Improved Recovery of Hepatocytes Isolated From Warm Ischemic Rat Liver by Citrate Phosphate Dextrose (CPD)-Supplemented Euro-Collins Solution

PubMed Central

Hsu, Huai-Che; Matsuno, Naoto; Machida, Noboru; Enosawa, Shin

2013-01-01

Demand for human primary hepatocytes is increasing, particularly for clinical trials of hepatocyte transplantation. However, due to the severe shortage of organ transplant donors, the source of cells for these endeavors is restricted to untransplantable livers, such as those from non-heart-beating donors and surgically resected liver tissues. To improve cell recovery from such sources after warm ischemia, we evaluated the efficacy of applying perfusion solutions, focusing on improvement of hepatocyte recovery. Warm ischemia was induced by clamping both portal vein and hepatic artery for 10 or 15 min in rats. The liver was perfused with either Euro-Collins (EC) or extracellular-type trehalose-containing Kyoto (ETK) solutions supplemented with an anticoagulant, either heparin or citrate phosphate dextrose solution (CPD), compared to Ca2+, Mg2+-free Hanks solution. While the viability of recovered cells was 81.5 ± 4.2% and cell yield was 2.27 ± 0.53 × 108 in nonwarm ischemia controls (n = 11), these values were only 74.7 ± 2.9% and 0.38 ± 0.17 × 108, respectively, in the 10-min warm ischemia group, using the Hanks as the perfusion solution. Although the addition of heparin increased the live cell number only twofold (0.71 ± 0.40 × 108, n = 4), the best improvement was achieved by adding CPD to EC. This resulted in a recovery of 1.41 ± 0.50 × 108 in the 10-min ischemia group (n = 7) and 1.37 ± 0.28 × 108 in the 15-min group (n = 3). Macroscopic observation showed that blood had been completely flushed out by the solution, suggesting good restoration of the microcirculation in ischemic liver. Using ETK instead of EC resulted in a slight decrease in efficacy. These results demonstrate that CPD, as opposed to heparin, is effective in ensuring liver microcirculation and flushing out the blood and that EC is the best perfusion solution for obtaining hepatocytes from ischemic liver. PMID:26858872

Neuroprotective Role of Exogenous Brain-Derived Neurotrophic Factor in Hypoxia-Hypoglycemia-Induced Hippocampal Neuron Injury via Regulating Trkb/MiR134 Signaling.

PubMed

Huang, Weidong; Meng, Facai; Cao, Jie; Liu, Xiaobin; Zhang, Jie; Li, Min

2017-05-01

Hypoxic-ischemic brain injury is an important cause of neonatal mortality and morbidity. Brain-derived neurotrophic factor (BDNF) has been reported to play a neuroprotective role in hypoxic-ischemic brain injury; however, the specific effects and mechanism of BDNF on hypoxic-hypoglycemic hippocampal neuron injury remains unknown. The current study investigated the action of BDNF in regulating cerebral hypoxic-ischemic injury by simulating hippocampal neuron ischemia and hypoxia. We found that BDNF, p-Trkb, and miR-134 expression levels decreased, and that exogenous BDNF increased survival and reduced apoptosis in hypoxic-hypoglycemic hippocampal neurons. The results also show that BDNF inhibits MiR-134 expression by activating the TrkB pathway. Transfection with TrkB siRNA and pre-miR-134 abrogated the neuroprotective role of BDNF in hypoxic-hypoglycemic hippocampal neurons. Our results suggest that exogenous BDNF alleviates hypoxic-ischemic brain injury through the Trkb/MiR-134 pathway. These findings may help to identify a potential therapeutic agent for the treatment of hypoxic-ischemic brain injury.

Postischemic dementia with Alzheimer phenotype: selectively vulnerable versus resistant areas of the brain and neurodegeneration versus β-amyloid peptide.

PubMed

Pluta, Ryszard; Jabłoński, Mirosław; Czuczwar, Stanisław J

2012-01-01

The road to clarity for postischemic dementia mechanisms has been one fraught with a wide range of complications and numerous revisions with a lack of a final solution. Importantly, brain ischemia is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Data from animal models and clinical pioneering studies of brain ischemia have demonstrated an increase in expression and processing of amyloid precursor protein to a neurotoxin oligomeric β-amyloid peptide. Functional and memory brain restoration after ischemic brain injury is delayed and incomplete due to a lesion related increase in the amount of the neurotoxin amyloid protein. Moreover, ischemic injury is strongly accelerated by aging, too. In this review, we will present our current thinking about biogenesis of amyloid from the amyloid precursor protein in ischemic brain injury, and how this factor presents etiological, therapeutic and diagnostic targets that are now under consideration. Progressive injury of the ischemic brain parenchyma may be caused not only by degeneration of selectively vulnerable neurons destroyed during ischemia but also by acute and chronic damage of resistant areas of the brain and progressive damage in the blood-brain barrier. We propose that in postischemic dementia an initial ischemic injury precedes the cerebrovascular and brain parenchyma accumulation of Alzheimer disease related neurotoxin β-amyloid peptide, which in turn amplifies the neurovascular dysfunction triggering focal ischemic episodes as a vicious cycle preceding final neurodegenerative pathology. Persistent ischemic blood-brain barrier insufficiency with accumulation of neurotoxin β-amyloid protein in the brain tissue, especially in extracellular perivascular space and blood-brain barrier microvessels, may gradually, over a lifetime, progress to brain atrophy and to full-blown ischemic dementia with Alzheimer phenotype.

[Molecular mechanisms of ischemic-reperfusion syndrome and its personalized therapy].

PubMed

Grebenchikov, O A; Likhvantsev, V V; Plotnikov, E Iu; Silachev, D N; Pevzner, I B; Zorova, L D; Zorov, D B

2014-01-01

Cardiovascular pathologies are the major causes of morbidity and mortality in the world. Cessation of the blood flow in large vessels, supplying tissues with oxygen and substrates, leads to ischemic conditions accompanied by unwanted shifts of oxidative metabolism and rise of the reactive oxygen species (ROS) generation. Small amounts of ROS are essential elements of the cell metabolism, however pathological elevation of ROS jeopardizes the survival of cells, organs and even organisms. Paradoxically, blood flow restoration during prolonged ischemia leads to oxidative stress that is often fatal for a live system. Oxygen paradox appears to be a limiting factor in clinical practice that intuitively seeks for immediate and complete restoration of a damaged blood flow. Mitochondrion is a major ROS source and a key element of pro-apoptotic signaling, however it is clear, that mitochondria are the main target for anti-ischemic treatment. In the present review we consider two ways of such anti-ischemic strategy, bringing ischemic tolerance to the organ through mitochondrial involvement, such as intrinsic, biological, or artificial, pharmacological adaptive systems (preconditioning). The latter is aimed to simulate elements and high efficiency of intrinsic protective system. The role of antioxidants in anti-ischemic therapy and their effects on preconditioning signaling are discussed in the review.

Application of ET-Kyoto solution in clinical lung transplantation.

PubMed

Omasa, Mitsugu; Hasegawa, Seiki; Bando, Toru; Hanaoka, Nobuharu; Yoshimura, Takashi; Nakamura, Takayuki; Wada, Hiromi

2004-01-01

We have developed a new organ preservation solution called extracellular-type trehalose-containing Kyoto (ET-Kyoto) solution. ET-Kyoto solution has been applied in clinical lung transplantation. The patient was a 49-year-old woman with diffuse panbronchiolitis. She underwent bilateral lobar lung transplantation from living donors. Each lobe was flushed with ET-Kyoto solution. After reperfusion, PaO(2) with inhalation of 100% oxygen was more than 500 Torr. Posttransplantation course was uneventful. Despite the relatively short ischemic time of this case report, ET-Kyoto solution may be feasible and safely applied in clinical lung transplantation.

Patient-specific core decompression surgery for early-stage ischemic necrosis of the femoral head

PubMed Central

Wang, Wei; Hu, Wei; Yang, Pei; Dang, Xiao Qian; Li, Xiao Hui; Wang, Kun Zheng

2017-01-01

Introduction Core decompression is an efficient treatment for early stage ischemic necrosis of the femoral head. In conventional procedures, the pre-operative X-ray only shows one plane of the ischemic area, which often results in inaccurate drilling. This paper introduces a new method that uses computer-assisted technology and rapid prototyping to enhance drilling accuracy during core decompression surgeries and presents a validation study of cadaveric tests. Methods Twelve cadaveric human femurs were used to simulate early-stage ischemic necrosis. The core decompression target at the anterolateral femoral head was simulated using an embedded glass ball (target). Three positioning Kirschner wires were drilled into the top and bottom of the large rotor. The specimen was then subjected to computed tomography (CT). A CT image of the specimen was imported into the Mimics software to construct a three-dimensional model including the target. The best core decompression channel was then designed using the 3D model. A navigational template for the specimen was designed using the Pro/E software and manufactured by rapid prototyping technology to guide the drilling channel. The specimen-specific navigation template was installed on the specimen using positioning Kirschner wires. Drilling was performed using a guide needle through the guiding hole on the templates. The distance between the end point of the guide needle and the target was measured to validate the patient-specific surgical accuracy. Results The average distance between the tip of the guide needle drilled through the guiding template and the target was 1.92±0.071 mm. Conclusions Core decompression using a computer-rapid prototyping template is a reliable and accurate technique that could provide a new method of precision decompression for early-stage ischemic necrosis. PMID:28464029

Patient-specific core decompression surgery for early-stage ischemic necrosis of the femoral head.

PubMed

Wang, Wei; Hu, Wei; Yang, Pei; Dang, Xiao Qian; Li, Xiao Hui; Wang, Kun Zheng

2017-01-01

Core decompression is an efficient treatment for early stage ischemic necrosis of the femoral head. In conventional procedures, the pre-operative X-ray only shows one plane of the ischemic area, which often results in inaccurate drilling. This paper introduces a new method that uses computer-assisted technology and rapid prototyping to enhance drilling accuracy during core decompression surgeries and presents a validation study of cadaveric tests. Twelve cadaveric human femurs were used to simulate early-stage ischemic necrosis. The core decompression target at the anterolateral femoral head was simulated using an embedded glass ball (target). Three positioning Kirschner wires were drilled into the top and bottom of the large rotor. The specimen was then subjected to computed tomography (CT). A CT image of the specimen was imported into the Mimics software to construct a three-dimensional model including the target. The best core decompression channel was then designed using the 3D model. A navigational template for the specimen was designed using the Pro/E software and manufactured by rapid prototyping technology to guide the drilling channel. The specimen-specific navigation template was installed on the specimen using positioning Kirschner wires. Drilling was performed using a guide needle through the guiding hole on the templates. The distance between the end point of the guide needle and the target was measured to validate the patient-specific surgical accuracy. The average distance between the tip of the guide needle drilled through the guiding template and the target was 1.92±0.071 mm. Core decompression using a computer-rapid prototyping template is a reliable and accurate technique that could provide a new method of precision decompression for early-stage ischemic necrosis.

Major role of the PI3K/Akt pathway in ischemic tolerance induced by sublethal oxygen-glucose deprivation in cortical neurons in vitro.

PubMed

Bhuiyan, Mohammad Iqbal Hossain; Jung, Seo Yun; Kim, Hyoung Ja; Lee, Yong Sup; Jin, Changbae

2011-06-01

Ischemic preconditioning can provide protection to neurons from subsequent lethal ischemia. The molecular mechanisms of neuronal ischemic tolerance, however, are still not well-known. The present study, therefore, examined the role of MAPK and PI3K/Akt pathways in ischemic tolerance induced by preconditioning with sublethal oxygen-glucose deprivation (OGD) in cultured rat cortical neurons. Ischemic tolerance was simulated by preconditioning of the neurons with sublethal 1-h OGD imposed 12 h before lethal 3-h OGD. The time-course studies of relative phosphorylation and expression levels of ERK1/2, JNK and p38 MAPK showed lack of their involvement in ischemic tolerance. However, there were significant increases in Akt phosphorylation levels during the reperfusion period following preconditioned lethal OGD. In addition, Bcl-2 associated death promoter (Bad) and GSK-3β were also found to be inactivated during that reperfusion period. Finally, treatment with an inhibitor of PI3K, wortmannin, applied from 15 min before and during lethal OGD abolished not only the preconditioning-induced neuroprotection but also the Akt activation. Concomitant with blockade of the Akt activation, PI3K inhibition also resulted in activation of Bad and GSK-3β. The results suggest that ischemic tolerance induced by sublethal OGD preconditioning is primarily mediated through activation of the PI3K/Akt pathway, but not the MAPK pathway, in rat cortical neurons.

Comparison of the chloride channel activator lubiprostone and the oral laxative Polyethylene Glycol 3350 on mucosal barrier repair in ischemic-injured porcine intestine.

PubMed

Moeser, Adam-J; Nighot, Prashant-K; Roerig, Birgit; Ueno, Ryuji; Blikslager, Anthony-T

2008-10-21

To investigate the effects of lubiprostone and Polyethylene Glycol 3350 (PEG) on mucosal barrier repair in ischemic-injured porcine intestine. Ileum from 6 piglets (approximately 15 kg body weight) was subjected to ischemic conditions by occluding the local mesenteric circulation for 45 min in vivo. Ileal tissues from each pig were then harvested and mounted in Ussing chambers and bathed in oxygenated Ringer's solution in vitro. Intestinal barrier function was assessed by measuring transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of (3)H-mannitol and (14)C-inulin. Statistical analyses of data collected over a 120-min time course included 2-way ANOVA for the effects of time and treatment on indices of barrier function. Application of 1 micromol/L lubiprostone to the mucosal surface of ischemic-injured ileum in vitro induced significant elevations in TER compared to non-treated tissue. Lubiprostone also reduced mucosal-to-serosal fluxes of (3)H-mannitol and (14)C-inulin. Alternatively, application of a polyethylene laxative (PEG, 20 mmol/L) to the mucosal surface of ischemic tissues significantly increased flux of (3)H-mannitol and (14)C-inulin. This experiment demonstrates that lubiprostone stimulates recovery of barrier function in ischemic intestinal tissues whereas the PEG laxative had deleterious effects on mucosal repair. These results suggest that, unlike osmotic laxatives, lubiprostone stimulates repair of the injured intestinal barrier.

