantly improved arm function in survivors of chronic stroke by an average of 4.9 Fugl-Meyer upper limb assessment points. This research shows that a larger-scale randomized trial of this device is warranted and highlights the potential value of using virtual reality technology (eg, computer games) in a rehabilitation setting. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Effect of Compound 21, a Selective Angiotensin II Type 2 Receptor Agonist, in a Murine Xenograft Model of Dupuytren Disease.

PubMed

Chisholm, Jessica; Gareau, Alison J; Byun, Stephanie; Paletz, Justin L; Tang, David; Williams, Jason; LeVatte, Terry; Bezuhly, Michael

2017-11-01

Although surgical excision and intralesional collagenase injection are mainstays in Dupuytren disease treatment, no effective medical therapy exists for recurrent disease. Compound 21, a selective agonist of the angiotensin II type 2 receptor, has been shown to protect against fibrosis in models of myocardial infarction and stroke. The authors investigated the potential use of compound 21 in the treatment of Dupuytren disease. Human dermal fibroblasts were treated in vitro with compound 21 and assessed for viability using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration by means of scratch assay, and profibrotic gene transcription by means of quantitative reverse transcription polymerase chain reaction. Compound 21 effects in vivo were assessed using a xenograft model. Dupuytren disease cord specimens from patients undergoing open partial fasciectomy were divided into two segments. Segments were implanted under the dorsal skin of nude mouse pairs. Beginning on day 5, one mouse from each pair received daily intraperitoneal injections of compound 21 (10 μg/kg/day), and the other received vehicle. On day 10, segments were explanted and submitted for immunohistochemistry. Human dermal fibroblasts treated with compound 21 displayed decreased migration and decreased gene expression of connective tissue growth factor, fibroblast specific protein-1, transforming growth factor-β1, Smad3, and Smad4. Dupuytren disease segments from compound 21-treated mice demonstrated significantly reduced alpha-smooth muscle actin and Ki67 staining, with increased density of CD31 staining vessels. Compound 21 significantly decreases expression of profibrotic genes and decreases myofibroblast proliferation as indicated by reduced Ki67 and alpha-smooth muscle actin expression. These findings support compound 21 as a potential novel treatment modality for Dupuytren disease.

Critical Buckling Pressure in Mouse Carotid Arteries with Altered Elastic Fibers

PubMed Central

Luetkemeyer, Callan M.; James, Rhys H.; Devarakonda, Siva Teja; Le, Victoria P.; Liu, Qin; Han, Hai-Chao; Wagenseil, Jessica E.

2015-01-01

Arteries can buckle axially under applied critical buckling pressure due to a mechanical instability. Buckling can cause arterial tortuosity leading to flow irregularities and stroke. Genetic mutations in elastic fiber proteins are associated with arterial tortuosity in humans and mice, and may be the result of alterations in critical buckling pressure. Hence, the objective of this study is to investigate how genetic defects in elastic fibers affect buckling pressure. We use mouse models of human disease with reduced amounts of elastin (Eln+/−) and with defects in elastic fiber assembly due to the absence of fibulin-5 (Fbln5−/−). We find that Eln+/− arteries have reduced buckling pressure compared to their wild-type controls. Fbln5−/− arteries have similar buckling pressure to wild-type at low axial stretch, but increased buckling pressure at high stretch. We fit material parameters to mechanical test data for Eln+/−, Fbln5−/− and wild-type arteries using Fung and four-fiber strain energy functions. Fitted parameters are used to predict theoretical buckling pressure based on equilibrium of an inflated, buckled, thick-walled cylinder. In general, the theoretical predictions underestimate the buckling pressure at low axial stretch and overestimate the buckling pressure at high stretch. The theoretical predictions with both models replicate the increased buckling pressure at high stretch for Fbln5−/− arteries, but the four-fiber model predictions best match the experimental trends in buckling pressure changes with axial stretch. This study provides experimental and theoretical methods for further investigating the influence of genetic mutations in elastic fibers on buckling behavior and the development of arterial tortuosity. PMID:25771258

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.

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

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.

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.

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.

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.

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.

The two-stroke poppet valve engine. Part 2: Numerical investigations of intake and exhaust flow behaviour

NASA Astrophysics Data System (ADS)

Kamili Zahidi, M.; Razali Hanipah, M.

2017-10-01

A two-stroke poppet valve engine is developed to overcome the common problems in conventional two-stroke engine designs. However, replacing piston control port with poppet valve will resulted different flow behaviour. This paper presents the model and simulation result of three-dimensional (3D) port flow investigation of a two-stroke poppet valve engine. The objective of the investigation is to conduct a numerical investigation on port flow performance of two-stroke poppet valve engine and compare the results obtained from the experimental investigation. The model is to be used for the future numerical study of the engine. The volume flow rate results have been compared with the results obtained experimentally as presented in first part of this paper. The model has shown good agreement in terms of the flow rate at initial and final valve lifts but reduced by about 50% during half-lift region.

Dietary patterns are associated with incident stroke and contribute to excess risk of stroke in Black Americans

PubMed Central

Judd, Suzanne E; Gutiérrez, Orlando M.; Newby, PK; Howard, George; Howard, Virginia J; Locher, Julie L; Kissela, Brett M; Shikany, James M

2014-01-01

Background and Purpose 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. Methods Between 2003–2007, the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study enrolled 30,239 black and white Americans aged 45 years or older. 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. Results Over 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 (HR=0.71; 95% CI=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 (HR=1.39; 95% CI=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%. Conclusions These data suggest that adherence to a Southern style diet may increase the risk of stroke while adherence to a more plant-based diet may reduce stroke risk. Given the consistency of finding a dietary impact on stroke risk across studies, discussing nutrition patterns during risk screening may be an important step in reducing stroke. PMID:24159061

Effect of duration and age at exposure to the Stroke Belt on incident stroke in adulthood

PubMed Central

McClure, Leslie A.; Glymour, M. Maria; Cunningham, Solveig A.; Kleindorfer, Dawn O.; Crowe, Michael; Wadley, Virginia G.; Peace, Fredrick; Howard, George; Lackland, Daniel T.

2013-01-01

Objective: To assess whether there are differences in the strength of association with incident stroke for specific periods of life in the Stroke Belt (SB). Methods: The risk of stroke was studied in 24,544 black and white stroke-free participants, aged 45+, in the Reasons for Geographic and Racial Differences in Stroke study, a national population-based cohort enrolled 2003–2007. Incident stroke was defined as first occurrence of stroke over an average 5.8 years of follow-up. Residential histories (city/state) were obtained by questionnaire. SB exposure was quantified by combinations of SB birthplace and current residence and proportion of years in SB during discrete age categories (0–12, 13–18, 19–30, 31–45, last 20 years) and entire life. Proportional hazards models were used to establish association of incident stroke with indices of exposure to SB, adjusted for demographic, socioeconomic (SES), and stroke risk factors. Results: In the demographic and SES models, risk of stroke was significantly associated with proportion of life in the SB and with all other exposure periods except birth, ages 31–45, and current residence. The strongest association was for the proportion of the entire life in SB. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in SB in adolescence (hazard ratio 1.17, 95% confidence interval 1.00–1.37). Conclusions: Childhood emerged as the most important period of vulnerability to SB residence as a predictor of future stroke. Improvement in childhood health circumstances should be considered as part of long-term health improvement strategies in the SB. PMID:23616168

Assessing the predictive value of a neuropsychological model on concurrent function in acute stroke recovery and rehabilitation.

PubMed

Leitner, Damian; Miller, Harry; Libben, Maya

2018-06-25

Few studies have examined the relationship between cognition and function for acute stroke inpatients utilizing comprehensive methods. This study aimed to assess the relationship of a neuropsychological model, above and beyond a baseline model, with concurrent functional status across multiple domains in the early weeks of stroke recovery and rehabilitation. Seventy-four acute stroke patients were administered a comprehensive neuropsychological assessment. Functional domains of ability, adjustment, and participation were assessed using the Mayo-Portland Adaptability Inventory - 4 (MPAI-4). Hierarchical linear regression was used to assess a neuropsychological model comprised of cognitive tests scores on domains of executive function, memory, and visuospatial-constructional skills (VSC), after accounting for a baseline model comprised of common demographic and stroke variants used to predict outcome. The neuropsychological model was significantly associated, above and beyond the baseline model, with MPAI-4 Ability, Participation, and Total scores (all p-values < .05). The strength of association varied across functional domains. Analyzing tests of executive function, the Color Trails Test-Part 2 predicted MPAI-4 Participation (β = -.46, p = .001), and Total score (β = -.32, p = .02). Neuropsychological assessment contributes independently to the determination of multiple domains of functional function, above and beyond common medical variants of stroke, in the early weeks of recovery and rehabilitation. Multiple tests of executive function are recommended to develop a greater appreciation of a patient's concurrent functional abilities.

EMBOLIC MIDDLE CEREBRAL ARTERY OCCLUSION MODEL USING THROMBIN AND FIBRINOGEN COMPOSED CLOTS IN RAT

PubMed Central

Ren, Ming; Lin, Zi-Jing; Qian, Hai; Gourav, Choudhury Roy; liu, Ran; Liu, Hanli; Yang, Shao-Hua

2012-01-01

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model. In the present study, we modified the homologous clots formation by addition of thrombin and fibrinogen which produced even distribution of fibrin with tight cross linkage of red blood cells. We optimized the embolic MCA occlusion model in rats using different size of the mixed clots. A precise lodgment of the clots at the MCA bifurcation and highly reproducible ischemic lesion in the MCA territory were demonstrated in the embolic MCA occlusion model induced by injection of 10 pieces of 1-mm long mixed clots made in PE-60 catheter. We further tested the effect of recombinant tissue plasminogen activator (rtPA) in this embolic MCA occlusion model. rtPA induced thrombolysis, improved neurological outcome, and significantly reduced ischemic lesion volume when administered at 1 hour after embolism as compared with control. In summary, we have established a reproducible embolic MCA occlusion model using clots made of homologous blood, thrombin and fibrinogen. The mixed clots enable precise lodgment at the MCA bifurcation which is responsive to thrombolytic therapy of rtPA. PMID:22985597

Embolic middle cerebral artery occlusion model using thrombin and fibrinogen composed clots in rat.

PubMed

Ren, Ming; Lin, Zi-Jing; Qian, Hai; Choudhury, Gourav Roy; Liu, Ran; Liu, Hanli; Yang, Shao-Hua

2012-11-15

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model. In the present study, we modified the homologous clots formation by addition of thrombin and fibrinogen which produced even distribution of fibrin with tight cross linkage of red blood cells. We optimized the embolic MCA occlusion model in rats using different size of the mixed clots. A precise lodgment of the clots at the MCA bifurcation and highly reproducible ischemic lesion in the MCA territory were demonstrated in the embolic MCA occlusion model induced by injection of 10 pieces of 1-mm long mixed clots made in PE-60 catheter. We further tested the effect of recombinant tissue plasminogen activator (rtPA) in this embolic MCA occlusion model. rtPA induced thrombolysis, improved neurological outcome, and significantly reduced ischemic lesion volume when administered at 1h after embolism as compared with control. In summary, we have established a reproducible embolic MCA occlusion model using clots made of homologous blood, thrombin and fibrinogen. The mixed clots enable precise lodgment at the MCA bifurcation which is responsive to thrombolytic therapy of rtPA. Copyright © 2012 Elsevier B.V. All rights reserved.

Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke

PubMed Central

Inman, Cory S.; James, G. Andrew; Hamann, Stephan; Rajendra, Justin K.; Pagnoni, Giuseppe; Butler, Andrew J.

2011-01-01

Previous brain imaging work suggests that stroke alters the effective connectivity (the influence neural regions exert upon each other) of motor execution networks. The present study examines the intrinsic effective connectivity of top-down motor control in stroke survivors (n=13) relative to healthy participants (n=12). Stroke survivors exhibited significant deficits in motor function, as assessed by the Fugl-Meyer Motor Assessment. We used structural equation modeling (SEM) of resting-state fMRI data to investigate the relationship between motor deficits and the intrinsic effective connectivity between brain regions involved in motor control and motor execution. An exploratory adaptation of SEM determined the optimal model of motor execution effective connectivity in healthy participants, and confirmatory SEM assessed stroke survivors’ fit to that model. We observed alterations in spontaneous resting-state effective connectivity from fronto-parietal guidance systems to the motor network in stroke survivors. More specifically, diminished connectivity was found in connections from the superior parietal cortex to primary motor cortex and supplementary motor cortex. Furthermore, the paths demonstrated large individual variance in stroke survivors but less variance in healthy participants. These findings suggest that characterizing the deficits in resting-state connectivity of top-down processes in stroke survivors may help optimize cognitive and physical rehabilitation therapies by individually targeting specific neural pathway. PMID:21839174

Game design in virtual reality systems for stroke rehabilitation.

PubMed

Goude, Daniel; Björk, Staffan; Rydmark, Martin

2007-01-01

We propose a model for the structured design of games for post-stroke rehabilitation. The model is based on experiences with game development for a haptic and stereo vision immersive workbench intended for daily use in stroke patients' homes. A central component of this rehabilitation system is a library of games that are simultaneously entertaining for the patient and beneficial for rehabilitation [1], and where each game is designed for specific training tasks through the use of the model.

Mortality and nursing care dependency one year after first ischemic stroke: an analysis of German statutory health insurance data.

PubMed

Kemper, Claudia; Koller, Daniela; Glaeske, Gerd; van den Bussche, Hendrik

2011-01-01

Aphasia, dementia, and depression are important and common neurological and neuropsychological disorders after ischemic stroke. We estimated the frequency of these comorbidities and their impact on mortality and nursing care dependency. Data of a German statutory health insurance were analyzed for people aged 50 years and older with first ischemic stroke. Aphasia, dementia, and depression were defined on the basis of outpatient medical diagnoses within 1 year after stroke. Logistic regression models for mortality and nursing care dependency were calculated and were adjusted for age, sex, and other relevant comorbidity. Of 977 individuals with a first ischemic stroke, 14.8% suffered from aphasia, 12.5% became demented, and 22.4% became depressed. The regression model for mortality showed a significant influence of age, aphasia, and other relevant comorbidity. In the regression model for nursing care dependency, the factors age, aphasia, dementia, depression, and other relevant comorbidity were significant. Aphasia has a high impact on mortality and nursing care dependency after ischemic stroke, while dementia and depression are strongly associated with increasing nursing care dependency.

The Risk of Paradoxical Embolism (RoPE) Study: developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke.

PubMed

Kent, David M; Thaler, David E

2011-07-27

Despite the diffusion into practice of percutaneous closure of a patent foramen ovale (PFO) in patients with cryptogenic stroke (CS), the benefits have not been demonstrated, and remain unclear. For any individual presenting with a PFO in the setting of CS, it is not clear whether the PFO is pathogenically-related to the index event or an incidental finding. Further, the overall rate of stroke recurrence is low in patients with CS and PFO. How patient-specific factors affect the likelihood that a discovered PFO is related to an index stroke or affect the risk of recurrence is not well understood. These probabilities are likely to be important determinants of the benefits of PFO closure in CS. The goal of the Risk of Paradoxical Embolism (RoPE) Study is to develop and test a set of predictive models that can identify those patients most likely to benefit from preventive treatments for PFO-related stroke recurrence, such as PFO closure. To do this, we will construct a database of patients with CS, both with and without PFO, by combining existing cohort studies. We will use this pooled database to identify patient characteristics associated with the presence (versus the absence) of a PFO, and to use this "PFO propensity" to estimate the patient-specific probability that a PFO was pathogenically related to the index stroke (Model #1). We will also develop, among patients with both a CS and a PFO, a predictive model to estimate patient-specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics. (Model #2). We will then combine Models #1 and #2 into a composite index that can rank patients with CS and PFO by their conditional probability that their PFO was pathogenically related to the index stroke and the risk of stroke recurrence. Finally, we will apply this composite index to completed clinical trials (currently on-going) testing endovascular PFO closure against medical therapy, to stratify patients from low-expected-benefit to high-expected-benefit.

Dodecafluoropentane Emulsion Decreases Infarct Volume in a Rabbit Ischemic Stroke Model

PubMed Central

Culp, William C.; Woods, Sean D.; Skinner, Robert D.; Brown, Aliza T.; Lowery, John D.; Johnson, Jennifer L. H.; Unger, Evan C.; Hennings, Leah J.; Borrelli, Michael J.; Roberson, Paula K.

2011-01-01

Purpose To assess the efficacy of dodecafluoropentane emulsion (DDFPe), a nano droplet emulsion with significant oxygen transport potential, in decreasing infarct volume using an insoluble emboli rabbit stroke model. Methods New Zealand White rabbits (n=64; 5.1±0.50 kg) received angiography and embolic spheres in the internal carotid artery occluding branches. Rabbits were randomly assigned to groups in 4-hour and 7-hour studies. Four-hour groups included: control (n=7, embolized without treatment) or DDFPe treatment 30-min before stroke (n=7), or at stroke onset (n=8), 30-min after stroke (n=5), 1-hour after stroke (n=7), 2-hours after stroke (n=5), or 3-hours after stroke (n=6). Seven-hour groups included control (n=6), DDFPe at 1-hour after stroke (n=8), and DDFPe at 6-hours after stroke (n=5). DDFPe dose was 2% w/v (weight/volume) intravenous injection, 0.6 mL/kg, and repeated every 90 minutes as time allowed. Following euthanasia infarct volume was determined using vital stains on brain sections. Results At 4-hours, median percent infarct volume decreased for all DDFPe treatment times (pre-treatment=0.30%, p=0.004; onset=0.20%, p=0.004; 30-min=0.35%, p=0.009, 1-hour=0.30%, p=0.01, 2-hours=0.40%, p=0.009, 3-hours=0.25%, p=0.003) compared with controls (3.20%). At 7-hours, median percent infarct volume decreased with treatment at 1-hour (0.25%, p=0.007) but not for 6-hours (1.4%, p=0.49) compared with controls (2.2%). Conclusions Intravenous DDFPe in an animal model decreases infarct volumes and protects brain tissue from ischemia justifying further investigation. PMID:22079515

Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness.

PubMed

Halabi, Carmen M; Broekelmann, Thomas J; Knutsen, Russell H; Ye, Li; Mecham, Robert P; Kozel, Beth A

2015-09-01

Increased arterial stiffness is a common characteristic of humans with Williams-Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4-6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency. Copyright © 2015 the American Physiological Society.

A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors.

PubMed

Zhu, Xiaoyan; Fréchou, Magalie; Liere, Philippe; Zhang, Shaodong; Pianos, Antoine; Fernandez, Neïké; Denier, Christian; Mattern, Claudia; Schumacher, Michael; Guennoun, Rachida

2017-11-08

Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower and levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes. SIGNIFICANCE STATEMENT The brain responds to injury with protective signaling and has a remarkable capacity to protect itself. We show here that, in response to ischemic stroke, levels of progesterone and its neuroactive metabolite 5α-dihydroprogesterone are upregulated rapidly in the male mouse brain but not in the female brain. An important role of endogenous progesterone in cerebroprotection was demonstrated by the conditional inactivation of its receptor in neural cells. These results show the importance of endogenous progesterone, its metabolites, and neural progesterone receptors in acute cerebroprotection after stroke. This new concept could be exploited therapeutically by taking into account the progesterone status of patients and by supplementing and reinforcing endogenous progesterone signaling for attaining its full cerebroprotective potential. Copyright © 2017 the authors 0270-6474/17/3710998-23$15.00/0.

Evaluating infant core temperature response in a hot car using a heat balance model.

PubMed

Grundstein, Andrew J; Duzinski, Sarah V; Dolinak, David; Null, Jan; Iyer, Sujit S

2015-03-01

Using a 1-year old male infant as the model subject, the objectives of this study were to measure increased body temperature of an infant inside an enclosed vehicle during the work day (8:00 am-4:00 pm) during four seasons and model the time to un-compensable heating, heat stroke [>40 °C (>104 °F)], and critical thermal maximum [>42 °C (>107.6 °F)]. A human heat balance model was used to simulate a child's physiological response to extreme heat exposure within an enclosed vehicle. Environmental variables were obtained from the nearest National Weather Service automated surface observing weather station and from an observational vehicular temperature study conducted in Austin, Texas in 2012. In all four seasons, despite differences in starting temperature and solar radiation, the model infant reached heat stroke and demise before 2:00 pm. Time to heat stroke and demise occurred most rapidly in summer, at intermediate durations in fall and spring, and most slowly in the winter. In August, the model infant reached un-compensable heat within 20 min, heat stroke within 105 min, and demise within 125 min. The average rate of heating from un-compensable heat to heat stroke was 1.7 °C/h (3.0 °F/h) and from heat stroke to demise was 4.8 °C/h (8.5 °F/h). Infants left in vehicles during the workday can reach hazardous thermal thresholds quickly even with mild environmental temperatures. These results provide a seasonal analogue of infant heat stroke time course. Further effort is required to create a universally available forensic tool to predict vehicular hyperthermia time course to demise.

Feasibility and effectiveness of circuit training in acute stroke rehabilitation.

PubMed

Rose, Dorian; Paris, Trevor; Crews, Erin; Wu, Samuel S; Sun, Anqi; Behrman, Andrea L; Duncan, Pamela

2011-02-01

Task-specificity, repetition and progression are key variables in the acquisition of motor skill however they have not been consistently implemented in post-stroke rehabilitation. To evaluate the effectiveness of a stroke rehabilitation plan of care that incorporated task-specific practice, repetition and progression to facilitate functional gain compared to standard physical therapy for individuals admitted to an inpatient stroke unit. Individuals participated in either a circuit training (CTPT) model (n = 72) or a standard (SPT) model (n = 108) of physical therapy, 5 days/week. Each 60 minute circuit training session, delivered according to severity level, consisted of four functional mobility tasks. Daily exercise logs documented both task repetition and progression. The CTPT model was successfully implemented in an acute rehabilitation setting. The CTPT group showed a significantly greater improved change in gait speed from hospital admission to discharge than the SPT group (0.21 ± 0.25 m/sec vs. 0.13 ± 0.22 m/sec; p = 0.03). The difference between groups occurred primarily among those who were ambulatory upon admission. There were no significant differences between the two cohorts at 90 days post-stroke as measured by the FONE-FIM, SF-36 and living location. Therapy focused on systematically progressed functional tasks can be successfully implemented in an inpatient rehabilitation stroke program. This circuit-training model resulted in greater gains in gait velocity over the course of inpatient rehabilitation compared to the standard model of care. Community-based services following hospital discharge to maintain these gains should be included in the continuum of post-stroke care.

Left atrial function to identify patients with atrial fibrillation at high risk of stroke: new insights from a large registry.

PubMed

Leung, Melissa; van Rosendael, Philippe J; Abou, Rachid; Ajmone Marsan, Nina; Leung, Dominic Y; Delgado, Victoria; Bax, Jeroen J

2018-04-21

Atrial fibrillation (AF) is an independent risk factor for ischaemic stroke. The CHA2DS2-VASc is the most widely used risk stratification model; however, echocardiographic refinement may be useful, particularly in low risk AF patients. The present study examined the association between advanced echocardiographic parameters and ischaemic stroke, independent of CHA2DS2-VASc score. One thousand, three hundred and sixty-one patients (mean age 65±12 years, 74% males) with first diagnosis of AF and baseline transthoracic echocardiogram were followed by chart review for the occurrence of stroke over a mean of 7.9 years. Left atrial (LA) volumes, LA reservoir strain, P-wave to A' duration on tissue Doppler imaging (PA-TDI, reflecting total atrial conduction time), and left ventricular (LV) global longitudinal strain (GLS) were evaluated in patients with and without stroke. The independent association of these echocardiographic parameters with the occurrence of ischaemic stroke was evaluated with Cox proportional hazard models. One-hundred patients (7%) developed an ischaemic stroke, representing an annualized stroke rate of 0.9%. The incident stroke rate in the year following the first diagnosis of AF was 2.6% in the entire population and higher than the remainder of the follow-up period. Left atrial reservoir (14.5% vs. 18.9%, P = 0.005) and conduit strains were reduced (10.5% vs. 13.5%, P = 0.013), and PA-TDI lengthened (166 ms vs. 141 ms, P < 0.001) in the stroke compared with non-stroke group, despite similar LV dimensions, LV ejection fraction, GLS, and LA volumes. Left atrial reservoir strain and PA-TDI were independently associated with risk of stroke in a model including CHA2DS2-VASc score, age, and anticoagulant use. The assessment of LA reservoir strain and PA-TDI on echocardiography after initial CHA2DS2-VASc scoring provides additional risk stratification for stroke and may be useful to guide decisions regarding anticoagulation for patients upon first diagnosis of AF.

Alterations in anxiety and social behaviour in Npas4 deficient mice following photochemically-induced focal cortical stroke.

PubMed

Klarić, T S; Jaehne, E J; Koblar, S A; Baune, B T; Lewis, M D

2017-01-01

In addition to causing widespread cell death and loss of brain function, cerebral ischaemia also induces extensive neuroplasticity. In humans, stroke is often accompanied by severe cognitive and psychiatric changes that are thought to arise as a consequence of this infarct-induced remodelling. A candidate for producing these post-stroke neuropsychiatric changes is Npas4, an activity-dependent transcription factor involved in synaptic plasticity whose expression is aberrantly up-regulated following ischaemic injury. In this study we investigated the role of Npas4 in modulating these stroke-induced neuropsychiatric responses by comparing the performance of wildtype and Npas4 -/- mice in various cognitive and behavioural tasks in a photochemical model of focal cortical stroke. We show that this stroke model results in impaired spatial recognition memory and a reduction in despair-like behaviour that affect both genotypes to a similar degree. Moreover, mice lacking Npas4 also show differences in some aspects of post-stroke sociability and anxiety. Specifically, we show that while stroke had no effect on anxiety levels in wildtype mice, Npas4 -/- mice became significantly more anxious following stroke. In addition, Npas4 -/- mice retained a greater level of sociability in the acute post-stroke period in comparison to their wildtype littermates. Thus, our findings suggest that Npas4 may be involved in post-stroke psychiatric changes related to anxiety and sociability. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

On the behavior of return stroke current and the remotely detected electric field change waveform

NASA Astrophysics Data System (ADS)

Shao, Xuan-Min; Lay, Erin; Jacobson, Abram R.

2012-04-01

After accumulating a large number of remotely recorded negative return stroke electric field change waveforms, a subtle but persistent kink was found following the main return stroke peak by several microseconds. To understand the corresponding return stroke current properties behind the kink and the general return stroke radiation waveform, we analyze strokes occurring in triggered lightning flashes for which have been measured both the channel base current and simultaneous remote electric radiation field. In this study, the channel base current is assumed to propagate along the return stroke channel in a dispersive and lossy manner. The measured channel base current is band-pass filtered, and the higher-frequency component is assumed to attenuate faster than the lower-frequency component. The radiation electric field is computed for such a current behavior and is then propagated to distant sensors. It is found that such a return stroke model is capable of very closely reproducing the measured electric waveforms at multiple stations for the triggered return strokes, and such a model is considered applicable to the common behavior of the natural return stroke as well. On the basis of the analysis, a number of other observables are derived. The time-evolving current dispersion and attenuation compare well with previously reported optical observations. The observable speed tends to agree with optical and VHF observations. Line charge density that is removed or deposited by the return stroke is derived, and the implication of the charge density distribution on leader channel decay is discussed.

Prediction of Post-stroke Falls by Quantitative Assessment of Balance.

PubMed

Lee, Hyun Haeng; Jung, Se Hee

2017-06-01

To evaluate characteristics of the postural instability in patients with stroke and to present a prediction model of post-stroke falls. Patients with a first-ever stroke who had been evaluated by the Balance Master (BM) at post-stroke 3 months (±1 month) between August 2011 and December 2015 were enrolled. Parameters for the postural instability, such as the weight bearing asymmetry (WBA) and postural sway velocity (PSV), were obtained. The fall events in daily lives were assessed via structured telephone interview with a fall related questionnaire. A total of 71 patients (45 men; 45 with ischemic stroke) were enrolled in this study. All subjects underwent BM evaluation at 3.03±0.40 months after stroke. The mean WBA was 17.18%±13.10% and mean PSV (measured as °/s) were noted as 0.66±0.37 (eyes-open on firm surface), 0.89±0.75 (eyes-closed on firm surface), 1.45±1.09 (eyes-open on soft surface), and 3.10±1.76 (eyes-closed on soft surface). A prediction model of post-stroke falls was drawn by multiple logistic regression analysis as follows: Risk of post-stroke falls = -2.848 + 1.878 x (PSV ECSS ) + 0.154 x (age=1 if age≥65; age=0 if age<65). The weight bearing asymmetry and postural sway were significantly increased in patients with stroke. Older age and impaired postural control increased the risk of post-stroke falls.

Atrial fibrillation and risk of stroke in dialysis patients

PubMed Central

Wetmore, James B.; Ellerbeck, Edward F.; Mahnken, Jonathan D.; Phadnis, Milind; Rigler, Sally K.; Mukhopadhyay, Purna; Spertus, John A.; Zhou, Xinhua; Hou, Qingjiang; Shireman, Theresa I.

2013-01-01

Purpose Both stroke and chronic atrial fibrillation (AF) are common in dialysis patients, but uncertainty exists in the incidence of new strokes and the risk conferred by chronic AF. Methods A cohort of dually-eligible (Medicare & Medicaid) incident dialysis patients was constructed. Medicare claims were used to determine the onset of chronic AF, which was specifically treated as a time-dependent covariate. Cox proportional hazards models were used to model time to stroke. Results Of 56,734 patients studied, 5629 (9.9%) developed chronic AF. There were 22.8 ischemic and 5.0 hemorrhagic strokes per 1000 patient-years, a ratio of approximately 4.5:1. Chronic AF was independently associated with time to ischemic (HR 1.26, 99% CI’s 1.06 – 1.49, P = 0.0005), but not hemorrhagic, stroke. Race was strongly associated with hemorrhagic stroke: African-Americans (HR 1.46, 99% CI’s 1.08 – 1.96), Hispanics (HR 1.64, 99% CI’s 1.16 – 2.31), and others (HR 1.76, 99% CI’s 1.16 – 2.78) had higher rates than did Caucasians (P < 0.001 for all). Conclusions Chronic AF has a significant, but modest, association with ischemic stroke. Race/ethnicity is strongly associated with hemorrhagic strokes. The proportion of strokes due to hemorrhage is much higher than in the general population. PMID:23332588

Atrial fibrillation and risk of stroke in dialysis patients.

PubMed

Wetmore, James B; Ellerbeck, Edward F; Mahnken, Jonathan D; Phadnis, Milind; Rigler, Sally K; Mukhopadhyay, Purna; Spertus, John A; Zhou, Xinhua; Hou, Qingjiang; Shireman, Theresa I

2013-03-01

Both stroke and chronic atrial fibrillation (AF) are common in dialysis patients, but uncertainty exists in the incidence of new strokes and the risk conferred by chronic AF. A cohort of dually eligible (Medicare and Medicaid) incident dialysis patients was constructed. Medicare claims were used to determine the onset of chronic AF, which was specifically treated as a time-dependent covariate. Cox proportional hazards models were used to model time to stroke. Of 56,734 patients studied, 5629 (9.9%) developed chronic AF. There were 22.8 ischemic and 5.0 hemorrhagic strokes per 1000 patient-years, a ratio of approximately 4.5:1. Chronic AF was independently associated with time to ischemic (hazard ratio [HR], 1.26; 99% confidence interval [CI], 1.06-1.49; P = .0005), but not hemorrhagic, stroke. Race was strongly associated with hemorrhagic stroke: African Americans (HR, 1.46; 99% CI, 1.08-1.96), Hispanics (HR, 1.64; 99% CI, 1.16-2.31), and others (HR, 1.76; 99% CI, 1.16-2.78) had higher rates than did Caucasians (all P < .001). Chronic AF has a significant, but modest, association with ischemic stroke. Race/ethnicity is strongly associated with hemorrhagic strokes. The proportion of strokes owing to hemorrhage is much higher than in the general population. Copyright © 2013 Elsevier Inc. All rights reserved.

Omega-3 fatty acids in neurodegenerative diseases: focus on mitochondria.

PubMed

Eckert, Gunter P; Lipka, Uta; Muller, Walter E

2013-01-01

Mitochondrial dysfunction represents a common early pathological event in brain aging and in neurodegenerative diseases, e.g., in Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD), as well as in ischemic stroke. In vivo and ex vivo experiments using animal models of aging and AD, PD, and HD mainly showed improvement of mitochondrial function after treatment with polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA). Thereby, PUFA are particular beneficial in animals treated with mitochondria targeting toxins. However, DHA showed adverse effects in a transgenic PD mouse model and it is not clear if a diet high or low in PUFA might provide neuroprotective effects in PD. Post-treatment with PUFA revealed conflicting results in ischemic animal models, but intravenous administered DHA provided neuroprotective efficacy after acute occlusion of the middle cerebral artery. In summary, the majority of preclinical data indicate beneficial effects of n-3 PUFA in neurodegenerative diseases, whereas most controlled clinical trials did not meet the expectations. Because of the high half-life of DHA in the human brain clinical studies may have to be initiated much earlier and have to last much longer to be more efficacious. Copyright © 2012 Elsevier Ltd. All rights reserved.

Derivation and validation of a discharge disposition predicting model after acute stroke.

PubMed

Tseng, Hung-Pin; Lin, Feng-Jenq; Chen, Pi-Tzu; Mou, Chih-Hsin; Lee, Siu-Pak; Chang, Chun-Yuan; Chen, An-Chih; Liu, Chung-Hsiang; Yeh, Chung-Hsin; Tsai, Song-Yen; Hsiao, Yu-Jen; Lin, Ching-Huang; Hsu, Shih-Pin; Yu, Shih-Chieh; Hsu, Chung-Y; Sung, Fung-Chang

2015-06-01

Discharge disposition planning is vital for poststroke patients. We investigated clinical factors associated with discharging patients to nursing homes, using the Taiwan Stroke Registry data collected from 39 major hospitals. We randomly assigned 21,575 stroke inpatients registered from 2006 to 2008 into derivation and validation groups at a 3-to-1 ratio. We used the derivation group to develop a prediction model by measuring cumulative risk scores associated with potential predictors: age, sex, hypertension, diabetes mellitus, heart diseases, stroke history, snoring, main caregivers, stroke types, and National Institutes of Health Stroke Scale (NIHSS). Probability of nursing home care and odds ratio (OR) of nursing home care relative to home care by cumulative risk scores were measured for the prediction. The area under the receiver operating characteristic curve (AUROC) was used to assess the model discrimination against the validation group. Except for hypertension, all remaining potential predictors were significant independent predictors associated with stroke patient disposition to nursing home care after discharge from hospitals. The risk sharply increased with age and NIHSS. Patients with a cumulative risk score of 15 or more had an OR of 86.4 for the nursing home disposition. The AUROC plots showed similar areas under curves for the derivation group (.86, 95% confidence interval [CI], .85-.87) and for the validation group (.84, 95% CI, .83-.86). The cumulative risk score is an easy-to-estimate tool for preparing stroke patients and their family for disposition on discharge. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence.

PubMed

Buchtele, Nina; Schwameis, Michael; Gilbert, James C; Schörgenhofer, Christian; Jilma, Bernd

2018-06-01

Despite great efforts in stroke research, disability and recurrence rates in ischaemic stroke remain unacceptably high. To address this issue, one potential target for novel therapeutics is the glycoprotein von Willebrand factor (vWF), which increases in thrombogenicity especially under high shear rates as it bridges between vascular sub-endothelial collagen and platelets. The rationale for vWF as a potential target in stroke comes from four bodies of evidence. (1) Animal models which recapitulate the pathogenesis of stroke and validate the concept of targeting vWF for stroke prevention and the use of the vWF cleavage enzyme ADAMTS13 in acute stroke treatment. (2) Extensive epidemiologic data establishing the prognostic role of vWF in the clinical setting showing that high vWF levels are associated with an increased risk of first stroke, stroke recurrence or stroke-associated mortality. As such, vWF levels may be a suitable marker for further risk stratification to potentially fine-tune current risk prediction models which are mainly based on clinical and imaging data. (3) Genetic studies showing an association between vWF levels and stroke risk on genomic levels. Finally, (4) studies of patients with primary disorders of excess or deficiency of function in the vWF axis (e.g. thrombotic thrombocytopenic purpura and von Willebrand disease, respectively) which demonstrate the crucial role of vWF in atherothrombosis. Therapeutic inhibition of VWF by novel agents appears particularly promising for secondary prevention of stroke recurrence in specific sub-groups of patients such as those suffering from large artery atherosclerosis, as designated according to the TOAST classification. Schattauer GmbH Stuttgart.

A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

PubMed Central

Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J

2015-01-01

Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

Variation in mortality of ischemic and hemorrhagic strokes in relation to high temperature.

PubMed

Lim, Youn-Hee; Kim, Ho; Hong, Yun-Chul

2013-01-01

Outdoor temperature has been reported to have a significant influence on the seasonal variations of stroke mortality, but few studies have investigated the effect of high temperature on the mortality of ischemic and hemorrhagic strokes. The main study goal was to examine the effect of temperature, particularly high temperature, on ischemic and hemorrhagic strokes. We investigated the association between outdoor temperature and stroke mortality in four metropolitan cities in Korea during 1992-2007. We used time series analysis of the age-adjusted mortality rate for ischemic and hemorrhagic stroke deaths by using generalized additive and generalized linear models, and estimated the percentage change of mortality rate associated with a 1°C increase of mean temperature. The temperature-responses for the hemorrhagic and ischemic stroke mortality differed, particularly in the range of high temperature. The estimated percentage change of ischemic stroke mortality above a threshold temperature was 5.4 % (95 % CI, 3.9-6.9 %) in Seoul, 4.1 % (95 % CI, 1.6-6.6 %) in Incheon, 2.3 % (-0.2 to 5.0 %) in Daegu and 3.6 % (0.7-6.6 %) in Busan, after controlling for daily mean humidity, mean air pressure, day of the week, season, and year. Additional adjustment of air pollution concentrations in the model did not change the effects. Hemorrhagic stroke mortality risk significantly decreased with increasing temperature without a threshold in the four cities after adjusting for confounders. These findings suggest that the mortality of hemorrhagic and ischemic strokes show different patterns in relation to outdoor temperature. High temperature was harmful for ischemic stroke but not for hemorrhagic stroke. The risk of high temperature to ischemic stroke did not differ by age or gender.

Variation in mortality of ischemic and hemorrhagic strokes in relation to high temperature

NASA Astrophysics Data System (ADS)

Lim, Youn-Hee; Kim, Ho; Hong, Yun-Chul

2013-01-01

Outdoor temperature has been reported to have a significant influence on the seasonal variations of stroke mortality, but few studies have investigated the effect of high temperature on the mortality of ischemic and hemorrhagic strokes. The main study goal was to examine the effect of temperature, particularly high temperature, on ischemic and hemorrhagic strokes. We investigated the association between outdoor temperature and stroke mortality in four metropolitan cities in Korea during 1992-2007. We used time series analysis of the age-adjusted mortality rate for ischemic and hemorrhagic stroke deaths by using generalized additive and generalized linear models, and estimated the percentage change of mortality rate associated with a 1°C increase of mean temperature. The temperature-responses for the hemorrhagic and ischemic stroke mortality differed, particularly in the range of high temperature. The estimated percentage change of ischemic stroke mortality above a threshold temperature was 5.4 % (95 % CI, 3.9-6.9 %) in Seoul, 4.1 % (95 % CI, 1.6-6.6 %) in Incheon, 2.3 % (-0.2 to 5.0 %) in Daegu and 3.6 % (0.7-6.6 %) in Busan, after controlling for daily mean humidity, mean air pressure, day of the week, season, and year. Additional adjustment of air pollution concentrations in the model did not change the effects. Hemorrhagic stroke mortality risk significantly decreased with increasing temperature without a threshold in the four cities after adjusting for confounders. These findings suggest that the mortality of hemorrhagic and ischemic strokes show different patterns in relation to outdoor temperature. High temperature was harmful for ischemic stroke but not for hemorrhagic stroke. The risk of high temperature to ischemic stroke did not differ by age or gender.

Functional and motor outcome 5 years after stroke is equivalent to outcome at 2 months: follow-up of the collaborative evaluation of rehabilitation in stroke across Europe.

PubMed

Meyer, Sarah; Verheyden, Geert; Brinkmann, Nadine; Dejaeger, Eddy; De Weerdt, Willy; Feys, Hilde; Gantenbein, Andreas R; Jenni, Walter; Laenen, Annouschka; Lincoln, Nadina; Putman, Koen; Schuback, Birgit; Schupp, Wilfried; Thijs, Vincent; De Wit, Liesbet

2015-06-01

Recovery of patients within the first 6 months after stroke is well documented, but there has been little research on long-term recovery. The aim of this study was to analyze functional and motor recovery between admission to rehabilitation centres and 5 years after stroke. This follow-up of the Collaborative Evaluation of Rehabilitation in Stroke Across Europe study, included patients from 4 European rehabilitation centres. Patients were assessed on admission, at 2 and 6 months, and 5 years after stroke, using the Barthel Index, Rivermead Motor Assessment Gross Function, Leg and Trunk function, and Arm function. Linear mixed models were used, corrected for baseline characteristics. To account for the drop-out during follow-up, the analysis is likelihood-based (assumption of missingness at random). A total of 532 patients were included in this study, of which 238 were followed up at 5 years post stroke. Mean age at stroke onset was 69 (±10 SD) years, 53% were men, 84% had ischemic strokes, and 53% had left-sided motor impairment. Linear mixed model analysis revealed a significant deterioration for all 4 outcomes between 6 months and 5 years (P<0.0001). Scores at 2 months were not statistically significant different from scores at 5 years after stroke. Higher age (P<0.0001) and increasing stroke severity on admission (P<0.0001) negatively affected long-term functional and motor recovery. Five-year follow-up revealed deterioration in functional and motor outcome, with a return to the level measured at 2 months. Increasing age and increasing stroke severity negatively affected recovery up to 5 years after stroke. © 2015 American Heart Association, Inc.

Two-stroke S.I. engine competitive to four-stroke engine in terms of the exhaust emission

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

Pavletic, R.; Trenc, F.

1994-09-01

A model engine with disintegrated working cycle was built. Its operation is not autonomous; compression of the working air is performed separately outside the engine by the compressed-air line supply. Pre-compressed charge together with the injected fuel is introduced in the combustion chamber. The model engine makes possible to determine indicated performance characteristics and its emission capability. Effective measured engine characteristics are of course not comparable with those obtained by a practical engine. The model presented is a two-stroke cycle engine. Exhaust emission picture of the presented engine is comparable with the emission of a modern four-stroke engine. 2 refs.,more » 13 figs., 2 tabs.« less

Emodin from Polygonum multiflorum ameliorates oxidative toxicity in HT22 cells and deficits in photothrombotic ischemia.

PubMed

Ahn, Sung Min; Kim, Ha Neui; Kim, Yu Ri; Choi, Young Whan; Kim, Cheol Min; Shin, Hwa Kyoung; Choi, Byung Tae

2016-07-21

Polygonum multiflorum Thunb. has been used widely in East Asia in treatment of diseases associated with aging. Emodin, an active component from Polygonum multiflorum Thunb., provides benefits for brain disturbances induced by severe cerebral injury. We investigated the neuroprotective effect of emodin from Polygonum multiflorum Thunb. against glutamate-induced oxidative toxicity and cerebral ischemia. For examination of neuroprotective effects of emodin, cell viability, cytotoxicity, flow cytometry, and Western blot were performed in HT22 cells and infarct volume, behavioral tests and Western blot in a mouse model of photothrombotic ischemic stroke. Pretreatment with emodin resulted in significantly reduced glutamate-induced apoptotic cell death in HT22 cells. However, blocking of phosphatidylinositol-3 kinase (PI3K) activity with LY294002 resulted in significantly inhibited cell survival by emodin. Exposure of glutamate-treated cells to emodin induced an increase in the level of Bcl-2 expression, whereas the expression of Bax and active caspase-3 proteins was significantly reduced. In addition, treatment with emodin resulted in increased phosphorylation of Akt and cAMP response element binding protein (CREB), and expression of mature brain-derived neurotrophic factor (BDNF). This expression by emodin was also significantly inhibited by blocking of PI3K activity. In a photothrombotic ischemic stroke model, treatment with emodin resulted in significantly reduced infarct volume and improved motor function. We confirmed the critical role of the expression levels of Bcl-2/Bax, active caspase-3, phosphorylated (p)Akt, p-CREB, and mature BDNF for potent neuroprotective effects of emodin in cerebral ischemia. These results suggest that emodin may afford a significant neuroprotective effect against glutamate-induced apoptosis through activation of the PI3K/Akt signaling pathway, and subsequently enhance behavioral function in cerebral ischemia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice.

PubMed

Marumo, Toshiyuki; Eto, Kei; Wake, Hiroaki; Omura, Tomohiro; Nabekura, Junichi

2010-11-01

20-Hydroxyeicosatetraenoic acid is a potent vasoconstrictor that contributes to cerebral ischaemia. An inhibitor of 20-Hydroxyeicosatetraenoic acid synthesis, TS-011, reduces infarct volume and improves neurological deficits in animal stroke models. However, little is known about how TS-011 affects the microvessels in ischaemic brain. Here, we investigated the effect of TS-011 on microvessels after cerebral ischaemia. TS-011 (0.3 mg·kg(-1) ) or a vehicle was infused intravenously for 1 h every 6 h in a mouse model of stroke, induced by transient occlusion of the middle cerebral artery occlusion following photothrombosis. The cerebral blood flow velocity and the vascular perfusion area of the peri-infarct microvessels were measured using in vivo two-photon imaging. The cerebral blood flow velocities in the peri-infarct microvessels decreased at 1 and 7 h after reperfusion, followed by an increase at 24 h after reperfusion in the vehicle-treated mice. We found that TS-011 significantly inhibited both the decrease and the increase in the blood flow velocities in the peri-infarct microvessels seen in the vehicle-treated mice after reperfusion. In addition, TS-011 significantly inhibited the reduction in the microvascular perfusion area after reperfusion, compared with the vehicle-treated group. Moreover, TS-011 significantly reduced the infarct volume by 40% at 72 h after middle cerebral artery occlusion. These findings demonstrated that infusion of TS-011 improved defects in the autoregulation of peri-infarct microcirculation and reduced the infarct volume. Our results could be relevant to the treatment of cerebral ischaemia. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

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

2007 International Brain Mapping and Intraoperative Surgical Planning Society’s (IBMISPS) Annual World Congress

DTIC Science & Technology

2008-02-01

and Stroke Two Long Term Consequences of Penetrating Head Injuries : Exacerbated Decline and Post-Traumatic Stress Disorder Key Note speaker: Michael L...an intuitively obvious first principle that if modern medicine hopes to repair adult brains (damaged by war injuries , automobile accidents, stroke ...Imaging Animal Models of Brain Disease Background and Animal Model Quantization of Structure Cerebral Blood Flow Mini- Strokes Cancer Future

Radiation from lightning return strokes over a finitely conducting earth

NASA Technical Reports Server (NTRS)

Le Vine, D. M.; Gesell, L.; Kao, Michael

1986-01-01

The effects of the conductivity of the earth on radiation from lightning return strokes are examined theoretically using a piecewise linear transmission line model for the return stroke. First, calculations are made of the electric field radiated during the return stroke, and then this electric field is used to compute the response of conventional AM radio receivers and electric field change systems during the return stroke. The calculations apply to the entire transient waveform (they are not restricted to the initial portions of the return stroke) and yield fast field changes and RF radiation in agreement with measurements made during real lightning. This research was motivated by measurements indicating that a time delay exists between the time of arrival of the fast electric field change and the RF radiation from first return strokes. The time delay is on the order of 20 microsec for frequencies in the HF-UHF range for lightning in Florida. The time delay is obtained theoretically in this paper. It occurs when both the effects of attenuation due to conductivity of the earth, and the finite velocity of propagation of the current pulse up the return stroke channel, are taken into account in the model.

The psychosocial work environment is associated with risk of stroke at working age.

PubMed

Jood, Katarina; Karlsson, Nadine; Medin, Jennie; Pessah-Rasmussen, Hélène; Wester, Per; Ekberg, Kerstin

2017-07-01

Objective The aim of this study was to explore the relation between the risk of first-ever stroke at working age and psychological work environmental factors. Methods A consecutive multicenter matched 1:2 case-control study of acute stroke cases (N=198, age 30-65 years) who had been working full-time at the time of their stroke and 396 sex- and age-matched controls. Stroke cases and controls answered questionnaires on their psychosocial situation during the previous 12 months. The psychosocial work environment was assessed using three different measures: the job-control-demand model, the effort-reward imbalance (ERI) score, and exposures to conflict at work. Results Among 198 stroke cases and 396 controls, job strain [odds ratio (OR) 1.30, 95% confidence interval (95% CI) 1.05-1.62], ERI (OR 1.28, 95% CI 1.01-1.62), and conflict at work (OR 1.75, 95% CI 1.07-2.88) were independent risk factors of stroke in multivariable regression models. Conclusions Adverse psychosocial working conditions during the past 12 months were more frequently observed among stroke cases. Since these factors are presumably modifiable, interventional studies targeting job strain and emotional work environment are warranted.

Early-life Sodium-exposure Unmasks Susceptibility to Stroke in hyperlipidemic-hypertensive Tg[hCETP]25-Rats

PubMed Central

Decano, Julius L.; Viereck, Jason C.; McKee, Ann C.; Hamilton, James A.; Ruiz-Opazo, Nelson; Herrera, Victoria L.M.

2009-01-01

Background Early-life risk factor exposure increases aortic atherosclerosis and blood pressure in humans and animal models, however, limited insight has been made into end-organ complications. Methods and Results We investigated the effects of early-life Na-exposure (0.23% vs 0.4%NaCl regular-rat chow) on vascular disease outcomes using the inbred, transgenic[hCETP]25 Dahl salt-sensitive hypertensive rat model of male-predominant coronary atherosclerosis, Tg25. Rather than the expected increased coronary heart disease, fetal 0.4%Na-exposure (≤2g-Na/2000cal/diet/day) induced adult-onset stroke in both sexes (ANOVA P<0.0001), with earlier stroke-onset in Tg25-females. Analysis of later onsets of 0.4%Na-exposure resulted in decreased stroke-risk and later stroke-onsets, despite longer 0.4%Na-exposure durations, indicating increasing risk with earlier onsets of 0.4%Na-exposure. Histological analysis of stroke+rat brains revealed cerebral cortical hemorrhagic infarctions, microhemorrhages, neuronal ischemia, microvascular injury. Ex-vivo MRI of stroke+ rat brains detected cerebral hemorrhages, microhemorrhages and ischemia with middle cerebral artery-distribution, and cerebellar non-involvement. Ultrasound micro-imaging detected carotid artery disease. Pre-stroke analysis detected neuronal ischemia, and decreased mass of isolated cerebral, but not cerebellar, microvessels. Conclusions Early-life Na-exposure exacerbated hypertension and unmasked stroke susceptibility with greater female vulnerability in hypertensive-hyperlipidemic Tg25-rats. The reproducible modeling in Tg25sp rats of carotid artery disease, cerebral hemorrhagic-infarctions, neuronal ischemia, microhemorrhages, and microvascular alterations suggests a pathogenic spectrum with causal interrelationships. This “mixed-stroke” spectrum could represent paradigms of ischemic-hemorrhagic transformation, and/or a microangiopathic basis for the association of ischemic-lesions, microhemorrhages, and strokes in humans. Altogether, the data reveal early-life Na-exposure as a significant modifier of hypertension and stroke disease-course, hence a potential modifiable prevention target deserving systematic study. PMID:19273719

Budget impact analysis of thrombolysis for stroke in Spain: a discrete event simulation model.

PubMed

Mar, Javier; Arrospide, Arantzazu; Comas, Mercè

2010-01-01

Thrombolysis within the first 3 hours after the onset of symptoms of a stroke has been shown to be a cost-effective treatment because treated patients are 30% more likely than nontreated patients to have no residual disability. The objective of this study was to calculate by means of a discrete event simulation model the budget impact of thrombolysis in Spain. The budget impact analysis was based on stroke incidence rates and the estimation of the prevalence of stroke-related disability in Spain and its translation to hospital and social costs. A discrete event simulation model was constructed to represent the flow of patients with stroke in Spain. If 10% of patients with stroke from 2000 to 2015 would receive thrombolytic treatment, the prevalence of dependent patients in 2015 would decrease from 149,953 to 145,922. For the first 6 years, the cost of intervention would surpass the savings. Nevertheless, the number of cases in which patient dependency was avoided would steadily increase, and after 2006 the cost savings would be greater, with a widening difference between the cost of intervention and the cost of nonintervention, until 2015. The impact of thrombolysis on society's health and social budget indicates a net benefit after 6 years, and the improvement in health grows continuously. The validation of the model demonstrates the adequacy of the discrete event simulation approach in representing the epidemiology of stroke to calculate the budget impact.

Nitrogen dioxide (NO(2)) pollution as a potential risk factor for developing vascular dementia and its synaptic mechanisms.

PubMed

Li, Hongyan; Xin, Xiaoyun

2013-06-01

Recent epidemiological literatures reported that NO(2) is a potential risk factor of ischemic stroke in polluted area. Meanwhile, our previous in vivo study found that NO(2) could delay the recovery of nerve function after stroke, implying a possible risk of vascular dementia (VaD) with NO(2) inhalation, which is often a common cognitive complication resulting from stroke. However, the effect and detailed mechanisms have not been fully elucidated. In the present study, synaptic mechanisms, the foundation of neuronal function and viability, were investigated in both model rats of ischemic stroke and healthy rats after NO(2) exposure. Transmission electron microscope (TEM) observation showed that 5 mg m(-3) NO(2) exposure not only exacerbated the ultrastructural impairment of synapses in stroke model rats, but also induced neuronal damage in healthy rats. Meantime, we found that the expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), two structural markers of synapses in ischemic stroke model were inhibited by NO(2) inhalation; and so it was with the key proteins mediating long-term potentiation (LTP), the major form of synaptic plasticity. On the contrary, NO(2) inhalation induced the expression of nearly all these proteins in healthy rats in a concentration-dependent manner. Our results implied that NO(2) exposure could increase the risk of VaD through inducing excitotoxicity in healthy rats but weakening synaptic plasticity directly in stroke model rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

Severity and outcomes according to stroke etiology in patients under 50 years of age with ischemic stroke.

PubMed

Prefasi, Daniel; Martínez-Sánchez, Patricia; Fuentes, Blanca; Díez-Tejedor, Exuperio

2016-08-01

To analyze the association of stroke etiological subtypes with severity and outcomes at 3 and 12 months in patients ≤50 years. Observational study of patients admitted to a stroke unit (2007-2013). demographic data, vascular risk factors, comorbidities, severity on admission (NIHSS), and good functional outcome (mRS ≤ 1) at 3 and 12 months. We used multivariate analyses to evaluate the influence of stroke etiology on severity and outcomes. We included 214 patients, 58.3 % men, mean age 41.4 years. General linear models showed all etiologies were more severe than lacunar strokes (P < 0.05). Atherothrombotic strokes showed greater severity than those of undetermined and uncommon etiology, whereas cardioembolic strokes were more severe than cryptogenic. Taking into account specific etiologies, atherothrombotic strokes (B = 5.860; 95 % CI 2.979-8.751), cervical artery dissection (CAD) [B = 7.485; 95 % confidence interval (CI) 4.734-10.237], and atrial fibrillation (AF) strokes (B = 5.773; 95 % CI 2.704-8.132) were more severe than other etiologies. Logistic regression models showed that strokes of uncommon etiology, especially those not related to CAD, had a lower probability of good outcome at 3 months [odds ratio (OR) = 0.197; CI 95 % 0.044-0.873], whereas atherothrombotic strokes were associated with this probability at 12 months (OR = 0.187; 95 % CI 0.037-0.951; P = 0.007). In patients ≤50 years of age, strokes of atherothrombotic, cardioembolic (particularly those due to AF), and uncommon etiology had a greater severity than the rest. Furthermore, strokes of uncommon etiology, especially those different from CAD, decreased the probability of a good outcome at 3 months, as did atherothrombotic strokes at 1 year.

Differences Between US and UK Adults in Stroke Preparedness

PubMed Central

Ford, Gary A.; Morgenstern, Lewis B.; White, Martin; Sniehotta, Falko F.; Mackintosh, Joan E.; Gellert, Paul; Skolarus, Lesli E.

2015-01-01

Background and Purpose— Although time-dependent treatment is available, most people delay contacting emergency medical services for stroke. Given differences in the healthcare system and public health campaigns, exploring between-country differences in stroke preparedness may identify novel ways to increase acute stroke treatment. Methods— A survey was mailed to population-based samples in Ingham County, Michigan, US (n=2500), and Newcastle upon Tyne, UK (n=2500). Surveys included stroke perceptions and stroke/nonstroke scenarios to assess recognition and response to stroke. Between-country differences and associations with stroke preparedness were examined using t tests and linear mixed models. Results— Overall response rate was 27.4%. The mean age of participants was 55 years, and 58% were female. US participants were better in recognizing stroke (70% versus 63%, d=0.27) and were more likely to call emergency medical services (55% versus 52%, d=0.11). After controlling for demographics and comorbidities, US participants remained more likely to recognize stroke but were not more likely to respond appropriately. A greater belief that medical treatment can help with stroke and understanding of stroke was associated with improved stroke recognition and response. Conclusions— Overall, stroke recognition and response were moderate. US participants were modestly better at recognizing stroke, although there was little difference in response to stroke. Future stroke awareness interventions could focus more on stroke outcome expectations and developing a greater understanding of stroke among the public. PMID:26419968

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.

Pancreatic β-Cell Function and Prognosis of Nondiabetic Patients With Ischemic Stroke.

PubMed

Pan, Yuesong; Chen, Weiqi; Jing, Jing; Zheng, Huaguang; Jia, Qian; Li, Hao; Zhao, Xingquan; Liu, Liping; Wang, Yongjun; He, Yan; Wang, Yilong

2017-11-01

Pancreatic β-cell dysfunction is an important factor in the development of type 2 diabetes mellitus. This study aimed to estimate the association between β-cell dysfunction and prognosis of nondiabetic patients with ischemic stroke. Patients with ischemic stroke without a history of diabetes mellitus in the ACROSS-China (Abnormal Glucose Regulation in Patients with Acute Stroke across China) registry were included. Disposition index was estimated as computer-based model of homeostatic model assessment 2-β%/homeostatic model assessment 2-insulin resistance based on fasting C-peptide level. Outcomes included stroke recurrence, all-cause death, and dependency (modified Rankin Scale, 3-5) at 12 months after onset. Among 1171 patients, 37.2% were women with a mean age of 62.4 years. At 12 months, 167 (14.8%) patients had recurrent stroke, 110 (9.4%) died, and 184 (16.0%) had a dependency. The first quartile of the disposition index was associated with an increased risk of stroke recurrence (adjusted hazard ratio, 3.57; 95% confidence interval, 2.13-5.99) and dependency (adjusted hazard ratio, 2.30; 95% confidence interval, 1.21-4.38); both the first and second quartiles of the disposition index were associated with an increased risk of death (adjusted hazard ratio, 5.09; 95% confidence interval, 2.51-10.33; adjusted hazard ratio, 2.42; 95% confidence interval, 1.17-5.03) compared with the fourth quartile. Using a multivariable regression model with restricted cubic spline, we observed an L-shaped association between the disposition index and the risk of each end point. In this large-scale registry, β-cell dysfunction was associated with an increased risk of 12-month poor prognosis in nondiabetic patients with ischemic stroke. © 2017 American Heart Association, Inc.

Neuronal PirB Upregulated in Cerebral Ischemia Acts as an Attractive Theranostic Target for Ischemic Stroke.