Comparison of the chloride channel activator lubiprostone and the oral laxative Polyethylene Glycol 3350 on mucosal barrier repair in ischemic-injured porcine intestine

PubMed Central

Moeser, Adam J; Nighot, Prashant K; Roerig, Birgit; Ueno, Ryuji; Blikslager, Anthony T

2008-01-01

AIM: To investigate the effects of lubiprostone and Polyethylene Glycol 3350 (PEG) on mucosal barrier repair in ischemic-injured porcine intestine. METHODS: Ileum from 6 piglets (approximately 15 kg body weight) was subjected to ischemic conditions by occluding the local mesenteric circulation for 45 min in vivo. Ileal tissues from each pig were then harvested and mounted in Ussing chambers and bathed in oxygenated Ringer’s solution in vitro. Intestinal barrier function was assessed by measuring transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of 3H-mannitol and 14C-inulin. Statistical analyses of data collected over a 120-min time course included 2-way ANOVA for the effects of time and treatment on indices of barrier function. RESULTS: Application of 1 μmol/L lubiprostone to the mucosal surface of ischemic-injured ileum in vitro induced significant elevations in TER compared to non-treated tissue. Lubiprostone also reduced mucosal-to-serosal fluxes of 3H-mannitol and 14C-inulin. Alternatively, application of a polyethylene laxative (PEG, 20 mmol/L) to the mucosal surface of ischemic tissues significantly increased flux of 3H-mannitol and 14C-inulin. CONCLUSION: This experiment demonstrates that lubiprostone stimulates recovery of barrier function in ischemic intestinal tissues whereas the PEG laxative had deleterious effects on mucosal repair. These results suggest that, unlike osmotic laxatives, lubiprostone stimulates repair of the injured intestinal barrier. PMID:18932279

Inverse Electrocardiographic Source Localization of Ischemia: An Optimization Framework and Finite Element Solution

PubMed Central

Wang, Dafang; Kirby, Robert M.; MacLeod, Rob S.; Johnson, Chris R.

2013-01-01

With the goal of non-invasively localizing cardiac ischemic disease using body-surface potential recordings, we attempted to reconstruct the transmembrane potential (TMP) throughout the myocardium with the bidomain heart model. The task is an inverse source problem governed by partial differential equations (PDE). Our main contribution is solving the inverse problem within a PDE-constrained optimization framework that enables various physically-based constraints in both equality and inequality forms. We formulated the optimality conditions rigorously in the continuum before deriving finite element discretization, thereby making the optimization independent of discretization choice. Such a formulation was derived for the L2-norm Tikhonov regularization and the total variation minimization. The subsequent numerical optimization was fulfilled by a primal-dual interior-point method tailored to our problem’s specific structure. Our simulations used realistic, fiber-included heart models consisting of up to 18,000 nodes, much finer than any inverse models previously reported. With synthetic ischemia data we localized ischemic regions with roughly a 10% false-negative rate or a 20% false-positive rate under conditions up to 5% input noise. With ischemia data measured from animal experiments, we reconstructed TMPs with roughly 0.9 correlation with the ground truth. While precisely estimating the TMP in general cases remains an open problem, our study shows the feasibility of reconstructing TMP during the ST interval as a means of ischemia localization. PMID:23913980

Mitral leaflet geometry perturbations with papillary muscle displacement and annular dilatation: an in-vitro study of ischemic mitral regurgitation.

PubMed

He, Shengqiu; Jimenez, Jorge; He, Zhaoming; Yoganathan, Ajit P

2003-05-01

Perturbations of leaflet geometry are the final end point through which left ventricular (LV) ischemia causes incomplete mitral leaflet closure and resultant mitral regurgitation (MR). Geometric inconsistencies observed with valvular or subvalvular structural alterations raise several questions. A new in-vitro LV flexible bag model was developed in order to visualize and analyze leaflet geometric changes under simulated pathological ischemic MR conditions. Papillary muscle (PM) displacement and annular dilatation decreased leaflet coaptation length, leading to significant MR. Symmetrical PM displacement shifted the coaptation line towards the leaflet edges and created central gaps along this line. Asymmetric PM displacement generated diametrically uneven coaptation with a tent-shaped leaflet at the tethered PM side, while the leaflet bulged at the opposite side towards the left atrium. Leaflet geometry during systole is affected by subvalvular structures. Asymmetric PM displacement, which may occur in regional or acute myocardial infarction, induces irregular deformation of the leaflet's coaptation line and, as a result, MR at the tethered side. Direct visualization of leaflet perturbation under these simulated pathological conditions may promote understanding of mechanisms present in ischemic MR.

Altered responsiveness of the guinea-pig isolated ileum to smooth muscle stimulants and to electrical stimulation after in situ ischemia.

PubMed

Rodriguez, Rodolfo; Ventura-Martinez, Rosa; Santiago-Mejia, Jacinto; Avila-Costa, Maria R; Fortoul, Teresa I

2006-02-01

1. We evaluated changes in contractility of the guinea-pig isolated ileum, using intact segments and myenteric plexus-longitudinal muscle (MPLM) preparations, after several times (5-160 min) of ischemia in situ. 2. Intestinal ischemia was produced by clamping the superior mesenteric artery. Ischemic and nonischemic segments, obtained from the same guinea-pig, were mounted in organ baths containing Krebs-bicarbonate (K-B) solution, maintained at 37 degrees C and gassed with 95% O2/5% CO2. The preparations were allowed to equilibrate for 60 min under continuous superfusion of warm K-B solution and then electrically stimulated at 40 V (0.3 Hz, 3.0 ms). Thereafter, complete noncumulative concentration-response curves were constructed for acetylcholine (ACh), histamine (HIS), potassium chloride (KCl), and barium chloride (BaCl2). Mean Emax (maximal response) values were calculated for each drug. 3. Our study shows that alterations of chemically and electrically evoked contractions are dependent on ischemic periods. It also demonstrates that contractile responses of ischemic tissues to neurogenic stimulation decreases earlier and to a significantly greater extent than the non-nerve mediated responses of the intestinal smooth muscle. Contractile responses to smooth muscle stimulants were all similarly affected by ischemia. Electron microscopy images indicated necrotic neuronal death. The decrease in reactivity of ischemic tissues to electrical stimulation was ameliorated by dexrazoxane, an antioxidant agent. 4. We consider the guinea-pig isolated ileum as a useful model system to study the processes involved in neuronal ischemia, and we propose that the reduction in maximal responses to electrical stimulation is a useful parameter to study neuroprotection.

Binary optimization for source localization in the inverse problem of ECG.

PubMed

Potyagaylo, Danila; Cortés, Elisenda Gil; Schulze, Walther H W; Dössel, Olaf

2014-09-01

The goal of ECG-imaging (ECGI) is to reconstruct heart electrical activity from body surface potential maps. The problem is ill-posed, which means that it is extremely sensitive to measurement and modeling errors. The most commonly used method to tackle this obstacle is Tikhonov regularization, which consists in converting the original problem into a well-posed one by adding a penalty term. The method, despite all its practical advantages, has however a serious drawback: The obtained solution is often over-smoothed, which can hinder precise clinical diagnosis and treatment planning. In this paper, we apply a binary optimization approach to the transmembrane voltage (TMV)-based problem. For this, we assume the TMV to take two possible values according to a heart abnormality under consideration. In this work, we investigate the localization of simulated ischemic areas and ectopic foci and one clinical infarction case. This affects only the choice of the binary values, while the core of the algorithms remains the same, making the approximation easily adjustable to the application needs. Two methods, a hybrid metaheuristic approach and the difference of convex functions (DC), algorithm were tested. For this purpose, we performed realistic heart simulations for a complex thorax model and applied the proposed techniques to the obtained ECG signals. Both methods enabled localization of the areas of interest, hence showing their potential for application in ECGI. For the metaheuristic algorithm, it was necessary to subdivide the heart into regions in order to obtain a stable solution unsusceptible to the errors, while the analytical DC scheme can be efficiently applied for higher dimensional problems. With the DC method, we also successfully reconstructed the activation pattern and origin of a simulated extrasystole. In addition, the DC algorithm enables iterative adjustment of binary values ensuring robust performance.

Reduction of Diffusion-Weighted Imaging Contrast of Acute Ischemic Stroke at Short Diffusion Times.

PubMed

Baron, Corey Allan; Kate, Mahesh; Gioia, Laura; Butcher, Kenneth; Emery, Derek; Budde, Matthew; Beaulieu, Christian

2015-08-01

Diffusion-weighted imaging (DWI) of tissue water is a sensitive and specific indicator of acute brain ischemia, where reductions of the diffusion of tissue water are observed acutely in the stroke lesion core. Although these diffusion changes have been long attributed to cell swelling, the precise nature of the biophysical mechanisms remains uncertain. The potential cause of diffusion reductions after stroke was investigated using an advanced DWI technique, oscillating gradient spin-echo DWI, that enables much shorter diffusion times and can improve specificity for alterations of structure at the micron level. Diffusion measurements in the white matter lesions of patients with acute ischemic stroke were reduced by only 8% using oscillating gradient spin-echo DWI, in contrast to a 37% decrease using standard DWI. Neurite beading has recently been proposed as a mechanism for the diffusion changes after ischemic stroke with some ex vivo evidence. To explore whether beading could cause such differential results, simulations of beaded cylinders and axonal swelling were performed, yielding good agreement with experiment. Short diffusion times result in dramatically reduced diffusion contrast of human stroke. Simulations implicate a combination of neuronal beading and axonal swelling as the key structural changes leading to the reduced apparent diffusion coefficient after stroke. © 2015 American Heart Association, Inc.

Hypothermic in situ perfusion of the porcine liver using Celsior or Ringer-lactate solution.

PubMed

Dinant, S; Roseboom, H J; Levi, M; van Vliet, A K; van Gulik, T M

2009-01-01

Hypothermic perfusion (HP) of the liver is applied during total vascular exclusion (TVE) to reduce ischemic injury during liver resection. No studies have been performed comparing different perfusion solutions for HP. The aim of this experimental study was to compare Ringer-lactate solution (RL) with Celsior solution (Cs) for HP in a pig model of 60-min TVE. Twenty pigs underwent 60-min TVE of the liver. Groups were TVE without HP (no-HP, n = 9), TVE with HP using RL (n = 6), and TVE with HP using Cs (n = 5). Blood and liver tissue samples were taken before TVE and during 24-h reperfusion. In the no-HP group, plasma aspartate aminotransferase values were significantly increased during reperfusion (p < 0.05), while liver tissue pO(2) levels (p < 0.01) were decreased when compared to the HP groups. After 24-h reperfusion, bile production and liver tissue glutathione content were significantly higher (p < 0.05) in the Cs group (42.0 +/- 1.7 mL/h and 44.9 +/- 2.2 nmol/mg, respectively) as compared to the RL group (31.5 +/- 3.5 mL/h and 19.6 +/- 1.8 nmol/mg, respectively). The protective effect of HP during TVE was confirmed in this study. HP with Cs was more effective in reducing ischemic injury as compared to HP with RL.

Electrophysiological effects of haloperidol on isolated rabbit Purkinje fibers and guinea pigs papillary muscles under normal and simulated ischemia.

PubMed

Yan, Dong; Cheng, Lu-feng; Song, Hong-Yan; Turdi, Subat; Kerram, Parhat

2007-08-01

Overdoses of haloperidol are associated with major ventricular arrhythmias, cardiac conduction block, and sudden death. The aim of this experiment was to study the effect of haloperidol on the action potentials in cardiac Purkinje fibers and papillary muscles under normal and simulated ischemia conditions in rabbits and guinea pigs. Using the standard intracellular microelectrode technique, we examined the effects of haloperidol on the action potential parameters [action potential amplitude (APA), phase 0 maximum upstroke velocity (V(max)), action potential amplitude at 90% of repolarization (APD(90)), and effective refractory period (ERP)] in rabbit cardiac Purkinje fibers and guinea pig cardiac papillary cells, in which both tissues were under simulated ischemic conditions. Under ischemic conditions, different concentrations of haloperidol depressed APA and prolonged APD(90) in a concentration-dependent manner in rabbit Purkinje fibers. Haloperidol (3 micromol/L) significantly depressed APA and prolonged APD(90), and from 1 micromol/L, haloperidol showed significant depression on V(max); ERP was not significantly affected. In guinea pig cardiac papillary muscles, the thresholds of significant reduction in APA, V(max), EPR, and APD(90) were 10, 0.3, 1, and 1 mumol/L, respectively, for haloperidol. Compared with cardiac conductive tissues, papillary muscles were more sensitive to ischemic conditions. Under ischemia, haloperidol prolonged ERP and APD(90) in a concentration-dependent manner and precipitated the decrease in V(max) induced by ischemia. The shortening of ERP and APD(90) in papillary muscle action potentials may be inhibited by haloperidol.

Nitric Oxide Donors as Neuroprotective Agents after an Ischemic Stroke-Related Inflammatory Reaction

PubMed Central

Rojas-Mayorquín, Argelia E.; Ortuño-Sahagún, Daniel

2013-01-01

Cerebral ischemia initiates a cascade of detrimental events including glutamate-associated excitotoxicity, intracellular calcium accumulation, formation of Reactive oxygen species (ROS), membrane lipid degradation, and DNA damage, which lead to the disruption of cellular homeostasis and structural damage of ischemic brain tissue. Cerebral ischemia also triggers acute inflammation, which exacerbates primary brain damage. Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke. Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date. Because of their ability to modulate both oxidative stress and the inflammatory response, much attention has been focused on the role of nitric oxide donors (NOD) as neuroprotective agents in the pathophysiology of cerebral ischemia-reperfusion injury. Given their short therapeutic window, NOD appears to be appropriate for use during neurosurgical procedures involving transient arterial occlusions, or in very early treatment of acute ischemic stroke, and also possibly as complementary treatment for neurodegenerative diseases such as Parkinson or Alzheimer, where oxidative stress is an important promoter of damage. In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment. PMID:23691263

[Effects of exogenous high mobility group protein box 1 on angiogenesis in ischemic zone of early scald wounds of rats].

PubMed

Dai, L; Guo, X; Huang, H J; Liao, X M; Luo, X Q; Li, D; Zhou, H; Gao, X C; Tan, M Y

2018-04-20

Objective: To observe effects of exogenous high mobility group protein box 1 (HMGB1) on angiogenesis in ischemic zone of early scald wounds of rats. Methods: Thirty-six Sprague-Dawley rats were divided into HMGB1 group and simple scald (SS) group according to the random number table, with 18 rats in each group. Comb-like copper mould was placed on the back of rats for 20 s after being immersed in 100 ℃ hot water for 3 to 5 min to make three ischemic zones of wound. Immediately after scald, rats in HMGB1 group were subcutaneously injected with 0.4 μg HMGB1 and 0.1 mL phosphate buffer solution (PBS), and rats in SS group were subcutaneously injected with 0.1 mL PBS from boarders of ischemic zone of scald wound. At post scald hour (PSH) 24, 48, and 72, 6 rats in each group were collected. Protein expressions of vascular endothelial growth factor (VEGF) in ischemic zone of wound at PSH 24, 48, and 72 and protein expressions of CD31 in ischemic zone of wound at PSH 48 and 72 were detected by immunohistochemistry. The number of microvessel in CD31 immunohistochemical sections of ischemic zone of wound at PSH 48 and 72 was calculated after observing by the microscope. The mRNA expressions of VEGF and CD31 in ischemic zone of wound were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction at PSH 24, 48, and 72. Data were processed with analysis of variance of factorial design, t test, and Bonferroni correction. Results: (1) At PSH 24, 48, and 72, protein expressions of VEGF in ischemic zone of wound of rats in HMGB1 group were significantly higher than those of rats in SS group ( t =7.496, 4.437, 5.402, P <0.05 or P <0.01). At PSH 48 and 72, protein expressions of CD31 in ischemic zone of wound of rats in HMGB1 group were 0.038 8±0.007 9 and 0.057 7±0.001 2 respectively, significantly higher than 0.013 4±0.004 9 and 0.030 3±0.004 0 of rats in SS group ( t =10.257, 15.055, P <0.01). (2) At PSH 48 and 72, the number of microvessel in ischemic zone of wound of rats in HMGB1 group was obviously more than that of rats in SS group ( t =3.536, 4.000, P <0.05). (3) At PSH 24, 48, and 72, mRNA expressions of VEGF in ischemic zone of wound of rats in HMGB1 group were significantly higher than those of rats in SS group ( t =4.406, 3.821, 3.356, P <0.05). At PSH 24 and 48, mRNA expressions of CD31 in ischemic zone of wound of rats in HMGB1 group were significantly higher than those of rats in SS group ( t =4.113, 3.466, P <0.05). At PSH 72, mRNA expressions of CD31 in ischemic zone of wound of rats in 2 groups were close ( t =0.010, P >0.05). Conclusions: Exogenous HMGB1 can promote angiogenesis in ischemic zone of early scald wounds of rats by increasing expressions of VEGF and CD31.