PubMed

Wang, Jie; Zhang, Ying; Xia, Jing; Cai, Tingting; Du, Jiawei; Chen, Jinpeng; Li, Ping; Shen, Yuqing; Zhang, Aifeng; Fu, Bo; Gao, Xueren; Miao, Fenqin; Zhang, Jianqiong; Teng, Gaojun

2018-01-29

Ischemic stroke is a complex disease with multiple etiologies and clinical manifestations. Paired immunoglobulin-like receptor B (PirB), which is originally thought to function exclusively in the immune system, is now also known to be expressed by neurons. A growing number of studies indicate that PirB can inhibit neurite outgrowth and restrict neuronal plasticity. The aim of the study is to investigate whether PirB can be an attractive theranostic target for ischemic stroke. First, we investigated the spatial-temporal expression of PirB in multiple ischemic stroke models, including transient middle cerebral artery occlusion, photothrombotic cerebral cortex ischemia, and the neuronal oxygen glucose deprivation model. Then, anti-PirB immunoliposome nanoprobe was developed by thin-film hydration method and investigated its specific targeting in vitro and in vivo. Finally, soluble PirB ectodomain (sPirB) protein delivered by polyethylene glycol-modified nanoliposome was used as a therapeutic reagent for ischemic stroke by blocking PirB binding to its endogenous ligands. These results showed that PirB was significantly upregulated after cerebral ischemic injury in ischemic stroke models. Anti-PirB immunoliposome nanoprobe was successfully developed and specifically bound to PirB in vitro. There was accumulation of anti-PirB immunoliposome nanoprobe in the ischemic hemisphere in vivo. Soluble PirB ectodomains remarkably improved ischemic stroke model recovery by liposomal delivery system. These data indicated that PirB was a significant element in the pathological process of cerebral ischemia. Therefore, PirB may act as a novel theranostic target for ischemic stroke. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

The Influence of OLR1 and PCSK9 Gene Polymorphisms on Ischemic Stroke: Evidence from a Meta-Analysis

PubMed Central

Au, Anthony; Griffiths, Lyn R.; Cheng, Kian-Kai; Wee Kooi, Cheah; Irene, Looi; Keat Wei, Loo

2015-01-01

Both OLR1 and PCSK9 genes are associated with atherosclerosis, cardiovascular disease and ischemic stroke. The overall prevalence of PCSK9 rs505151 and OLR1 rs11053646 variants in ischemic stroke were 0.005 and 0.116, respectively. However, to date, association between these polymorphisms and ischemic stroke remains inconclusive. Therefore, this first meta-analysis was carried out to clarify the presumed influence of these polymorphisms on ischemic stroke. All eligible case-control and cohort studies that met the search terms were retrieved in multiple databases. Demographic and genotyping data were extracted from each study, and the meta-analysis was performed using RevMan 5.3 and Metafor R 3.2.1. The pooled odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed- and random-effect models. Seven case-control studies encompassing 1897 cases and 2119 controls were critically evaluated. Pooled results from the genetic models indicated that OLR1 rs11053646 dominant (OR = 1.33, 95%  CI:1.11–1.58) and co-dominant models (OR = 1.24, 95%  CI:1.02–1.51) were significantly associated with ischemic stroke. For the PCSK9 rs505151 polymorphism, the OR of co-dominant model (OR = 1.36, 95%  CI:1.01–1.58) was found to be higher among ischemic stroke patients. In conclusion, the current meta-analysis highlighted that variant allele of OLR1 rs11053646 G > C and PCSK9 rs505151 A > G may contribute to the susceptibility risk of ischemic stroke. PMID:26666837

Confirmatory Factor Analysis of the Validity of the SF-12 for Persons with and without a History of Stroke

PubMed Central

Okonkwo, Ozioma C.; Roth, David L.; Pulley, LeaVonne; Howard, George

2010-01-01

Purpose To assess the validity of the Physical and Mental Component Summary scores (PCS and MCS) of the 12-item Short Form Health Survey (SF-12), a measure of health-related quality of life (HRQoL), among persons with a history of stroke. Methods Persons with (n = 2,581) and without (n = 38,066) a reported history of stroke were enrolled in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Confirmatory factor analysis methods were used to evaluate the fit of a 2-factor model that underlies the PCS and MCS and to examine the equivalence of the factors across both study groups. Results The 2-factor model provided good fit to the data among individuals with and those without a self-reported history of stroke. Item factor loadings were found to be largely invariant across both groups, and correlational analyses confirmed that the two latent factors were highly related to the PCS and MCS scores, calculated by the standard scoring algorithms. The effect of stroke history on physical health was more than twice its effect on mental health. Conclusions The psychometric measurement model that underlies the PCS and MCS summary scores is comparable between persons with and without a history of stroke. This suggests that the SF-12 has adequate validity for measuring HRQoL not only in the general population, but also in cohorts following stroke. PMID:20567914

Serum S100B is a useful surrogate marker for long-term outcomes in photochemically-induced thrombotic stroke rat models.

PubMed

Tanaka, Yu; Koizumi, Chie; Marumo, Toshiyuki; Omura, Tomohiro; Yoshida, Shigeru

2007-08-02

In recent years, serum S100B has been used as a secondary endpoint in some clinical trials, in which serum S100B has successfully indicated the benefits or harm done by the tested agents. Compared to clinical stroke studies, few experimental stroke studies report using serum S100B as a surrogate marker for estimating the long-term effects of neuroprotectants. This study sought to observe serum S100B kinetics in PIT stroke models and to clarify the association between serum S100B and both final infarct volumes and long-term neurological outcomes. Furthermore, to demonstrate that early elevations in serum S100B reflect successful neuroprotective treatment, a pharmacological study was performed with a non-competitive NMDA glutamate receptor antagonist, MK-801. Serum S100B levels were significantly elevated after PIT stroke, reaching peak values 48 h after the onset and declining thereafter. Single measurements of serum S100B as early as 48 h after PIT stroke correlated significantly with final infarct volumes and long-term neurological outcomes. Elevated serum S100B was significantly attenuated by MK-801, correlating significantly with long-term beneficial effects of MK-801 on infarct volumes and neurological outcomes. Our results showed that single measurements of serum S100B 48 h after PIT stroke would serve as an early and simple surrogate marker for long-term evaluation of histological and neurological outcomes in PIT stroke rat models.

User experience of a centralized hyperacute stroke service: a prospective evaluation.

PubMed

Moynihan, Barry; Paul, Selina; Markus, Hugh S

2013-10-01

Centralizing hyperacute stroke unit (HASU) care services allows improved access to thrombolysis but could be associated with worse patient experience, particularly when early repatriation to a local stroke recovery unit occurs as this may result in discontinuity of care. A centralized model of care was introduced in London, United Kingdom, with 8 HASUs providing acute care for the whole 8.3 million population, with repatriation on day 3 to a local stroke recovery unit. The patient and carer experience of this model of care has not been previously reported. We undertook a prospective observational study of the new model of care in the South West London sector. Patient and carer experiences were evaluated using a modified Picker Questionnaire. Separate questionnaires were used for patients discharged directly home from the HASU, those repatriated to local stroke recovery units, and for carers of patients admitted to the HASU. Despite moving from a selected to nonselected admission pattern, thrombolysis rates increased from 6% to 9%. High satisfaction rates were reported among both patients and carers. Patients discharged directly home had higher satisfaction levels than those requiring repatriation to their local stroke unit, who were older and had more severe stroke. A total of 47% of carers expressed anxiety over the repatriation from the HASU back to the local stroke recovery unit, but few patients and carers reported an impact of this move on patient recovery. Centralized HASU care is associated with good levels of patient and carer satisfaction.

Finding mouse models of human lymphomas and leukemia's using the Jackson laboratory mouse tumor biology database.

PubMed

Begley, Dale A; Sundberg, John P; Krupke, Debra M; Neuhauser, Steven B; Bult, Carol J; Eppig, Janan T; Morse, Herbert C; Ward, Jerrold M

2015-12-01

Many mouse models have been created to study hematopoietic cancer types. There are over thirty hematopoietic tumor types and subtypes, both human and mouse, with various origins, characteristics and clinical prognoses. Determining the specific type of hematopoietic lesion produced in a mouse model and identifying mouse models that correspond to the human subtypes of these lesions has been a continuing challenge for the scientific community. The Mouse Tumor Biology Database (MTB; http://tumor.informatics.jax.org) is designed to facilitate use of mouse models of human cancer by providing detailed histopathologic and molecular information on lymphoma subtypes, including expertly annotated, on line, whole slide scans, and providing a repository for storing information on and querying these data for specific lymphoma models. Copyright © 2015 Elsevier Inc. All rights reserved.

Ischemia-Reperfusion Injury in Stroke

PubMed Central

Nour, May; Scalzo, Fabien; Liebeskind, David S.

2013-01-01

Despite ongoing advances in stroke imaging and treatment, ischemic and hemorrhagic stroke continue to debilitate patients with devastating outcomes at both the personal and societal levels. While the ultimate goal of therapy in ischemic stroke is geared towards restoration of blood flow, even when mitigation of initial tissue hypoxia is successful, exacerbation of tissue injury may occur in the form of cell death, or alternatively, hemorrhagic transformation of reperfused tissue. Animal models have extensively demonstrated the concept of reperfusion injury at the molecular and cellular levels, yet no study has quantified this effect in stroke patients. These preclinical models have also demonstrated the success of a wide array of neuroprotective strategies at lessening the deleterious effects of reperfusion injury. Serial multimodal imaging may provide a framework for developing therapies for reperfusion injury. PMID:25187778

A study on the influence of corona on currents and electromagnetic fields predicted by a nonlinear lightning return-stroke model

NASA Astrophysics Data System (ADS)

De Conti, Alberto; Silveira, Fernando H.; Visacro, Silvério

2014-05-01

This paper investigates the influence of corona on currents and electromagnetic fields predicted by a return-stroke model that represents the lightning channel as a nonuniform transmission line with time-varying (nonlinear) resistance. The corona model used in this paper allows the calculation of corona currents as a function of the radial electric field in the vicinity of the channel. A parametric study is presented to investigate the influence of corona parameters, such as the breakdown electric field and the critical electric field for the stable propagation of streamers, on predicted currents and electromagnetic fields. The results show that, regardless of the assumed corona parameters, the incorporation of corona into the nonuniform and nonlinear transmission line model under investigation modifies the model predictions so that they consistently reproduce most of the typical features of experimentally observed lightning electromagnetic fields and return-stroke speed profiles. In particular, it is shown that the proposed model leads to close vertical electric fields presenting waveforms, amplitudes, and decay with distance in good agreement with dart leader electric field changes measured in triggered lightning experiments. A comparison with popular engineering return-stroke models further confirms the model's ability to predict consistent electric field waveforms in the close vicinity of the channel. Some differences observed in the field amplitudes calculated with the different models can be related to the fact that current distortion, while present in the proposed model, is ultimately neglected in the considered engineering return-stroke models.

Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

PubMed

Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

2015-07-15

Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path forward to critically evaluate and improve animal models of human disease. Copyright © 2015 Elsevier B.V. All rights reserved.

The risk of paradoxical embolism (RoPE) study: initial description of the completed database.

PubMed

Thaler, David E; Di Angelantonio, Emanuele; Di Tullio, Marco R; Donovan, Jennifer S; Griffith, John; Homma, Shunichi; Jaigobin, Cheryl; Mas, Jean-Louis; Mattle, Heinrich P; Michel, Patrik; Mono, Marie-Luise; Nedeltchev, Krassen; Papetti, Federica; Ruthazer, Robin; Serena, Joaquín; Weimar, Christian; Elkind, Mitchell S V; Kent, David M

2013-12-01

Detecting a benefit from closure of patent foramen ovale in patients with cryptogenic stroke is hampered by low rates of stroke recurrence and uncertainty about the causal role of patent foramen ovale in the index event. A method to predict patent foramen ovale-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence. The aim of this study was to develop a database to support modeling of patent foramen ovale-attributable recurrence risk by combining extant data sets. We identified investigators with extant databases including subjects with cryptogenic stroke investigated for patent foramen ovale, determined the availability and characteristics of data in each database, collaboratively specified the variables to be included in the Risk of Paradoxical Embolism database, harmonized the variables across databases, and collected new primary data when necessary and feasible. The Risk of Paradoxical Embolism database has individual clinical, radiologic, and echocardiographic data from 12 component databases, including subjects with cryptogenic stroke both with (n = 1925) and without (n = 1749) patent foramen ovale. In the patent foramen ovale subjects, a total of 381 outcomes (stroke, transient ischemic attack, death) occurred (median follow-up 2·2 years). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling. While individual studies are inadequate for modeling patent foramen ovale-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a patent foramen ovale-related stroke recurrence who may have the greatest potential benefit from patent foramen ovale closure. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

A History of Falls is Associated with a Significant Increase in Acute Mortality in Women after Stroke.

PubMed

Foster, Emma J; Barlas, Raphae S; Wood, Adrian D; Bettencourt-Silva, Joao H; Clark, Allan B; Metcalf, Anthony K; Bowles, Kristian M; Potter, John F; Myint, Phyo K

2017-10-01

The risks of falls and fractures increase after stroke. Little is known about the prognostic significance of previous falls and fractures after stroke. This study examined whether having a history of either event is associated with poststroke mortality. We analyzed stroke register data collected prospectively between 2003 and 2015. Eight sex-specific models were analyzed, to which the following variables were incrementally added to examine their potential confounding effects: age, type of stroke, Oxfordshire Community Stroke Project classification, previous comorbidities, frailty as indicated by the prestroke modified Rankin Scale score, and acute illness parameters. Logistic regression was applied to investigate in-hospital and 30-day mortality, and Cox proportional-hazards models were applied to investigate longer-term outcomes of mortality. In total, 10,477 patients with stroke (86.1% ischemic) were included in the analysis. They were aged 77.7±11.9 years (mean±SD), and 52.2% were women. A history of falls was present in 8.6% of the men (n=430) and 20.2% of the women (n=1,105), while 3.8% (n=189) of the men and 12.9% of the women (n=706) had a history of both falls and fractures. Of the outcomes examined, a history of falls alone was associated with increased in-hospital mortality [odds ratio (OR)=1.33, 95% confidence interval (CI)=1.03-1.71] and 30-day mortality (OR=1.34, 95% CI=1.03-1.73) in women in the fully adjusted models. The Cox proportional-hazards models for longer-term outcomes and the history of falls and fractures combined showed no significant results. The history of falls is an important factor for acute stroke mortality in women. A previous history of falls may therefore be an important factor to consider in the short-term stroke prognosis, particularly in women. Copyright © 2017 Korean Neurological Association

Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings.

PubMed

Feng, Dayun; Wang, Bao; Wang, Lei; Abraham, Neeta; Tao, Kai; Huang, Lu; Shi, Wei; Dong, Yushu; Qu, Yan

2017-04-01

Melatonin has demonstrated a potential protective effect in central nervous system. Thus, it is interesting to determine whether pre-ischemia melatonin administration could protect against cerebral ischemia/reperfusion (IR)-related injury and the underlying molecular mechanisms. In this study, we revealed that IR injury significantly activated endoplasmic reticulum (ER) stress and autophagy in a middle cerebral artery occlusion mouse model. Pre-ischemia melatonin treatment was able to attenuate IR-induced ER stress and autophagy. In addition, with tandem RFP-GFP-LC3 adeno-associated virus, we demonstrated pre-ischemic melatonin significantly alleviated IR-induced autophagic flux. Furthermore, we showed that IR induced neuronal apoptosis through ER stress related signalings. Moreover, IR-induced autophagy was significantly blocked by ER stress inhibitor (4-PBA), as well as ER-related signaling inhibitors (PERK inhibitor, GSK; IRE1 inhibitor, 3,5-dibromosalicylaldehyde). Finally, we revealed that melatonin significantly alleviated cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency, which were remarkably abolished by tunicamycin (ER stress activator) and rapamycin (autophagy activator), respectively. In summary, our study provides strong evidence that pre-ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress-dependent autophagy. Our findings shed light on the novel preventive and therapeutic strategy of daily administration of melatonin, especially among the population with high risk of cerebral ischemic stroke. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

In vivo flow cytometry of circulating clots using negative photothermal and photoacoustic contrasts.

PubMed

Galanzha, Ekaterina I; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A; Keyrouz, Salah G; Mehta, Jawahar L; Zharov, Vladimir P

2011-10-01

Conventional photothermal (PT) and photoacousic (PA) imaging, spectroscopy, and cytometry are preferentially based on positive PT/PA effects, when signals are above background. Here, we introduce PT/PA technique based on detection of negative signals below background. Among various new applications, we propose label-free in vivo flow cytometry of circulating clots. No method has been developed for the early detection of clots of different compositions as a source of thromboembolism including ischemia at strokes and myocardial infarction. When a low-absorbing, platelet-rich clot passes a laser-irradiated vessel volume, a transient decrease in local absorption results in an ultrasharp negative PA hole in blood background. Using this phenomenon alone or in combination with positive contrasts, we demonstrated identification of white, red, and mixed clots on a mouse model of myocardial infarction and human blood. The concentration and size of clots were measured with threshold down to few clots in the entire circulation with size as low as 20 μm. This multiparameter diagnostic platform using portable personal high-speed flow cytometer with negative dynamic contrast mode has potential to real-time defining risk factors for cardiovascular diseases, and for prognosis and prevention of stroke or use clot count as a marker of therapy efficacy. Possibility for label-free detection of platelets, leukocytes, tumor cells or targeting themby negative PA probes (e.g., nonabsorbing beads or bubbles) is also highlighted. Copyright © 2011 International Society for Advancement of Cytometry.

In vivo flow cytometry of circulating clots using negative phototothermal and photoacoustic contrasts

PubMed Central

Galanzha, Ekaterina I.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Keyrouz, Salah G.; Mehta, Jawahar L.; Zharov, Vladimir P.

2012-01-01

Conventional photothermal (PT) and photoacousic (PA) imaging, spectroscopy, and cytometry are preferentially based on positive PT/PA effects, when signals are above background. Here, we introduce PT/PA technique based on detection of negative signals below background. Among various new applications, we propose label-free in vivo flow cytometry of circulating clots. No method has been developed for the early detection of clots of different compositions as a source of severe thromboembolisms including ischemia at strokes and myocardial dysfunction at heart attack. When a low-absorbing, platelet-rich clot passes a laser-irradiated vessel volume, a transient decrease in local absorption results in an ultrasharp negative PA hole in blood background. Using this phenomenon alone or in combination with positive contrasts, we demonstrated identification of white, red and mixed clots on a mouse model of myocardial infarction and human blood. The concentration and size of clots were measured with threshold down to few clots in the entire circulation with size as low as 20 µm. This multiparameter diagnostic platform using portable personal high-speed flow cytometer with negative dynamic contrast mode has potential to real-time defining risk factors for cardiovascular diseases, and for prognosis and prevention of stroke or use clot count as a marker of therapy efficacy. Possibility for label-free detection of platelets, leukocytes, tumor cells or targeting them by negative PA probes (e.g., nonabsorbing beads or bubbles) is also highlighted. PMID:21976458

Automated touch sensing in the mouse tapered beam test using Raspberry Pi.

PubMed

Ardesch, Dirk Jan; Balbi, Matilde; Murphy, Timothy H

2017-11-01

Rodent models of neurological disease such as stroke are often characterized by motor deficits. One of the tests that are used to assess these motor deficits is the tapered beam test, which provides a sensitive measure of bilateral motor function based on foot faults (slips) made by a rodent traversing a gradually narrowing beam. However, manual frame-by-frame scoring of video recordings is necessary to obtain test results, which is time-consuming and prone to human rater bias. We present a cost-effective method for automated touch sensing in the tapered beam test. Capacitive touch sensors detect foot faults onto the beam through a layer of conductive paint, and results are processed and stored on a Raspberry Pi computer. Automated touch sensing using this method achieved high sensitivity (96.2%) as compared to 'gold standard' manual video scoring. Furthermore, it provided a reliable measure of lateralized motor deficits in mice with unilateral photothrombotic stroke: results indicated an increased number of contralesional foot faults for up to 6days after ischemia. The automated adaptation of the tapered beam test produces results immediately after each trial, without the need for labor-intensive post-hoc video scoring. It also increases objectivity of the data as it requires less experimenter involvement during analysis. Automated touch sensing may provide a useful adaptation to the existing tapered beam test in mice, while the simplicity of the hardware lends itself to potential further adaptations to related behavioral tests. Copyright © 2017 Elsevier B.V. All rights reserved.

Pollution dilemma in Asian population: CNG and wound healing.

PubMed

Ejaz, Sohail; Chekarova, Irina; Ahmad, Mukhtar; Nasir, Amir; Ashraf, Muhammad; Lim, Chae Woong

2009-11-01

Automobile exhaust constituents contribute significantly to air pollution in urban areas and compressed natural gas (CNG) is considered one of the most promising fuel alternatives for the future. CNG-powered four-stroke engine auto-rickshaws are ubiquitous in South Asian cities as taxi and for commercial transportation. Automotive exhaust contains several toxins, which are overwhelmingly toxic to the processes of wound healing. By utilizing the in vivo mouse model of wound healing, this report analyzes the effects of CNG-powered four-stroke auto-rickshaws smoke solution (4SARSS) on different events of wound healing; dermal matrix regeneration, re-epithelialization and neovascularization. A total of 72 adult mice, divided in eight groups were exposed to 4SARSS for 12 days. A highly significant reduction (P<0.001) in wound closure was observed among all 4SARSS treated groups, at each time point of the experiment. An immature development in both the neoepidermis and the neodermis was observed among all 4SARSS treated wounds with defective re-epithelialization, dermal matrix regeneration and maturation of collagen bundles. Abbott curve, angular spectrum, 3D surface topographies, and histological investigations of wounds explicated highly significant activation (P<0.001) of delayed-neovascularization among 4SARSS treated wounds. All these annotations advocate excessive toxicity of emission from CNG-powered auto-rickshaws to the process of wound healing and people occupationally exposed to this toxic emissions may suffer varying degree of delayed wound healing. Crown Copyright © 2009. Published by Elsevier B.V. All rights reserved.

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

Do Women With Atrial Fibrillation Experience More Severe Strokes? Results From the Austrian Stroke Unit Registry.

PubMed

Lang, Clemens; Seyfang, Leonhard; Ferrari, Julia; Gattringer, Thomas; Greisenegger, Stefan; Willeit, Karin; Toell, Thomas; Krebs, Stefan; Brainin, Michael; Kiechl, Stefan; Willeit, Johann; Lang, Wilfried; Knoflach, Michael

2017-03-01

Ischemic strokes associated with atrial fibrillation (AF) are more severe than those of other cause. We aim to study potential sex effects in this context. In this cross-sectional study, 74 425 adults with acute ischemic stroke from the Austrian Stroke Unit Registry were included between March 2003 and January 2016. In 63 563 patients, data on the National Institutes of Health Stroke Scale on admission to the stroke unit, presence of AF, vascular risk factors, and comorbidities were complete. Analysis was done by a multivariate regression model. Stroke severity in general increased with age. AF-related strokes were more severe than strokes of other causes. Sex-related differences in stroke severity were only seen in stroke patients with AF. Median (Q 25 , 75 ) National Institutes of Health Stroke Scale score points were 9 (4,17) in women and 6 (3,13) in men ( P <0.001). The interaction between AF and sex on stroke severity was independent of age, previous functional status, vascular risk factors, and vascular comorbidities and remained significant in various subgroups. Women with AF do not only have an increased risk of stroke when compared with men but also experience more severe strokes. © 2017 American Heart Association, Inc.

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

A prognostic role for Low tri-iodothyronine syndrome in acute stroke patients: A systematic review and meta-analysis.

PubMed

Lamba, Nayan; Liu, Chunming; Zaidi, Hasan; Broekman, M L D; Simjian, Thomas; Shi, Chen; Doucette, Joanne; Ren, Steven; Smith, Timothy R; Mekary, Rania A; Bunevicius, Adomas

2018-06-01

Low triiodothyronine (T3) syndrome could be a powerful prognostic factor for acute stroke; yet, a prognostic role for low T3 has not been given enough importance in stroke management. This meta-analysis aimed to evaluate whether low T3 among acute stroke patients could be used as a prognostic biomarker for stroke severity, functional outcome, and mortality. Studies that investigated low T3 prognostic roles in acute stroke patients were sought from PubMed/Medline, Embase, and Cochrane databases through 11/23/2016. Pooled estimates of baseline stroke severity, mortality, and functional outcomes were assessed from fixed-effect (FE) and random-effects (RE) models. Eighteen studies met the inclusion criteria. Six studies (1,203 patients) provided data for low-T3 and normal-T3 patients and were meta-analyzed. Using the FE model, pooled results revealed low-T3 patients exhibited a significantly higher stroke severity, as assessed by the National Institutes of Health Stroke Scale (NIHSS) score at admission (mean difference = 3.18; 95%CI = 2.74, 3.63; I 2  = 61.9%), had 57% higher risk of developing poor functional outcome (RR = 1.57; 95%CI = 1.33,1.8), and had 83% higher odds of mortality (Peto-OR = 1.83; 95%CI = 1.21, 1.99) compared to normal-T3 patients. In a univariate meta-regression analysis, the low-T3 and stroke severity association was reduced in studies with higher smokers% (slope = -0.11; P = 0.02), higher hypertension% (slope = -0.11; P = 0.047), older age (slope = -0.54; P = 0.02), or longer follow-up (slope = -0/17, P < 0.01). RE models yielded similar results. No significant publication bias was observed for either outcome using Begg's and Egger's tests. Low-T3 syndrome in acute stroke patients is an effective prognostic factor for predicting greater baseline stroke severity, poorer functional outcome, and higher overall mortality risk. Copyright © 2018 Elsevier B.V. All rights reserved.

Window Of Opportunity: Estrogen As A Treatment For Ischemic Stroke✰

PubMed Central

Liu, Ran; Yang, Shao-Hua

2013-01-01

The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue plasminogen activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the “critical period” and newly emerged “biomarkers window” hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials. PMID:23340160

From dictatorship to a reluctant democracy: stroke therapists talking about self-management

PubMed Central

Kilbride, Cherry

2014-01-01

Purpose Self-management is being increasingly promoted within chronic conditions including stroke. Concerns have been raised regarding professional ownership of some programmes, yet little is known of the professional’s experience. This paper aims to present the views of trained therapists about the utility of a specific self-management approach in stroke rehabilitation. Method Eleven stroke therapists trained in the self-management approach participated in semi-structured interviews. These were audio recorded, transcribed verbatim and analysed thematically. Results Two overriding themes emerged. The first was the sense that in normal practice therapists act as “benign dictators”, committed to help their patients, but most comfortable when they, the professional, are in control. Following the adoption of the self-management approach therapists challenged themselves to empower stroke survivors to take control of their own recovery. However, therapists had to confront many internal and external challenges in this transition of power resulting in the promotion of a somewhat “reluctant democracy”. Conclusions This study illustrates that stroke therapists desire a more participatory approach to rehabilitation. However, obstacles challenged the successful delivery of this goal. If self-management is an appropriate model to develop in post stroke pathways, then serious consideration must be given to how and if these obstacles can be overcome. Implications for Rehabilitation Stroke therapists perceive that self-management is appropriate for encouraging ownership of rehabilitation post stroke. Numerous obstacles were identified as challenging the implementation of self-management post stroke. These included: professional models, practices and expectations; institutional demands and perceived wishes of stroke survivors. For self-management to be effectively implemented by stroke therapists, these obstacles must be considered and overcome. This should be as part of an integrated therapy service, rather than as an add-on. PMID:23594054

From dictatorship to a reluctant democracy: stroke therapists talking about self-management.

PubMed

Norris, Meriel; Kilbride, Cherry

2014-01-01

Self-management is being increasingly promoted within chronic conditions including stroke. Concerns have been raised regarding professional ownership of some programmes, yet little is known of the professional's experience. This paper aims to present the views of trained therapists about the utility of a specific self-management approach in stroke rehabilitation. Eleven stroke therapists trained in the self-management approach participated in semi-structured interviews. These were audio recorded, transcribed verbatim and analysed thematically. Two overriding themes emerged. The first was the sense that in normal practice therapists act as "benign dictators", committed to help their patients, but most comfortable when they, the professional, are in control. Following the adoption of the self-management approach therapists challenged themselves to empower stroke survivors to take control of their own recovery. However, therapists had to confront many internal and external challenges in this transition of power resulting in the promotion of a somewhat "reluctant democracy". This study illustrates that stroke therapists desire a more participatory approach to rehabilitation. However, obstacles challenged the successful delivery of this goal. If self-management is an appropriate model to develop in post stroke pathways, then serious consideration must be given to how and if these obstacles can be overcome. Stroke therapists perceive that self-management is appropriate for encouraging ownership of rehabilitation post stroke. Numerous obstacles were identified as challenging the implementation of self-management post stroke. These included: professional models, practices and expectations; institutional demands and perceived wishes of stroke survivors. For self-management to be effectively implemented by stroke therapists, these obstacles must be considered and overcome. This should be as part of an integrated therapy service, rather than as an add-on.

Persistent post-stroke depression in mice following unilateral medial prefrontal cortical stroke

PubMed Central

Vahid-Ansari, F; Lagace, D C; Albert, P R

2016-01-01

Post-stroke depression (PSD) is a common outcome following stroke that is associated with poor recovery. To develop a preclinical model of PSD, we targeted a key node of the depression–anxiety circuitry by inducing a unilateral ischemic lesion to the medial prefrontal cortex (mPFC) stroke. Microinjection of male C57/BL6 mice with endothelin-1 (ET-1, 1600 pmol) induced a small (1 mm3) stroke consistently localized within the left mPFC. Compared with sham control mice, the stroke mice displayed a robust behavioral phenotype in four validated tests of anxiety including the elevated plus maze, light–dark, open-field and novelty-suppressed feeding tests. In addition, the stroke mice displayed depression-like behaviors in both the forced swim and tail suspension test. In contrast, there was no effect on locomotor activity or sensorimotor function in the horizontal ladder, or cylinder and home cage activity tests, indicating a silent stroke due to the absence of motor abnormalities. When re-tested at 6 weeks post stroke, the stroke mice retained both anxiety and depression phenotypes. Surprisingly, at 6 weeks post stroke the lesion site was infiltrated by neurons, suggesting that the ET-1-induced neuronal loss in the mPFC was reversible over time, but was insufficient to promote behavioral recovery. In summary, unilateral ischemic lesion of the mPFC results in a pronounced and persistent anxiety and depression phenotype with no evident sensorimotor deficits. This precise lesion of the depression circuitry provides a reproducible model to study adaptive cellular changes and preclinical efficacy of novel interventions to alleviate PSD symptoms. PMID:27483381

Ethnic comparison of 30-day potentially preventable readmissions after stroke in Hawaii

PubMed Central

Nakagawa, Kazuma; Ahn, Hyeong Jun; Taira ScD, Deborah A.; Miyamura, Jill; Sentell, Tetine L.

2016-01-01

Background and Purpose Ethnic disparities in readmission after stroke have been inadequately studied. We sought to compare potentially preventable readmissions (PPR) among a multiethnic population in Hawaii. Methods Hospitalization data in Hawaii from 2007-2012 were assessed to compare ethnic differences in 30-day PPR following stroke-related hospitalizations. Multivariable models using logistic regression were performed to assess the impact of ethnicity on 30-day PPR after controlling for age group (<65, ≥65 years), sex, insurance, county of residence, substance use, history of mental illness and Charlson Comorbidity Index (CCI). Results Thirty-day PPR was seen in 840 (8.4%) of 10,050 any stroke-related hospitalizations, 712 (8.7%) of 8,161 ischemic stroke hospitalizations, and 128 (6.8%) of 1,889 hemorrhagic stroke hospitalizations. In the multivariable models, only the Chinese ethnicity, compared to whites, was associated with 30-day PPR after any stroke hospitalizations (OR [95% CI]: 1.40 [1.05, 1.88]) and ischemic stroke hospitalizations (1.42 [1.04, 1.96]). When considering only one hospitalization per individual, the impact of Chinese ethnicity on PPR after any stroke hospitalization (1.22 [0.89, 1.68]) and ischemic stroke hospitalization (1.21 [0.86, 1.71]) were attenuated. Other factors associated with 30-day PPR after any stroke hospitalizations were CCI [per unit increase] (1.21 [1.18, 1.24]), Medicaid (1.42 [1.07, 1.88]), Hawaii county (0.78 [0.62, 0.97]), and mental illness (1.37 [1.10, 1.70]). Conclusion In Hawaii, Chinese may have a higher risk of 30-day PPR after stroke compared to whites. However, this appears to be driven by the high number of repeated PPR within the Chinese ethnic group. PMID:27608816

Dietary Sodium to Potassium Ratio and Risk of Stroke in a Multiethnic Urban Population: The Northern Manhattan Study.

PubMed

Willey, Joshua; Gardener, Hannah; Cespedes, Sandino; Cheung, Ying K; Sacco, Ralph L; Elkind, Mitchell S V

2017-11-01

There is growing evidence that increased dietary sodium (Na) intake increases the risk of vascular diseases, including stroke, at least in part via an increase in blood pressure. Higher dietary potassium (K), seen with increased intake of fruits and vegetables, is associated with lower blood pressure. The goal of this study was to determine the association of a dietary Na:K with risk of stroke in a multiethnic urban population. Stroke-free participants from the Northern Manhattan Study, a population-based cohort study of stroke incidence, were followed-up for incident stroke. Baseline food frequency questionnaires were analyzed for Na and K intake. We estimated the hazard ratios and 95% confidence intervals for the association of Na:K with incident total stroke using multivariable Cox proportional hazards models. Among 2570 participants with dietary data (mean age, 69±10 years; 64% women; 21% white; 55% Hispanic; 24% black), the mean Na:K ratio was 1.22±0.43. Over a mean follow-up of 12 years, there were 274 strokes. In adjusted models, a higher Na:K ratio was associated with increased risk for stroke (hazard ratio, 1.6; 95% confidence interval, 1.2-2.1) and specifically ischemic stroke (hazard ratio, 1.6; 95% confidence interval, 1.2-2.1). Na:K intake is an independent predictor of stroke risk. Further studies are required to understand the joint effect of Na and K intake on risk of cardiovascular disease. © 2017 American Heart Association, Inc.

Brain natriuretic peptide predicts functional outcome in ischemic stroke

PubMed Central

Rost, Natalia S; Biffi, Alessandro; Cloonan, Lisa; Chorba, John; Kelly, Peter; Greer, David; Ellinor, Patrick; Furie, Karen L

2011-01-01

Background Elevated serum levels of brain natriuretic peptide (BNP) have been associated with cardioembolic (CE) stroke and increased post-stroke mortality. We sought to determine whether BNP levels were associated with functional outcome after ischemic stroke. Methods We measured BNP in consecutive patients aged ≥18 years admitted to our Stroke Unit between 2002–2005. BNP quintiles were used for analysis. Stroke subtypes were assigned using TOAST criteria. Outcomes were measured as 6-month modified Rankin Scale score (“good outcome” = 0–2 vs. “poor”) as well as mortality. Multivariate logistic regression was used to assess association between the quintiles of BNP and outcomes. Predictive performance of BNP as compared to clinical model alone was assessed by comparing ROC curves. Results Of 569 ischemic stroke patients, 46% were female; mean age was 67.9 ± 15 years. In age- and gender-adjusted analysis, elevated BNP was associated with lower ejection fraction (p<0.0001) and left atrial dilatation (p<0.001). In multivariate analysis, elevated BNP decreased the odds of good functional outcome (OR 0.64, 95%CI 0.41–0.98) and increased the odds of death (OR 1.75, 95%CI 1.36–2.24) in these patients. Addition of BNP to multivariate models increased their predictive performance for functional outcome (p=0.013) and mortality (p<0.03) after CE stroke. Conclusions Serum BNP levels are strongly associated with CE stroke and functional outcome at 6 months after ischemic stroke. Inclusion of BNP improved prediction of mortality in patients with CE stroke. PMID:22116811

Mobile Interventional Stroke Teams Lead to Faster Treatment Times for Thrombectomy in Large Vessel Occlusion.

PubMed

Wei, Daniel; Oxley, Thomas J; Nistal, Dominic A; Mascitelli, Justin R; Wilson, Natalie; Stein, Laura; Liang, John; Turkheimer, Lena M; Morey, Jacob R; Schwegel, Claire; Awad, Ahmed J; Shoirah, Hazem; Kellner, Christopher P; De Leacy, Reade A; Mayer, Stephan A; Tuhrim, Stanley; Paramasivam, Srinivasan; Mocco, J; Fifi, Johanna T

2017-12-01

Endovascular recanalization treatment for acute ischemic stroke is a complex, time-sensitive intervention. Trip-and-treat is an interhospital service delivery model that has not previously been evaluated in the literature and consists of a shared mobile interventional stroke team that travels to primary stroke centers to provide on-site interventional capability. We compared treatment times between the trip-and-treat model and the traditional drip-and-ship model. We performed a retrospective analysis on 86 consecutive eligible patients with acute ischemic stroke secondary to large vessel occlusion who received endovascular treatment at 4 hospitals in Manhattan. Patients were divided into 2 cohorts: trip-and-treat (n=39) and drip-and-ship (n=47). The primary outcome was initial door-to-puncture time, defined as the time between arrival at any hospital and arterial puncture. We also recorded and analyzed the times of last known well, IV-tPA (intravenous tissue-type plasminogen activator) administration, transfer, and reperfusion. Mean initial door-to-puncture time was 143 minutes for trip-and-treat and 222 minutes for drip-and-ship ( P <0.0001). Although there was a trend in longer puncture-to-recanalization times for trip-and-treat ( P =0.0887), initial door-to-recanalization was nonetheless 79 minutes faster for trip-and-treat ( P <0.0001). There was a trend in improved admission-to-discharge change in National Institutes of Health Stroke Scale for trip-and-treat compared with drip-and-ship ( P =0.0704). Compared with drip-and-ship, the trip-and-treat model demonstrated shorter treatment times for endovascular therapy in our series. The trip-and-treat model offers a valid alternative to current interhospital stroke transfers in urban environments. © 2017 American Heart Association, Inc.

Induction and imaging of photothrombotic stroke in conscious and freely moving rats

NASA Astrophysics Data System (ADS)

Lu, Hongyang; Li, Yao; Yuan, Lu; Li, Hangdao; Lu, Xiaodan; Tong, Shanbao

2014-09-01

In experimental stroke research, anesthesia is common and serves as a major reason for translational failure. Real-time cerebral blood flow (CBF) monitoring during stroke onset can provide important information for the prediction of brain injury; however, this is difficult to achieve in clinical practice due to various technical problems. We created a photothrombotic focal ischemic stroke model utilizing our self-developed miniature headstage in conscious and freely moving rats. In this model, a high spatiotemporal resolution imager using laser speckle contrast imaging technology was integrated to acquire real-time two-dimensional CBF information during thrombosis. The feasibility, stability, and reliability of the system were tested in terms of CBF, behavior, and T2-weighted magnetic resonance imaging (MRI) findings. After completion of occlusion, the CBF in the targeted cortex of the stroke group was reduced to 16±9% of the baseline value. The mean infarct volume measured by MRI 24 h postmodeling was 77±11 mm3 and correlated well with CBF (R2=0.74). This rodent model of focal cerebral ischemia and real-time blood flow imaging opens the possibility of performing various fundamental and translational studies on stroke without the influence of anesthetics.

Considerations for the Optimization of Induced White Matter Injury Preclinical Models

PubMed Central

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

2015-01-01

White matter (WM) injury in relation to acute neurologic conditions, especially stroke, has remained obscure until recently. Current advances in imaging technologies in the field of stroke have confirmed that WM injury plays an important role in the prognosis of stroke and suggest that WM protection is essential for functional recovery and post-stroke rehabilitation. However, due to the lack of a reproducible animal model of WM injury, the pathophysiology and mechanisms of this injury are not well studied. Moreover, producing selective WM injury in animals, especially in rodents, has proven to be challenging. Problems associated with inducing selective WM ischemic injury in the rodent derive from differences in the architecture of the brain, most particularly, the ratio of WM to gray matter in rodents compared to humans, the agents used to induce the injury, and the location of the injury. Aging, gender differences, and comorbidities further add to this complexity. This review provides a brief account of the techniques commonly used to induce general WM injury in animal models (stroke and non-stroke related) and highlights relevance, optimization issues, and translational potentials associated with this particular form of injury. PMID:26322013

Improved survival after stroke: is admission to hospital the major explanation? Trend analyses of the Auckland Regional Community Stroke Studies.

PubMed

Carter, Kristie N; Anderson, Craig S; Hackett, Maree L; Barber, P Alan; Bonita, Ruth

2007-01-01

There is uncertainty regarding the impact of changes in stroke care and natural history of stroke in the community. We examined factors responsible for trends in survival after stroke in a series of population-based studies. We used statistical models to assess temporal trends in 28-day and 1-year case fatality after first-ever stroke cases registered in 3 stroke incidence studies undertaken in Auckland, New Zealand, over uniform 12-month calendar periods in 1981-1982 (n = 1,030), 1991-1992 (1,305) and 2001-2002 (1,423). Cox proportional hazards regression was used to evaluate the significance of pre-defined 'patient', 'disease' and 'service/care' factors on these trends. Overall, there was a 40% decline in 28-day case fatality after stroke over the study periods, from 32% (95% confidence interval, 29-35%) in 1981-1982 to 23% (21-25%) in 1991-1992 and then 19% (17-21%) in 2002-2003. Similar relative declines were seen in 1-year case fatality. In regression models, the trends were still significant after adjusting for patient and disease factors. However, further adjustment for care factors (higher hospital admission and neuroimaging) explained most of the improvement in survival. These data show significant downwards trends in case fatality after stroke in Auckland over 20 years, which can largely be attributed to improved stroke care associated with increases in hospital admission and brain imaging during the acute phase of the illness.

Green and black tea consumption and risk of stroke: a meta-analysis.

PubMed

Arab, Lenore; Liu, Weiqing; Elashoff, David

2009-05-01

Experimental models of stroke provide consistent evidence of smaller stroke volumes in animals ingesting tea components or tea extracts. To assess whether a similar association of black or green tea consumption with reduced risk is evident in human populations, we sought to identify and summarize all human clinical and observational data on tea and stroke. We searched PubMed and Web of Science for all studies on stroke and tea consumption in humans with original data, including estimation or measurement of tea consumption and outcomes of fatal or nonfatal stroke. Data from 9 studies involving 4378 strokes among 194 965 individuals were pooled. The main outcome was the occurrence of fatal or nonfatal stroke. We tested for heterogeneity and calculated the summary effect estimate associated with consumption of >or=3 cups of tea (green or black) per day using random-effects and fixed-effects models for the homogeneous studies. Publication bias was also evaluated. Regardless of their country of origin, individuals consuming >or=3 cups of tea per day had a 21% lower risk of stroke than those consuming <1 cup per day (absolute risk reduction, 0.79; CI, 0.73 to 0.85). The proportion of heterogeneity not explained by chance alone was 23.8%. Although a randomized clinical trial would be necessary to confirm the effect, this meta-analysis suggests that daily consumption of either green or black tea equaling 3 cups per day could prevent the onset of ischemic stroke.

Determination of the myosin step size from mechanical and kinetic data.

PubMed Central

Pate, E; White, H; Cooke, R

1993-01-01

During muscle contraction, work is generated when a myosin cross-bridge attaches to an actin filament and exerts a force on it through some power-stroke distance, h. At the end of this power stroke, attached myosin heads are carried into regions where they exert a negative force on the actin filament (the drag stroke) and where they are released rapidly from actin by ATP binding. Although the length of the power stroke remains controversial, average distance traversed in the drag-stroke region can be determined when one knows both rate of cross-bridge dissociation and filament-sliding velocity. At maximum contraction velocity, the average force exerted in the drag stroke must balance that exerted in the power stroke. We discuss here a simple model of cross-bridge interaction that allows one to calculate the force exerted in the drag stroke and to relate this to the power-stroke distance h traversed by cross-bridges in the positive-force region. Both the rate at which myosin can be dissociated from actin and the velocity at which an actin filament can be translated have been measured for a series of myosin isozymes and for different substrates, producing a wide range of values for each. Nonetheless, we show here that the rate of myosin dissociation from actin correlates well with the velocity of filament sliding, providing support for the simple model presented and suggesting that the power stroke is approximately 10 nm in length. PMID:8460156

Differentiating the effects of characteristics of PM pollution on mortality from ischemic and hemorrhagic strokes.

PubMed

Lin, Hualiang; Tao, Jun; Du, Yaodong; Liu, Tao; Qian, Zhengmin; Tian, Linwei; Di, Qian; Zeng, Weilin; Xiao, Jianpeng; Guo, Lingchuan; Li, Xing; Xu, Yanjun; Ma, Wenjun

2016-03-01

Though increasing evidence supports significant association between particulate matter (PM) air pollution and stroke, it remains unclear what characteristics, such as particle size and chemical constituents, are responsible for this association. A time-series model with quasi-Poisson function was applied to assess the association of PM pollution with different particle sizes and chemical constituents with mortalities from ischemic and hemorrhagic strokes in Guangzhou, China, we controlled for potential confounding factors in the model, such as temporal trends, day of the week, public holidays, meteorological factors and influenza epidemic. We found significant association between stroke mortality and various PM fractions, such as PM10, PM2.5 and PM1, with generally larger magnitudes for smaller particles. For the PM2.5 chemical constituents, we found that organic carbon (OC), elemental carbon (EC), sulfate, nitrate and ammonium were significantly associated with stroke mortality. The analysis for specific types of stroke suggested that it was hemorrhagic stroke, rather than ischemic stroke, that was significantly associated with PM pollution. Our study shows that various PM pollution fractions are associated with stroke mortality, and constituents primarily from combustion and secondary aerosols might be the harmful components of PM2.5 in Guangzhou, and this study suggests that PM pollution is more relevant to hemorrhagic stroke in the study area, however, more studies are warranted due to the underlying limitations of this study. Copyright © 2015 Elsevier GmbH. All rights reserved.

Risk of metabolic syndrome for stroke is not greater than the sum of its components: Thai Epidemiologic Stroke (TES) study.

PubMed

Hanchaiphiboolkul, Suchat; Suwanwela, Nijasri Charnnarong; Poungvarin, Niphon; Nidhinandana, Samart; Puthkhao, Pimchanok; Towanabut, Somchai; Tantirittisak, Tasanee; Suwantamee, Jithanorm; Samsen, Maiyadhaj

2013-11-01

Limited information is available on the association between the metabolic syndrome (MetS) and stroke. Whether or not MetS confers a risk greater than the sum of its components is controversial. This study aimed to assess the association of MetS with stroke, and to evaluate whether the risk of MetS is greater than the sum of its components. The Thai Epidemiologic Stroke (TES) study is a community-based cohort study with 19,997 participants, aged 45-80 years, recruited from the general population from 5 regions of Thailand. Baseline survey data were analyzed in cross-sectional analyses. MetS was defined according to criteria from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III, the American Heart Association/National Heart, Lung, and Blood Institute (revised NCEP), and International Diabetes Federation (IDF). Logistic regression analysis was used to estimate association of MetS and its components with stroke. Using c statistics and the likelihood ratio test we compared the capability of discriminating participants with and without stroke of a logistic model containing all components of MetS and potential confounders and a model also including the MetS variable. We found that among the MetS components, high blood pressure and hypertriglyceridemia were independently and significantly related to stroke. MetS defined by the NCEP (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.32-2.04), revised NCEP (OR, 2.27; 95% CI, 1.80-2.87), and IDF definitions (OR, 1.70; 95% CI, 1.37-2.13) was significantly associated with stroke after adjustment for age, sex, geographical area, education level, occupation, smoking status, alcohol consumption, and low-density lipoprotein cholesterol. After additional adjustment for all MetS components, these associations were not significant. There were no statistically significant difference (P=.723-.901) in c statistics between the model containing all MetS components and potential confounders and the model also including the MetS variable. The likelihood ratio test also showed no statistically significant (P=.166-.718) difference between these 2 models. Our findings suggest that MetS is associated with stroke, but not to a greater degree than the sum of its components. Thus, the focus should be on identification and appropriate control of its individual components, particularly high blood pressure and hypertriglyceridemia, rather than of MetS itself. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Association between mental health conditions and rehospitalization, mortality, and functional outcomes in patients with stroke following inpatient rehabilitation.

PubMed

Dossa, Almas; Glickman, Mark E; Berlowitz, Dan

2011-11-15

Limited evidence exists regarding the association of pre-existing mental health conditions in patients with stroke and stroke outcomes such as rehospitalization, mortality, and function. We examined the association between mental health conditions and rehospitalization, mortality, and functional outcomes in patients with stroke following inpatient rehabilitation. Our observational study used the 2001 VA Integrated Stroke Outcomes database of 2162 patients with stroke who underwent rehabilitation at a Veterans Affairs Medical Center. Separate models were fit to our outcome measures that included 6-month rehospitalization or death, 6-month mortality post-discharge, and functional outcomes post inpatient rehabilitation as a function of number and type of mental health conditions. The models controlled for patient socio-demographics, length of stay, functional status, and rehabilitation setting. Patients had an average age of 68 years. Patients with stroke and two or more mental health conditions were more likely to be readmitted or die compared to patients with no conditions (OR: 1.44, p = 0.04). Depression and anxiety were associated with a greater likelihood of rehospitalization or death (OR: 1.33, p = 0.04; OR:1.47, p = 0.03). Patients with anxiety were more likely to die at six months (OR: 2.49, p = 0.001). Patients with stroke with pre-existing mental health conditions may need additional psychotherapy interventions, which may potentially improve stroke outcomes post-hospitalization.

Neighborhood disadvantage and ischemic stroke: the Cardiovascular Health Study (CHS).

PubMed

Brown, Arleen F; Liang, Li-Jung; Vassar, Stefanie D; Stein-Merkin, Sharon; Longstreth, W T; Ovbiagele, Bruce; Yan, Tingjian; Escarce, José J

2011-12-01

Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status and incident ischemic stroke and examine potential mediators of these associations. We analyzed data from 3834 whites and 785 blacks enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages≥65 years from 4 US counties. The primary outcome was adjudicated incident ischemic stroke. Neighborhood socioeconomic status was measured using a composite of 6 census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed adjusted for sociodemographic, behavioral, and biological risk factors. Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared with the highest neighborhood socioeconomic status quartile (hazard ratio, 1.32; 95% CI, 1.01-1.72) with greater attenuation of the hazard ratio after adjustment for biological risk factors (hazard ratio, 1.16; 0.88-1.52) than for behavioral risk factors (hazard ratio, 1.30; 0.99-1.70). Among blacks, we found no significant associations between neighborhood socioeconomic status and ischemic stroke. Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among blacks. The relationship between neighborhood socioeconomic status and stroke among whites appears to be mediated more strongly by biological than behavioral risk factors.

Effect of a care plan based on Roy adaptation model biological dimension on stroke patients' physiologic adaptation level.

PubMed

Alimohammadi, Nasrollah; Maleki, Bibi; Shahriari, Mohsen; Chitsaz, Ahmad

2015-01-01

Stroke is a stressful event with several functional, physical, psychological, social, and economic problems that affect individuals' different living balances. With coping strategies, patients try to control these problems and return to their natural life. The aim of this study is to investigate the effect of a care plan based on Roy adaptation model biological dimension on stroke patients' physiologic adaptation level. This study is a clinical trial in which 50 patients, affected by brain stroke and being admitted in the neurology ward of Kashani and Alzahra hospitals, were randomly assigned to control and study groups in Isfahan in 2013. Roy adaptation model care plan was administered in biological dimension in the form of four sessions and phone call follow-ups for 1 month. The forms related to Roy adaptation model were completed before and after intervention in the two groups. Chi-square test and t-test were used to analyze the data through SPSS 18. There was a significant difference in mean score of adaptation in physiological dimension in the study group after intervention (P < 0.001) compared to before intervention. Comparison of the mean scores of changes of adaptation in the patients affected by brain stroke in the study and control groups showed a significant increase in physiological dimension in the study group by 47.30 after intervention (P < 0.001). The results of study showed that Roy adaptation model biological dimension care plan can result in an increase in adaptation in patients with stroke in physiological dimension. Nurses can use this model for increasing patients' adaptation.

Multimedia-Based Therapy Model for Non-Pharmacological Stroke with Decrease Impaired Muscle Strength

NASA Astrophysics Data System (ADS)

Hajar Puji Sejati, Rr; Muhimmah, Izzati; Mahtarami, Affan

2016-01-01

Stroke patients who experience a decrease in muscle strength need to do exercises so that they can increase their muscle strength. In order to enable the patient does exercise independently the multimedia-based stroke therapy model is needed. These exercises can be done independently, with supervision of the family member at home. So, we develop prototype of the multimedia-based therapy for the family member so that they can assist patients performing exercises without attending therapy session in hospital. This model was built according to the advices from physiotherapist and a medical rehabilitation doctor. This model has been evaluated through focused group discussion by physiotherapists. And they gave positive responses to this proposed model.

Comparing language outcomes in monolingual and bilingual stroke patients

PubMed Central

Parker Jones, ‘Ōiwi; Grogan, Alice; Crinion, Jenny; Rae, Johanna; Ruffle, Louise; Leff, Alex P.; Seghier, Mohamed L.; Price, Cathy J.; Green, David W.

2015-01-01

Post-stroke prognoses are usually inductive, generalizing trends learned from one group of patients, whose outcomes are known, to make predictions for new patients. Research into the recovery of language function is almost exclusively focused on monolingual stroke patients, but bilingualism is the norm in many parts of the world. If bilingual language recruits qualitatively different networks in the brain, prognostic models developed for monolinguals might not generalize well to bilingual stroke patients. Here, we sought to establish how applicable post-stroke prognostic models, trained with monolingual patient data, are to bilingual stroke patients who had been ordinarily resident in the UK for many years. We used an algorithm to extract binary lesion images for each stroke patient, and assessed their language with a standard tool. We used feature selection and cross-validation to find ‘good’ prognostic models for each of 22 different language skills, using monolingual data only (174 patients; 112 males and 62 females; age at stroke: mean = 53.0 years, standard deviation = 12.2 years, range = 17.2–80.1 years; time post-stroke: mean = 55.6 months, standard deviation = 62.6 months, range = 3.1–431.9 months), then made predictions for both monolinguals and bilinguals (33 patients; 18 males and 15 females; age at stroke: mean = 49.0 years, standard deviation = 13.2 years, range = 23.1–77.0 years; time post-stroke: mean = 49.2 months, standard deviation = 55.8 months, range = 3.9–219.9 months) separately, after training with monolingual data only. We measured group differences by comparing prediction error distributions, and used a Bayesian test to search for group differences in terms of lesion-deficit associations in the brain. Our models distinguish better outcomes from worse outcomes equally well within each group, but tended to be over-optimistic when predicting bilingual language outcomes: our bilingual patients tended to have poorer language skills than expected, based on trends learned from monolingual data alone, and this was significant (P < 0.05, corrected for multiple comparisons) in 13/22 language tasks. Both patient groups appeared to be sensitive to damage in the same sets of regions, though the bilinguals were more sensitive than the monolinguals. PMID:25688076

Comparison of cardiovascular risk factors and survival in patients with ischemic or hemorrhagic stroke.

PubMed

Henriksson, Karin M; Farahmand, Bahman; Åsberg, Signild; Edvardsson, Nils; Terént, Andreas

2012-06-01

Differences in risk factor profiles between patients with ischemic and hemorrhagic stroke may have an impact on subsequent mortality. To explore cardiovascular disease risk factors, including the CHADS(2) score, with survival after ischemic or hemorrhagic stroke. Between 2001 and 2005, 87 111 (83%) ischemic stroke, 12 497 (12%) hemorrhagic stroke, and 5435 (5%) patients with unspecified stroke were identified in the Swedish Stroke Register. Data on gender, age, and cardiovascular disease risk factors were linked to the Swedish Hospital Discharge and Cause of Death Registers. Adjusted odds and hazard ratios and 95% confidence interval were calculated using logistic and Cox proportional hazard regression models. Hemorrhagic stroke patients were younger than ischemic stroke patients. All cardiovascular disease risk factors studied, alone or combined in the CHADS(2) score, were associated with higher odds ratios for ischemic stroke vs. hemorrhagic stroke. Higher CHADS(2) scores and all studied risk factors except hypertension were associated with higher odds ratio for death by ischemic stroke than hemorrhagic stroke. Ischemic stroke was associated with lower early mortality (within 30 days) vs. hemorrhagic stroke (hazard ratio = 0·28, confidence interval 0·27 to 0·29). Patients with hemorrhagic stroke had a higher risk of dying within the first 30 days after stroke, but the risk of death was similar in the two groups after one-month. Hypertension was the only cardiovascular disease risk factor associated with an increased mortality rate for hemorrhagic stroke as compared to ischemic stroke. © 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.

Can We Predict Individual Combined Benefit and Harm of Therapy? Warfarin Therapy for Atrial Fibrillation as a Test Case

PubMed Central

Li, Guowei; Thabane, Lehana; Delate, Thomas; Witt, Daniel M.; Levine, Mitchell A. H.; Cheng, Ji; Holbrook, Anne

2016-01-01

Objectives To construct and validate a prediction model for individual combined benefit and harm outcomes (stroke with no major bleeding, major bleeding with no stroke, neither event, or both) in patients with atrial fibrillation (AF) with and without warfarin therapy. Methods Using the Kaiser Permanente Colorado databases, we included patients newly diagnosed with AF between January 1, 2005 and December 31, 2012 for model construction and validation. The primary outcome was a prediction model of composite of stroke or major bleeding using polytomous logistic regression (PLR) modelling. The secondary outcome was a prediction model of all-cause mortality using the Cox regression modelling. Results We included 9074 patients with 4537 and 4537 warfarin users and non-users, respectively. In the derivation cohort (n = 4632), there were 136 strokes (2.94%), 280 major bleedings (6.04%) and 1194 deaths (25.78%) occurred. In the prediction models, warfarin use was not significantly associated with risk of stroke, but increased the risk of major bleeding and decreased the risk of death. Both the PLR and Cox models were robust, internally and externally validated, and with acceptable model performances. Conclusions In this study, we introduce a new methodology for predicting individual combined benefit and harm outcomes associated with warfarin therapy for patients with AF. Should this approach be validated in other patient populations, it has potential advantages over existing risk stratification approaches as a patient-physician aid for shared decision-making PMID:27513986

Predicting discharge mortality after acute ischemic stroke using balanced data.

PubMed

Ho, King Chung; Speier, William; El-Saden, Suzie; Liebeskind, David S; Saver, Jeffery L; Bui, Alex A T; Arnold, Corey W

2014-01-01

Several models have been developed to predict stroke outcomes (e.g., stroke mortality, patient dependence, etc.) in recent decades. However, there is little discussion regarding the problem of between-class imbalance in stroke datasets, which leads to prediction bias and decreased performance. In this paper, we demonstrate the use of the Synthetic Minority Over-sampling Technique to overcome such problems. We also compare state of the art machine learning methods and construct a six-variable support vector machine (SVM) model to predict stroke mortality at discharge. Finally, we discuss how the identification of a reduced feature set allowed us to identify additional cases in our research database for validation testing. Our classifier achieved a c-statistic of 0.865 on the cross-validated dataset, demonstrating good classification performance using a reduced set of variables.

Nonlinear lymphangion pressure-volume relationship minimizes edema

PubMed Central

Venugopal, Arun M.; Stewart, Randolph H.; Laine, Glen A.

2010-01-01

Lymphangions, the segments of lymphatic vessel between two valves, contract cyclically and actively pump, analogous to cardiac ventricles. Besides having a discernable systole and diastole, lymphangions have a relatively linear end-systolic pressure-volume relationship (with slope Emax) and a nonlinear end-diastolic pressure-volume relationship (with slope Emin). To counter increased microvascular filtration (causing increased lymphatic inlet pressure), lymphangions must respond to modest increases in transmural pressure by increasing pumping. To counter venous hypertension (causing increased lymphatic inlet and outlet pressures), lymphangions must respond to potentially large increases in transmural pressure by maintaining lymph flow. We therefore hypothesized that the nonlinear lymphangion pressure-volume relationship allows transition from a transmural pressure-dependent stroke volume to a transmural pressure-independent stroke volume as transmural pressure increases. To test this hypothesis, we applied a mathematical model based on the time-varying elastance concept typically applied to ventricles (the ratio of pressure to volume cycles periodically from a minimum, Emin, to a maximum, Emax). This model predicted that lymphangions increase stroke volume and stroke work with transmural pressure if Emin < Emax at low transmural pressures, but maintain stroke volume and stroke work if Emin= Emax at higher transmural pressures. Furthermore, at higher transmural pressures, stroke work is evenly distributed among a chain of lymphangions. Model predictions were tested by comparison to previously reported data. Model predictions were consistent with reported lymphangion properties and pressure-flow relationships of entire lymphatic systems. The nonlinear lymphangion pressure-volume relationship therefore minimizes edema resulting from both increased microvascular filtration and venous hypertension. PMID:20601461

TMS measures of motor cortex function after stroke: A meta-analysis.

PubMed

McDonnell, Michelle N; Stinear, Cathy M

Transcranial magnetic stimulation (TMS) is commonly used to measure the effects of stroke on corticomotor excitability, intracortical function, and interhemispheric interactions. The interhemispheric inhibition model posits that recovery of motor function after stroke is linked to rebalancing of asymmetric interhemispheric inhibition and corticomotor excitability. This model forms the rationale for using neuromodulation techniques to suppress unaffected motor cortex excitability, and facilitate affected motor cortex excitability. However, the evidence base for using neuromodulation techniques to promote post-stroke motor recovery is inconclusive. The aim of this meta-analysis was to compare measures of corticomotor excitability, intracortical function, and interhemispheric inhibition, between the affected and unaffected hemispheres of people with stroke, and measures made in healthy adults. A literature search was conducted to identify studies that made TMS measures of the motor cortex in adult stroke patients. Two authors independently extracted data, and the quality of included studies was assessed. TMS measures were compared between the affected and unaffected hemispheres of stroke patients, between the affected hemisphere and healthy controls, and between the unaffected hemisphere and healthy controls. Analyses were carried out with data grouped according to the muscle from which responses were recorded, and separately according to time post-stroke (<3 months, and ≥6 months). Meta-analyses were carried out using a random effects model. There were 844 studies identified, and 112 studies included in the meta-analysis. Results were very similar across muscle groups. Affected hemisphere M1 excitability is lower than unaffected and healthy control M1 excitability after stroke. Affected hemisphere short interval intracortical inhibition (SICI) is lower than unaffected and healthy control SICI early after stroke, and not different in the chronic phase. There were no differences detected between the unaffected hemisphere and healthy controls. There were only seven studies of interhemispheric inhibition that could be included, with no clear effects of hemisphere or time post-stroke. The neurophysiological effects of stroke are primarily localised to the affected hemisphere, and there is no clear evidence for hyper-excitability of the unaffected hemisphere or imbalanced interhemispheric inhibition. This indicates that facilitating affected M1 excitability directly may be more beneficial than suppressing unaffected M1 excitability for promoting post-stroke recovery. Copyright © 2017 Elsevier Inc. All rights reserved.