The mechanism of protection from 5 (N-ethyl-N-isopropyl)amiloride differs from that of ischemic preconditioning in rabbit heart.

PubMed

Sato, H; Miki, T; Vallabhapurapu, R P; Wang, P; Liu, G S; Cohen, M V; Downey, J M

1997-10-01

We investigated the effects of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) on infarction in isolated rabbit hearts and cardiomyocytes. Thirty min of regional ischemia caused 29.6 +/- 2.8% of the risk zone to infarct in untreated Krebs buffer-perfused hearts. Treatment with EIPA (1 microM) for 20 min starting either 15 min before ischemia or 15 min after the onset of ischemia significantly reduced infarction to 5.4 +/- 2.0% and 7.0 +/- 1.0%, respectively (p < 0.01 versus untreated hearts). In both cases salvage was very similar to that seen with ischemic preconditioning (PC) (7.1 +/- 1.5% infarction). Unlike the case with ischemic preconditioning, however, protection from EIPA was not blocked by 50 microM polymyxin B, a PKC inhibitor, or 1 microM glibenclamide, a KATP channel blocker. Forty-five min of regional ischemia caused 51.0 +/- 2.9% infarction in untreated hearts. Ischemic preconditioning reduced infarction to 23.4 +/- 3.1% (p < 0.001 versus untreated hearts). In these hearts with longer periods of ischemia pretreatment with EIPA reduced infarction similarly to 28.8 +/- 2.1% (p < 0.01 versus untreated hearts). However, when EIPA was combined with ischemic PC, no further reduction in infarction was seen (23.8 +/- 3.5% infarction). To further elucidate the mechanism of EIPA's cardioprotective effect, this agent was also examined in isolated rabbit cardiomyocytes. Preconditioning caused a delay of about 30 min in the progressive increase in osmotic fragility that occurs during simulated ischemia. In contrast, EIPA had no effect on the time course of ischemia-induced osmotic fragility. Furthermore, EIPA treatment did not alter the salutary effect of ischemic preconditioning when the two were combined in this model. We conclude that Na+/H+ exchange inhibition limits myocardial infarction in the isolated rabbit heart by a mechanism which is quite different from that of ischemic preconditioning. Despite the apparently divergent mechanisms, EIPA's cardioprotective effect could not be added to that of ischemic or metabolic preconditioning in these models.

Therapeutic angiogenesis in ischemic muscles after local injection of fragmented fibers with loaded traditional Chinese medicine

NASA Astrophysics Data System (ADS)

Li, Huiyan; Wan, Huiying; Xia, Tian; Chen, Maohua; Zhang, Yun; Luo, Xiaoming; Li, Xiaohong

2015-07-01

Therapeutic angiogenesis remains the most effective method to re-establish a proper blood flow in ischemic tissues. There is a great clinical need to identify an injectable format to achieve a well accumulation following local administration and a sustained delivery of biological factors at the ischemic sites. In the current study, fragmented nanofibers with loaded traditional Chinese medicines, astragaloside IV (AT), the main active ingredient of astragalus, and ferulic acid (FA), the main ingredient of angelica, were proposed to promote the microvessel formation after intramuscular injection into ischemic hindlimbs. Fragmented fibers with average lengths of 5 (FF-5), 20 (FF-20) and 80 μm (FF-80) were constructed by the cryocutting of aligned electrospun fibers. Their dispersion in sodium alginate solution (0.2%) indicated good injectability. After injection into the quadriceps muscles of the hindlimbs, FF-20 and FF-80 fiber fragments showed higher tissue retentions than FF-5, and around 90% of the injected doses were determined after 7 days. On a hindlimb ischemia model established by ligating the femoral arteries, intramuscular injection of the mixtures of FA-loaded and AT-loaded FF-20 fiber fragments substantially reduced the muscle degeneration with minimal fibrosis formation, significantly enhanced the neovessel formation and hindlimb perfusion in the ischemic tissues, and efficiently promoted the limb salvage with few limb losses. Along with the easy manipulation and lower invasiveness for in vivo administration, fragmented fibers should become potential drug carriers for disease treatment, wound recovery and tissue repair after local injection.

Modeling the response of normal and ischemic cardiac tissue to electrical stimulation

NASA Astrophysics Data System (ADS)

Kandel, Sunil Mani

Heart disease, the leading cause of death worldwide, is often caused by ventricular fibrillation. A common treatment for this lethal arrhythmia is defibrillation: a strong electrical shock that resets the heart to its normal rhythm. To design better defibrillators, we need a better understanding of both fibrillation and defibrillation. Fundamental mysteries remain regarding the mechanism of how the heart responds to a shock, particularly anodal shocks and the resultant hyperpolarization. Virtual anodes play critical roles in defibrillation, and one cannot build better defibrillators until these mechanisms are understood. We are using mathematical modeling to numerically simulate observed phenomena, and are exploring fundamental mechanisms responsible for the heart's electrical behavior. Such simulations clarify mechanisms and identify key parameters. We investigate how systolic tissue responds to an anodal shock and how refractory tissue reacts to hyperpolarization by studying the dip in the anodal strength-interval curve. This dip is due to electrotonic interaction between regions of depolarization and hyperpolarization following a shock. The dominance of the electrotonic mechanism over calcium interactions implies the importance of the spatial distribution of virtual electrodes. We also investigate the response of localized ischemic tissue to an anodal shock by modeling a regional elevation of extracellular potassium concentration. This heterogeneity leads to action potential instability, 2:1 conduction block (alternans), and reflection-like reentry at the boarder of the normal and ischemic regions. This kind of reflection (reentry) occurs due to the delay between proximal and distal segments to re-excite the proximal segment. Our numerical simulations are based on the bidomain model, the state-of-the-art mathematical description of how cardiac tissue responds to shocks. The dynamic LuoRudy model describes the active properties of the membrane. To model ischemia, the Luo-Rudy model is modified by adding ischemic-related ion currents and concentrations to mimic conditions during the initial phase of ischemia. The stimulus is applied through a unipolar electrode that induces a complicated spatial distribution of transmembrane potential, including adjacent regions of depolarization and hyperpolarization. This research is significant because it uncovers basic properties of excitation that are fundamental for understanding cardiac pacing and defibrillation.

Anesthesia Technique and Outcomes of Mechanical Thrombectomy in Patients With Acute Ischemic Stroke.

PubMed

Bekelis, Kimon; Missios, Symeon; MacKenzie, Todd A; Tjoumakaris, Stavropoula; Jabbour, Pascal

2017-02-01

The impact of anesthesia technique on the outcomes of mechanical thrombectomy for acute ischemic stroke remains an issue of debate. We investigated the association of general anesthesia with outcomes in patients undergoing mechanical thrombectomy for ischemic stroke. We performed a cohort study involving patients undergoing mechanical thrombectomy for ischemic stroke from 2009 to 2013, who were registered in the New York Statewide Planning and Research Cooperative System database. An instrumental variable (hospital rate of general anesthesia) analysis was used to simulate the effects of randomization and investigate the association of anesthesia technique with case-fatality and length of stay. Among 1174 patients, 441 (37.6%) underwent general anesthesia and 733 (62.4%) underwent conscious sedation. Using an instrumental variable analysis, we identified that general anesthesia was associated with a 6.4% increased case-fatality (95% confidence interval, 1.9%-11.0%) and 8.4 days longer length of stay (95% confidence interval, 2.9-14.0) in comparison to conscious sedation. This corresponded to 15 patients needing to be treated with conscious sedation to prevent 1 death. Our results were robust in sensitivity analysis with mixed effects regression and propensity score-adjusted regression models. Using a comprehensive all-payer cohort of acute ischemic stroke patients undergoing mechanical thrombectomy in New York State, we identified an association of general anesthesia with increased case-fatality and length of stay. These considerations should be taken into account when standardizing acute stroke care. © 2017 American Heart Association, Inc.

Comprehensive Modeling and Visualization of Cardiac Anatomy and Physiology from CT Imaging and Computer Simulations

PubMed Central

Sun, Peng; Zhou, Haoyin; Ha, Seongmin; Hartaigh, Bríain ó; Truong, Quynh A.; Min, James K.

2016-01-01

In clinical cardiology, both anatomy and physiology are needed to diagnose cardiac pathologies. CT imaging and computer simulations provide valuable and complementary data for this purpose. However, it remains challenging to gain useful information from the large amount of high-dimensional diverse data. The current tools are not adequately integrated to visualize anatomic and physiologic data from a complete yet focused perspective. We introduce a new computer-aided diagnosis framework, which allows for comprehensive modeling and visualization of cardiac anatomy and physiology from CT imaging data and computer simulations, with a primary focus on ischemic heart disease. The following visual information is presented: (1) Anatomy from CT imaging: geometric modeling and visualization of cardiac anatomy, including four heart chambers, left and right ventricular outflow tracts, and coronary arteries; (2) Function from CT imaging: motion modeling, strain calculation, and visualization of four heart chambers; (3) Physiology from CT imaging: quantification and visualization of myocardial perfusion and contextual integration with coronary artery anatomy; (4) Physiology from computer simulation: computation and visualization of hemodynamics (e.g., coronary blood velocity, pressure, shear stress, and fluid forces on the vessel wall). Substantially, feedback from cardiologists have confirmed the practical utility of integrating these features for the purpose of computer-aided diagnosis of ischemic heart disease. PMID:26863663

Blood-Brain Barrier Integrity and Glial Support: Mechanisms that can be targeted for Novel Therapeutic Approaches in Stroke

PubMed Central

Ronaldson, Patrick T.; Davis, Thomas P.

2014-01-01

The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics (i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this “barrier,” brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a “neurovascular unit.” Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB in an effort to identify novel targets for optimization of CNS delivery of therapeutics in the setting of ischemic stroke. PMID:22574987

DIGE Proteome Analysis Reveals Suitability of Ischemic Cardiac In Vitro Model for Studying Cellular Response to Acute Ischemia and Regeneration

PubMed Central

Haas, Sina; Jahnke, Heinz-Georg; Moerbt, Nora; von Bergen, Martin; Aharinejad, Seyedhossein; Andrukhova, Olena; Robitzki, Andrea A.

2012-01-01

Proteomic analysis of myocardial tissue from patient population is suited to yield insights into cellular and molecular mechanisms taking place in cardiovascular diseases. However, it has been limited by small sized biopsies and complicated by high variances between patients. Therefore, there is a high demand for suitable model systems with the capability to simulate ischemic and cardiotoxic effects in vitro, under defined conditions. In this context, we established an in vitro ischemia/reperfusion cardiac disease model based on the contractile HL-1 cell line. To identify pathways involved in the cellular alterations induced by ischemia and thereby defining disease-specific biomarkers and potential target structures for new drug candidates we used fluorescence 2D-difference gel electrophoresis. By comparing spot density changes in ischemic and reperfusion samples we detected several protein spots that were differentially abundant. Using MALDI-TOF/TOF-MS and ESI-MS the proteins were identified and subsequently grouped by functionality. Most prominent were changes in apoptosis signalling, cell structure and energy-metabolism. Alterations were confirmed by analysis of human biopsies from patients with ischemic cardiomyopathy. With the establishment of our in vitro disease model for ischemia injury target identification via proteomic research becomes independent from rare human material and will create new possibilities in cardiac research. PMID:22384053

[Cardioprotective effects of glutamine in patients with ischemic heart disease operated under conditions of extracorporeal blood circulation].

PubMed

Lomivorotov, V V; Efremov, S M; Shmyrev, V A; Ponomarev, D N; Sviatchenko, A V; Kniaz'kova, L G

2012-01-01

It was conducted a study of glutamine cardioptotective effects during perioperative use in patients with ischemic heart disease, operated under CB. Exclusion criteria were: left ventricular ejection fraction less than 50%, diabetes melitus, myocardial infarction less than 3 months ago, Patients of the study group (n=25) had glutamine (20% solution N(2)-L-alanine-L-glutamine ("Dipeptiven" Fresenius Kabi, Germany); 0.4 g/kg/day. Patients of control group (n=25) received placebo (0.9% NaCl solution). The main indicators were the dynamics of troponin I, as well as central hemodynamics parameters. On the 1-st day after operation the concentration of troponin I was significantly lower in the glutamine-group compared placebo-group (1.280 (0.840-2.230) 2.410 (1.060-6.600) ng/ml; p=0.035). 4 hours after CB in a glutamine-group also had significantly large indicators of cardiac index (2.58 (2.34-2.91) l/min/m2 vs 2.03 (1.76-2.32)) l/min/m2; p=0,002) and stroke index (32.8 (27.8-36.0.) ml/m2 vs 26.1 (22.6-31.8) ml/m2; p=0.023). Systemic vascular resistance index was significantly lower in glutamine-group (1942 (1828-2209) dyn x s/cm(-5)/m2 vs 2456 (2400-3265) dyn x s/cm(-5)/m2; p=0.001). Conclusion. Perioperative use of N(2)-L-alanine-L-glutamine during the first 24 hours ofperioperative period gives cardioprotective effect in patients with ischemic heart disease operated under CB.

Marginal donors: can older donor hearts tolerate prolonged cold ischemic storage?

PubMed

Korkmaz, Sevil; Bährle-Szabó, Susanne; Loganathan, Sivakkanan; Li, Shiliang; Karck, Matthias; Szabó, Gábor

2013-10-01

Both advanced donor age and prolonged ischemic time are significant risk factors for the 1-year mortality. However, its functional consequences have not been fully evaluated in the early-phase after transplantation; even early graft dysfunction is the main determinant of long-term outcome following transplantation. We evaluated in vivo left-ventricular (LV) cardiac and coronary vascular function of old-donor grafts after short and prolonged cold ischemic times in rats 1 h after heart transplantation. The hearts were excised from young donor (3-month-old) or old donor (18-month-old) rats, stored in cold preservation solution for either 1 or 8 h, and heterotopically transplanted. After 1 h of ischemic period, in the old-donor group, LV pressure, maximum pressure development (dP/dt max), time constant of LV pressure decay (τ), LV end-diastolic pressure and coronary blood flow did not differ compared with young donors. However, endothelium-dependent vasodilatation to acetylcholine resulted in a significantly lower response of coronary blood flow in the old-donor group (33 ± 4 vs. 51 ± 15 %, p < 0.05). After 8 h preservation, two of the old-donor hearts showed no mechanical activity upon reperfusion. LV pressure (55 ± 6 vs. 72 ± 5 mmHg, p < 0.05), dP/dt max (899 ± 221 vs. 1530 ± 217 mmHg/s, p < 0.05), coronary blood flow and response to acetylcholine were significantly reduced and τ was increased in the old-donor group in comparison to young controls. During the early-phase after transplantation, the ischemic tolerance of older-donor hearts is reduced after prolonged preservation time and the endothelium is more vulnerable to ischemia/reperfusion.

Acute Ischemia Induced by High-Density Culture Increases Cytokine Expression and Diminishes the Function and Viability of Highly Purified Human Islets of Langerhans.

PubMed

Smith, Kate E; Kelly, Amy C; Min, Catherine G; Weber, Craig S; McCarthy, Fiona M; Steyn, Leah V; Badarinarayana, Vasudeo; Stanton, J Brett; Kitzmann, Jennifer P; Strop, Peter; Gruessner, Angelika C; Lynch, Ronald M; Limesand, Sean W; Papas, Klearchos K

2017-11-01

Encapsulation devices have the potential to enable cell-based insulin replacement therapies (such as human islet or stem cell-derived β cell transplantation) without immunosuppression. However, reasonably sized encapsulation devices promote ischemia due to high β cell densities creating prohibitively large diffusional distances for nutrients. It is hypothesized that even acute ischemic exposure will compromise the therapeutic potential of cell-based insulin replacement. In this study, the acute effects of high-density ischemia were investigated in human islets to develop a detailed profile of early ischemia induced changes and targets for intervention. Human islets were exposed in a pairwise model simulating high-density encapsulation to normoxic or ischemic culture for 12 hours, after which viability and function were measured. RNA sequencing was conducted to assess transcriptome-wide changes in gene expression. Islet viability after acute ischemic exposure was reduced compared to normoxic culture conditions (P < 0.01). Insulin secretion was also diminished, with ischemic β cells losing their insulin secretory response to stimulatory glucose levels (P < 0.01). RNA sequencing revealed 657 differentially expressed genes following ischemia, with many that are associated with increased inflammatory and hypoxia-response signaling and decreased nutrient transport and metabolism. In order for cell-based insulin replacement to be applied as a treatment for type 1 diabetes, oxygen and nutrient delivery to β cells will need to be maintained. We demonstrate that even brief ischemic exposure such as would be experienced in encapsulation devices damages islet viability and β cell function and leads to increased inflammatory signaling.

A novel atherothrombotic model of ischemic stroke induced by injection of collagen into the cerebral vasculature

PubMed Central

Schunke, Kathryn J.; Toung, Thomas K.; Zhang, Jian; Pathak, Arvind P.; Xu, Jiadi; Zhang, Jiangyang; Koehler, Raymond C.; Faraday, Nauder

2017-01-01

Background Most ischemic strokes in humans are caused by ruptured arterial atheroma, which activate platelets and produce thrombi that occlude cerebral vessels. Methods To simulate these events, we threaded a catheter through the internal carotid artery toward the middle cerebral artery (MCA) orifice and injected collagen directly into the cerebral circulation of male C57Bl/6 mice and Wistar rats. Results Laser-Doppler flowmetry demonstrated reductions in cerebral blood flow (CBF) of ~80% in mice and ~60% in rats. CBF spontaneously increased but remained depressed after catheter withdrawal. Magnetic resonance imaging showed that ipsilateral CBF was reduced at 3 h after collagen injection and markedly improved at 48 h. Micro-computed tomography revealed reduced blood vessel density in the ipsilateral MCA territory at 3 h. Gross examination of excised brains revealed thrombi within ipsilateral cerebral arteries at 3 h, but not 24 h, after collagen injection. Immunofluorescence microscopy confirmed that platelets and fibrinogen/fibrin were major components of these thrombi at both macrovascular and microvascular levels. Cerebral infarcts comprising ~30% of hemispheric volume and neurobehavioral deficits were observed 48 h after ischemic injury in both mice and rats. Comparison with existing methods Collagen injection caused brain injury that was similar in magnitude and variability to mechanical MCA occlusion or injection of a pre-formed clot; however, alterations in CBF and the mechanism of vascular occlusion were more consistent with clinical ischemic stroke. Conclusion This novel rodent model of ischemic stroke has pathophysiologic characteristics consistent with clinical atherothrombotic stroke, is technically feasible, and creates reproducible brain injury. PMID:25314906

[The effect of nitrates on the outcome of acute experimental ischemic stroke].

PubMed

Kuzenkov, V S; Krushinskiĭ, A L; Reutov, V P

2012-01-01

Effects of nitrates NaNO(3), KNO(3), Mg(NO(3)) 2 on animals (Wistar rats) were studied on the basis of the experimental model of ischemic stroke induced by the occlusion of two carotid arteries. The animals were divided into two groups: the main group (n=60) and the control group (n=30). Three series of experiments were conducted. In each experiment, the rats of the main group were treated with one of nitrates and the control group was treated with physiological solution. It has been shown that nitrates exert either positive or negative effect depending on the cation type, nitrate concentration and the duration of their action on the dynamics of neurologic disturbances. Conditions of the development of neuroprotective effect of nitrates are discussed.

Effect of aniracetam on phosphatidylinositol transfer protein alpha in cytosolic and plasma membrane fractions of astrocytes subjected to simulated ischemia in vitro.

PubMed

Gabryel, Bozena; Chalimoniuk, Małgorzata; Małecki, Andrzej; Strosznajder, Joanna B

2005-01-01

Brain ischemia affects phosphoinositide metabolism and the level of lipid-derived second messengers. Phosphatidylinositol transfer proteins (PI-PTs) are responsible for the transport of phosphatidylinositol (PI) and other phospholipids through membranes. Isoform of PI-TPs (PI-TPalpha) is an essential component in ensuring substrate supply for phospholipase C (PLC). The current study was conducted to examine potential effect of aniracetam on PI-TPalpha expression and to characterize the PI-TPalpha isoform distribution between membrane and cytosol fractions of astrocytes exposed to simulated ischemia in vitro. After 8 h period of ischemia, the level of PI-TPalpha was significantly higher in cytosol (by about 28%) as well as in membrane fraction (by about 80%) in comparison with control. We have found that aniracetam treatment of astrocytes in normoxia significantly increased the level of PI-TPalpha in membrane fraction with a maximal effect at 0.1 microM concentration of aniracetam (by about 195% of control). In membrane fractions of ischemic cells, aniracetam increased PI-TPalpha expression in a concentration-dependent manner. In ischemic cells, aniracetam (10 microM) has elevated PI-TPalpha expression up to 155% and 428% in cytosolic and membrane fractions in comparison with ischemic untreated cells, respectively. The study has shown that aniracetam significantly activates PI-TPalpha in cell membrane fraction and this effect might be connected with previously described activation of MAP kinase cascade.

Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and delta-opioid receptors.

PubMed

Patel, Hemal H; Head, Brian P; Petersen, Heidi N; Niesman, Ingrid R; Huang, Diane; Gross, Garrett J; Insel, Paul A; Roth, David M

2006-07-01

The role of caveolae, membrane microenvironments enriched in signaling molecules, in myocardial ischemia is poorly defined. In the current study, we used cardiac myocytes prepared from adult rats to test the hypothesis that opioid receptors (OR), which are capable of producing cardiac protection in vivo, promote cardiac protection in cardiac myocytes in a caveolae-dependent manner. We determined protein expression and localization of delta-OR (DOR) using coimmunohistochemistry, caveolar fractionation, and immunoprecipitations. DOR colocalized in fractions with caveolin-3 (Cav-3), a structural component of caveolae in muscle cells, and could be immunoprecipitated by a Cav-3 antibody. Immunohistochemistry confirmed plasma membrane colocalization of DOR with Cav-3. Cardiac myocytes were subjected to simulated ischemia (2 h) or an ischemic preconditioning (IPC) protocol (10 min ischemia, 30 min recovery, 2 h ischemia) in the presence and absence of methyl-beta-cyclodextrin (MbetaCD, 2 mM), which binds cholesterol and disrupts caveolae. We also assessed the cardiac protective effects of SNC-121 (SNC), a selective DOR agonist, on cardiac myocytes with or without MbetaCD and MbetaCD preloaded with cholesterol. Ischemia, simulated by mineral oil layering to inhibit gas exchange, promoted cardiac myocyte cell death (trypan blue staining), a response blunted by SNC (37 +/- 3 vs. 59 +/- 3% dead cells in the presence and absence of 1 muM SNC, respectively, P < 0.01) or by use of the IPC protocol (35 +/- 4 vs. 62 +/- 3% dead cells, P < 0.01). MbetaCD treatment, which disrupted caveolae (as detected by electron microscopy), fully attenuated the protective effects of IPC or SNC, resulting in cell death comparable to that of the ischemic group. By contrast, SNC-induced protection was not abrogated in cells incubated with cholesterol-saturated MbetaCD, which maintained caveolae structure and function. These findings suggest a key role for caveolae, perhaps through enrichment of signaling molecules, in contributing to protection of cardiac myocytes from ischemic damage.

Virtual monochromatic imaging in dual-source and dual-energy CT for visualization of acute ischemic stroke

NASA Astrophysics Data System (ADS)

Hara, Hidetake; Muraishi, Hiroshi; Matsuzawa, Hiroki; Inoue, Toshiyuki; Nakajima, Yasuo; Satoh, Hitoshi; Abe, Shinji

2015-07-01

We have recently developed a phantom that simulates acute ischemic stroke. We attempted to visualize an acute-stage cerebral infarction by using dual-energy Computed tomography (DECT) to obtain virtual monochromatic images of this phantom. Virtual monochromatic images were created by using DECT voltages from 40 to 100 keV in steps of 10 keV and from 60 to 80 keV in steps of 1 keV, under three conditions of the tube voltage with thin (Sn) filters. Calculation of the CNR values allowed us to evaluate the visualization of acute-stage cerebral infarction. The CNR value of a virtual monochromatic image was the highest at 68 keV under 80 kV / Sn 140 kV, at 72 keV under 100 kV / Sn 140 kV, and at 67 keV under 140 kV / 80 kV. The CNR values of virtual monochromatic images at voltages between 65 and 75 keV were significantly higher than those obtained for all other created images. Therefore, the optimal conditions for visualizing acute ischemic stroke were achievable.

Influence of minoxidil on ischemic cutaneous flaps in rats.

PubMed

Bittencourt, Rogério de Castro; Biondo-Simões, Maria de Lourdes Pessole; Paula, Josué Brunginski de; Martynetz, Juliano; Groth, Anne

2005-01-01

To evaluate the influence of minoxidil, a well known vasodilator, on ischemic flap necrosis prevention in rats. Ventral cutaneous flaps, measuring 8x4 cm, were designed in 20 Wistar rats based on the right cranial epigastric artery. In the experiment group, 50 mg/kg/day of minoxidil sulfate was administered by orogastric tube and the same amount of saline solution was administered to the control group. Such procedure was initiated 24 h before surgery and kept once a day through the 7th postoperative day. Microcirculation was evaluated with laser fluxometry 24 h before surgical procedure, at immediate postoperative and at the 7th postoperative day. Flap necrosis area was evaluated by 2 methods: planimetry and weight/paper ratio. A significant flow increase in distal and medial extremity at M1 (medial point 1) (p=0.0484) was observed in the experiment group. There was significant difference in flap necrosis prevention in the experiment group (p=0.0433), although after necrosis took place there was no significant difference in necrosis size. (p=0.1051 and p=0.2799). Minoxidil sulfate is effective in avoiding necrosis in ischemic flaps, but after necrosis is present there is no difference in survival area between experimental and control groups.

Comparison of Baseline Wander Removal Techniques considering the Preservation of ST Changes in the Ischemic ECG: A Simulation Study

PubMed Central

Pilia, Nicolas; Schulze, Walther H. W.; Dössel, Olaf

2017-01-01

The most important ECG marker for the diagnosis of ischemia or infarction is a change in the ST segment. Baseline wander is a typical artifact that corrupts the recorded ECG and can hinder the correct diagnosis of such diseases. For the purpose of finding the best suited filter for the removal of baseline wander, the ground truth about the ST change prior to the corrupting artifact and the subsequent filtering process is needed. In order to create the desired reference, we used a large simulation study that allowed us to represent the ischemic heart at a multiscale level from the cardiac myocyte to the surface ECG. We also created a realistic model of baseline wander to evaluate five filtering techniques commonly used in literature. In the simulation study, we included a total of 5.5 million signals coming from 765 electrophysiological setups. We found that the best performing method was the wavelet-based baseline cancellation. However, for medical applications, the Butterworth high-pass filter is the better choice because it is computationally cheap and almost as accurate. Even though all methods modify the ST segment up to some extent, they were all proved to be better than leaving baseline wander unfiltered. PMID:28373893

Dynamic modeling of uteroplacental blood flow in IUGR indicates vortices and elevated pressure in the intervillous space - a pilot study

NASA Astrophysics Data System (ADS)

Roth, Christian J.; Haeussner, Eva; Ruebelmann, Tanja; Koch, Franz V.; Schmitz, Christoph; Frank, Hans-Georg; Wall, Wolfgang A.

2017-01-01

Ischemic placental disease is a concept that links intrauterine growth retardation (IUGR) and preeclampsia (PE) back to insufficient remodeling of uterine spiral arteries. The rheological consequences of insufficient remodeling of uterine spiral arteries were hypothesized to mediate the considerably later manifestation of obstetric disease. However, the micro-rheology in the intervillous space (IVS) cannot be examined clinically and rheological animal models of the human IVS do not exist. Thus, an in silico approach was implemented to provide in vivo inaccessible data. The morphology of a spiral artery and the inflow region of the IVS were three-dimensionally reconstructed to provide a morphological stage for the simulations. Advanced high-end supercomputing resources were used to provide blood flow simulations at high spatial resolution. Our simulations revealed turbulent blood flow (high-velocity jets and vortices) combined with elevated blood pressure in the IVS and increased wall shear stress at the villous surface in conjunction with insufficient spiral artery remodeling only. Post-hoc histological analysis of uterine veins showed evidence of increased trophoblast shedding in an IUGR placenta. Our data support that rheological alteration in the IVS is a relevant mechanism linking ischemic placental disease to altered structural integrity and function of the placenta.

Simulations of exercise and brain effects of acute exposure to carbon monoxide in normal and vascular-diseased persons.