Risk factors of hemorrhagic and ischemic stroke among hospitalized patients in Bangladesh--A case control study.

PubMed

Riaz, B K; Chowdhury, S H; Karim, M N; Feroz, S; Selim, S; Rahman, M R

2015-04-01

The risk factor profiles, management and outcome have significant difference between stroke subsets. Aim of this study was to investigate the risk for the two most common subtypes of stroke in Bangladeshi population. Seventy cases of hemorrhagic stroke (HS) and 105 cases of confirmed ischemic stroke (IS) were recruited from the Shaheed Suhrawardy Medical College Hospital (ShSMCH) and Dhaka Medical College Hospital between January-June 2011. Total 171 age, sex matched controls were selected from the hospitalized patients with history of no stroke ever. Average hemorrhagic stroke patients (60.4 ± 12.3 years) were younger than both ischemic strokes (63.5 ± 13 years). Family history of premature cardiovascular death was found more in HS patients (p = 0.001). Multivariate logistic regression showed, in IS model 'less fruit consumption (OR 4.6), table salt intake (OR 8.15), psychosocial stress (OR 3.5), abnormal ECG (OR 3.6) and Increased WHR (OR 6.9) appeared as significant predictors adjusted for all potential candidate confounders. In HS model less fruit consumption (OR 5.0), table salt intake (OR 9.9), Stress (OR 4.1), family history of cardiovascular disease (CVD) death (OR 11.3), hypertension (OR 43), aspirin intake (OR 4.5) and increased WHR (OR 3.7) remained as significant predictors.

25(OH)D deficiency is associated with fatal stroke among whites but not blacks: The NHANES-III linked mortality files

PubMed Central

Michos, Erin D.; Reis, Jared P.; Post, Wendy S.; Lutsey, Pamela L.; Gottesman, Rebecca F.; Mosley, Thomas H.; Sharrett, A. Richey; Melamed, Michal L.

2011-01-01

Objective Deficient 25-hydroxyvitamin D [25(OH)D] levels are associated with cardiovascular disease (CVD) events and mortality. Both 25(OH)D deficiency and stroke are more prevalent among blacks. We examined whether low 25(OH)D contributes to the excess risk of fatal stroke in blacks compared to whites. Research Methods and Procedures The Third National Health and Nutrition Examination Survey, a probability sample of US civilians, measured 25(OH)D levels and CVD risk factors between 1988–1994. Vital status through December 2006 was obtained via linkage with the National Death Index. Among white and black adults without CVD reported at baseline (n=7981), Cox regression models were fit to estimate hazard ratios (HR) for fatal stroke by 25(OH)D status and race. Results During a median of 14.1 years, there were 116 and 60 fatal strokes among whites and blacks respectively. The risk of fatal stroke was greater in blacks compared to whites in models adjusted for socio-economic status and CVD risk factors, [HR 1.60 (95% CI 1.01–2.53)]. Mean baseline 25(OH)D levels were significantly lower in blacks compared to whites (19.4 vs 30.8 ng/mL, respectively). In multivariable-adjusted models, deficient 25(OH)D levels <15 ng/mL were associated with fatal stroke among whites [HR 2.13 (1.01–4.50)] but not blacks [HR 0.93 (0.49–1.80)]. Conclusions Vitamin D deficiency was associated with increased risk of stroke death in whites but not blacks. Although blacks had a higher rate of fatal stroke compared to whites, the low 25(OH)D levels in blacks were unrelated to stroke incidence and therefore 25(OH)D levels did not explain this excess risk. PMID:22261577

Prediction of morbidity and mortality in patients with type 2 diabetes.

PubMed

Wells, Brian J; Roth, Rachel; Nowacki, Amy S; Arrigain, Susana; Yu, Changhong; Rosenkrans, Wayne A; Kattan, Michael W

2013-01-01

Introduction. The objective of this study was to create a tool that accurately predicts the risk of morbidity and mortality in patients with type 2 diabetes according to an oral hypoglycemic agent. Materials and Methods. The model was based on a cohort of 33,067 patients with type 2 diabetes who were prescribed a single oral hypoglycemic agent at the Cleveland Clinic between 1998 and 2006. Competing risk regression models were created for coronary heart disease (CHD), heart failure, and stroke, while a Cox regression model was created for mortality. Propensity scores were used to account for possible treatment bias. A prediction tool was created and internally validated using tenfold cross-validation. The results were compared to a Framingham model and a model based on the United Kingdom Prospective Diabetes Study (UKPDS) for CHD and stroke, respectively. Results and Discussion. Median follow-up for the mortality outcome was 769 days. The numbers of patients experiencing events were as follows: CHD (3062), heart failure (1408), stroke (1451), and mortality (3661). The prediction tools demonstrated the following concordance indices (c-statistics) for the specific outcomes: CHD (0.730), heart failure (0.753), stroke (0.688), and mortality (0.719). The prediction tool was superior to the Framingham model at predicting CHD and was at least as accurate as the UKPDS model at predicting stroke. Conclusions. We created an accurate tool for predicting the risk of stroke, coronary heart disease, heart failure, and death in patients with type 2 diabetes. The calculator is available online at http://rcalc.ccf.org under the heading "Type 2 Diabetes" and entitled, "Predicting 5-Year Morbidity and Mortality." This may be a valuable tool to aid the clinician's choice of an oral hypoglycemic, to better inform patients, and to motivate dialogue between physician and patient.

Linked Sensitivity Analysis, Calibration, and Uncertainty Analysis Using a System Dynamics Model for Stroke Comparative Effectiveness Research.

PubMed

Tian, Yuan; Hassmiller Lich, Kristen; Osgood, Nathaniel D; Eom, Kirsten; Matchar, David B

2016-11-01

As health services researchers and decision makers tackle more difficult problems using simulation models, the number of parameters and the corresponding degree of uncertainty have increased. This often results in reduced confidence in such complex models to guide decision making. To demonstrate a systematic approach of linked sensitivity analysis, calibration, and uncertainty analysis to improve confidence in complex models. Four techniques were integrated and applied to a System Dynamics stroke model of US veterans, which was developed to inform systemwide intervention and research planning: Morris method (sensitivity analysis), multistart Powell hill-climbing algorithm and generalized likelihood uncertainty estimation (calibration), and Monte Carlo simulation (uncertainty analysis). Of 60 uncertain parameters, sensitivity analysis identified 29 needing calibration, 7 that did not need calibration but significantly influenced key stroke outcomes, and 24 not influential to calibration or stroke outcomes that were fixed at their best guess values. One thousand alternative well-calibrated baselines were obtained to reflect calibration uncertainty and brought into uncertainty analysis. The initial stroke incidence rate among veterans was identified as the most influential uncertain parameter, for which further data should be collected. That said, accounting for current uncertainty, the analysis of 15 distinct prevention and treatment interventions provided a robust conclusion that hypertension control for all veterans would yield the largest gain in quality-adjusted life years. For complex health care models, a mixed approach was applied to examine the uncertainty surrounding key stroke outcomes and the robustness of conclusions. We demonstrate that this rigorous approach can be practical and advocate for such analysis to promote understanding of the limits of certainty in applying models to current decisions and to guide future data collection. © The Author(s) 2016.

System parameters for erythropoiesis control model: Comparison of normal values in human and mouse model

NASA Technical Reports Server (NTRS)

1979-01-01

The computer model for erythropoietic control was adapted to the mouse system by altering system parameters originally given for the human to those which more realistically represent the mouse. Parameter values were obtained from a variety of literature sources. Using the mouse model, the mouse was studied as a potential experimental model for spaceflight. Simulation studies of dehydration and hypoxia were performed. A comparison of system parameters for the mouse and human models is presented. Aside from the obvious differences expected in fluid volumes, blood flows and metabolic rates, larger differences were observed in the following: erythrocyte life span, erythropoietin half-life, and normal arterial pO2.

Smoking and Risk of Ischemic Stroke in Young Men.

PubMed

Markidan, Janina; Cole, John W; Cronin, Carolyn A; Merino, Jose G; Phipps, Michael S; Wozniak, Marcella A; Kittner, Steven J

2018-05-01

There is a strong dose-response relationship between smoking and risk of ischemic stroke in young women, but there are few data examining this association in young men. We examined the dose-response relationship between the quantity of cigarettes smoked and the odds of developing an ischemic stroke in men under age 50 years. The Stroke Prevention in Young Men Study is a population-based case-control study of risk factors for ischemic stroke in men ages 15 to 49 years. The χ 2 test was used to test categorical comparisons. Logistic regression models were used to calculate the odds ratio for ischemic stroke occurrence comparing current and former smokers to never smokers. In the first model, we adjusted solely for age. In the second model, we adjusted for potential confounding factors, including age, race, education, hypertension, myocardial infarction, angina, diabetes mellitus, and body mass index. The study population consisted of 615 cases and 530 controls. The odds ratio for the current smoking group compared with never smokers was 1.88. Furthermore, when the current smoking group was stratified by number of cigarettes smoked, there was a dose-response relationship for the odds ratio, ranging from 1.46 for those smoking <11 cigarettes per day to 5.66 for those smoking 40+ cigarettes per day. We found a strong dose-response relationship between the number of cigarettes smoked daily and ischemic stroke among young men. Although complete smoking cessation is the goal, even smoking fewer cigarettes may reduce the risk of ischemic stroke in young men. © 2018 American Heart Association, Inc.

Validity of the growth model of the 'computerized visual perception assessment tool for Chinese characters structures'.

PubMed

Wu, Huey-Min; Li, Cheng-Hsaun; Kuo, Bor-Chen; Yang, Yu-Mao; Lin, Chin-Kai; Wan, Wei-Hsiang

2017-08-01

Morphological awareness is the foundation for the important developmental skills involved with vocabulary, as well as understanding the meaning of words, orthographic knowledge, reading, and writing. Visual perception of space and radicals in two-dimensional positions of Chinese characters' morphology is very important in identifying Chinese characters. The important predictive variables of special and visual perception in Chinese characters identification were investigated in the growth model in this research. The assessment tool is the "Computerized Visual Perception Assessment Tool for Chinese Characters Structures" developed by this study. There are two constructs, basic stroke and character structure. In the basic stroke, there are three subtests of one, two, and more than three strokes. In the character structure, there are three subtests of single-component character, horizontal-compound character, and vertical-compound character. This study used purposive sampling. In the first year, 551 children 4-6 years old participated in the study and were monitored for one year. In the second year, 388 children remained in the study and the successful follow-up rate was 70.4%. This study used a two-wave cross-lagged panel design to validate the growth model of the basic stroke and the character structure. There was significant correlation of the basic stroke and the character structure at different time points. The abilities in the basic stroke and in the character structure steadily developed over time for preschool children. Children's knowledge of the basic stroke effectively predicted their knowledge of the basic stroke and the character structure. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effect of long working hours on 10-year risk of coronary heart disease and stroke in the Korean population: the Korea National Health and Nutrition Examination Survey (KNHANES), 2007 to 2013.

PubMed

Lee, Dong-Wook; Hong, Yun-Chul; Min, Kyoung-Bok; Kim, Tae-Shik; Kim, Min-Seok; Kang, Mo-Yeol

2016-01-01

Recently, the emergence of long working hours and the associated conditions such as coronary heart disease (CHD) and stroke have gained attention. The aim of this study was to investigate the association between long working hours and the 10-year-risk of CHD and stroke, estimated by Jee's health risk-appraisal model for ischemic heart disease. We analyzed data from Koreans who randomly enrolled in Korean National Health and Nutrition Examination Survey 2008-2012 and finally included 13,799 participants. The participants were classified as per their working hours: 0-30 h/week, 31-39 h/week, 40 h/week, 41-50 h/week, 51-60 h/week, 61-70 h/week, 71-80 h/week, and >80 h/week. The risks for CHD and stroke were determined using Jee's health risk-appraisal model. Multiple logistic regression was used to analyze the association between working hours and 10-year risk for CHD. The 10-year risks for CHD and stroke were significantly and positively associated with working hours in both men and women. Furthermore, higher risks for CHD and stroke were associated with longer working hours in women. Long working hours are significantly associated with the risks of CHD and stroke, estimated by Jee's health risk-appraisal model. This study suggests the need for proper management of working hours to reduce CHD risk and stroke risk in the Korean population.

Stroke and the "stroke belt" in dialysis: contribution of patient characteristics to ischemic stroke rate and its geographic variation.

PubMed

Wetmore, James B; Ellerbeck, Edward F; Mahnken, Jonathan D; Phadnis, Milind A; Rigler, Sally K; Spertus, John A; Zhou, Xinhua; Mukhopadhyay, Purna; Shireman, Theresa I

2013-12-01

Geographic variation in stroke rates is well established in the general population, with higher rates in the South than in other areas of the United States. ESRD is a potent risk factor for stroke, but whether regional variations in stroke risk exist among dialysis patients is unknown. Medicare claims from 2000 to 2005 were used to ascertain ischemic stroke events in a large cohort of 265,685 incident dialysis patients. A Poisson generalized linear mixed model was generated to determine factors associated with stroke and to ascertain state-by-state geographic variability in stroke rates by generating observed-to-expected (O/E) adjusted rate ratios for stroke. Older age, female sex, African American race and Hispanic ethnicity, unemployed status, diabetes, hypertension, history of stroke, and permanent atrial fibrillation were positively associated with ischemic stroke, whereas body mass index >30 kg/m(2) was inversely associated with stroke (P<0.001 for each). After full multivariable adjustment, the three states with O/E rate ratios >1.0 were all in the South: North Carolina, Mississippi, and Oklahoma. Regional efforts to increase primary prevention in the "stroke belt" or to better educate dialysis patients on the signs of stroke so that they may promptly seek care may improve stroke care and outcomes in dialysis patients.

Aortic Valve Calcification and Risk of Stroke: The Rotterdam Study.

PubMed

Bos, Daniel; Bozorgpourniazi, Atefeh; Mutlu, Unal; Kavousi, Maryam; Vernooij, Meike W; Moelker, Adriaan; Franco, Oscar H; Koudstaal, Peter J; Ikram, M Arfan; van der Lugt, Aad

2016-11-01

It remains uncertain whether aortic valve calcification (AVC) is a risk factor for stroke. From the population-based Rotterdam Study, 2471 participants (mean age: 69.6 years; 51.8% women) underwent computed tomography to quantify AVC. We assessed prevalent stroke and continuously monitored the remaining participants for the incidence of stroke. Logistic and Cox regression models were used to investigate associations of AVC with prevalent stroke and risk of incident stroke. AVC was present in 33.1% of people. At baseline, 97 participants had ever suffered a stroke. During 18 665 person-years of follow-up (mean: 7.9 years), 135 people experienced a first-ever stroke. The presence of AVC was not associated with prevalent stroke (fully adjusted odds ratio: 0.97 (95% confidence interval, 0.61-1.53]) or with an increased risk of stroke (fully adjusted hazard ratio: 0.99 (95% confidence interval, 0.69-1.44]). Although AVC is a common finding in middle-aged and elderly community-dwelling people, our results suggest that AVC is not associated with an increased risk of stroke. © 2016 American Heart Association, Inc.

Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core.

PubMed

Sivaprakasam, Prasanna; Han, Xiaojun; Civiello, Rita L; Jacutin-Porte, Swanee; Kish, Kevin; Pokross, Matt; Lewis, Hal A; Ahmed, Nazia; Szapiel, Nicolas; Newitt, John A; Baldwin, Eric T; Xiao, Hong; Krause, Carol M; Park, Hyunsoo; Nophsker, Michelle; Lippy, Jonathan S; Burton, Catherine R; Langley, David R; Macor, John E; Dubowchik, Gene M

2015-05-01

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses. Copyright © 2015 Elsevier Ltd. All rights reserved.

The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury

PubMed Central

Zhou, Yanlong; Zhou, Beiqun; Tu, Hui; Tang, Yan; Xu, Chen; Chen, Yanbo; Zhao, Zhong; Miao, Zhigang

2017-01-01

Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. Further, we found NSA reduced MLKL levels via the ubiquitination proteasome pathway, but not by inhibiting RNA transcription. Interestingly, NSA administration increased cleaved PARP-1 levels, indicating the protective effects of MLKL inhibition is not related to apoptosis. These findings suggest MLKL is a new therapeutic target for neurological pathologies like stroke. Therefore, promoting degradation of MLKL may be a novel avenue to reduce necrotic cell death after ischemic brain injury. PMID:28978125

Prediction of new-onset atrial fibrillation after first-ever ischemic stroke: A comparison of CHADS2, CHA2DS2-VASc and HATCH scores and the added value of stroke severity.

PubMed

Hsieh, Cheng-Yang; Lee, Cheng-Han; Wu, Darren Philbert; Sung, Sheng-Feng

2018-05-01

Early detection of atrial fibrillation after stroke is important for secondary prevention in stroke patients without known atrial fibrillation (AF). We aimed to compare the performance of CHADS 2 , CHA 2 DS 2 -VASc and HATCH scores in predicting AF detected after stroke (AFDAS) and to test whether adding stroke severity to the risk scores improves predictive performance. Adult patients with first ischemic stroke event but without a prior history of AF were retrieved from a nationwide population-based database. We compared C-statistics of CHADS 2 , CHA 2 DS 2 -VASc and HATCH scores for predicting the occurrence of AFDAS during stroke admission (cohort I) and during follow-up after hospital discharge (cohort II). The added value of stroke severity to prediction models was evaluated using C-statistics, net reclassification improvement, and integrated discrimination improvement. Cohort I comprised 13,878 patients and cohort II comprised 12,567 patients. Among them, 806 (5.8%) and 657 (5.2%) were diagnosed with AF, respectively. The CHADS 2 score had the lowest C-statistics (0.558 in cohort I and 0.597 in cohort II), whereas the CHA 2 DS 2 -VASc score had comparable C-statistics (0.603 and 0.644) to the HATCH score (0.612 and 0.653) in predicting AFDAS. Adding stroke severity to each of the three risk scores significantly increased the model performance. In stroke patients without known AF, all three risk scores predicted AFDAS during admission and follow-up, but with suboptimal discrimination. Adding stroke severity improved their predictive abilities. These risk scores, when combined with stroke severity, may help prioritize patients for continuous cardiac monitoring in daily practice. Copyright © 2018 Elsevier B.V. All rights reserved.

Association of the ankle-brachial index with history of myocardial infarction and stroke.

PubMed

Jones, W Schuyler; Patel, Manesh R; Rockman, Caron B; Guo, Yu; Adelman, Mark; Riles, Thomas; Berger, Jeffrey S

2014-04-01

Ankle-brachial index (ABI) testing is a simple, noninvasive method to diagnose peripheral artery disease (PAD) and is associated with all-cause mortality. The association of ABI levels and myocardial infarction (MI) and stroke is less certain. We sought to further characterize the association between ABI levels and history of MI and stroke. Using data from the Life Line Screening program, 3.6 million self-referred participants from 2003 to 2008 completed a medical questionnaire and had bilateral ABIs performed. Logistic regression was used to estimate the association between ABI cutoff points (ABI <0.90 and ABI >1.40) and ABI levels with history of MI, stroke, and MI or stroke (MI/stroke). Models were adjusted for age, sex, race/ethnicity, smoking, diabetes, hypertension, hypercholesterolemia, physical activity, and family history of cardiovascular disease. Separate sex-specific models were performed. Overall, 155,552 (4.5%) had an ABI <0.90, and 42,890 (1.2%) had an ABI >1.40. An ABI <0.90 was associated with higher odds of MI (adjusted odds ratio [OR] 1.67, 95% CI 1.63-1.71), stroke (OR 1.77, 95% CI 1.72-1.82), and MI/stroke (OR 1.71, 95% CI 1.67-1.74), all P < .001. An ABI >1.40 was also associated with higher odds of MI (OR 1.19, 95% CI 1.14-1.24), stroke (OR 1.30, 95% CI 1.22-1.38), and MI/stroke (OR 1.22, 95% CI 1.17-1.27), all P < .001. The ORs for MI/stroke for different ABI levels formed a reverse J-shaped curve in both women and men. In a large national screening database, there is a strong, consistent relationship between ABI levels and a history of prevalent MI, stroke, and MI/stroke. Copyright © 2014 Mosby, Inc. All rights reserved.

Dietary Supplementations as Neuroprotective Therapies: Focus on NT-020 Diet Benefits in a Rat Model of Stroke

PubMed Central

Kaneko, Yuji; Cortes, Lourdes; Sanberg, Cyndy; Acosta, Sandra; Bickford, Paula C.; Borlongan, Cesar V.

2012-01-01

Stroke remains the number one cause of disability in the adult population. Despite scientific progress in our understanding of stroke pathology, only one treatment (tissue plasminogen activator or tPA) is able to afford benefits but to less than 3% of ischemic stroke patients. The development of experimental dietary supplement therapeutics designed to stimulate endogenous mechanisms that confer neuroprotection is likely to open new avenues for exploring stroke therapies. The present review article evaluates the recent literature supporting the benefits of dietary supplementation for the therapy of ischemic stroke. This article focuses on discussing the medical benefits of NT-020 as an adjunct agent for stroke therapy. Based on our preliminary data, a pre-stroke treatment with dietary supplementation promotes neuroprotection by decreasing inflammation and enhancing neurogenesis. However, we recognize that a pre-stroke treatment holds weak clinical relevance. Thus, the main goal of this article is to provide information about recent data that support the assumption of natural compounds as neuroprotective and to evaluate the therapeutic effects of a dietary supplement called NT-020 as in a stroke model. We focus on a systematic assessment of practical treatment parameters so that NT-020 and other dietary supplementations can be developed as an adjunct agent for the prevention or treatment of chronic diseases. We offer rationale for determining the optimal dosage, therapeutic window, and mechanism of action of NT-020 as a dietary supplement to produce neuroprotection when administered immediately after stroke onset. We highlight our long-standing principle in championing both translational and basic science approaches in an effort to fully reveal the therapeutic potential of NT-020 as dietary supplementation in the treatment of stroke. We envision dietary supplementation as an adjunct therapy for stroke at acute, subacute, and even chronic periods. PMID:22837703

Heart rate and ischemic stroke: the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

PubMed

O'Neal, Wesley T; Qureshi, Waqas T; Judd, Suzanne E; Meschia, James F; Howard, Virginia J; Howard, George; Soliman, Elsayed Z

2015-12-01

The association between resting heart rate and ischemic stroke remains unclear. To examine the association between resting heart rate and ischemic stroke. A total of 24 730 participants (mean age: 64 ± 9·3 years; 59% women; 41% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of stroke at the time of enrollment (2003-2007) were included in this analysis. Resting heart rate was determined from baseline electrocardiogram data. Heart rate was examined as a continuous variable per 10 bpm increase and also as a categorical variable using tertiles ( <61 bpm, 61 to 70 bpm, and >70 bpm). First-time ischemic stroke events were identified during follow-up and adjudicated by physician review. Over a median follow-up of 7·6 years, a total of 646 ischemic strokes occurred. In a Cox regression model adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, each 10 bpm increase in heart rate was associated with a 10% increase in the risk of ischemic stroke (hazard ratio = 1·10, 95% confidence interval = 1·02, 1·18). In the categorical model, an increased risk of ischemic stroke was observed for heart rates in the middle (hazard ratio = 1·29, 95% confidence interval = 1·06, 1·57) and upper (hazard ratio = 1·37, 95% confidence interval = 1·12, 1·67) tertiles compared with the lower tertile. The results were consistent when the analysis was stratified by age, gender, race, exercise habits, hypertension, and coronary heart disease. In REGARDS, high resting heart rates were associated with an increased risk of ischemic stroke compared with low heart rates. Further research is needed to examine whether interventions aimed to reduce heart rate decrease stroke risk. © 2015 World Stroke Organization.

Modeling stroke rehabilitation processes using the Unified Modeling Language (UML).

PubMed

Ferrante, Simona; Bonacina, Stefano; Pinciroli, Francesco

2013-10-01

In organising and providing rehabilitation procedures for stroke patients, the usual need for many refinements makes it inappropriate to attempt rigid standardisation, but greater detail is required concerning workflow. The aim of this study was to build a model of the post-stroke rehabilitation process. The model, implemented in the Unified Modeling Language, was grounded on international guidelines and refined following the clinical pathway adopted at local level by a specialized rehabilitation centre. The model describes the organisation of the rehabilitation delivery and it facilitates the monitoring of recovery during the process. Indeed, a system software was developed and tested to support clinicians in the digital administration of clinical scales. The model flexibility assures easy updating after process evolution. Copyright © 2013 Elsevier Ltd. All rights reserved.

Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

PubMed

Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

2015-02-01

During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

Calculations of lightning return stroke electric and magnetic fields above ground

NASA Technical Reports Server (NTRS)

Master, M. J.; Uman, M. A.; Ling, Y. T.; Standler, R. B.

1981-01-01

Lin et al., (1980) presented a lightning return stroke model with which return stroke electric and magnetic fields measured at ground level could be reproduced. This model and a modified version of it, in which the initial current peak decays with height above ground, are used to compute waveforms for altitudes from 0-10 km and at ranges of 20 m to 10 km. Both the original and modified models gave accurate predictions of measured ground-based fields. The use of the calculated fields in calibrating airborne field measurements from simultaneous ground and airborne data is discussed.

Does the 'diffusion of innovations' model enrich understanding of research use? Case studies of the implementation of thrombolysis services for stroke.

PubMed

Boaz, Annette; Baeza, Juan; Fraser, Alec

2016-10-01

To test whether the model of 'diffusion of innovations' enriches understanding of the implementation of evidence-based thrombolysis services for stroke patients. Four case studies of the implementation of evidence on thrombolysis in stroke services in England and Sweden. Semistructured interviews with 95 staff including doctors, nurses and managers working in stroke units, emergency medicine, radiology, the ambulance service, community rehabilitation services and commissioners. The implementation of thrombolysis in acute stroke management benefited from a critical mass of the factors featured in the model including: the support of national and local opinion leaders; a strong evidence base and financial incentives. However, while the model provided a starting point as an organizational framework for mapping the critical factors influencing implementation, to understand properly the process of implementation and the importance of the different factors identified, more detailed analyses of context and, in particular, of the human and social dimensions of change was needed. While recognising the usefulness of the model of diffusion of innovations in mapping the processes by which diffusion occurs, the use of methods that lend themselves to in-depth analysis, such as ethnography and the application of relevant bodies of social theory, are needed. © The Author(s) 2016.

Impact of comorbidities on stroke rehabilitation outcomes: does the method matter?

PubMed

Berlowitz, Dan R; Hoenig, Helen; Cowper, Diane C; Duncan, Pamela W; Vogel, W Bruce

2008-10-01

To examine the impact of comorbidities in predicting stroke rehabilitation outcomes and to examine differences among 3 commonly used comorbidity measures--the Charlson Index, adjusted clinical groups (ACGs), and diagnosis cost groups (DCGs)--in how well they predict these outcomes. Inception cohort of patients followed for 6 months. Department of Veterans Affairs (VA) hospitals. A total of 2402 patients beginning stroke rehabilitation at a VA facility in 2001 and included in the Integrated Stroke Outcomes Database. Not applicable. Three outcomes were evaluated: 6-month mortality, 6-month rehospitalization, and change in FIM score. During 6 months of follow-up, 27.6% of patients were rehospitalized and 8.6% died. The mean FIM score increased an average of 20 points during rehabilitation. Addition of comorbidities to the age and sex models improved their performance in predicting these outcomes based on changes in c statistics for logistic and R(2) values for linear regression models. While ACG and DCG models performed similarly, the best models, based on DCGs, had a c statistic of .74 for 6-month mortality and .63 for 6-month rehospitalization, and an R(2) of .111 for change in FIM score. Comorbidities are important predictors of stroke rehabilitation outcomes. How they are classified has important implications for models that may be used in assessing quality of care.

The effect of the introduction of a case-mix-based funding model of rehabilitation for severe stroke: an Australian experience.

PubMed

Brock, Kim A; Vale, Stephen J; Cotton, Susan M

2007-07-01

To compare resource use of, and outcomes for, rehabilitation for severe stroke before and after the implementation of the Casemix and Rehabilitation Funding Tree case-mix-based funding model. Prospective, observational cohort study. Eight inpatient rehabilitation centers in Australia. Consecutive sample of 609 patients with severe stroke. Not applicable. Rehabilitation length of stay (LOS), discharge destination, and FIM instrument motor score at discharge. The average rehabilitation LOS changed significantly between the preimplementation year and the implementation year (Mann-Whitney U, P=.001). There were no significant differences in discharge destination. FIM motor score at discharge showed significant reduction in improvement (Mann-Whitney U, P=.001) between the preimplementation year and the implementation year. There were no significant correlations between LOS in rehabilitation and gain in function for either the preimplementation year (Spearman rho, P=.07) or the implementation year (P=.15). The change in funding model was associated with a decrease in inpatient costs and with an associated increase in disability at discharge. Our results suggest that the rate of improvement in severe stroke is variable; also, they support the use of funding models for stroke rehabilitation that allow flexibility in resource allocation.

Periodic Limb Movements and White Matter Hyperintensities in First-Ever Minor Stroke or High-Risk Transient Ischemic Attack.

PubMed

Boulos, Mark I; Murray, Brian J; Muir, Ryan T; Gao, Fuqiang; Szilagyi, Gregory M; Huroy, Menal; Kiss, Alexander; Walters, Arthur S; Black, Sandra E; Lim, Andrew S; Swartz, Richard H

2017-03-01

Emerging evidence suggests that periodic limb movements (PLMs) may contribute to the development of cerebrovascular disease. White matter hyperintensities (WMHs), a widely accepted biomarker for cerebral small vessel disease, are associated with incident stroke and death. We evaluated the association between increased PLM indices and WMH burden in patients presenting with stroke or transient ischemic attack (TIA), while controlling for vascular risk factors and stroke severity. Thirty patients presenting within 2 weeks of a first-ever minor stroke or high-risk TIA were prospectively recruited. PLM severity was measured with polysomnography. WMH burden was quantified using the Age Related White Matter Changes (ARWMC) scale based on neuroimaging. Partial Spearman's rank-order correlations and multiple linear regression models tested the association between WMH burden and PLM severity. Greater WMH burden was correlated with elevated PLM index and stroke volume. Partial Spearman's rank-order correlations demonstrated that the relationship between WMH burden and PLM index persisted despite controlling for vascular risk factors. Multivariate linear regression models revealed that PLM index was a significant predictor of an elevated ARWMC score while controlling for age, stroke volume, stroke severity, hypertension, and apnea-hypopnea index. The quantity of PLMs was associated with WMH burden in patients with first-ever minor stroke or TIA. PLMs may be a risk factor for or marker of WMH burden, even after considering vascular risk factors and stroke severity. These results invite further investigation of PLMs as a potentially useful target to reduce WMH and stroke burden. © Sleep Research Society (SRS) 2016. All rights reserved. For permissions, please email: journals.permissions@oup.com

Severe edentulism is a major risk factor influencing stroke incidence in rural Ecuador (The Atahualpa Project).