EPA Science Inventory

At some level, carboxyhemoglobin (RbCO) due to inhalation of carbon monoxide (CO) reduces maximum exercise duration in normal and ischemic heart patients. At high RbCO levels in normal subjects, brain function is also affected and behavioral performance is impaired. These are fin...

Modelling Ischemic Stroke and Temperature Intervention Using Vascular Porous Method

NASA Astrophysics Data System (ADS)

Blowers, Stephen; Valluri, Prashant; Marshall, Ian; Andrews, Peter; Harris, Bridget; Thrippleton, Michael

2017-11-01

In the event of cerebral infarction, a region of tissue is supplied with insufficient blood flow to support normal metabolism. This can lead to an ischemic reaction which incurs cell death. Through a reduction of temperature, the metabolic demand can be reduced, which then offsets the onset of necrosis. This allows extra time for the patient to receive medical attention and could help prevent permanent brain damage from occurring. Here, we present a vascular-porous (VaPor) blood flow model that can simulate such an event. Cerebral blood flow is simulated using a combination of 1-Dimensional vessels embedded in 3-Dimensional porous media. This allows for simple manipulation of the structure and determining the effect of an obstructed vessel. Results show regional temperature increase of 1-1.5°C comparable with results from literature (in contrast to previous simpler models). Additionally, the application of scalp cooling in such an event dramatically reduces the temperature in the affected region to near hypothermic temperatures, which points to a potential rapid form of first intervention.

3D-printed soft-tissue physical models of renal malignancies for individualized surgical simulation: a feasibility study.

PubMed

Maddox, Michael M; Feibus, Allison; Liu, James; Wang, Julie; Thomas, Raju; Silberstein, Jonathan L

2018-03-01

To construct patient-specific physical three-dimensional (3D) models of renal units with materials that approximates the properties of renal tissue to allow pre-operative and robotic training surgical simulation, 3D physical kidney models were created (3DSystems, Rock Hill, SC) using computerized tomography to segment structures of interest (parenchyma, vasculature, collection system, and tumor). Images were converted to a 3D surface mesh file for fabrication using a multi-jet 3D printer. A novel construction technique was employed to approximate normal renal tissue texture, printers selectively deposited photopolymer material forming the outer shell of the kidney, and subsequently, an agarose gel solution was injected into the inner cavity recreating the spongier renal parenchyma. We constructed seven models of renal units with suspected malignancies. Partial nephrectomy and renorrhaphy were performed on each of the replicas. Subsequently all patients successfully underwent robotic partial nephrectomy. Average tumor diameter was 4.4 cm, warm ischemia time was 25 min, RENAL nephrometry score was 7.4, and surgical margins were negative. A comparison was made between the seven cases and the Tulane Urology prospectively maintained robotic partial nephrectomy database. Patients with surgical models had larger tumors, higher nephrometry score, longer warm ischemic time, fewer positive surgical margins, shorter hospitalization, and fewer post-operative complications; however, the only significant finding was lower estimated blood loss (186 cc vs 236; p = 0.01). In this feasibility study, pre-operative resectable physical 3D models can be constructed and used as patient-specific surgical simulation tools; further study will need to demonstrate if this results in improvement of surgical outcomes and robotic simulation education.

Modeling the influence of the VV delay for CRT on the electrical activation patterns in absence of conduction through the AV node

NASA Astrophysics Data System (ADS)

Romero, D. A.; Sebastián, Rafael; Plank, Gernot; Vigmond, Edward J.; Frangi, Alejandro F.

2008-03-01

From epidemiological studies, it has been shown that 0.2% of men and 0.1% of women suffer from a degree of atrioventricular (AV) block. In recent years, the palliative treatment for third degree AV block has included Cardiac Resynchronization Therapy (CRT). It was found that patients show more clinical improvement in the long term with CRT compared with single chamber devices. Still, an important group of patients does not improve their hemodynamic function as much as could be expected. A better understanding of the basis for optimizing the devices settings (among which the VV delay) will help to increase the number of responders. In this work, a finite element model of the left and right ventricles was generated using an atlas-based approach for their segmentation, which includes fiber orientation. The electrical activity was simulated with the electrophysiological solver CARP, using the Ten Tusscher et al. ionic model for the myocardium, and the DiFrancesco-Noble for Purkinje fibers. The model is representative of a patient without dilated or ischemic cardiomyopathy. The simulation results were analyzed for total activation times and latest activated regions at different VV delays and pre-activations (RV pre-activated, LV pre-activated). To optimize the solution, simulations are compared against the His-Purkinje network activation (normal physiological conduction), and interventricular septum activation (as collision point for the two wave fronts). The results were analyzed using Pearson's coefficient of correlation for point to point comparisons between simulation cases. The results of this study contribute to gain insight on the VV delay and how its adjustment might influence response to CRT and how it can be used to optimize the treatment.

Dabigatran Etexilate Reduces Thrombin-Induced Inflammation and Thrombus Formation in Experimental Ischemic Stroke.

PubMed

Dittmeier, Melanie; Wassmuth, Kathrin; Schuhmann, Michael K; Kraft, Peter; Kleinschnitz, Christoph; Fluri, Felix

2016-01-01

Dabigatran etexilate (DE), a direct-acting, oral inhibitor of thrombin, significantly reduces the risk of stroke compared with traditional anticoagulants, without increasing the risk of major bleeding. However, studies on the fate of cerebral tissue after ischemic stroke in patients receiving DE are sparse and the role of dabigatran-mediated reduction of thrombin in this context has not yet been investigated. Here, we investigated whether pretreatment with DE reduces thrombin-mediated pro-inflammatory mechanisms and leakage of the blood-brain barrier (BBB) following ischemic stroke in rats. Male Wistar rats received DE (15 mg/kg) or a vehicle solution 1 hour before transient middle cerebral artery occlusion (tMCAO) for 90 minutes. Infarct volume, neurologic outcome and intracranial hemorrhage (ICH) were determined after tMCAO. Thrombin generation was indirectly assessed by measuring thrombin/antithrombin III complex. Microvascular patency was evaluated histologically. Cytokine expression and immunoreactivity of cluster of differentiation (CD) 68 were examined to characterize inflammatory processes after pretreatment with DE. BBB integrity was examined by quantifying brain edema. Rats given DE revealed a significant reduction in infarct size without an increase in ICH and significant recovery of neurologic deficits compared to controls. Administration of DE decreased thrombin generation and thrombus formation, dampened the CD68-immunoreactivity and attenuated pro-inflammatory cytokine expression in the cerebral parenchyma ipsilateral to the ischemic lesion. BBB permeability was unaltered following treatment with DE. In summary, prophylactic anticoagulation with DE improves stroke outcome by reducing thrombin-induced inflammation and thrombus formation without increasing the rate of ICH.

Ischemic Preconditioning Increases the Tolerance of Fatty Liver to Hepatic Ischemia-Reperfusion Injury in the Rat

PubMed Central

Serafín, Anna; Roselló-Catafau, Joan; Prats, Neus; Xaus, Carme; Gelpí, Emilio; Peralta, Carmen

2002-01-01

Hepatic steatosis is a major risk factor in ischemia-reperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. PMID:12163383

Amelioration of myocardial ischemic reperfusion injury with Calendula officinalis.

PubMed

Ray, Diptarka; Mukherjee, Subhendu; Falchi, Mario; Bertelli, Aldo; Das, Dipak K

2010-12-01

Calendula officinalis of family Asteraceae, also known as marigold, has been widely used from time immemorial in Indian and Arabic cultures as an anti-inflammatory agent to treat minor skin wound and infections, burns, bee stings, sunburn and cancer. At a relatively high dose, calendula can lower blood pressure and cholesterol. Since inflammatory responses are behind many cardiac diseases, we sought to evaluate if calendula could be cardioprotective against ischemic heart disease Two groups of hearts were used: the treated rat hearts were perfused with calendula solution at 50 mM in KHB buffer (in mM: sodium chloride 118, potassium chloride 4.7, calcium chloride 1.7, sodium bicarbonate 25, potassium biphosphate 0.36, magnesium sulfate 1.2, and glucose 10) for 15 min prior to subjecting the heart to ischemia, while the control group was perfused with the buffer only. Calendula achieved cardioprotection by stimulating left ventricular developed pressure and aortic flow as well as by reducing myocardial infarct size and cardiomyocyte apoptosis. Cardioprotection appears to be achieved by changing ischemia reperfusion-mediated death signal into a survival signal by modulating antioxidant and anti-inflammatory pathways as evidenced by the activation of Akt and Bcl2 and depression of TNFα. The results further strengthen the concept of using natural products in degeneration diseases like ischemic heart disease.

The Role of Influenza in the Delay between Low Temperature and Ischemic Heart Disease: Evidence from Simulation and Mortality Data from Japan

PubMed Central

Imai, Chisato; Barnett, Adrian G.; Hashizume, Masahiro; Honda, Yasushi

2016-01-01

Many studies have found that cardiovascular deaths mostly occur within a few days of exposure to heat, whereas cold-related deaths can occur up to 30 days after exposure. We investigated whether influenza infection could explain the delayed cold effects on ischemic heart diseases (IHD) as they can trigger IHD. We hypothesized two pathways between cold exposure and IHD: a direct pathway and an indirect pathway through influenza infection. We created a multi-state model of the pathways and simulated incidence data to examine the observed delayed patterns in cases. We conducted cross-correlation and time series analysis with Japanese daily pneumonia and influenza (P&I) mortality data to help validate our model. Simulations showed the IHD incidence through the direct pathway occurred mostly within 10 days, while IHD through influenza infection peaked at 4–6 days, followed by delayed incidences of up to 20–30 days. In the mortality data from Japan, P&I lagged IHD in cross-correlations. Time series analysis showed strong delayed cold effects in the older population. There was also a strong delay on intense days of influenza which was more noticeable in the older population. Influenza can therefore be a plausible explanation for the delayed association between cold exposure and cardiovascular mortality. PMID:27136571

Thrombolysis in Acute Ischemic Stroke: A Simulation Study to Improve Pre- and in-Hospital Delays in Community Hospitals

PubMed Central

Lahr, Maarten M. H.; van der Zee, Durk-Jouke; Vroomen, Patrick C. A. J.; Luijckx, Gert-Jan; Buskens, Erik

2013-01-01

Background Various studies demonstrate better patient outcome and higher thrombolysis rates achieved by centralized stroke care compared to decentralized care, i.e. community hospitals. It remains largely unclear how to improve thrombolysis rate in decentralized care. The aim of this simulation study was to assess the impact of previously identified success factors in a central model on thrombolysis rates and patient outcome when implemented for a decentral model. Methods Based on a prospectively collected dataset of 1084 ischemic stroke patients, simulation was used to replicate current practice and estimate the effect of re-organizing decentralized stroke care to resemble a centralized model. Factors simulated included symptom onset call to help, emergency medical services transportation, and in-hospital diagnostic workup delays. Primary outcome was proportion of patients treated with thrombolysis; secondary endpoints were good functional outcome at 90 days, Onset-Treatment-Time (OTT), and OTT intervals, respectively. Results Combining all factors might increase thrombolysis rate by 7.9%, of which 6.6% ascribed to pre-hospital and 1.3% to in-hospital factors. Good functional outcome increased by 11.4%, 8.7% ascribed to pre-hospital and 2.7% to in-hospital factors. The OTT decreased 17 minutes, 7 minutes ascribed to pre-hospital and 10 minutes to in-hospital factors. An increase was observed in the proportion thrombolyzed within 1.5 hours; increasing by 14.1%, of which 5.6% ascribed to pre-hospital and 8.5% to in-hospital factors. Conclusions Simulation technique may target opportunities for improving thrombolysis rates in acute stroke. Pre-hospital factors proved to be the most promising for improving thrombolysis rates in an implementation study. PMID:24260151

Organotypic lung culture: A new model for studying ischemia and ex vivo perfusion in lung transplantation.

PubMed

Baste, Jean-Marc; Gay, Arnaud; Smail, Hassiba; Noël, Romain; Bubenheim, Michael; Begueret, Hugues; Morin, Jean-Paul; Litzler, Pierre-Yves

2015-01-01

Donors after cardiac death (DCD) in lung transplantation is considered as a solution for organ shortage. However, it is characterized by warm ischemic period, which could be involved in severe Ischemia-Reperfusion lesion (IR) with early graft dysfunction. We describe a new hybrid model combining in vivo ischemia followed by in vitro reoxygenation using organ-specific culture. A hybrid model using in vivo ischemic period followed by in vitro lung slice reoxygenation was set up in rat to mimic DCD in lung transplantation with in vitro perfusion. Different markers (bioenergetics, oxidant stress assays, and histology) were measured to evaluate the viability of lung tissue after different ischemic times (I-0, I-1, I-2, I-4, I-15 hours) and reoxygenation times (R-0, R-1, R-4, R-24 hours). No differences were found in cell viability, ATP concentrations, extracellular LDH assays or histology, demonstrating extensive viability of up to 4 hours in lung tissue warm ischemia. We found oxidative stress mainly during the ischemic period with no burst at reoxygenation. Cytosolic anti-oxidant system was involved first (I-0,I-1,I-2) followed by mitochondrial anti-oxidant system for extensive ischemia (I-4). Histological features showed differences in this model of ischemia-reoxygenation between bronchial epithelium and lung parenchymal cells, with epithelium regeneration after 2 hours of warm ischemia and 24 hours of perfusion. The results of our hybrid model experiment suggest extensive lung viability of up to 4 hours ischemia. Our model could be an interesting tool to evaluate ex vivo reconditioning techniques after different in vivo lung insults.

Nanomaterial Solutions for the Protection of Insulin Producing Beta Cells

NASA Astrophysics Data System (ADS)

Atchison, Nicole Ann

Islet transplantation is a promising treatment for type 1 diabetes. However, even with the many successes, islet transplantation has yet to reach its full potential. Limited islet sources, loss of cell viability during isolation and culture, and post-transplant graft loss are a few of the issues preventing extensive use of islet transplantation. The application of biomaterial systems to alleviate some of the stresses affecting islet viability has led to improvements in isolation and transplantation outcomes, but problems persist. In this work we approach two distinct issues affecting islet viability; ischemic conditions and immunological attack post-transplant. Ischemic conditions have been linked to a loss of islet graft function and occur during organ preservation, islet isolation and culture, and after islets are transplanted. We show that liposomal delivery of adenosine triphosphate (ATP) to beta cells can limit cell death and loss of function in ischemic conditions. We demonstrate that by functionalizing liposomes with the fibronectin-mimetic peptide PR_b, delivery of liposomes to porcine islets and rat beta cells is increased compared to nontargeted controls. Additionally, liposomes are shown to protect by providing both ATP and lipids to the ischemic cells. The delivery of ATP was investigated here but application of PR_b functionalized liposomes could be extended to other interesting cargos as well. The second area of investigation involves encapsulation of islets with silica nanoparticles to create a permselective barrier. Silica nanoparticles are an interesting material for encapsulation given their ability to be fine-tuned and further functionalized. We demonstrate that size-tunable, fluorescent silica nanoparticles can be assembled layer-by-layer on the surface of cells and that silica nanoparticle encapsulated islets are able to secrete insulin in response to a glucose challenge.

Nicotine and estrogen synergistically exacerbate cerebral ischemic injury.

PubMed

Raval, A P; Hirsch, N; Dave, K R; Yavagal, D R; Bramlett, H; Saul, I

2011-05-05

The greater incidence of myocardial infarction, cardiac arrest, and ischemic stroke among women who smoke and use oral contraception (OC) compared to women who do not smoke and who do or do not use OC may be due in part to how nicotine influences endocrine function in women. For example, we recently demonstrated that chronic exposure to nicotine, the addictive agent in tobacco smoke responsible for the elevated risk of cardiac arrest, abolishes the endogenous or exogenous 17β-estradiol-conferred protection of the hippocampus against global cerebral ischemia (a potential outcome of cardiac arrest) in naive or ovariectomized female rats. In the current study we examined the hypotheses that (1) a synergistic deleterious effect of nicotine plus oral contraceptives exacerbates post-ischemic hippocampal damage in female rats, and (2) nicotine directly inhibits estrogen-mediated intracellular signaling in the hippocampus. To test first hypothesis and to simulate smoking behavior-induced nicotine levels in the human body, we implanted osmotic pumps containing nicotine in the female rats for 16 days. Furthermore, we mimicked the use of oral contraceptives in females by administering oral contraceptives orally to the rat. Rats exposed to either nicotine alone or in combination with oral contraceptives were subjected to an episode of cerebral ischemia and the resultant brain damage was quantified. These results showed for the first time that nicotine with oral contraceptives did indeed exacerbate post-ischemic CA1 damage as compared to nicotine alone in naive female rats. In ex vivo hippocampal slice cultures, we found that nicotine alone or with 17β-estradiol directly hinders estrogen receptors-mediated phosphorylation of cyclic-AMP element binding protein, a process required for neuronal survival and also exacerbates ischemic damage. Thus, nicotine can affect the outcome of cerebral ischemia by influencing brain endocrine function directly rather than through indirect systemic effects. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

DOR activation inhibits anoxic/ischemic Na+ influx through Na+ channels via PKC mechanisms in the cortex.

PubMed

Chao, Dongman; He, Xiaozhou; Yang, Yilin; Bazzy-Asaad, Alia; Lazarus, Lawrence H; Balboni, Gianfranco; Kim, Dong H; Xia, Ying

2012-08-01

Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na(+) influx through TTX-sensitive voltage-gated Na(+) channels may be a main mechanism for hypoxia-induced disruption of K(+) homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na(+) channels. In the present study we examined the role of DOR in the regulation of Na(+) influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na(+) influx induced by a Na(+) channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na(+) activity in mouse cortical slices with Na(+) selective electrodes and found that (1) anoxia-induced Na(+) influx occurred mainly through TTX-sensitive Na(+) channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na(+) influx; (3) veratridine, a Na(+) channel opener, enhanced the anoxia-induced Na(+) influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na(+) influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKCβII peptide inhibitor, and PKCθ pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na(+) influx through Na(+) channels via PKC (especially PKCβII and PKCθ isoforms) dependent mechanisms in the cortex. Copyright © 2012 Elsevier Inc. All rights reserved.

Recent Advances in Cerebellar Ischemic Stroke Syndromes Causing Vertigo and Hearing Loss.

PubMed

Kim, Hyun-Ah; Yi, Hyon-Ah; Lee, Hyung

2016-12-01

Cerebellar ischemic stroke is one of the common causes of vascular vertigo. It usually accompanies other neurological symptoms or signs, but a small infarct in the cerebellum can present with vertigo without other localizing symptoms. Approximately 11 % of the patients with isolated cerebellar infarction simulated acute peripheral vestibulopathy, and most patients had an infarct in the territory of the medial branch of the posterior inferior cerebellar artery (PICA). A head impulse test can differentiate acute isolated vertigo associated with PICA territory cerebellar infarction from more benign disorders involving the inner ear. Acute hearing loss (AHL) of a vascular cause is mostly associated with cerebellar infarction in the territory of the anterior inferior cerebellar artery (AICA), but PICA territory cerebellar infarction rarely causes AHL. To date, at least eight subgroups of AICA territory infarction have been identified according to the pattern of neurotological presentations, among which the most common pattern of audiovestibular dysfunction is the combined loss of auditory and vestibular functions. Sometimes acute isolated audiovestibular loss can be the initial symptom of impending posterior circulation ischemic stroke (particularly within the territory of the AICA). Audiovestibular loss from cerebellar infarction has a good long-term outcome than previously thought. Approximately half of patients with superior cerebellar artery territory (SCA) cerebellar infarction experienced true vertigo, suggesting that the vertigo and nystagmus in the SCA territory cerebellar infarctions are more common than previously thought. In this article, recent findings on clinical features of vertigo and hearing loss from cerebellar ischemic stroke syndrome are summarized.

Risk factors for ischemic stroke and its subtypes in Chinese vs. Caucasians: Systematic review and meta-analysis.

PubMed

Tsai, Chung-Fen; Anderson, Niall; Thomas, Brenda; Sudlow, Cathie L M

2015-06-01

Chinese populations are reported to have a different distribution of ischemic stroke subtypes compared with Caucasians. To understand this better, we aimed to evaluate the differences in prevalence of risk factors in ischemic stroke and their distributions among ischemic stroke subtypes in Chinese vs. Caucasians. We systematically sought studies conducted since 1990 with data on frequency of risk factors among ischemic stroke subtypes in Chinese or Caucasians. For each risk factor, we calculated study-specific and random effects pooled estimates in Chinese and Caucasians separately for: prevalence among ischemic stroke; odds ratios, comparing prevalence for each ischemic stroke subtype vs. all others. We included seven studies among 16,199 Chinese, and eleven among 16,189 Caucasian ischemic stroke patients. Risk factors studied were hypertension, diabetes, atrial fibrillation, ischemic heart disease, hypercholesterolemia, smoking and alcohol. Chinese ischemic stroke patients had younger onset of stroke than Caucasians, similar prevalence of hypertension, diabetes, smoking and alcohol, and significantly lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia. Risk factor associations with ischemic stroke subtypes were mostly similar among Chinese and Caucasian ischemic stroke patients. Compared with all other ischemic subtypes, diabetes was more common in large artery stroke, atrial fibrillation and ischemic heart disease in cardioembolic stroke, and hypertension and diabetes in lacunar stroke. Our study showed a lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia in Chinese, and mostly similar risk factor associations in Chinese and Caucasian ischemic stroke patients. Further analyses of individual patient data to allow adjustment for confounders are needed to confirm and extend these findings. © 2015 World Stroke Organization.

Ischemic Strokes (Clots)

MedlinePlus

... Month Infographic Stroke Hero F.A.S.T. Quiz Ischemic Strokes (Clots) Updated:May 21,2018 Ischemic stroke accounts for about 87 percent of all cases. View a detailed animation of ischemic stroke . Ischemic strokes occur as a result of an ...

Validation of a model to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD: the rotterdam ischemic heart disease and stroke computer simulation (RISC) model.

PubMed

van Kempen, Bob J H; Ferket, Bart S; Hofman, Albert; Steyerberg, Ewout W; Colkesen, Ersen B; Boekholdt, S Matthijs; Wareham, Nicholas J; Khaw, Kay-Tee; Hunink, M G Myriam

2012-12-06

We developed a Monte Carlo Markov model designed to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD. Internal, predictive, and external validity of the model have not yet been established. The Rotterdam Ischemic Heart Disease and Stroke Computer Simulation (RISC) model was developed using data covering 5 years of follow-up from the Rotterdam Study. To prove 1) internal and 2) predictive validity, the incidences of coronary heart disease (CHD), stroke, CVD death, and non-CVD death simulated by the model over a 13-year period were compared with those recorded for 3,478 participants in the Rotterdam Study with at least 13 years of follow-up. 3) External validity was verified using 10 years of follow-up data from the European Prospective Investigation of Cancer (EPIC)-Norfolk study of 25,492 participants, for whom CVD and non-CVD mortality was compared. At year 5, the observed incidences (with simulated incidences in brackets) of CHD, stroke, and CVD and non-CVD mortality for the 3,478 Rotterdam Study participants were 5.30% (4.68%), 3.60% (3.23%), 4.70% (4.80%), and 7.50% (7.96%), respectively. At year 13, these percentages were 10.60% (10.91%), 9.90% (9.13%), 14.20% (15.12%), and 24.30% (23.42%). After recalibrating the model for the EPIC-Norfolk population, the 10-year observed (simulated) incidences of CVD and non-CVD mortality were 3.70% (4.95%) and 6.50% (6.29%). All observed incidences fell well within the 95% credibility intervals of the simulated incidences. We have confirmed the internal, predictive, and external validity of the RISC model. These findings provide a basis for analyzing the effects of modifying cardiovascular disease risk factors on the burden of CVD with the RISC model.

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

PubMed Central

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

2011-01-01

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

Patient-specific structural effects on hemodynamics in the ischemic lower limb artery

NASA Astrophysics Data System (ADS)

Xu, Pengcheng; Liu, Xin; Song, Qi; Chen, Guishan; Wang, Defeng; Zhang, Heye; Yan, Li; Liu, Dan; Huang, Wenhua

2016-12-01

Lower limb peripheral artery disease is a prevalent chronic non-communicable disease without obvious symptoms. However, the effect of ischemic lower limb peripheral arteries on hemodynamics remains unclear. In this study, we investigated the variation of the hemodynamics caused by patient-specific structural artery characteristics. Computational fluid dynamic simulations were performed on seven lower limb (including superficial femoral, deep femoral and popliteal) artery models that were reconstructed from magnetic resonance imaging. We found that increased wall shear stress (WSS) was mainly caused by the increasing severity of stenosis, bending, and branching. Our results showed that the increase in the WSS value at a stenosis at the bifurcation was 2.7 Pa. In contrast, the isolated stenosis and branch caused a WSS increase of 0.7 Pa and 0.5 Pa, respectively. The WSS in the narrow popliteal artery was more sensitive to a reduction in radius. Our results also demonstrate that the distribution of the velocity and pressure gradient are highly structurally related. At last, Ultrasound Doppler velocimeter measured result was presented as a validation. In conclusion, the distribution of hemodynamics may serve as a supplement for clinical decision-making to prevent the occurrence of a morbid or mortal ischemic event.

Streamlining Workflow for Endovascular Mechanical Thrombectomy: Lessons Learned from a Comprehensive Stroke Center.

PubMed

Wang, Hongjin; Thevathasan, Arthur; Dowling, Richard; Bush, Steven; Mitchell, Peter; Yan, Bernard

2017-08-01

Recently, 5 randomized controlled trials confirmed the superiority of endovascular mechanical thrombectomy (EMT) to intravenous thrombolysis in acute ischemic stroke with large-vessel occlusion. The implication is that our health systems would witness an increasing number of patients treated with EMT. However, in-hospital delays, leading to increased time to reperfusion, are associated with poor clinical outcomes. This review outlines the in-hospital workflow of the treatment of acute ischemic stroke at a comprehensive stroke center and the lessons learned in reduction of in-hospital delays. The in-hospital workflow for acute ischemic stroke was described from prehospital notification to femoral arterial puncture in preparation for EMT. Systematic review of literature was also performed with PubMed. The implementation of workflow streamlining could result in reduction of in-hospital time delays for patients who were eligible for EMT. In particular, time-critical measures, including prehospital notification, the transfer of patients from door to computed tomography (CT) room, initiation of intravenous thrombolysis in the CT room, and the mobilization of neurointervention team in parallel with thrombolysis, all contributed to reduction in time delays. We have identified issues resulting in in-hospital time delays and have reported possible solutions to improve workflow efficiencies. We believe that these measures may help stroke centers initiate an EMT service for eligible patients. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Dietary Intake of α-Linolenic Acid Is Not Appreciably Associated with Risk of Ischemic Stroke among Middle-Aged Danish Men and Women.

PubMed

Bork, Christian S; Venø, Stine K; Lundbye-Christensen, Søren; Jakobsen, Marianne U; Tjønneland, Anne; Schmidt, Erik B; Overvad, Kim

2018-06-01

Intake of the plant-derived omega-3 (n-3) fatty acid α-linolenic acid (ALA) may reduce the risk of ischemic stroke. We have investigated the associations between dietary intake of ALA and the risk of ischemic stroke and ischemic stroke subtypes. This was a follow-up study. A total of 57,053 participants aged 50-64 y were enrolled into the Danish Diet, Cancer and Health cohort between 1993 and 1997. Intake of ALA was assessed by a validated semiquantitative food frequency questionnaire. Potential incident cases of ischemic stroke were identified in the Danish National Patient Register, validated, and classified into subtypes based on assumed etiology. Statistical analyses were performed via Cox proportional hazard regression with adjustment for established ischemic stroke risk factors. A total of 1859 ischemic stroke cases were identified during a median of 13.5 y of follow-up. In multivariable analyses using restricted cubic splines adjusting for traditional risk factors for ischemic stroke, we observed no clear associations between dietary intake of ALA and the risk of total ischemic stroke or any of its subtypes including ischemic stroke due to large artery atherosclerosis, ischemic stroke due to small-vessel occlusion, and ischemic stroke due to cardio-embolism. Dietary intake of ALA was neither consistently nor appreciably associated with the risk of ischemic stroke or ischemic stroke subtypes among middle-aged Danish men and women. This study was registered at clinicaltrials.gov as NCT03258983.

Minimum intravenous thrombolysis utilization rates in acute ischemic stroke to achieve population effects on disability: A discrete-event simulation model.

PubMed

Hoffmeister, Lorena; Lavados, Pablo M; Mar, Javier; Comas, Merce; Arrospide, Arantzazu; Castells, Xavier

2016-06-15

The only pharmacological treatment with proven cost-effectiveness in reducing acute ischemic stroke (AIS) associated disability is intravenous thrombolysis with recombinant tissue plasminogen activator but it's utilization rate is still low in most of the world. We estimated the minimum thrombolysis utilization rate needed to decrease the prevalence of stroke-related disability at a population level by using a discrete-event simulation model. The model included efficacy according to time to treatment up to 4.5h, and four scenarios for the utilization of intravenous thrombolysis in eligible patients with AIS: a) 2%; b) 12% c) 25% and d) 40%. We calculated the prevalence of AIS related disability in each scenario, using population based data. The simulation was performed from 2002 to 2017 using the ARENA software. A 2% utilization rate yielded a prevalence of disability of 359.1 per 100,000. Increasing thrombolysis to 12% avoided 779 disabled patients. If the utilization rate was increased to 25%, 1783 disabled patients would be avoided. The maximum scenario of 40% decreased disability to 335.7 per 100,000, avoiding 17% of AIS-related disability. The current utilization rate of intravenous thrombolysis of 2% has minimal population impact. Increasing the rate of utilization to more than 12% is the minimum to have a significant population effect on disability and should be a public policy aim. Copyright © 2016 Elsevier B.V. All rights reserved.