PubMed

Del Brutto, Oscar H; Mera, Robertino M; Zambrano, Mauricio; Del Brutto, Victor J

2017-02-01

Background There is no information on stroke incidence in rural areas of Latin America, where living conditions and cardiovascular risk factors are different from urban centers. Aim Using a population-based prospective cohort study design, we aimed to assess risk factors influencing stroke incidence in community-dwelling adults living in rural Ecuador. Methods First-ever strokes occurring from 1 June 2012 to 31 May 2016, in Atahualpa residents aged ≥40 years, were identified from yearly door-to-door surveys and other overlapping sources. Poisson regression models adjusted for demographics, cardiovascular risk factors, edentulism and the length of observation time per subject were used to estimate stroke incidence rate ratio as well as factors influencing such incidence. Results Of 807 stroke-free individuals prospectively enrolled in the Atahualpa Project, follow-up was achieved in 718 (89%), contributing 2,499 years of follow-up (average 3.48 ± 0.95 years). Overall stroke incidence rate was 2.97 per 100 person-years of follow-up (95% CI: 1.73-4.2), which increased to 4.77 (95% CI: 1.61-14.1) when only persons aged ≥57 years were considered. Poisson regression models, adjusted for relevant confounders, showed that high blood pressure (IRR: 5.24; 95% CI: 2.55-7.93) and severe edentulism (IRR: 5.06; 95% CI: 2.28-7.85) were the factors independently increasing stroke incidence. Conclusions Stroke incidence in this rural setting is comparable to that reported from the developed world. Besides age and high blood pressure, severe edentulism is a major factor independently predicting incident strokes. Public awareness of the consequences of poor dental care might reduce stroke incidence in rural settings.

Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus.

PubMed

Chen, Weiqi; Pan, Yuesong; Jing, Jing; Zhao, Xingquan; Liu, Liping; Meng, Xia; Wang, Yilong; Wang, Yongjun

2017-06-01

We aimed to determine the risk conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent stroke in patients with minor ischemic stroke or transient ischemic attack from the CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events) trial. In total, 3044 patients were included. Patients were stratified into 4 groups: neither, METS only, DM only, or both. METS was defined using the Chinese Diabetes Society (CDS) and International Diabetes Foundation (IDF) definitions. The primary outcome was new stroke (including ischemic and hemorrhagic) at 90 days. A multivariable Cox regression model was used to assess the relationship of METS and DM status to the risk of recurrent stroke adjusted for potential covariates. Using the CDS criteria of METS, 53.2%, 17.2%, 19.8%, and 9.8% of patients were diagnosed as neither, METS only, DM only, and both, respectively. After 90 days of follow-up, there were 299 new strokes (293 ischemic, 6 hemorrhagic). Patients with DM only (16.1% versus 6.8%; adjusted hazard ratio 2.50, 95% CI 1.89-3.39) and both (17.1% versus 6.8%; adjusted hazard ratio 2.76, 95% CI 1.98-3.86) had significantly increased rates of recurrent stroke. No interaction effect of antiplatelet therapy by different METS or DM status for the risk of recurrent stroke ( P =0.82 for interaction in the fully adjusted model of CDS) was observed. Using the METS (IDF) criteria demonstrated similar results. Concurrent METS and DM was associated with an increased risk of recurrent stroke in patients with minor stroke and transient ischemic attack. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Cerebrovascular dysfunction is an attractive target for therapy in heat stroke.

PubMed

Chen, Sheng-Hsien; Niu, Ko-Chi; Lin, Mao-Tsun

2006-08-01

1. The aim of the present review is to summarize clinical observations and results of animal models that advance the knowledge of the attenuation of cerebrovascular dysfunction in the setting of heat stroke. It is a narrative review of selected published literature from Medline over the period 1959-2005. 2. All heat-stressed rodents, even under general anaesthesia, have hyperthermia, systemic inflammation, hypercoagulable state, arterial hypotension and tissue ischaemia and injury in multiple organs. These findings demonstrate that rodent heat stroke models can nearly mirror the full spectrum of human heat stroke. Experimental heat stroke fulfills the empirical triad used for the diagnosis of classical human heat stroke, namely hyperthermia, central nervous system alterations and a history of heat stress. 3. These physiological dysfunctions and survival during heat stroke can be improved by whole-body or brain cooling therapy adopted immediately after the onset of heat stroke. 4. However, in the absence of body or brain cooling, these heat stroke reactions can still be reduced by the following measures: (i) fluid replacement with 3% NaCl solution, 10% human albumin or hydroxyethyl starch; (ii) intravenous delivery of anti-inflammatory drugs, free radical scavengers or interleukin-1 receptor antagonists; (iii) hyperbaric oxygen therapy; or (iv) transplantation of human umbilical cord blood cells. 5. In addition, before initiation of heat stress, prior manipulations with one of the following measures was found to be able to protect against heat stroke reactions: (i) systemic delivery of alpha-tocopherol, mannitol, inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin ETA receptor antagonists, serotoninergic nerve depletors or receptor antagonists, or glutamate receptor antagonists; or (ii) heat shock protein 72 preconditioning. 6. There is compelling evidence that cerebrovascular dysfunction is an attractive target for therapy in heat stroke.

Increased pulse wave velocity in patients with acute lacunar infarction doubled the risk of future ischemic stroke.

PubMed

Saji, Naoki; Murotani, Kenta; Shimizu, Hirotaka; Uehara, Toshiyuki; Kita, Yasushi; Toba, Kenji; Sakurai, Takashi

2017-04-01

The aim of this study was to determine whether pulse wave velocity (PWV), a marker of vascular endothelial impairment and arteriosclerosis, predicts future ischemic stroke in patients who developed acute lacunar infarction. Patients with a first-ever ischemic stroke due to acute lacunar infarction were enrolled in this study. An oscillometric device (Form PWV/ABI; Omron Colin, Tokyo, Japan) was used to measure brachial-ankle PWV 1 week after stroke onset. Patients were followed for at least 5 years. The main end point of the study was recurrent ischemic stroke. Event-free survival was analyzed using Kaplan-Meier plots and log-rank tests. The risk of recurrent ischemic stroke was estimated using the Cox proportional-hazards model. Of the 156 patients (61% male, mean age: 69.2±11.3 years) assessed in this study, 29 developed recurrent ischemic stroke. The median brachial-ankle PWV value was 20.4 m s -1 . Patients with high PWV values had a greater risk of recurrent ischemic stroke than patients with low PWV values (28% vs. 15%, P=0.08). Kaplan-Meier curve analysis showed that patients with high PWV values had a less favorable (that is, free of recurrent ischemic stroke) survival time (P=0.015). A multivariate Cox proportional-hazards model identified high PWV as an independent predictor of recurrent ischemic stroke after adjusting for age, sex and blood pressure (hazard ratio 2.35, 95% confidence interval, 1.02-5.70, P=0.044). In patients with acute lacunar infarction, a high PWV predicts a twofold greater risk of future ischemic stroke, independent of patient age, sex and blood pressure levels.

Revised Framingham Stroke Risk Profile to Reflect Temporal Trends.

PubMed

Dufouil, Carole; Beiser, Alexa; McLure, Leslie A; Wolf, Philip A; Tzourio, Christophe; Howard, Virginia J; Westwood, Andrew J; Himali, Jayandra J; Sullivan, Lisa; Aparicio, Hugo J; Kelly-Hayes, Margaret; Ritchie, Karen; Kase, Carlos S; Pikula, Aleksandra; Romero, Jose R; D'Agostino, Ralph B; Samieri, Cécilia; Vasan, Ramachandran S; Chêne, Genevieve; Howard, George; Seshadri, Sudha

2017-03-21

Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies. We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals ≥55 years of age and for the subsample ≥65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5- and 10-year stroke risks. The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration χ 2 of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks. A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors. © 2017 American Heart Association, Inc.

Modelling mortality and discharge of hospitalized stroke patients using a phase-type recovery model.

PubMed

Jones, Bruce; McClean, Sally; Stanford, David

2018-05-01

We model the length of in-patient hospital stays due to stroke and the mode of discharge using a phase-type stroke recovery model. The model allows for three different types of stroke: haemorrhagic (the most severe, caused by ruptured blood vessels that cause brain bleeding), cerebral infarction (less severe, caused by blood clots) and transient ischemic attack or TIA (the least severe, a mini-stroke caused by a temporary blood clot). A four-phase recovery process is used, where the initial phase depends on the type of stroke, and transition from one phase to the next depends on the age of the patient. There are three differing modes of absorption for this phase-type model: from a typical recovery phase, a patient may die (mode 1), be transferred to a nursing home (mode 2) or be discharged to the individual's usual residence (mode 3). The first recovery phase is characterized by a very high rate of mortality and very low rates of discharge by the other two modes. The next two recovery phases have progressively lower mortality rates and higher mode 2 and 3 discharge rates. The fourth recovery phase is visited only by those who experience a very mild TIA, and they are discharged to home after a short stay. The novelty of our approach to phase representation is two-fold: first, it aligns the phases with labelled diagnosis states, representing stages of illness severity; second, the model allows us to obtain expressions for Key Performance Indicators that are of use to healthcare professionals. This allows us to use a backward estimation process where we leverage the fact that we know the phase of admission (the diagnosis), but not which phases are subsequently entered or when this happens; this strategy improves both computational efficiency and accuracy. The model has clear practical value as it yields length of stay distributions by age and type of stroke, which are useful in resource planning. Also, inclusion of the three modes of discharge permits analyses of outcomes.

Relationship Between Visceral Infarction and Ischemic Stroke Subtype.

PubMed

Finn, Caitlin; Hung, Peter; Patel, Praneil; Gupta, Ajay; Kamel, Hooman

2018-03-01

Most cryptogenic strokes are thought to have an embolic source. We sought to determine whether cryptogenic strokes are associated with visceral infarcts, which are usually embolic. Among patients prospectively enrolled in CAESAR (Cornell Acute Stroke Academic Registry), we selected those with a contrast-enhanced abdominal computed tomographic scan within 1 year of admission. Our exposure variable was adjudicated stroke subtype per the Trial of ORG 10172 in Acute Stroke Treatment classification. Our outcome was renal or splenic infarction as assessed by a single radiologist blinded to stroke subtype. We used Fisher exact test and multiple logistic regression to compare the prevalence of visceral infarcts among cardioembolic strokes, strokes of undetermined etiology, and noncardioembolic strokes (large- or small-vessel strokes). Among 227 patients with ischemic stroke and a contrast-enhanced abdominal computed tomographic scan, 59 had a visceral infarct (35 renal and 27 splenic). The prevalence of visceral infarction was significantly different among cardioembolic strokes (34.2%; 95% confidence interval [CI], 23.7%-44.6%), strokes of undetermined etiology (23.9%; 95% CI, 15.0%-32.8%), and strokes from large-artery atherosclerosis or small-vessel occlusion (12.5%; 95% CI, 1.8%-23.2%; P =0.03). In multiple logistic regression models adjusted for demographics and vascular comorbidities, we found significant associations with visceral infarction for both cardioembolic stroke (odds ratio, 3.5; 95% CI, 1.2-9.9) and stroke of undetermined source (odds ratio, 3.3; 95% CI, 1.1-10.5) as compared with noncardioembolic stroke. The prevalence of visceral infarction differed significantly across ischemic stroke subtypes. Cardioembolic and cryptogenic strokes were associated with a higher prevalence of visceral infarcts than noncardioembolic strokes. © 2018 American Heart Association, Inc.

Impact of Neighborhood Socioeconomic Conditions on the Risk of Stroke in Japan

PubMed Central

Honjo, Kaori; Iso, Hiroyasu; Nakaya, Tomoki; Hanibuchi, Tomoya; Ikeda, Ai; Inoue, Manami; Sawada, Norie; Tsugane, Shoichiro

2015-01-01

Background Neighborhood deprivation has been shown in many studies to be an influential factor in cardiovascular disease risk. However, no previous studies have examined the effect of neighborhood socioeconomic conditions on the risk of stroke in Asian countries. Methods This study investigated whether neighborhood deprivation was associated with the risk of stroke and stroke death using data from the Japan Public Health Center-based Prospective Study. We calculated the adjusted hazard ratios of stroke mortality (mean follow-up, 16.4 years) and stroke incidence (mean follow-up, 15.4 years) according to the area deprivation index (ADI) among 90 843 Japanese men and women aged 40–69 years. A Cox proportional-hazard regression model using a shared frailty model was applied. Results The adjusted hazard ratios of stroke incidence, in order of increasing deprivation with reference to the least deprived area, were 1.16 (95% CI, 1.04–1.29), 1.12 (95% CI, 1.00–1.26), 1.18 (95% CI, 1.02–1.35), and 1.19 (95% CI, 1.01–1.41), after adjustment for individual socioeconomic conditions. Behavioral and psychosocial factors attenuated the association, but the association remained significant. The associations were explained by adjusting for biological cardiovascular risk factors. No significant association with stroke mortality was identified. Conclusions Our results indicate that the neighborhood deprivation level influences stroke incidence in Japan, suggesting that area socioeconomic conditions could be a potential target for public health intervention to reduce the risk of stroke. PMID:25757802

Aphasia As a Predictor of Stroke Outcome.

PubMed

Lazar, Ronald M; Boehme, Amelia K

2017-09-19

Aphasia is a common feature of stroke, affecting 21-38% of acute stroke patients and an estimated 1 million stroke survivors. Although stroke, as a syndrome, is the leading cause of disability in the USA, less is known about the independent impact of aphasia on stroke outcomes. During the acute stroke period, aphasia has been found to increase length of stay, inpatient complications, overall neurological disability, mortality, and to alter discharge disposition. Outcomes during the sub-acute and chronic stroke periods show that aphasia is associated with lower Functional Independence Measures (FIM) scores, longer stays in rehabilitation settings, poorer function in activities of daily living, and mortality. Factors that complicate the analysis of aphasia on post-stroke outcomes, however, include widely different systems of care across international settings that result in varying admission patterns to acute stroke units, allowable length of stays based on reimbursement, and criteria for rehabilitation placement. Aphasia arising from stroke is associated with worse outcomes both in the acute and chronic periods. Future research will have to incorporate disparate patterns in analytic models, and to take into account specific aphasia profiles and evolving methods of post-stroke speech-language therapy.

Return stroke velocities and currents using a solid state silicon detector system

NASA Technical Reports Server (NTRS)

Mach, Douglas M.; Rust, W. David

1988-01-01

A small, portable device has been developed to measure return stroke velocities. With the device, velocities from 135 strokes that consist of 92 natural return strokes and 43 triggered return strokes have been analyzed. The average return stroke velocity for longer channels, greater than 500 meters, is 1.2 + or - 0.3 x 10 to the 8th m/s for both natural and triggered return strokes. For shorter channel lengths, less than 500 m, natural lightning has a statistically higher average return stroke velocity of 1.9 + or - 0.7 x 10 to the 8th m/s than triggered lightning with an average return stroke velocity of 1.4 + or - 0.4 x 10 to the 8th m/s. Using the transmission line model of the return stroke, natural lightning has a peak current distribution that is log-normal with a median value of 19 kA. Return stroke velocities and currents were determined for two distant single stroke natural positive cloud-to-ground flashes. The velocities were 1.0 and 1.7 x 10 to the 8th ms/s while the estimated peak current for each positive flash was over 125 kA.

Photoelectric return-stroke velocity and peak current estimates in natural and triggered lightning

NASA Technical Reports Server (NTRS)

Mach, Douglas M.; Rust, W. David

1989-01-01

Two-dimensional photoelectric return stroke velocities from 130 strokes are presented, including 86 negative natural, 41 negative triggered, one positive triggered, and two positive natural return strokes. For strokes starting near the ground and exceeding 500 m in length, the average velocity is 1.3 + or - 0.3 X 10 to the 8th m/s for natural return strokes and 1.2 + or - 0.3 X 10 to the 8th m/s for triggered return strokes. For strokes with lengths less than 500 m, the average velocities are slightly higher. Using the transmission line model (TLM), the shortest segment one-dimensional return stroke velocity, and either the maximum or plateau electric field, it is shown that natural strokes have a peak current distribution that is lognormal with a median value of 16 kA (maximum E) or 12 kA (plateau E). Triggered lightning has a medium peak current value of 21 kA (maximum E) or 15 kA (plateau E). Correlations are found between TLM peak currents and velocities for triggered and natural subsequent return strokes, but not between TLM peak currents and natural first return stroke velocities.

Fusion of multiscale wavelet-based fractal analysis on retina image for stroke prediction.

PubMed

Che Azemin, M Z; Kumar, Dinesh K; Wong, T Y; Wang, J J; Kawasaki, R; Mitchell, P; Arjunan, Sridhar P

2010-01-01

In this paper, we present a novel method of analyzing retinal vasculature using Fourier Fractal Dimension to extract the complexity of the retinal vasculature enhanced at different wavelet scales. Logistic regression was used as a fusion method to model the classifier for 5-year stroke prediction. The efficacy of this technique has been tested using standard pattern recognition performance evaluation, Receivers Operating Characteristics (ROC) analysis and medical prediction statistics, odds ratio. Stroke prediction model was developed using the proposed system.

Factors related to community participation by stroke victims six month post-stroke.

PubMed

Jalayondeja, Chutima; Kaewkungwal, Jaranit; Sullivan, Patricia E; Nidhinandana, Samart; Pichaiyongwongdee, Sopa; Jareinpituk, Sutthi

2011-07-01

Participation in the community socially by stroke victims is an optimal outcome post-stroke. We carried out a cohort study to evaluate a model for community participation by Thai stroke victims 6 months post-stroke. Six standardized instruments were used to assess the patient's status 1, 3 and 6 months after stroke. These were the modified Rankin Scale, the National Institute of Health Stroke Scale, the Fugl-Meyer Assessment and the Berg Balance Scale. The performance of activities of daily living and community ambulation were measured using the Barthel Index and walking velocity. Participation in the community was measured by the Stroke Impact Scale. The outcomes demographics and stroke related variables were analyzed using the Generalized Estimating Equations. Of the 98 subjects who completed the follow-up assessment, 72 (86.5%) felt they had more participation in the community 6 months post-stroke. The level of disability, performance of independent activities and length of time receiving physical therapy were associated with the perceived level of participation in the community among stroke victims 6 months post-stroke. To achieve a goal of good participation in the community among stroke victims, health care planning should focus on improving the stroke victim's ability to independently perform daily activities. The average length of physical therapy ranged from 1 to 6 months, at 3 to 8 hours/month. Clinical practice guidelines should be explored to optimize participation in the community.

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

PubMed

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Sexual dimorphism in ischemic stroke: lessons from the laboratory

PubMed Central

Manwani, Bharti; McCullough, Louise D

2011-01-01

Ischemic stroke is emerging as a major health problem for elderly women. Women have lower stroke incidence than men until an advanced age, when the epidemiology of ischemic stroke shifts and incidence rises dramatically in women. Experimental models of rodent stroke have replicated this clinical epidemiology, with exacerbated injury in older compared with young female rodents Many of the detrimental effects of aging on ischemic stroke outcome in females can be replicated by ovariectomy, suggesting that hormones such as estrogen play a neuroprotective role. However, emerging data suggest that the molecular mechanisms leading to ischemic cell death differ in the two sexes, and these effects may be independent of circulating hormone levels. This article highlights recent clinical and experimental literature on sex differences in stroke outcomes and mechanisms. PMID:21612353

Acute effect of ambient air pollution on stroke mortality in the China air pollution and health effects study.

PubMed

Chen, Renjie; Zhang, Yuhao; Yang, Chunxue; Zhao, Zhuohui; Xu, Xiaohui; Kan, Haidong

2013-04-01

There have been no multicity studies on the acute effects of air pollution on stroke mortality in China. This study was undertaken to examine the associations between daily stroke mortality and outdoor air pollution (particulate matter <10 μm in aerodynamic diameter, sulfur dioxide, and nitrogen dioxide) in 8 Chinese cities. We used Poisson regression models with natural spline-smoothing functions to adjust for long-term and seasonal trends, as well as other time-varying covariates. We applied 2-stage Bayesian hierarchical statistical models to estimate city-specific and national average associations of air pollution with daily stroke mortality. Air pollution was associated with daily stroke mortality in 8 Chinese cities. In the combined analysis, an increase of 10 μg/m(3) of 2-day moving average concentrations of particulate matter <10 μm in aerodynamic diameter, sulfur dioxide, and nitrogen dioxide corresponded to 0.54% (95% posterior intervals, 0.28-0.81), 0.88% (95% posterior intervals, 0.54-1.22), and 1.47% (95% posterior intervals, 0.88-2.06) increase of stroke mortality, respectively. The concentration-response curves indicated linear nonthreshold associations between air pollution and risk of stroke mortality. To our knowledge, this is the first multicity study in China, or even in other developing countries, to report the acute effect of air pollution on stroke mortality. Our results contribute to very limited data on the effect of air pollution on stroke for high-exposure settings typical in developing countries.

Association Between Brain-Derived Neurotrophic Factor Genotype and Upper Extremity Motor Outcome After Stroke.

PubMed

Chang, Won Hyuk; Park, Eunhee; Lee, Jungsoo; Lee, Ahee; Kim, Yun-Hee

2017-06-01

The identification of intrinsic factors for predicting upper extremity motor outcome could aid the design of individualized treatment plans in stroke rehabilitation. The aim of this study was to identify prognostic factors, including intrinsic genetic factors, for upper extremity motor outcome in patients with subacute stroke. A total of 97 patients with subacute stroke were enrolled. Upper limb motor impairment was scored according to the upper limb of Fugl-Meyer assessment score at 3 months after stroke. The prediction of upper extremity motor outcome at 3 months was modeled using various factors that could potentially influence this impairment, including patient characteristics, baseline upper extremity motor impairment, functional and structural integrity of the corticospinal tract, and brain-derived neurotrophic factor genotype. Multivariate ordinal logistic regression models were used to identify the significance of each factor. The independent predictors of motor outcome at 3 months were baseline upper extremity motor impairment, age, stroke type, and corticospinal tract functional integrity in all stroke patients. However, in the group with severe motor impairment at baseline (upper limb score of Fugl-Meyer assessment <25), the number of Met alleles in the brain-derived neurotrophic factor genotype was also an independent predictor of upper extremity motor outcome 3 months after stroke. Brain-derived neurotrophic factor genotype may be a potentially useful predictor of upper extremity motor outcome in patients with subacute stroke with severe baseline motor involvement. © 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.

Academic-industry Collaborations in Translational Stroke Research.

PubMed

Boltze, Johannes; Wagner, Daniel-Christoph; Barthel, Henryk; Gounis, Matthew J

2016-08-01

Academic-industry collaborations are an emerging format of translational stroke research. Next to classic contract research models, a multitude of collaboration models has been developed, some of which even allowing for multinational or intercontinental research programs. This development has recently been paralleled by first successful attempts to overcome the translational stroke research road block, such as the unprecedented success of novel endovascular approaches or the advent of the multicenter preclinical trial concept. While the first underlines the role of the industry as a major innovation driver in stroke research, the latter will require enrollment of industrial partners for optimal output. Moreover, academic-industry partnerships are invaluable to bridge the translational "valley of death" as well as funding gaps in times of dwindling public funding and declining high risk capital investments. However, these collaborations are also subject to relevant challenges because interests, values, and aims often significantly differ between cademia and industry. Here, we describe common academic-industry collaboration models as well as associated benefits and challenges in the stroke research arena. We also suggest strategies for improved planning, implementation, guidance, and utilization of academic-industry collaborations to the maximum mutual benefit.

Community Based Participatory Research: A New approach to engaging community members to rapidly call 911 for Stroke

PubMed Central

Skolarus, Lesli E.; Zimmerman, Marc A.; Murphy, Jillian; Brown, Devin L.; Kerber, Kevin A.; Bailey, Sarah; Fowlkes, Sophronia; Morgenstern, Lewis B.

2014-01-01

Background and Purpose Acute stroke treatments are underutilized primarily due to delayed hospital arrival. Using a community based participatory research approach, we explored stroke self-efficacy, knowledge and perceptions of stroke among a predominately African American population in Flint, Michigan. Methods In March 2010, a survey was administered to youth and adults after religious services at three churches and one church health day. The survey consisted of vignettes (12 stroke, 4 non-stroke) to assess knowledge of stroke warning signs and behavioral intent to call 911. The survey also assessed stroke self-efficacy, personal knowledge of someone who had had a stroke, personal history of stroke and barriers to calling 911. Linear regression models explored the association of stroke self-efficacy with behavioral intent to call 911 among adults. Results Two hundred forty two adults and 90 youth completed the survey. Ninety two percent of adults and 90% of youth respondents were African American. Responding to 12 stroke vignettes, adults would call 911 in 72% (sd=0.26) of the vignettes while youth would call 911 in 54% (sd=0.29) (p<0.001). Adults correctly identified stroke in 51% (sd=0.32) of the stroke vignettes and youth in 46% (sd=0.28) of the stroke vignettes (p=0.28). Stroke self-efficacy predicted behavioral intent to call 911 (p=0.046). Conclusion In addition to knowledge of stroke warning signs, behavioral interventions to increase both stroke self-efficacy and behavioral intent may be useful for helping people make appropriate 911 calls for stroke. A community based participatory research approach may be effective in reducing stroke disparities. PMID:21617148

Community-based participatory research: a new approach to engaging community members to rapidly call 911 for stroke.

PubMed

Skolarus, Lesli E; Zimmerman, Marc A; Murphy, Jillian; Brown, Devin L; Kerber, Kevin A; Bailey, Sarah; Fowlkes, Sophronia; Morgenstern, Lewis B

2011-07-01

Acute stroke treatments are underutilized primarily because of delayed hospital arrival. Using a community-based participatory research approach, we explored stroke self-efficacy, knowledge, and perceptions of stroke among a predominately African American population in Flint, Michigan. In March 2010, a survey was administered to youth and adults after religious services at 3 churches and during 1 church health day. The survey consisted of vignettes (12 stroke, 4 nonstroke) to assess knowledge of stroke warning signs and behavioral intent to call 911. The survey also assessed stroke self-efficacy, personal knowledge of someone who had experienced a stroke, personal history of stroke, and barriers to calling 911. Linear regression models explored the association of stroke self-efficacy with behavioral intent to call 911 among adults. Two hundred forty-two adults and 90 youths completed the survey. Ninety-two percent of adults and 90% of youth respondents were African American. Responding to 12 stroke vignettes, adults would call 911 in 72% (SD, 0.26) of the vignettes, whereas youths would call 911 in 54% of vignettes (SD, 0.29; P<0.001). Adults correctly identified stroke in 51% (SD, 0.32) of the stroke vignettes and youth correctly identified stroke in 46% (SD, 0.28) of the stroke vignettes (P=0.28). Stroke self-efficacy predicted behavioral intent to call 911 (P=0.046). In addition to knowledge of stroke warning signs, behavioral interventions to increase both stroke self-efficacy and behavioral intent may be useful for helping people make appropriate 911 calls for stroke. A community-based participatory research approach may be effective in reducing stroke disparities.

A Unified Model of Cloud-to-Ground Lightning Stroke

NASA Astrophysics Data System (ADS)

Nag, A.; Rakov, V. A.

2014-12-01

The first stroke in a cloud-to-ground lightning discharge is thought to follow (or be initiated by) the preliminary breakdown process which often produces a train of relatively large microsecond-scale electric field pulses. This process is poorly understood and rarely modeled. Each lightning stroke is composed of a downward leader process and an upward return-stroke process, which are usually modeled separately. We present a unified engineering model for computing the electric field produced by a sequence of preliminary breakdown, 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 through the relatively-high-field region between the main negative and lower positive charge centers and then through the relatively-low-field region below the lower positive charge center. A relatively-high-field region is also assumed to exist near ground. The preliminary breakdown pulse train is assumed to be generated when the negatively-charged channel interacts with the lower positive charge region. At each step, an equivalent current source is activated at the lower extremity of the channel, resulting in a step current wave that propagates upward along the channel. The leader deposits net negative charge onto the channel. Once the stepped leader attaches to ground (upward connecting leader is presently neglected), an upward-propagating return stroke is initiated, which neutralizes the charge deposited by the leader along the channel. We examine the effect of various model parameters, such as step length and current propagation speed, on model-predicted electric fields. We also compare the computed fields with pertinent measurements available in the literature.

Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors.

PubMed

Andersen, Klaus Kaae; Olsen, Tom Skyhøj; Dehlendorff, Christian; Kammersgaard, Lars Peter

2009-06-01

Stroke patients with hemorrhagic (HS) and ischemic strokes were compared with regard to stroke severity, mortality, and cardiovascular risk factors. A registry started in 2001, with the aim of registering all hospitalized stroke patients in Denmark, now holds information for 39,484 patients. The patients underwent an evaluation including stroke severity (Scandinavian Stroke Scale), CT, and cardiovascular risk factors. They were followed-up from admission until death or censoring in 2007. Independent predictors of death were identified by means of a survival model based on 25,123 individuals with a complete data set. Of the patients 3993 (10.1%) had HS. Stroke severity was almost linearly related to the probability of having HS (2% in patients with the mildest stroke and 30% in those with the most severe strokes). Factors favoring ischemic strokes vs HS were diabetes, atrial fibrillation, previous myocardial infarction, previous stroke, and intermittent arterial claudication. Smoking and alcohol consumption favored HS, whereas age, sex, and hypertension did not herald stroke type. Compared with ischemic strokes, HS was associated with an overall higher mortality risk (HR, 1.564; 95% CI, 1.441-1.696). The increased risk was, however, time-dependent; initially, risk was 4-fold, after 1 week it was 2.5-fold, and after 3 weeks it was 1.5-fold. After 3 months stroke type did not correlate to mortality. Strokes are generally more severe in patients with HS. Within the first 3 months after stroke, HS is associated with a considerable increase of mortality, which is specifically associated with the hemorrhagic nature of the lesion.

Real-time imaging for cerebral ischemia in rats using the multi-wavelength handheld photoacoustic system

NASA Astrophysics Data System (ADS)

Liu, Yu-Hang; Xu, Yu; Chan, Kim Chuan; Mehta, Kalpesh; Thakor, Nitish; Liao, Lun-De

2017-02-01

Stroke is the second leading cause of death worldwide. Rapid and precise diagnosis is essential to expedite clinical decision and improve functional outcomes in stroke patients; therefore, real-time imaging plays an important role to provide crucial information for post-stroke recovery analysis. In this study, based on the multi-wavelength laser and 18.5 MHz array-based ultrasound platform, a real-time handheld photoacoustic (PA) system was developed to evaluate cerebrovascular functions pre- and post-stroke in rats. Using this system, hemodynamic information such as cerebral blood volume (CBV) can be acquired for assessment. One rat stroke model (i.e., photothrombotic ischemia (PTI)) was employed for evaluating the effect of local ischemia. For achieving better intrinsic PA contrast, Vantage and COMSOL simulations were applied to optimize the light delivery (e.g., interval between two arms) from customized fiber bundle, while phantom experiment was conducted to evaluate the imaging performance of this system. Results of phantom experiment showed that hairs ( 150 μm diameter) and pencil lead (500 μm diameter) can be imaged clearly. On the other hand, results of in vivo experiments also demonstrated that stroke symptoms can be observed in PTI model poststroke. In the near future, with the help of PA specific contrast agent, the system would be able to achieve blood-brain barrier leakage imaging post-stroke. Overall, the real-time handheld PA system holds great potential in disease models involving impairments in cerebrovascular functions.

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).

Innovative approaches helpful to enhance knowledge on weather-related stroke events over a wide geographical area and a large population.

PubMed

Morabito, Marco; Crisci, Alfonso; Vallorani, Roberto; Modesti, Pietro Amedeo; Gensini, Gian Franco; Orlandini, Simone

2011-03-01

Results on the effect of weather on stroke occurrences are still confusing and controversial. The aim of this study was to retrospectively investigate in Tuscany (central Italy) the weather-related stroke events through the use of an innovative source of weather data (Reanalysis) together with an original statistical approach to quantify the prompt/delayed health effects of both cold and heat exposures. Daily stroke hospitalizations and meteorologic data from the Reanalysis 2 Achieve were obtained for the period 1997 to 2007. Generalized linear and additive models and an innovative modeling approach, the constrained segmented distributed lag model, were applied. Both daily averages and day-to-day changes of air temperature and geopotential height (a measure that approximates the mean surface pressure) were selected as independent predictors of all stroke occurrences. In particular, a 5°C temperature decrease was associated with 16.5% increase of primary intracerebral hemorrhage of people ≥65 years of age. A general short-term cold effect on hospitalizations limited to 1 week after exposure was observed and, for the first time, a clear harvesting effect (deficit of hospitalization) for cold-related primary intracerebral hemorrhage was described. Day-to-day changes of meteorologic parameters disclosed characteristic U- and J-shaped relationships with stroke occurrences. Thanks to the intrinsic characteristic of Reanalysis, these results might simply be implemented in an operative forecast system regarding weather-related stroke events with the aim to develop preventive health plans.

Physical Activity Patterns of Acute Stroke Patients Managed in a Rehabilitation Focused Stroke Unit

PubMed Central

2013-01-01

Background. Comprehensive stroke unit care, incorporating acute care and rehabilitation, may promote early physical activity after stroke. However, previous information regarding physical activity specific to the acute phase of stroke and the comprehensive stroke unit setting is limited to one stroke unit. This study describes the physical activity undertaken by patients within 14 days after stroke admitted to a comprehensive stroke unit. Methods. This study was a prospective observational study. Behavioural mapping was used to determine the proportion of the day spent in different activities. Therapist reports were used to determine the amount of formal therapy received on the day of observation. The timing of commencement of activity out of bed was obtained from the medical records. Results. On average, patients spent 45% (SD 25) of the day in some form of physical activity and received 58 (SD 34) minutes per day of physiotherapy and occupational therapy combined. Mean time to first mobilisation out of bed was 46 (SD 32) hours post-stroke. Conclusions. This study suggests that commencement of physical activity occurs earlier and physical activity is at a higher level early after stroke in this comprehensive stroke unit, when compared to studies of other acute stroke models of care. PMID:24024192

Incremental costs associated with myocardial infarction and stroke in patients with type 2 diabetes mellitus: an overview for economic modeling.

PubMed

Brennan, Victoria K; Colosia, Ann D; Copley-Merriman, Catherine; Mauskopf, Josephine; Hass, Bastian; Palencia, Roberto

2014-07-01

To identify cost estimates related to myocardial infarction (MI) or stroke in patients with type 2 diabetes mellitus (T2DM) for use in economic models. A systematic literature review was conducted. Electronic databases and conference abstracts were screened against inclusion criteria, which included studies performed in patients who had T2DM before experiencing an MI or stroke. Primary cost studies and economic models were included. Costs were converted to 2012 pounds sterling. Fifty-four studies were identified: 13 primary cost studies and 41 economic evaluations using secondary sources for complication costs. Primary studies provided costs from 10 countries. Estimates for a fatal event ranged from £2482-£5222 for MI and from £4900-£6694 for stroke. Costs for the year a non-fatal event occurred ranged from £5071-£29,249 for MI and from £5171-£38,732 for stroke. Annual follow-up costs ranged from £945-£1616 for an MI and from £4704-£12,926 for a stroke. Economic evaluations from 12 countries were identified, and costs of complications showed similar variability to the primary studies. The costs identified within primary studies varied between and within countries. Many studies used costs estimated in studies not specific to patients with T2DM. Data gaps included a detailed breakdown of resource use, which affected the ability to compare data across countries. In the development of economic models for patients with T2DM, the use of accurate estimates of costs associated with MI and stroke is important. When country-specific costs are not available, clear justification for the choice of estimates should be provided.

Clinical- and imaging-based prediction of stroke risk after transient ischemic attack: the CIP model.

PubMed

Ay, Hakan; Arsava, E Murat; Johnston, S Claiborne; Vangel, Mark; Schwamm, Lee H; Furie, Karen L; Koroshetz, Walter J; Sorensen, A Gregory

2009-01-01

Predictive instruments based on clinical features for early stroke risk after transient ischemic attack suffer from limited specificity. We sought to combine imaging and clinical features to improve predictions for 7-day stroke risk after transient ischemic attack. We studied 601 consecutive patients with transient ischemic attack who had MRI within 24 hours of symptom onset. A logistic regression model was developed using stroke within 7 days as the response criterion and diffusion-weighted imaging findings and dichotomized ABCD(2) score (ABCD(2) >/=4) as covariates. Subsequent stroke occurred in 25 patients (5.2%). Dichotomized ABCD(2) score and acute infarct on diffusion-weighted imaging were each independent predictors of stroke risk. The 7-day risk was 0.0% with no predictor, 2.0% with ABCD(2) score >/=4 alone, 4.9% with acute infarct on diffusion-weighted imaging alone, and 14.9% with both predictors (an automated calculator is available at http://cip.martinos.org). Adding imaging increased the area under the receiver operating characteristic curve from 0.66 (95% CI, 0.57 to 0.76) using the ABCD(2) score to 0.81 (95% CI, 0.74 to 0.88; P=0.003). The sensitivity of 80% on the receiver operating characteristic curve corresponded to a specificity of 73% for the CIP model and 47% for the ABCD(2) score. Combining acute imaging findings with clinical transient ischemic attack features causes a dramatic boost in the accuracy of predictions with clinical features alone for early risk of stroke after transient ischemic attack. If validated in relevant clinical settings, risk stratification by the CIP model may assist in early implementation of therapeutic measures and effective use of hospital resources.

Burden of stroke in Italy: an economic model highlights savings arising from reduced disability following thrombolysis.

PubMed

Chiumente, M; Gianino, M M; Minniti, D; Mattei, T J; Spass, B; Kamal, K M; Zimmerman, D E; Muca, A; Luda, E

2015-08-01

The consequences of stroke must be assessed not only in terms of incidence and mortality rates, but also in terms of disability, which may persist long after the acute phase. Thrombolysis, if timely administered, can effectively reduce post-stroke disability. The economic model presented herein aims to evaluate, in eligible patients, the effects of alteplase on post-stroke disability and related costs over three-years. The economic analysis was developed on the basis of four key components: clinical outcomes from international trials, economic consequences extracted from cost of illness studies, regulatory data from national and international agencies, and national epidemiological data. A population-level model estimated the difference in disability costs between patients treated with standard care versus those receiving thrombolytic therapy within 4×5 h of acute ischemic stroke. The analysis covered 36 months from discharge. Reduced costs related to post-stroke disability were observed in treated patients compared with those receiving standard care (control). The overall savings were €2330×15 per average patient: €1445×81 during the first 18 months, €362×25 between 18 and 24 months, and €522×09 in the 24-36 months period. The overall savings on 3174 Italian treated patients in 2013 were €7 395 907 over three-years. Our study reveals that performing thrombolytic therapy in eligible patients improves economic outcomes compared with patients receiving standard care. This model is useful for decision makers, both within and outside of the Italian national context, as a tool to assess the cost-effectiveness of thrombolysis in both short- and long-term period. © 2015 World Stroke Organization.

Modelling Future Cardiovascular Disease Mortality in the United States: National Trends and Racial and Ethnic Disparities

PubMed Central

Pearson-Stuttard, Jonathan; Guzman-Castillo, Maria; Penalvo, Jose L.; Rehm, Colin D.; Afshin, Ashkan; Danaei, Goodarz; Kypridemos, Chris; Gaziano, Tom; Mozaffarian, Dariush; Capewell, Simon; O’Flaherty, Martin

2016-01-01

Background Accurate forecasting of cardiovascular disease (CVD) mortality is crucial to guide policy and programming efforts. Prior forecasts have often not incorporated past trends in rates of reduction in CVD mortality. This creates uncertainties about future trends in CVD mortality and disparities. Methods and Results To forecast US CVD mortality and disparities to 2030, we developed a hierarchical Bayesian model to determine and incorporate prior age, period and cohort (APC) effects from 1979–2012, stratified by age, gender and race; which we combined with expected demographic shifts to 2030. Data sources included the National Vital Statistics System, SEER single year population estimates, and US Bureau of Statistics 2012 National Population projections. We projected coronary disease and stroke deaths to 2030, first based on constant APC effects at 2012 values, as most commonly done (conventional); and then using more rigorous projections incorporating expected trends in APC effects (trend-based). We primarily evaluated absolute mortality. The conventional model projected total coronary and stroke deaths by 2030 to increase by approximately 18% (67,000 additional coronary deaths/year) and 50% (64,000 additional stroke deaths/year). Conversely, the trend-based model projected that coronary mortality would fall by 2030 by approximately 27% (79,000 fewer deaths/year); and stroke mortality would remain unchanged (200 fewer deaths/year). Health disparities will be improved in stroke deaths, but not coronary deaths. Conclusions After accounting for prior mortality trends and expected demographic shifts, total US coronary deaths are expected to decline, while stroke mortality will remain relatively constant. Health disparities in stroke, but not coronary, deaths will be improved but not eliminated. These APC approaches offer more plausible predictions than conventional estimates. PMID:26846769

Prediction of Ischemic Heart Disease and Stroke in Survivors of Childhood Cancer.

PubMed

Chow, Eric J; Chen, Yan; Hudson, Melissa M; Feijen, Elizabeth A M; Kremer, Leontien C; Border, William L; Green, Daniel M; Meacham, Lillian R; Mulrooney, Daniel A; Ness, Kirsten K; Oeffinger, Kevin C; Ronckers, Cécile M; Sklar, Charles A; Stovall, Marilyn; van der Pal, Helena J; van Dijk, Irma W E M; van Leeuwen, Flora E; Weathers, Rita E; Robison, Leslie L; Armstrong, Gregory T; Yasui, Yutaka

2018-01-01

Purpose We aimed to predict individual risk of ischemic heart disease and stroke in 5-year survivors of childhood cancer. Patients and Methods Participants in the Childhood Cancer Survivor Study (CCSS; n = 13,060) were observed through age 50 years for the development of ischemic heart disease and stroke. Siblings (n = 4,023) established the baseline population risk. Piecewise exponential models with backward selection estimated the relationships between potential predictors and each outcome. The St Jude Lifetime Cohort Study (n = 1,842) and the Emma Children's Hospital cohort (n = 1,362) were used to validate the CCSS models. Results Ischemic heart disease and stroke occurred in 265 and 295 CCSS participants, respectively. Risk scores based on a standard prediction model that included sex, chemotherapy, and radiotherapy (cranial, neck, and chest) exposures achieved an area under the curve and concordance statistic of 0.70 and 0.70 for ischemic heart disease and 0.63 and 0.66 for stroke, respectively. Validation cohort area under the curve and concordance statistics ranged from 0.66 to 0.67 for ischemic heart disease and 0.68 to 0.72 for stroke. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were < 5%, compared with approximately 20% for high-risk groups ( P < .001); cumulative incidence was only 1% for siblings ( P < .001 v low-risk survivors). Conclusion Information available to clinicians soon after completion of childhood cancer therapy can predict individual risk for subsequent ischemic heart disease and stroke with reasonable accuracy and discrimination through age 50 years. These models provide a framework on which to base future screening strategies and interventions.

Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts.

PubMed

Piccini, Jonathan P; Stevens, Susanna R; Chang, YuChiao; Singer, Daniel E; Lokhnygina, Yuliya; Go, Alan S; Patel, Manesh R; Mahaffey, Kenneth W; Halperin, Jonathan L; Breithardt, Günter; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Nessel, Christopher C; Fox, Keith A A; Califf, Robert M

2013-01-15

We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R(2)CHADS(2)) improved net reclassification index by 6.2% compared with CHA(2)DS(2)VASc (C statistic=0.578) and by 8.2% compared with CHADS(2) (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R(2)CHADS(2) in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS(2). In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00403767.

Web-based tool for dynamic functional outcome after acute ischemic stroke and comparison with existing models.

PubMed

Ji, Ruijun; Du, Wanliang; Shen, Haipeng; Pan, Yuesong; Wang, Penglian; Liu, Gaifen; Wang, Yilong; Li, Hao; Zhao, Xingquan; Wang, Yongjun

2014-11-25

Acute ischemic stroke (AIS) is one of the leading causes of death and adult disability worldwide. In the present study, we aimed to develop a web-based risk model for predicting dynamic functional status at discharge, 3-month, 6-month, and 1-year after acute ischemic stroke (Dynamic Functional Status after Acute Ischemic Stroke, DFS-AIS). The DFS-AIS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Good functional outcome was defined as modified Rankin Scale (mRS) score ≤ 2 at discharge, 3-month, 6-month, and 1-year after AIS, respectively. Independent predictors of each outcome measure were obtained using multivariable logistic regression. The area under the receiver operating characteristic curve (AUROC) and plot of observed and predicted risk were used to assess model discrimination and calibration. A total of 12,026 patients were included and the median age was 67 (interquartile range: 57-75). The proportion of patients with good functional outcome at discharge, 3-month, 6-month, and 1-year after AIS was 67.9%, 66.5%, 66.9% and 66.9%, respectively. Age, gender, medical history of diabetes mellitus, stroke or transient ischemic attack, current smoking and atrial fibrillation, pre-stroke dependence, pre-stroke statins using, admission National Institutes of Health Stroke Scale score, admission blood glucose were identified as independent predictors of functional outcome at different time points after AIS. The DFS-AIS was developed from sets of predictors of mRS ≤ 2 at different time points following AIS. The DFS-AIS demonstrated good discrimination in the derivation and validation cohorts (AUROC range: 0.837-0.845). Plots of observed versus predicted likelihood showed excellent calibration in the derivation and validation cohorts (all r = 0.99, P < 0.001). When compared to 8 existing models, the DFS-AIS showed significantly better discrimination for good functional outcome and mortality at discharge, 3-month, 6-month, and 1-year after AIS (all P < 0.0001). The DFS-AIS is a valid risk model to predict functional outcome at discharge, 3-month, 6-month, and 1-year after AIS.

The influence of ground conductivity on the structure of RF radiation from return strokes

NASA Technical Reports Server (NTRS)

Levine, D. M.; Gesell, L.

1984-01-01

The combination of the finite conductivity of the Earth plus the propagation of the return stroke current up the channel which results in an apparent time delay between the fast field changes and RF radiation for distant observers is shown. The time delay predicted from model return strokes is on the order of 20 micro and the received signal has the characteristics of the data observed in Virginia and Florida. A piecewise linear model for the return stroke channel and a transmission line model for current propagation on each segment was used. Radiation from each segment is calculated over a flat Earth with finite conductivity using asymptotics approximations for the Sommerfeld integrals. The radiation at the observer is processed by a model AM radio receiver. The output voltage was calculated for several frequencies between HF-UHF assuming a system bandwidth (300 kHz) characteristic of the system used to collect data in Florida and Virginia. Comparison with the theoretical fast field changes indicates a time delay of 20 microns.

[Application of Competing Risks Model in Predicting Smoking Relapse Following Ischemic Stroke].

PubMed

Hou, Li-Sha; Li, Ji-Jie; Du, Xu-Dong; Yan, Pei-Jing; Zhu, Cai-Rong

2017-07-01

To determine factors associated with smoking relapse in men who survived from their first stroke. Data were collected through face to face interviews with stroke patients in the hospital, and then repeated every three months via telephone over the period from 2010 to 2014. Kaplan-Meier method and competing risk model were adopted to estimate and predict smoking relapse rates. The Kaplan-Meier method estimated a higher relapse rate than the competing risk model. The four-year relapse rate was 43.1% after adjustment of competing risk. Exposure to environmental tobacco smoking outside of home and workplace (such as bars and restaurants) ( P =0.01), single ( P <0.01), and prior history of smoking at least 20 cigarettes per day ( P =0.02) were significant predictors of smoking relapse. When competing risks exist, competing risks model should be used in data analyses. Smoking interventions should give priorities to those without a spouse and those with a heavy smoking history. Smoking ban in public settings can reduce smoking relapse in stroke patients.

Classifying Acute Ischemic Stroke Onset Time using Deep Imaging Features

PubMed Central

Ho, King Chung; Speier, William; El-Saden, Suzie; Arnold, Corey W.

2017-01-01

Models have been developed to predict stroke outcomes (e.g., mortality) in attempt to provide better guidance for stroke treatment. However, there is little work in developing classification models for the problem of unknown time-since-stroke (TSS), which determines a patient’s treatment eligibility based on a clinical defined cutoff time point (i.e., <4.5hrs). In this paper, we construct and compare machine learning methods to classify TSS<4.5hrs using magnetic resonance (MR) imaging features. We also propose a deep learning model to extract hidden representations from the MR perfusion-weighted images and demonstrate classification improvement by incorporating these additional imaging features. Finally, we discuss a strategy to visualize the learned features from the proposed deep learning model. The cross-validation results show that our best classifier achieved an area under the curve of 0.68, which improves significantly over current clinical methods (0.58), demonstrating the potential benefit of using advanced machine learning methods in TSS classification. PMID:29854156

A time-series analysis of the relation between unemployment rate and hospital admission for acute myocardial infarction and stroke in Brazil over more than a decade.

PubMed

Katz, Marcelo; Bosworth, Hayden B; Lopes, Renato D; Dupre, Matthew E; Morita, Fernando; Pereira, Carolina; Franco, Fabio G M; Prado, Rogerio R; Pesaro, Antonio E; Wajngarten, Mauricio

2016-12-01

The effect of socioeconomic stressors on the incidence of cardiovascular disease (CVD) is currently open to debate. Using time-series analysis, our study aimed to evaluate the relationship between unemployment rate and hospital admission for acute myocardial infarction (AMI) and stroke in Brazil over a recent 11-year span. Data on monthly hospital admissions for AMI and stroke from March 2002 to December 2013 were extracted from the Brazilian Public Health System Database. The monthly unemployment rate was obtained from the Brazilian Institute for Applied Economic Research, during the same period. The autoregressive integrated moving average (ARIMA) model was used to test the association of temporal series. Statistical significance was set at p<0.05. From March 2002 to December 2013, 778,263 admissions for AMI and 1,581,675 for stroke were recorded. During this time period, the unemployment rate decreased from 12.9% in 2002 to 4.3% in 2013, while admissions due to AMI and stroke increased. However, the adjusted ARIMA model showed a positive association between the unemployment rate and admissions for AMI but not for stroke (estimate coefficient=2.81±0.93; p=0.003 and estimate coefficient=2.40±4.34; p=0.58, respectively). From 2002 to 2013, hospital admissions for AMI and stroke increased, whereas the unemployment rate decreased. However, the adjusted ARIMA model showed a positive association between unemployment rate and admissions due to AMI but not for stroke. Further studies are warranted to validate our findings and to better explore the mechanisms by which socioeconomic stressors, such as unemployment, might impact on the incidence of CVD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Magnetic Resonance Imaging of Stroke in the Rat

PubMed Central

CHOPP, Michael; LI, Lian; ZHANG, Li; ZHANG, Zheng-gang; LI, Qing-jiang; JIANG, Quan

2014-01-01

Magnetic resonance imaging (MRI) is now a routine neuroimaging tool in the clinic. Throughout all phases of stroke from acute to chronic, MRI plays an important role to diagnose, evaluate and monitor the cerebral tissue undergoing stroke. This review provides a description of various MRI methods and an overview of selected MRI studies, with an embolic stroke model of rat, performed in the MRI laboratory of Department of Neurology, Henry Ford Hospital, Detroit, Michigan, US. PMID:24920874

The impact of APOA5, APOB, APOC3 and ABCA1 gene polymorphisms on ischemic stroke: Evidence from a meta-analysis.

PubMed

Au, Anthony; Griffiths, Lyn R; Irene, Looi; Kooi, Cheah Wee; Wei, Loo Keat

2017-10-01

Genetic studies have been reported on the association between APOA5, APOB, APOC3 and ABCA1 gene polymorphisms and ischemic stroke, but results remain controversial. Hence, this meta-analysis aimed to infer the causal relationships of APOA5 (rs662799, rs3135506), APOB (rs693, rs1042031, rs1801701), APOC3 (rs4520, rs5128, rs2854116, rs2854117) and ABCA1 rs2230806 with ischemic stroke risk. A systematic review was performed for all the articles retrieved from multiple databases, up until March 2017. Data were extracted from all eligible studies, and meta-analysis was carried out using RevMan 5.3 and R package 3.2.1. The strength of association between each studied polymorphism and ischemic stroke risk was measured as odds ratios (ORs) and 95% confidence intervals (CIs), under fixed- and random-effect models. A total of 79 studies reporting on the association between the studied polymorphisms and ischemic stroke risk were identified. The pooled data indicated that all genetic models of APOA5 rs662799 (ORs = 1.23-1.43), allelic and over-dominant models of APOA5 rs3135506 (ORs = 1.77-1.97), APOB rs1801701 (ORs = 1.72-2.13) and APOB rs1042031 (ORs = 1.66-1.88) as well as dominant model of ABCA1 rs2230806 (OR = 1.31) were significantly associated with higher risk of ischemic stroke. However, no significant associations were observed between ischemic stroke and the other five polymorphisms, namely ApoB (rs693) and APOC3 (rs4520, rs5128, rs2854116 and rs2854117), under any genetic model. The present meta-analysis confirmed a significant association of APOA5 rs662799 CC, APOA5 rs3135506 CG, APOB rs1801701 GA, APOB rs1042031 GA and ABCA1 rs2230806 GG with increased risk of ischemic stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

Trends in one-year mortality for stroke in a tertiary academic center in Saudi Arabia: a 5-year retrospective analysis.

PubMed

Almekhlafi, Mohammed A

2016-01-01

Numerous studies have reported a decline in stroke-related mortality in developed countries. To assess trends in one-year mortality following a stroke diagnosis in Saudi Arabia. Retrospective longitudinal cohort study. Single tertiary care center from 2010 through 2014. All patients admitted with a primary admitting diagnosis of stroke. Demographic data (age, gender, nationality), risk factor profile, stroke subtypes, in-hospital complications and mortality data as well as cause of death were collected for all patients. A multivariable logistic regression model was used to assess factors associated with one-year mortality following a stroke admission. One-year mortality. In 548 patients with a mean age of 62.9 years (SD 16.9), the most frequent vascular risk factors were hypertension (90.6%), diabetes (65.5%), and hyperlipidemia (27.2%). Hemorrhagic stroke was diagnosed in 9.9%. The overall mortality risk was 26.9%. Non-Saudis had a significantly higher one-year mortality risk compared with Saudis (25% vs. 16.8%, respectively; P=.025). The most frequently reported causes of mortality were neurological and related to the underlying stroke (32%), sepsis (30%), and cardiac or other organ dysfunction-related (each 9%) in addition to other etiologies (collectively 9.5%) such as pulmonary embolism or an underlying malignancy. Significant predictors in the multivariate model were age (P < .0001), non-Saudi nationality (OR 1.8, CI 95 1.1 to 2.9; P=.019), and hospital length of stay (OR 1.01, CI 95 1 to 1.004; P=.001). We observed no decline in stroke mortality in our center over the 5-year span. The establishment of stroke systems of care, use of thrombolytic agents, and opening of a stroke unit should play an important role in a decline in stroke mortality. Retrospective single center study. Mortality data were available only for patients who died in our hospital.

Ethnic Comparison of 30-Day Potentially Preventable Readmissions After Stroke in Hawaii.

PubMed

Nakagawa, Kazuma; Ahn, Hyeong Jun; Taira, Deborah A; Miyamura, Jill; Sentell, Tetine L

2016-10-01

Ethnic disparities in readmission after stroke have been inadequately studied. We sought to compare potentially preventable readmissions (PPR) among a multiethnic population in Hawaii. Hospitalization data in Hawaii from 2007 to 2012 were assessed to compare ethnic differences in 30-day PPR after stroke-related hospitalizations. Multivariable models using logistic regression were performed to assess the impact of ethnicity on 30-day PPR after controlling for age group (<65 and ≥65 years), sex, insurance, county of residence, substance use, history of mental illness, and Charlson Comorbidity Index. Thirty-day PPR was seen in 840 (8.4%) of 10 050 any stroke-related hospitalizations, 712 (8.7%) of 8161 ischemic stroke hospitalizations, and 128 (6.8%) of 1889 hemorrhagic stroke hospitalizations. In the multivariable models, only the Chinese ethnicity, compared with whites, was associated with 30-day PPR after any stroke hospitalizations (odds ratio [OR] [95% confidence interval {CI}], 1.40 [1.05-1.88]) and ischemic stroke hospitalizations (OR, 1.42 [CI, 1.04-1.96]). When considering only one hospitalization per individual, the impact of Chinese ethnicity on PPR after any stroke hospitalization (OR, 1.22 [CI, 0.89-1.68]) and ischemic stroke hospitalization (OR, 1.21 [CI, 0.86-1.71]) was attenuated. Other factors associated with 30-day PPR after any stroke hospitalizations were Charlson Comorbidity Index (per unit increase) (OR, 1.21 [CI, 1.18-1.24]), Medicaid (OR, 1.42 [CI, 1.07-1.88]), Hawaii county (OR, 0.78 [CI, 0.62-0.97]), and mental illness (OR, 1.37 [CI, 1.10-1.70]). In Hawaii, Chinese may have a higher risk of 30-day PPR after stroke compared with whites. However, this seems to be driven by the high number of repeated PPR within the Chinese ethnic group. © 2016 American Heart Association, Inc.

Vitamin D deficiency and incident stroke risk in community-living black and white adults.

PubMed

Judd, Suzanne E; Morgan, Charity J; Panwar, Bhupesh; Howard, Virginia J; Wadley, Virginia G; Jenny, Nancy S; Kissela, Brett M; Gutiérrez, Orlando M

2016-01-01

Black individuals are at greater risk of stroke and vitamin D deficiency than white individuals. Epidemiologic studies have shown that low 25-hydroxyvitamin D concentrations are associated with increased risk of stroke, but these studies had limited representation of black individuals. We examined the association of 25-hydroxyvitamin D with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years of age. Using a case-cohort study design, plasma 25-hydroxyvitamin D was measured in 610 participants who developed incident stroke (cases) and in 937 stroke-free individuals from a stratified cohort random sample of REGARDS participants (comparison cohort). In multivariable models adjusted for socio-demographic factors, co-morbidities and laboratory values including parathyroid hormone, lower 25-hydroxyvitamin D concentrations were associated with higher risk of stroke (25-hydroxyvitamin D >30 ng/mL reference; 25-hydroxyvitamin D concentrations 20-30 ng/mL, hazard ratio 1.33, 95% confidence interval (95% CI) 0.89,1.96; 25-hydroxyvitamin D <20 ng/mL, hazard ratio 1.85, 95% CI 1.17, 2.93). There were no statistically significant differences in the association of lower 25-hydroxyvitamin D with higher risk of stroke in black vs. white participants in fully adjusted models (hazard ratio comparing lowest vs. highest 25-hydroxyvitamin D category 2.62, 95% CI 1.18, 5.83 in blacks vs. 1.64, 95% CI 0.83, 3.24 in whites, P(interaction) = 0.82). The associations were qualitatively unchanged when restricted to ischemic or hemorrhagic stroke subtypes or when using race-specific cut-offs for 25-hydroxyvitamin D categories. Vitamin D deficiency is a risk factor for incident stroke and the strength of this association does not appear to differ by race. © 2016 World Stroke Organization.

The organisational context of nursing care in stroke units: a case study approach.

PubMed

Burton, Christopher R; Fisher, Andrea; Green, Theresa L

2009-01-01

Internationally the stroke unit is recognised as the evidence-based model for patient management, although clarity about the effective components of stroke units is lacking. Whilst skilled nursing care has been proposed as one component, the theoretical and empirical basis for stroke nursing is limited. We attempted to explore the organisational context of stroke unit nursing, to determine those features that staff perceived to be important in facilitating high quality care. A case study approach was used, that included interviews with nurses and members of the multidisciplinary teams in two Canadian acute stroke units. A total of 20 interviews were completed, transcribed and analysed thematically using the Framework Approach. Trustworthiness was established through the review of themes and their interpretation by members of the stroke units. Nine themes that comprised an organisational context that supported the delivery of high quality nursing care in acute stroke units were identified, and provide a framework for organisational development. The study highlighted the importance of an overarching service model to guide the organisation of care and the development of specialist and advanced nursing roles. Whilst multidisciplinary working appears to be a key component of stroke unit nursing, various organisational challenges to its successful implementation were highlighted. In particular the consequence of differences in the therapeutic approach of nurses and therapy staff needs to be explored in greater depth. Successful teamwork appears to depend on opportunities for the development of relationships between team members as much as the use of formal communication systems and structures. A co-ordinated approach to education and training, clinical leadership, a commitment to research, and opportunities for role and practice development also appear to be key organisational features of stroke unit nursing. Recommendations for the development of stroke nursing leadership and future research into teamwork in stroke settings are made.

Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke.