Carbon dioxide coronary angiography: A mechanical feasibility study with a cardiovascular simulator

NASA Astrophysics Data System (ADS)

Corazza, Ivan; Taglieri, Nevio; Pirazzini, Edoardo; Rossi, Pier Luca; Lombi, Alessandro; Scalise, Filippo; Caridi, James G.; Zannoli, Romano

2018-01-01

The aim of this study was to carry out a bench evaluation of the biomechanical feasibility of carbon dioxide (CO2) coronary arteriography. Many patients among the aging population of individuals requiring cardiac intervention have underlying renal insufficiency making them susceptible to contrast-induced nephropathy. To include those patients, it is imperative to find an alternative and safe technique to perform coronary imaging on cardiac ischemic patients. As CO2 angiography has no renal toxicity, it may be a possible solution offering good imaging with negligible collateral effects. Theoretically, by carefully controlling the gas injection process, new automatic injectors may avoid gas reflux into the aorta and possible cerebral damage. A feasibility study is mandatory. A mechanical mock of the coronary circulation was developed and employed. CO2 was injected into the coronary ostium with 2 catheters (2F and 6F) and optical images of bubbles flowing inside the vessels at different injection pressures were recorded. The gas behavior was then carefully studied for quantitative and qualitative analysis. Video recordings showed that CO2 injection at a precise pressure in the interval between the arterial dicrotic notch and the minimum diastolic value does not result in gas reflow into the aorta. Gas reflow was easier to control with the smaller catheter, but the gas bubbles were smaller with different vascular filling. Our simulation demonstrates that carefully selected injection parameters allow CO2 coronary imaging without any risk of gas reflux into the aorta.

Preserved Collateral Blood Flow in the Endovascular M2CAO Model Allows for Clinically Relevant Profiling of Injury Progression in Acute Ischemic Stroke.

PubMed

Little, Philip; Kvist, Ola; Grankvist, Rikard; Jonsson, Stefan; Damberg, Peter; Söderman, Michael; Arnberg, Fabian; Holmin, Staffan

2017-01-01

Interventional treatment regimens have increased the demand for accurate understanding of the progression of injury in acute ischemic stroke. However, conventional animal models severely inhibit collateral blood flow and mimic the malignant infarction profile not suitable for treatment. The aim of this study was to provide a clinically relevant profile of the emergence and course of ischemic injury in cases suitable for acute intervention, and was achieved by employing a M2 occlusion model (M2CAO) that more accurately simulates middle cerebral artery (MCA) occlusion in humans. Twenty-five Sprague-Dawley rats were subjected to Short (90 min), Intermediate (180 min) or Extended (600 min) transient M2CAO and examined longitudinally with interleaved diffusion-, T2- and arterial spin labeling perfusion-weighted magnetic resonance imaging before and after reperfusion. We identified a rapid emergence of cytotoxic edema within tissue regions undergoing infarction, progressing in several distinct phases in the form of subsequent moderation and then reversal at 230 min (p < 0.0001). We identified also the early emergence of vasogenic edema, which increased consistently before and after reperfusion (p < 0.0001). The perfusion of the penumbra correlated more strongly to the perfusion of adjacent tissue regions than did the perfusion of regions undergoing infarction (p = 0.0088). This was interpreted as an effect of preserved collateral blood flow during M2CAO. Accordingly, we observed only limited recruitment of penumbra regions to the infarction core. However, a gradual increase in infarction size was still occurring as late as 10 hours after M2CAO. Our results indicate that patients suffering MCA branch occlusion stand to benefit from interventional therapy for an extended time period after the emergence of ischemic injury.

TGF-β1/Smad3 Signaling Pathway Suppresses Cell Apoptosis in Cerebral Ischemic Stroke Rats

PubMed Central

Zhu, Haiping; Gui, Qunfeng; Hui, Xiaobo; Wang, Xiaodong; Jiang, Jian; Ding, Lianshu; Sun, Xiaoyang; Wang, Yanping; Chen, Huaqun

2017-01-01

Background We desired to observe the changes of transforming growth factor-β1/drosophila mothers against decapentaplegic protein (TGF-β1/Smad3) signaling pathway in the hippocampus region of cerebral ischemic stroke rats so that the effects of this pathway on nerve cells can be investigated. Material/Methods The ischemic stroke models were built by middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. TGF-β1 and TGF-β1 inhibitors were injected into rat models while TGF-β1, TGF-β1 siRNA, Smad3, and Smad3 siRNA were transfected into cells. Infarct sizes were measured using triphenyltetrazolium chloride (TTC) staining, while the apoptosis rate of cells were calculated by Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining. Levels of TGF-β1, Smad3, and Bcl-2 were examined by real-time polymerase chain reaction (RT-PCR), immunohistochemical, and Western blot analysis. Results The expressions of TGF-β1/Smad3 signal pathway were significantly increased in both model rats and BV2 cells, whereas the expression of Bcl-2 was down-regulated (P<0.05). The TGF-β1/Smad3 signal pathway exhibited protective effects, including the down-regulation of infarction size in cerebral tissues and the down-regulation of apoptosis rate of BV2 cells by increasing the expression of Bcl-2 (P<0.05). In addition, these effects could be antagonized by the corresponding inhibitors and siRNA (P<0.05). Conclusions The TGF-β1/Smad3 signaling pathway was up-regulated once cerebral ischemic stroke was simulated. TGF-β1 may activate the expression of Bcl-2 via Smad3 to suppress the apoptosis of neurons. PMID:28110342

Cost-Effectiveness of Thrombolysis within 4.5 Hours of Acute Ischemic Stroke in China

PubMed Central

Zhao, Xingquan; Liao, Xiaoling; Wang, Chunjuan; Du, Wanliang; Liu, Gaifen; Liu, Liping; Wang, Chunxue; Wang, Yilong; Wang, Yongjun

2014-01-01

Background Previous economic studies conducted in developed countries showed intravenous tissue-type plasminogen activator (tPA) is cost-effective for acute ischemic stroke. The present study aimed to determine the cost-effectiveness of tPA treatment in China, the largest developing country. Methods A combination of decision tree and Markov model was developed to determine the cost-effectiveness of tPA treatment versus non-tPA treatment within 4.5 hours after stroke onset. Outcomes and costs data were derived from the database of Thrombolysis Implementation and Monitor of acute ischemic Stroke in China (TIMS-China) study. Efficacy data were derived from a pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Costs and quality-adjusted life-years (QALYs) were compared in both short term (2 years) and long term (30 years). One-way and probabilistic sensitivity analyses were performed to test the robustness of the results. Results Comparing to non-tPA treatment, tPA treatment within 4.5 hours led to a short-term gain of 0.101 QALYs at an additional cost of CNY 9,520 (US$ 1,460), yielding an incremental cost-effectiveness ratio (ICER) of CNY 94,300 (US$ 14,500) per QALY gained in 2 years; and to a long-term gain of 0.422 QALYs at an additional cost of CNY 6,530 (US$ 1,000), yielding an ICER of CNY 15,500 (US$ 2,380) per QALY gained in 30 years. Probabilistic sensitivity analysis showed that tPA treatment is cost-effective in 98.7% of the simulations at a willingness-to-pay threshold of CNY 105,000 (US$ 16,200) per QALY. Conclusions Intravenous tPA treatment within 4.5 hours is highly cost-effective for acute ischemic strokes in China. PMID:25329637

Sodium Nitroprusside Enhanced Cardiopulmonary Resuscitation Improves Short Term Survival in a Porcine Model of Ischemic Refractory Ventricular Fibrillation

PubMed Central

Yannopoulos, Demetris; Bartos, Jason A.; George, Stephen A.; Sideris, George; Voicu, Sebastian; Oestreich, Brett; Matsuura, Timothy; Shekar, Kadambari; Rees, Jennifer; Aufderheide, Tom P.

2017-01-01

Introduction Sodium nitroprusside (SNP) enhanced CPR (SNPeCPR) demonstrates increased vital organ blood flow and survival in multiple porcine models. We developed a new, coronary occlusion/ischemia model of prolonged resuscitation, mimicking the majority of out-of-hospital cardiac arrests presenting with shockable rhythms. Hypothesis SNPeCPR will increase short term (4-hour) survival compared to standard 2015 Advanced Cardiac Life Support (ACLS) guidelines in an ischemic refractory ventricular fibrillation (VF), prolonged CPR model. Methods Sixteen anesthetized pigs had the ostial left anterior descending artery occluded leading to ischemic VF arrest. VF was untreated for 5 minutes. Basic life support was performed for 10 minutes. At minute 10 (EMS arrival), animals received either SNPeCPR (n=8) or standard ACLS (n=8). Defibrillation (200J) occurred every 3 minutes. CPR continued for a total of 45 minutes, then the balloon was deflated simulating revascularization. CPR continued until return of spontaneous circulation (ROSC) or a total of 60 minutes, if unsuccessful. SNPeCPR animals received 2 mg of SNP at minute 10 followed by 1 mg every 5 minutes until ROSC. Standard ACLS animals received 0.5 mg epinephrine every 5 minutes until ROSC. Primary endpoints were ROSC and 4-hour survival. Results All SNPeCPR animals (8/8) achieved sustained ROSC versus 2/8 standard ACLS animals within one hour of resuscitation (p=0.04). The 4-hour survival was significantly improved with SNPeCPR compared to standard ACLS, 7/8 versus 1/8 respectively, p=0.0019. Conclusion SNPeCPR significantly improved ROSC and 4-hour survival compared with standard ACLS CPR in a porcine model of prolonged ischemic, refractory VF cardiac arrest. PMID:27771299

Sodium nitroprusside enhanced cardiopulmonary resuscitation improves short term survival in a porcine model of ischemic refractory ventricular fibrillation.

PubMed

Yannopoulos, Demetris; Bartos, Jason A; George, Stephen A; Sideris, George; Voicu, Sebastian; Oestreich, Brett; Matsuura, Timothy; Shekar, Kadambari; Rees, Jennifer; Aufderheide, Tom P

2017-01-01

Sodium nitroprusside (SNP) enhanced CPR (SNPeCPR) demonstrates increased vital organ blood flow and survival in multiple porcine models. We developed a new, coronary occlusion/ischemia model of prolonged resuscitation, mimicking the majority of out-of-hospital cardiac arrests presenting with shockable rhythms. SNPeCPR will increase short term (4-h) survival compared to standard 2015 Advanced Cardiac Life Support (ACLS) guidelines in an ischemic refractory ventricular fibrillation (VF), prolonged CPR model. Sixteen anesthetized pigs had the ostial left anterior descending artery occluded leading to ischemic VF arrest. VF was untreated for 5min. Basic life support was performed for 10min. At minute 10 (EMS arrival), animals received either SNPeCPR (n=8) or standard ACLS (n=8). Defibrillation (200J) occurred every 3min. CPR continued for a total of 45min, then the balloon was deflated simulating revascularization. CPR continued until return of spontaneous circulation (ROSC) or a total of 60min, if unsuccessful. SNPeCPR animals received 2mg of SNP at minute 10 followed by 1mg every 5min until ROSC. Standard ACLS animals received 0.5mg epinephrine every 5min until ROSC. Primary endpoints were ROSC and 4-h survival. All SNPeCPR animals (8/8) achieved sustained ROSC versus 2/8 standard ACLS animals within one hour of resuscitation (p=0.04). The 4-h survival was significantly improved with SNPeCPR compared to standard ACLS, 7/8 versus 1/8 respectively, p=0.0019. SNPeCPR significantly improved ROSC and 4-h survival compared with standard ACLS CPR in a porcine model of prolonged ischemic, refractory VF cardiac arrest. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cost-effectiveness of thrombolysis within 4.5 hours of acute ischemic stroke in China.

PubMed

Pan, Yuesong; Chen, Qidong; Zhao, Xingquan; Liao, Xiaoling; Wang, Chunjuan; Du, Wanliang; Liu, Gaifen; Liu, Liping; Wang, Chunxue; Wang, Yilong; Wang, Yongjun

2014-01-01

Previous economic studies conducted in developed countries showed intravenous tissue-type plasminogen activator (tPA) is cost-effective for acute ischemic stroke. The present study aimed to determine the cost-effectiveness of tPA treatment in China, the largest developing country. A combination of decision tree and Markov model was developed to determine the cost-effectiveness of tPA treatment versus non-tPA treatment within 4.5 hours after stroke onset. Outcomes and costs data were derived from the database of Thrombolysis Implementation and Monitor of acute ischemic Stroke in China (TIMS-China) study. Efficacy data were derived from a pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Costs and quality-adjusted life-years (QALYs) were compared in both short term (2 years) and long term (30 years). One-way and probabilistic sensitivity analyses were performed to test the robustness of the results. Comparing to non-tPA treatment, tPA treatment within 4.5 hours led to a short-term gain of 0.101 QALYs at an additional cost of CNY 9,520 (US$ 1,460), yielding an incremental cost-effectiveness ratio (ICER) of CNY 94,300 (US$ 14,500) per QALY gained in 2 years; and to a long-term gain of 0.422 QALYs at an additional cost of CNY 6,530 (US$ 1,000), yielding an ICER of CNY 15,500 (US$ 2,380) per QALY gained in 30 years. Probabilistic sensitivity analysis showed that tPA treatment is cost-effective in 98.7% of the simulations at a willingness-to-pay threshold of CNY 105,000 (US$ 16,200) per QALY. Intravenous tPA treatment within 4.5 hours is highly cost-effective for acute ischemic strokes in China.

Protection of retinal function by sulforaphane following retinal ischemic injury.

PubMed

Ambrecht, Lindsay A; Perlman, Jay I; McDonnell, James F; Zhai, Yougang; Qiao, Liang; Bu, Ping

2015-09-01

Sulforaphane, a precursor of glucosinolate in cruciferous vegetables such as broccoli and cauliflower, has been shown to protect brain ischemic injury. In this study, we examined the effect of systemic administration of sulforaphane on retinal ischemic reperfusion injury. Intraocular pressure was elevated in two groups of C57BL/6 mice (n = 8 per group) for 45 min to induce retinal ischemic reperfusion injury. Following retinal ischemic reperfusion injury, vehicle (1% DMSO saline) or sulforaphane (25 mg/kg/day) was administered intraperitoneally daily for 5 days. Scotopic electroretinography (ERG) was used to quantify retinal function prior to and one-week after retinal ischemic insult. Retinal morphology was examined one week after ischemic insult. Following ischemic reperfusion injury, ERG a- and b-wave amplitudes were significantly reduced in the control mice. Sulforaphane treatment significantly attenuated ischemic-induced loss of retinal function as compared to vehicle treated mice. In vehicle treated mice, ischemic reperfusion injury produced marked thinning of the inner retinal layers, but the thinning of the inner retinal layers appeared significantly less with sulforaphane treatment. Thus, sulforaphane may be beneficial in the treatment of retinal disorders with ischemic reperfusion injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

One-Year Incidence, Time Trends, and Predictors of Recurrent Ischemic Stroke in Sweden From 1998 to 2010: An Observational Study.