PubMed

Gelderblom, Mathias; Weymar, Anna; Bernreuther, Christian; Velden, Joachim; Arunachalam, Priyadharshini; Steinbach, Karin; Orthey, Ellen; Arumugam, Thiruma V; Leypoldt, Frank; Simova, Olga; Thom, Vivien; Friese, Manuel A; Prinz, Immo; Hölscher, Christoph; Glatzel, Markus; Korn, Thomas; Gerloff, Christian; Tolosa, Eva; Magnus, Tim

2012-11-01

The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T cell-dependent proinflammatory pathways in ischemia-reperfusion injury. IFN-γ produced by CD4(+) T cells induced TNF-α production in macrophages, whereas IL-17A secreted by γδ T cells led to neutrophil recruitment. The synergistic effect of TNF-α and IL-17A on astrocytes resulted in enhanced secretion of CXCL-1, a neutrophil chemoattractant. Application of an IL-17A-blocking antibody within 3 hours after stroke induction decreased infarct size and improved neurologic outcome in the murine model. In autoptic brain tissue of patients who had a stroke, we detected IL-17A-positive lymphocytes, suggesting that this aspect of the inflammatory cascade is also relevant in the human brain. We propose that selective targeting of IL-17A signaling might provide a new therapeutic option for the treatment of stroke.

Rasch analysis of the London Handicap Scale in stroke patients: a cross-sectional study.

PubMed

Park, Eun-Young; Choi, Yoo-Im

2014-07-31

Although activity and participation are the target domains in stroke rehabilitation interventions, there is insufficient evidence available regarding the validity of participation measurement. The purpose of this study was to investigate the psychometric properties of the London Handicap Scale in community-dwelling stroke patients, using Rasch analysis. Participants were 170 community-dwelling stroke survivors. The data were analyzed using Winsteps (version 3.62) with the Rasch model to determine the unidimensionality of item fit, the distribution of item difficulty, and the reliability and suitability of the rating process for the London Handicap Scale. Data of 16 participants did not fit the Rasch model and there were no misfitting items. The person separation value was 2.42, and the reliability was .85; furthermore, the rating process for the London Handicap Scale was found to be suitable for use with stroke patients. This was the first trial to investigate the psychometric properties of the London Handicap Scale using Rasch analysis; the results supported the suitability of this scale for use with stroke patients.

Ethnic Differences in Post-Stroke Quality of Life in the Brain Attack Surveillance in Corpus Christi (BASIC) Project

PubMed Central

Reeves, Sarah L; Brown, Devin L; Baek, Jonggyu; Wing, Jeffrey J; Morgenstern, Lewis B; Lisabeth, Lynda D

2015-01-01

Background and Purpose Mexican Americans (MAs) have an increased risk of stroke and experience worse post-stroke disability than non-Hispanic whites (NHWs), which may translate into worse post-stroke quality of life (QOL). We assessed ethnic differences in post-stroke QOL, as well as potential modification of associations by age, sex, and initial stroke severity. Methods Ischemic stroke survivors were identified through the biethnic, population-based Brain Attack Surveillance in Corpus Christi (BASIC) Project. Data were collected from medical records, baseline interviews, and 90-day post-stroke interviews. Post-stroke QOL was measured at approximately 90 days by the validated short-form stroke-specific QOL in 3 domains: overall, physical, and psychosocial (range 0–5; higher scores represent better QOL). Tobit regression was used to model associations between ethnicity and post-stroke QOL scores, adjusted for demographics, clinical characteristics, and pre-stroke cognition and function. Results Among 290 eligible stroke survivors (66% MA, 34% NHW, median age=69 years), median scores for overall, physical, and psychosocial post-stroke QOL were 3.3, 3.8 and 2.7, respectively. Overall post-stroke QOL was lower for MAs than NHWs (mean difference = −0.30, 95%CI:−0.59,−0.01) and in the physical domain (mean difference = −0.47, 95%CI:−0.81,−0.14) after multivariable adjustment. No ethnic difference was found in the psychosocial domain. Age modified the associations between ethnicity and post-stroke QOL such that differences were present in older but not younger ages. Conclusions Disparities exist in post-stroke QOL for MAs and appear to be driven by differences in older stroke patients. Targeted interventions to improve outcomes among MA stroke survivors are urgently needed. PMID:26286542

Stroke type differentiation using spectrally constrained multifrequency EIT: evaluation of feasibility in a realistic head model.

PubMed

Malone, Emma; Jehl, Markus; Arridge, Simon; Betcke, Timo; Holder, David

2014-06-01

We investigate the application of multifrequency electrical impedance tomography (MFEIT) to imaging the brain in stroke patients. The use of MFEIT could enable early diagnosis and thrombolysis of ischaemic stroke, and therefore improve the outcome of treatment. Recent advances in the imaging methodology suggest that the use of spectral constraints could allow for the reconstruction of a one-shot image. We performed a simulation study to investigate the feasibility of imaging stroke in a head model with realistic conductivities. We introduced increasing levels of modelling errors to test the robustness of the method to the most common sources of artefact. We considered the case of errors in the electrode placement, spectral constraints, and contact impedance. The results indicate that errors in the position and shape of the electrodes can affect image quality, although our imaging method was successful in identifying tissues with sufficiently distinct spectra.

The Effects of Various Weather Conditions as a Potential Ischemic Stroke Trigger in Dogs

PubMed Central

Silver, Gena M.

2017-01-01

Stroke is the fifth leading cause of death in the United States, and is the leading cause of serious, long-term disability worldwide. There are at least 795,000 new or recurrent strokes each year, and approximately 85% of all stroke occurrences are ischemic. Unfortunately, companion animals are also at risk for ischemic stroke. Although the exact incidence of ischemic stroke in companion animals is unknown, some studies, and the veterinary information network (VIN), report that approximately 3% of neurological case referrals are due to a stroke. There is a long list of predisposing factors associated with the risk of ischemic stroke in both humans and canines; however, these factors do not explain why a stroke happens at a particular time on a particular day. Our understanding of these potential stroke “triggers” is limited, and the effect of transient environmental exposures may be one such “trigger”. The present study investigated the extent to which the natural occurrence of canine ischemic stroke was related to the weather conditions in the time-period immediately preceding the onset of stroke. The results of the present study demonstrated that the change in weather conditions could be a potential stroke trigger, with the strokes evaluated occurring after periods of rapid, large fluctuations in weather conditions. There are currently no epidemiological data on the seasonal variability of ischemic stroke in dogs, and determining whether canine stroke parallels human stroke would further validate the use of companion dogs as an appropriate naturally occurring model. PMID:29144407

Lacunar Infarcts, Depression, and Anxiety Symptoms One Year after Stroke.

PubMed

Arba, Francesco; Ali, Myzoon; Quinn, Terence J; Hankey, Graeme J; Lees, Kennedy R; Inzitari, Domenico

2016-04-01

Mood disorders are frequent after stroke and are associated with poorer quality of life. Previous studies have reported conflicting results as to stroke subtype in the incidence of poststroke mood disorders. We explored the relationship between subcortical ischemic stroke subtype (lacunar) and presence of such symptoms at 1 year after stroke. Anonymized data were accessed from the Virtual International Stroke Trials Archive. Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment classification. Depression and anxiety symptoms were assessed using Hospital Anxiety and Depression Scale. We investigated independent predictors of depression and anxiety symptoms using a logistic regression model. Data were available for 2160 patients. Almost one fifth of the patients developed both anxiety and depression at 1-year follow-up. After adjusting for confounders, the lacunar subtype was least associated with both anxiety (odds ratio [OR] = .61; 95% confidence interval [CI] = .46-.80) and depression symptoms (OR = .71; CI = .55-.93) versus other stroke subtypes. Lacunar strokes have a weaker association with presence of anxiety and depression symptoms compared with other subtypes. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Drug discovery in prostate cancer mouse models.

PubMed

Valkenburg, Kenneth C; Pienta, Kenneth J

2015-01-01

The mouse is an important, though imperfect, organism with which to model human disease and to discover and test novel drugs in a preclinical setting. Many experimental strategies have been used to discover new biological and molecular targets in the mouse, with the hopes of translating these discoveries into novel drugs to treat prostate cancer in humans. Modeling prostate cancer in the mouse, however, has been challenging, and often drugs that work in mice have failed in human trials. The authors discuss the similarities and differences between mice and men; the types of mouse models that exist to model prostate cancer; practical questions one must ask when using a mouse as a model; and potential reasons that drugs do not often translate to humans. They also discuss the current value in using mouse models for drug discovery to treat prostate cancer and what needs are still unmet in field. With proper planning and following practical guidelines by the researcher, the mouse is a powerful experimental tool. The field lacks genetically engineered metastatic models, and xenograft models do not allow for the study of the immune system during the metastatic process. There remain several important limitations to discovering and testing novel drugs in mice for eventual human use, but these can often be overcome. Overall, mouse modeling is an essential part of prostate cancer research and drug discovery. Emerging technologies and better and ever-increasing forms of communication are moving the field in a hopeful direction.

Simultaneous and Noninvasive Imaging of Cerebral Oxygen Metabolic Rate, Blood Flow and Oxygen Extraction Fraction in Stroke Mice

PubMed Central

Zhu, Xiao-Hong; Chen, James; Tu, Tsang-Wei; Chen, Wei; Song, Sheng-Kwei

2012-01-01

Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO2 and CBF. This study employed the recently developed in vivo 17O MR spectroscopic imaging to simultaneously assess CMRO2, CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of 17O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive 17O-MR approach for rapidly imaging CMRO2, CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO2 and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising 17O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This 17O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy. PMID:23000789

Simultaneous and noninvasive imaging of cerebral oxygen metabolic rate, blood flow and oxygen extraction fraction in stroke mice.

PubMed

Zhu, Xiao-Hong; Chen, James M; Tu, Tsang-Wei; Chen, Wei; Song, Sheng-Kwei

2013-01-01

Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO(2)) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO(2) and CBF. This study employed the recently developed in vivo (17)O MR spectroscopic imaging to simultaneously assess CMRO(2), CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of (17)O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive (17)O-MR approach for rapidly imaging CMRO(2), CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO(2) and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising (17)O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This (17)O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy. Copyright © 2012 Elsevier Inc. All rights reserved.

Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils

PubMed Central

Faraday, Nauder; Schunke, Kathryn; Saleem, Sofiyan; Fu, Juan; Wang, Bing; Zhang, Jian; Morrell, Craig; Dore, Sylvain

2013-01-01

Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutrophils enhanced aggregation of human platelets in vitro in dose-dependent fashion and this effect was diminished by pharmacologic inhibition of cathepsin G activity and knockdown of cathepsin G expression. Tail bleeding time in the mouse was prolonged by a cathepsin G inhibitor and in cathepsin G knockout mice, and formation of neutrophil-platelet conjugates in blood that was shed from transected tails was reduced in the absence of cathepsin G. Bleeding time was highly correlated with blood neutrophil count in wildtype but not cathepsin G deficient mice. In the presence of elevated blood neutrophil counts, the anti-thrombotic effect of cathepsin G inhibition was greater than that of aspirin and additive to it when administered in combination. Both pharmacologic inhibition of cathepsin G and its congenital absence prolonged the time for platelet thrombus to form in ferric chloride-injured mouse mesenteric arterioles. In a vaso-occlusive model of ischemic stroke, inhibition of cathepsin G and its congenital absence improved cerebral blood flow, reduced histologic brain injury, and improved neurobehavioral outcome. These experiments demonstrate that neutrophil cathepsin G is a physiologic modulator of platelet thrombus formation in vivo and has potential as a target for novel anti-thrombotic therapies. PMID:23940756

Using sensors to measure activity in people with stroke.

PubMed

Fulk, George D; Sazonov, Edward

2011-01-01

The purpose of this study was to determine the ability of a novel shoe-based sensor that uses accelerometers, pressure sensors, and pattern recognition with a support vector machine (SVM) to accurately identify sitting, standing, and walking postures in people with stroke. Subjects with stroke wore the shoe-based sensor while randomly assuming 3 main postures: sitting, standing, and walking. A SVM classifier was used to train and validate the data to develop individual and group models, which were tested for accuracy, recall, and precision. Eight subjects participated. Both individual and group models were able to accurately identify the different postures (99.1% to 100% individual models and 76.9% to 100% group models). Recall and precision were also high for both individual (0.99 to 1.00) and group (0.82 to 0.99) models. The unique combination of accelerometer and pressure sensors built into the shoe was able to accurately identify postures. This shoe sensor could be used to provide accurate information on community performance of activities in people with stroke as well as provide behavioral enhancing feedback as part of a telerehabilitation intervention.

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

Personalized medicine and stroke prevention: where are we?

PubMed

Kim, Joosup; Thrift, Amanda G; Nelson, Mark R; Bladin, Christopher F; Cadilhac, Dominique A

2015-01-01

There are many recommended pharmacological and non-pharmacological therapies for the prevention of stroke, and an ongoing challenge is to improve their uptake. Personalized medicine is seen as a possible solution to this challenge. Although the use of genetic information to guide health care could be considered as the apex of personalized medicine, genetics is not yet routinely used to guide prevention of stroke. Currently personalized aspects of prevention of stroke include tailoring interventions based on global risk, the utilization of individualized management plans within a model of organized care, and patient education. In this review we discuss the progress made in these aspects of prevention of stroke and present a case study to illustrate the issues faced by health care providers and patients with stroke that could be overcome with a personalized approach to the prevention of stroke.

A novel animal model of dysphagia following stroke.

PubMed

Sugiyama, Naoto; Nishiyama, Eiji; Nishikawa, Yukitoshi; Sasamura, Takashi; Nakade, Shinji; Okawa, Katsumasa; Nagasawa, Tadashi; Yuki, Akane

2014-02-01

Patients who have an ischemic stroke are at high risk of swallowing disorders. Aspiration due to swallowing disorders, specifically delayed trigger of the pharyngeal stage of swallowing, predisposes such patients to pneumonia. In the present study, we evaluated swallowing reflex in a rat model of transient middle cerebral artery occlusion (tMCAO), which is one of the most common experimental animal models of cerebral ischemia, in order to develop a novel animal model of dysphagia following ischemic stroke. A swallowing reflex was elicited by a 10-s infusion of distilled water (DW) to the pharyngolaryngeal region in the tMCAO rat model. Swallowing reflex was estimated using the electromyographic activity of the mylohyoid muscle from 1 to 3 weeks after surgery. Two weeks after tMCAO, the number of swallows significantly decreased and the onset latency of the first swallow was prolonged compared with that of the sham group. The number of swallows in rats significantly increased by infusions of 10 mM citric acid and 0.6 μM capsaicin to the pharyngolaryngeal region compared with the number from infusion of DW. It has been reported that sensory stimulation of the pharyngolaryngeal region with citric acid, capsaicin, and L-menthol ameliorates hypofunction of pharyngeal-stage swallowing in dysphagia patients. Therefore, the tMCAO rat model may show some of the symptoms of pharyngeal-stage swallowing disorders, similar to those in patients with ischemic stroke. This rat tMCAO model has the potential to become a novel animal model of dysphagia following stroke that is useful for development of therapeutic methods and drugs.

Stroke risk perception among participants of a stroke awareness campaign

PubMed Central

Kraywinkel, Klaus; Heidrich, Jan; Heuschmann, Peter U; Wagner, Markus; Berger, Klaus

2007-01-01

Background Subjective risk factor perception is an important component of the motivation to change unhealthy life styles. While prior studies assessed cardiovascular risk factor knowledge, little is known about determinants of the individual perception of stroke risk. Methods Survey by mailed questionnaire among 1483 participants of a prior public stroke campaign in Germany. Participants had been informed about their individual stroke risk based on the Framingham stroke risk score. Stroke risk factor knowledge, perception of lifetime stroke risk and risk factor status were included in the questionnaire, and the determinants of good risk factor knowledge and high stroke risk perception were identified using logistic regression models. Results Overall stroke risk factor knowledge was good with 67–96% of the participants recognizing established risk factors. The two exceptions were diabetes (recognized by 49%) and myocardial infarction (57%). Knowledge of a specific factor was superior among those affected by it. 13% of all participants considered themselves of having a high stroke risk, 55% indicated a moderate risk. All major risk factors contributed significantly to the perception of being at high stroke risk, but the effects of age, sex and education were non-significant. Poor self-rated health was additionally associated with high individual stroke risk perception. Conclusion Stroke risk factor knowledge was high in this study. The self perception of an increased stroke risk was associated with established risk factors as well as low perception of general health. PMID:17371603

Stress Hyperglycemia and Prognosis of Minor Ischemic Stroke and Transient Ischemic Attack: The CHANCE Study (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events).

PubMed

Pan, Yuesong; Cai, Xueli; Jing, Jing; Meng, Xia; Li, Hao; Wang, Yongjun; Zhao, Xingquan; Liu, Liping; Wang, David; Johnston, S Claiborne; Wei, Tiemin; Wang, Yilong

2017-11-01

We aimed to determine the association between stress hyperglycemia and risk of new stroke in patients with a minor ischemic stroke or transient ischemic attack. A subgroup of 3026 consecutive patients from 73 prespecified sites of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) were analyzed. Stress hyperglycemia was measured by glucose/glycated albumin (GA) ratio. Glucose/GA ratio was calculated by fasting plasma glucose divided by GA and categorized into 4 even groups according to the quartiles. The primary outcome was a new stroke (ischemic or hemorrhagic) at 90 days. We assessed the association between glucose/GA ratio and risk of stroke by multivariable Cox regression models adjusted for potential covariates. Among 3026 patients included, a total of 299 (9.9%) new stroke occurred at 3 months. Compared with patients with the lowest quartile, patients with the highest quartile of glucose/GA ratio was associated with an increased risk of stroke at 3 months after adjusted for potential covariates (12.0% versus 9.2%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.06-2.01). Similar results were observed after further adjusted for fasting plasma glucose. We also observed that higher level of glucose/GA ratio was associated with an increased risk of stroke with a threshold of 0.29 using a Cox regression model with restricted cubic spline. Stress hyperglycemia, measured by glucose/GA ratio, was associated with an increased risk of stroke in patients with a minor ischemic stroke or transient ischemic attack. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589. © 2017 American Heart Association, Inc.

Excessive Premature Atrial Complexes and the Risk of Recurrent Stroke or Death in an Ischemic Stroke Population.

PubMed

Vinther, Kristina H; Tveskov, Claus; Möller, Sören; Auscher, Soren; Osmanagic, Armin; Egstrup, Kenneth

2017-06-01

Our aim was to investigate the association of premature atrial complexes and the risk of recurrent stroke or death in patients with ischemic stroke in sinus rhythm. In a prospective cohort study, we used 24-hour Holter recordings to evaluate premature atrial complexes in patients consecutively admitted with ischemic strokes. Excessive premature atrial complexes were defined as >14 premature atrial complexes per hour and 3 or more runs of premature atrial complexes per 24 hours. During follow-up, 48-hour Holter recordings were performed after 6 and 12 months. Among patients in sinus rhythm, the association of excessive premature atrial complexes and the primary end point of recurrent stroke or death were estimated in both crude and adjusted Cox proportional hazards models. We further evaluated excessive premature atrial complexes contra atrial fibrillation in relation to the primary end point. Of the 256 patients included, 89 had atrial fibrillation. Of the patients in sinus rhythm (n = 167), 31 had excessive premature atrial complexes. During a median follow-up of 32 months, 50 patients (30% of patients in sinus rhythm) had recurrent strokes (n = 20) or died (n = 30). In both crude and adjusted models, excessive premature atrial complexes were associated with the primary end point, but not with newly diagnosed atrial fibrillation. Compared with patients in atrial fibrillation, those with excessive premature atrial complexes had similarly high risks of the primary end point. In patients with ischemic stroke and sinus rhythm, excessive premature atrial complexes were associated with a higher risk of recurrent stroke or death. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Prestroke Proteomic Changes in Cerebral Microvessels in Stroke-Prone, Transgenic[hCETP]-Hyperlipidemic, Dahl Salt-Sensitive Hypertensive Rats

PubMed Central

Bergerat, Agnes; Decano, Julius; Wu, Chang-Jiun; Choi, Hyungwon; Nesvizhskii, Alexey I; Moran, Ann Marie; Ruiz-Opazo, Nelson; Steffen, Martin; Herrera, Victoria LM

2011-01-01

Stroke is the third leading cause of death in the United States with high rates of morbidity among survivors. The search to fill the unequivocal need for new therapeutic approaches would benefit from unbiased proteomic analyses of animal models of spontaneous stroke in the prestroke stage. Since brain microvessels play key roles in neurovascular coupling, we investigated prestroke microvascular proteome changes. Proteomic analysis of cerebral cortical microvessels (cMVs) was done by tandem mass spectrometry comparing two prestroke time points. Metaprotein-pathway analyses of proteomic spectral count data were done to identify risk factor–induced changes, followed by QSPEC-analyses of individual protein changes associated with increased stroke susceptibility. We report 26 cMV proteome profiles from male and female stroke-prone and non–stroke-prone rats at 2 months and 4.5 months of age prior to overt stroke events. We identified 1,934 proteins by two or more peptides. Metaprotein pathway analysis detected age-associated changes in energy metabolism and cell-to-microenvironment interactions, as well as sex-specific changes in energy metabolism and endothelial leukocyte transmigration pathways. Stroke susceptibility was associated independently with multiple protein changes associated with ischemia, angiogenesis or involved in blood brain barrier (BBB) integrity. Immunohistochemical analysis confirmed aquaporin-4 and laminin-α1 induction in cMVs, representative of proteomic changes with >65 Bayes factor (BF), associated with stroke susceptibility. Altogether, proteomic analysis demonstrates significant molecular changes in ischemic cerebral microvasculature in the prestroke stage, which could contribute to the observed model phenotype of microhemorrhages and postischemic hemorrhagic transformation. These pathways comprise putative targets for translational research of much needed novel diagnostic and therapeutic approaches for stroke. PMID:21519634

Relation of dietary glycemic load with ischemic and hemorrhagic stroke: a cohort study in Greece and a meta-analysis.

PubMed

Rossi, Marta; Turati, Federica; Lagiou, Pagona; Trichopoulos, Dimitrios; La Vecchia, Carlo; Trichopoulou, Antonia

2015-03-01

High glycemic load (GL) has been associated with excess stroke risk. Data suggest a different role of diet in the etiology of ischemic and hemorrhagic stroke. We analyzed data from 19,824 participants of the Greek cohort of the population-based European Prospective Investigation into Cancer and nutrition (EPIC), who were free of cardiovascular diseases, cancer, and diabetes at baseline and had not developed diabetes. Diet was assessed at enrollment through a validated, interviewer-administered semi-quantitative food frequency questionnaire. The average daily GL was derived using standard tables. We also conducted a meta-analysis on GL and stroke (overall, ischemic and hemorrhagic), using random-effects models. In the Greek EPIC cohort, 304 incident stroke cases were identified (67 ischemic, 49 hemorrhagic). Using Cox proportional hazards regression models adjusted for potential confounders, the hazard ratios for the highest versus the lowest GL tertiles were 1.07 [95 % confidence interval (CI) 0.74-1.54] for overall stroke, 1.55 (95 % CI 0.72-3.36) for ischemic and 0.48 (95 % CI 0.18-1.25) for hemorrhagic stroke (p-heterogeneity <0.01). The meta-analysis, including a total of 3,088 incident cases and 247 deaths from stroke (1,469 cases and 126 deaths ischemic; 576 cases and 94 deaths hemorrhagic), estimated pooled relative risks for the highest versus the lowest GL levels of 1.23 (95 % CI 1.07-1.41) for overall, 1.35 (95 % CI 1.06-1.72) for ischemic, and 1.09 (95 % CI 0.81-1.47) for hemorrhagic stroke (p-heterogeneity = 0.275). This study indicates that GL is an important determinant of the more common ischemic-though not of the hemorrhagic-stroke.

Transcatheter Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke: A Meta-Analysis of Randomized Controlled Trials.

PubMed

Darmoch, Fahed; Al-Khadra, Yasser; Soud, Mohamad; Fanari, Zaher; Alraies, M Chadi

2018-01-01

Patent foramen ovale (PFO) with atrial septal aneurysm is suggested as an important potential source for cryptogenic strokes. Percutaneous PFO closure to reduce the recurrence of stroke compared to medical therapy has been intensely debated. The aim of this study is to assess whether PFO closure in patients with cryptogenic stroke is safe and effective compared with medical therapy. A search of PubMed, Medline, and Cochrane Central Register from January 2000 through September 2017 for randomized controlled trails (RCT), which compared PFO closure to medical therapy in patients with cryptogenic stroke was conducted. We used the items "PFO or patent foramen ovale", "paradoxical embolism", "PFO closure" and "stroke". Data were pooled for the primary outcome measure using the random-effects model as pooled rate ratio (RR). The primary outcome was reduction in recurrent strokes. Among 282 studies, 5 were selected. Our analysis included 3,440 patients (mean age 45 years, 55% men, mean follow-up 2.9 years), 1,829 in the PFO closure group and 1,611 in the medical therapy group. The I2 heterogeneity test was found to be 48%. A random effects model combining the results of the included studies demonstrated a statistically significant risk reduction in risk of recurrent stroke in the PFO closure group when compared with medical therapy (RR 0.42; 95% CI 0.20-0.91, p = 0.03). Pooled data from 5 large RCTs showed that PFO closure in patients with cryptogenic stroke is safe and effective intervention for prevention of stroke recurrence compared with medical therapy. © 2018 S. Karger AG, Basel.

Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study.

PubMed

Banerjee, Chirantan; Moon, Yeseon P; Paik, Myunghee C; Rundek, Tatjana; Mora-McLaughlin, Consuelo; Vieira, Julio R; Sacco, Ralph L; Elkind, Mitchell S V

2012-05-01

Diabetes increases stroke risk, but whether diabetes status immediately before stroke improves prediction and whether duration is important are less clear. We hypothesized that diabetes duration independently predicts ischemic stroke. Among 3298 stroke-free participants in the Northern Manhattan Study, baseline diabetes and age at diagnosis were determined. Incident diabetes was assessed annually (median, 9 years). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI for incident ischemic stroke using baseline diabetes, diabetes as a time-dependent covariate, and duration of diabetes as a time-varying covariate; models were adjusted for demographic and cardiovascular risk factors. Mean age was 69 ± 10 years (52% Hispanic, 21% white, and 24% black); 22% had diabetes at baseline and 10% had development of diabetes. There were 244 ischemic strokes, and both baseline diabetes (HR, 2.5; 95% CI, 1.9-3.3) and diabetes considered as a time-dependent covariate (HR, 2.4; 95% CI, 1.8-3.2) were similarly associated with stroke risk. Duration of diabetes was associated with ischemic stroke (adjusted HR, 1.03 per year with diabetes; 95% CI, 1.02-1.04). Compared to nondiabetic participants, those with diabetes for 0 to 5 years (adjusted HR, 1.7; 95% CI, 1.1-2.7), 5 to 10 years (adjusted HR, 1.8; 95% CI, 1.1-3.0), and ≥ 10 years (adjusted HR, 3.2; 95% CI, 2.4-4.5) were at increased risk. Duration of diabetes is independently associated with ischemic stroke risk adjusting for risk factors. The risk increases 3% each year, and triples with diabetes ≥ 10 years.

Enhanced Thalamic Functional Connectivity with No fMRI Responses to Affected Forelimb Stimulation in Stroke-Recovered Rats.

PubMed

Shim, Woo H; Suh, Ji-Yeon; Kim, Jeong K; Jeong, Jaeseung; Kim, Young R

2016-01-01

Neurological recovery after stroke has been extensively investigated to provide better understanding of neurobiological mechanism, therapy, and patient management. Recent advances in neuroimaging techniques, particularly functional MRI (fMRI), have widely contributed to unravel the relationship between the altered neural function and stroke-affected brain areas. As results of previous investigations, the plastic reorganization and/or gradual restoration of the hemodynamic fMRI responses to neural stimuli have been suggested as relevant mechanisms underlying the stroke recovery process. However, divergent study results and modality-dependent outcomes have clouded the proper interpretation of variable fMRI signals. Here, we performed both evoked and resting state fMRI (rs-fMRI) to clarify the link between the fMRI phenotypes and post-stroke functional recovery. The experiments were designed to examine the altered neural activity within the contra-lesional hemisphere and other undamaged brain regions using rat models with large unilateral stroke, which despite the severe injury, exhibited nearly full recovery at ∼6 months after stroke. Surprisingly, both blood oxygenation level-dependent and blood volume-weighted (CBVw) fMRI activities elicited by electrical stimulation of the stroke-affected forelimb were completely absent, failing to reveal the neural origin of the behavioral recovery. In contrast, the functional connectivity maps showed highly robust rs-fMRI activity concentrated in the contra-lesional ventromedial nucleus of thalamus (VM). The negative finding in the stimuli-induced fMRI study using the popular rat middle cerebral artery model denotes weak association between the fMRI hemodynamic responses and neurological improvement. The results strongly caution the indiscreet interpretation of stroke-affected fMRI signals and demonstrate rs-fMRI as a complementary tool for efficiently characterizing stroke recovery.

A Revised Framingham Stroke Risk Profile to Reflect Temporal Trends

PubMed Central

Dufouil, Carole; Beiser, Alexa; McLure, Leslie A.; Wolf, Philip A.; Tzourio, Christophe; Howard, Virginia J; Westwood, Andrew J.; Himali, Jayandra J.; Sullivan, Lisa; Aparicio, Hugo J.; Kelly-Hayes, Margaret; Ritchie, Karen; Kase, Carlos S.; Pikula, Aleksandra; Romero, Jose R.; D’Agostino, Ralph B.; Samieri, Cécilia; Vasan, Ramachandran S.; Chêne, Genevieve; Howard, George; Seshadri, Sudha

2017-01-01

Background Age-adjusted stroke incidence has decreased over the past 50 years, likely due to changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the Framingham Heart Study (FHS) and other cohorts. We compared the accuracy of the standard (Old), and of a revised (New) version of the FSRP in predicting the risk of all-stroke and ischemic stroke, and validated this new FSRP in two external cohorts, the 3 Cities (3C) and REGARDS studies. Methods We computed the old FSRP as originally described, and a new model that used the most recent epoch-specific risk factors' prevalence and hazard-ratios for persons ≥ 55 years and for the subsample ≥ 65 years (to match the age range in REGARDS and 3C studies respectively), and compared the efficacy of these models in predicting 5- and 10-year stroke risks. Results The new FSRP was a better predictor of current stroke risks in all three samples than the old FSRP (Calibration chi-squares of new/old FSRP: in men 64.0/12.1, 59.4/30.6 and 20.7/12.5; in women 42.5/4.1, 115.4/90.3 and 9.8/6.5 in FHS, REGARDS and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared to blacks. Conclusions A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors. PMID:28159800