PubMed

Bergström, Lisa; Irewall, Anna-Lotta; Söderström, Lars; Ögren, Joachim; Laurell, Katarina; Mooe, Thomas

2017-08-01

Recent data on the incidence, time trends, and predictors of recurrent ischemic stroke are limited for unselected patient populations. Data for ischemic stroke patients were obtained from The Swedish Stroke Register (Riksstroke) between 1998 and 2009 and merged with The Swedish National Inpatient Register. A reference group of patients was created by Statistics Sweden. The ischemic stroke patient cohort was divided into 4 time periods. Recurrent ischemic stroke within 1 year was recorded until 2010. Kaplan-Meier and Cox regression analyses were performed to study time trends and predictors of ischemic stroke recurrence. Of 196 765 patients with ischemic stroke, 11.3% had a recurrent ischemic stroke within 1 year. The Kaplan-Meier estimates of the 1-year cumulative incidence of recurrent ischemic stroke decreased from 15.0% in 1998 to 2001 to 12.0% in 2007 to 2010 in the stroke patient cohort while the cumulative incidence of ischemic stroke decreased from 0.7% to 0.4% in the reference population. Age >75 years, prior ischemic stroke or myocardial infarction, atrial fibrillation without warfarin treatment, diabetes mellitus, and treatment with β-blockers or diuretics were associated with a higher risk while warfarin treatment for atrial fibrillation, lipid-lowering medication, and antithrombotic treatment (acetylsalicylic acid, dipyridamole) were associated with a reduced risk of recurrent ischemic stroke. The risk of recurrent ischemic stroke decreased from 1998 to 2010. Well-known risk factors for stroke were associated with a higher risk of ischemic stroke recurrence; whereas, secondary preventive medication was associated with a reduced risk, emphasizing the importance of secondary preventive treatment. © 2017 American Heart Association, Inc.

Comparative efficacy of Belzer or Euro-Collins solutions for pancreatic preservation during cold ischemic storage in rats.

PubMed

Perez, Rogério Renato; Goldenberg, Alberto; Netto, Alcides Augusto Salzedas; Gonzalez, Adriano Miziara

2014-03-01

To compare the efficacy of different types of solutions (Belzer or Euro-Collins) for the preservation of rat pancreas during cold ischemia. Thirty Wistar rats were divided into three groups according to the perfusion or storage solution: Group E (perfusion and storage in Euro-Collins solution); Group B (perfusion and storage in Belzer solution) and Group BE (Perfusion in Belzer solution and storage in Euro-Collins solution). After perfusion, the pancreas was excised and stored at 4˚C for 18 hours. Amylase was measured at 6, 12 and 18h, and histological analysis of the pancreas was performed after 18h of cold storage. Amylase was elevated and comparable in Groups E and BE after 12 and 18 hours of ischemia (p<0.05). In the exocrine pancreas, histological differences in the amount of necrosis (p=0.049), lymphocytic infiltrate (p<0.001) and neutrophilic infiltrate (p=0.004) were observed, with more favorable features present in Group B. In the endocrine pancreas, Group B showed less edema (p<0.001), but other parameters were similar among all groups. The Euro-Collins solution is inferior to the Belzer solution for the preservation of rat pancreas during cold ischemia.

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

PubMed Central

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei

2017-01-01

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. PMID:28188218

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.

PubMed

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei; Iliff, Jeffrey J; Nedergaard, Maiken

2017-03-15

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. Copyright © 2017 the authors 0270-6474/17/372870-08$15.00/0.

A multicenter, randomized trial on neuroprotection with remote ischemic per-conditioning during acute ischemic stroke: the REmote iSchemic Conditioning in acUtE BRAin INfarction study protocol.

PubMed

Pico, Fernando; Rosso, Charlotte; Meseguer, Elena; Chadenat, Marie-Laure; Cattenoy, Amina; Aegerter, Philippe; Deltour, Sandrine; Yeung, Jennifer; Hosseini, Hassan; Lambert, Yves; Smadja, Didier; Samson, Yves; Amarenco, Pierre

2016-10-01

Rationale Remote ischemic per-conditioning-causing transient limb ischemia to induce ischemic tolerance in other organs-reduces final infarct size in animal stroke models. Aim To evaluate whether remote ischemic per-conditioning during acute ischemic stroke (<6 h) reduces brain infarct size at 24 h. Methods and design This study is being performed in five French hospitals using a prospective randomized open blinded end-point design. Adults with magnetic resonance imaging confirmed ischemic stroke within 6 h of symptom onset and clinical deficit of 5-25 according to National Institutes of Health Stroke Scale will be randomized 1:1 to remote ischemic per-conditioning or control (stratified by center and intravenous fibrinolysis use). Remote ischemic per-conditioning will consist of four cycles of electronic tourniquet inflation (5 min) and deflation (5 min) to a thigh within 6 h of symptom onset. Magnetic resonance imaging is repeated 24 h after stroke onset. Sample size estimates For a difference of 15 cm 3 in brain infarct growth between groups, 200 patients will be included for 5% significance and 80% power. Study outcomes The primary outcome will be the difference in brain infarct growth from baseline to 24 h in the intervention versus control groups (by diffusion-weighted image magnetic resonance imaging). Secondary outcomes include: National Institutes of Health Stroke Scale score absolute difference between baseline and 24 h, three-month modified Rankin score and daily living activities, mortality, and tolerance and side effects of remote ischemic per-conditioning. Discussion The only remote ischemic per-conditioning trial in humans with stroke did not show remote ischemic per-conditioning to be effective. REmote iSchemic Conditioning in acUtE BRAin INfarction, which has important design differences, should provide more information on the use of this intervention in patients with acute ischemic stroke.

Cross-linked polyhemoglobin-superoxide dismutase-catalase supplies oxygen without causing blood-brain barrier disruption or brain edema in a rat model of transient global brain ischemia-reperfusion.

PubMed

Powanda, D Douglas; Chang, Thomas M S

2002-01-01

In strokes, myocardial infarctions, severe sustained hemorrhagic shock, and donor organs, inadequate blood supply results in lack of oxygen to the tissue (ischemia). If ischemia is sustained, reperfusion with the needed oxygen can result in tissue injury (ischemia-reperfusion injury) due to formation of reactive oxygen species. We are studying an oxygen-carrying solution with anitoxidant activity formed by cross-linking hemoglobin, superoxide dismutase, and catalase to form PolyHb-SOD-CAT. The present report studies its effect on the blood-brain barrier and cerebral edema when used in a transient global brain ischemia-reperfusion rat model. We compare this solution to sham-control, oxygenated saline, stroma-free hemoglobin (SF-Hb), polymerized hemoglobin (PolyHb), and a mixture of SF-Hb, SOD, and CAT in free solution. The results show that the cross-linked PolyHb-SOD-CAT solution, unlike the other solutions, can supply oxygen to ischemic tissues without causing reperfusion injury in the transient global brain ischemia-reperfusion model.

Regulatory systems for hypoxia-inducible gene expression in ischemic heart disease gene therapy.

PubMed

Kim, Hyun Ah; Rhim, Taiyoun; Lee, Minhyung

2011-07-18

Ischemic heart diseases are caused by narrowed coronary arteries that decrease the blood supply to the myocardium. In the ischemic myocardium, hypoxia-responsive genes are up-regulated by hypoxia-inducible factor-1 (HIF-1). Gene therapy for ischemic heart diseases uses genes encoding angiogenic growth factors and anti-apoptotic proteins as therapeutic genes. These genes increase blood supply into the myocardium by angiogenesis and protect cardiomyocytes from cell death. However, non-specific expression of these genes in normal tissues may be harmful, since growth factors and anti-apoptotic proteins may induce tumor growth. Therefore, tight gene regulation is required to limit gene expression to ischemic tissues, to avoid unwanted side effects. For this purpose, various gene expression strategies have been developed for ischemic-specific gene expression. Transcriptional, post-transcriptional, and post-translational regulatory strategies have been developed and evaluated in ischemic heart disease animal models. The regulatory systems can limit therapeutic gene expression to ischemic tissues and increase the efficiency of gene therapy. In this review, recent progresses in ischemic-specific gene expression systems are presented, and their applications to ischemic heart diseases are discussed. Copyright © 2011 Elsevier B.V. All rights reserved.

Laparoscopic ischemic conditioning of the stomach increases neovascularization of the gastric conduit in patients undergoing esophagectomy for cancer.

PubMed

Pham, Thai H; Melton, Shelby D; McLaren, Patrick J; Mokdad, Ali A; Huerta, Sergio; Wang, David H; Perry, Kyle A; Hardaker, Hope L; Dolan, James P

2017-09-01

Gastric ischemic preconditioning has been proposed to improve blood flow and reduce the incidence of anastomotic complications following esophagectomy with gastric pull-up. This study aimed to evaluate the effect of prolonged ischemic preconditioning on the degree of neovascularization in the distal gastric conduit at the time of esophagectomy. A retrospective review of a prospectively maintained database identified 30 patients who underwent esophagectomy. The patients were divided into three groups: control (no preconditioning, n = 9), partial (short gastric vessel ligation only, n = 8), and complete ischemic preconditioning (left and short gastric vessel ligation, n = 13). Microvessel counts were assessed, using immunohistologic analysis to determine the degree of neovascularization at the distal gastric margin. The groups did not differ in age, gender, BMI, pathologic stage, or cancer subtype. Ischemic preconditioning durations were 163 ± 156 days for partial ischemic preconditioning, compared to 95 ± 50 days for complete ischemic preconditioning (P = 0.2). Immunohistologic analysis demonstrated an increase in microvessel counts of 29% following partial ischemic preconditioning (P = 0.3) and 67% after complete ischemic preconditioning (P < 0.0001), compared to controls. Our study indicates that prolonged ischemic preconditioning is safe and does not interfere with subsequent esophagectomy. Complete ischemic preconditioning increased neovascularization in the distal gastric conduit. © 2017 Wiley Periodicals, Inc.

In vivo monitoring of nanosphere onsite delivery using fiber optic microprobe

NASA Astrophysics Data System (ADS)

Lo, Leu-Wei; Yang, Chung-Shi

2005-02-01

To recognize the information of ischemia-induced blood vessel permeability would be valuable to formulate the drugs for optimal local delivery, we constructed an implantable needle type fiber-optic microprobe for the monitoring of in vivo fluorescent substances in anesthetized rats. This fiber-optic microprobe was composed of coaxial optical fibers and catheterized using a thin wall tubing of stainless steel (~400 um O.D. and ~300 um I.D.). The central fiber, with 100 um core diameter and 20 um cladding, coated with a 30 um layer of gold, was surrounded by 10 fibers with 50 um cores. The central fiber carried the light from the 488 nm Argon laser to the tissue while the surrounding fibers collected the emitted fluorescence to the detector. When the fiber-optic microprobe was placed in the solutions containing various concentrations of fluorescent nanospheres (20 nm), either with or without 10% lipofundin as optical phantom, nanosphere concentration-dependent responses of the fluorescence intensity were observed. The microprobe was then implanted into the liver and the brain of anesthetized rats to monitor the in situ extravasation of pre-administered fluorescent nanospheres from vasculature following the ischemic insults. Both the hepatic and cerebral ischemic insults showed immediate increases of the extracellular 20 nm fluorescent nanospheres. The implantable fiber-optic microprobe constructed in present study provides itself as a minimally-invasive technique capable of investigating the vascular permeability for in vivo nanosphere delivery in both ischemic liver and brain.

Liver free fatty acid (FFA) accumulation as an indicator of ischemic injury during cold preservation

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

Nemoto, E.M.; Kang, Y.; DeWolf, A.M.

1987-05-01

Reliable assessment of hepatic viability prior to harvest and transplant could improve graft success and aid in evaluating the efficacy of liver preservation techniques. Hepatic tissue metabolites, protein (Pr) synthesis, and ATP have been studied, but none reliably correlate with hepatic viability. Therefore, they studied changes in liver FFA relative to changes in ATP and Pr synthesis during cold ischemic preservation. Rats mechanically ventilated on 0.5% isoflurane/70% N/sub 2/O/30% O/sub 2/ were heparinized and their livers perfused with air-equilibrated Euro-Collins solution (ECS) at 0-4/sup 0/C and kept on ice. A piece of the liver was removed after 0, 2, 6,more » 8, 12, 24, 36 and 48 h of preservation for ATP and FFA analysis. A portion of the liver was sliced (250 ..mu..m thick) and incubated in vitro for /sup 14/C-lysine incorporation in albumin. ATP, FFA and Pr synthesis were unchanged in the first 8 h, but markedly decreased between 8 and 12 h with little change thereafter. In contrast, between 8 and 48 h, arachidonic and stearic acids increased by 5 and 2-fold, respectively. Changes in ATP and Pr synthesis correlate with the empirically derived clinical maximum of 8 to 12 h preservation. FFA accumulation appears to reflect hepatic ischemic injury and may be a means of evaluating the quality of a donor liver.« less

Age-related reduction of cerebral ischemic preconditioning: myth or reality?

PubMed Central

Della-Morte, David; Cacciatore, Francesco; Salsano, Elisa; Pirozzi, Gilda; Genio, Maria Teresa Del; D’Antonio, Iole; Gargiulo, Gaetano; Palmirotta, Raffaele; Guadagni, Fiorella; Rundek, Tatjana; Abete, Pasquale

2013-01-01

Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The “cerebral” ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the “cerebral” preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed. PMID:24204128

Enterocolic lymphocytic phlebitis: statistical analysis of histology features in viable and ischemic bowel.

PubMed

Medlicott, Shaun A C; Guggisberg, Kelly A; DesCôteaux, Jean-Gaston; Beck, Paul

2006-07-01

Enterocolic lymphocytic phlebitis is a rare cause of segmental ischemic enterocolitis. This artery-sparing transmural vasculitis is classically a circumferential phlebitis with perivenular lymphocyte cuffing and thrombi in the absence of systemic manifestations. Myointimal hyperplasia may represent a chronic phase of enterocolic lymphocytic phlebitis. Subclinical or early stage enterocolic lymphocytic phlebitis is not well delineated. We analyzed 600 submucosal and subserosal veins from both ischemic and intact bowel segments to discern if vascular morphology varied between sites. Crescentic and circumferential lymphocytic phlebitis is more common in viable bowel than in the ischemic segment. A nonsignificant trend was found for increased crescentic morphology between intact bowel remote from the ischemic focus compared with that adjacent to the ischemic focus. Hallmarks of ischemic bowel are necrotizing phlebitis and thrombi formation. Thrombophlebitis morphology is distinctly different in viable and ischemic bowel, changing from the classic lymphocytic to necrotizing lesions respectively.

[Economic evaluation of dabigatran for stroke prevention in patients with non-valvular atrial fibrillation].

PubMed

Silva Miguel, Luís; Rocha, Evangelista; Ferreira, Jorge

2013-01-01

To estimate the cost-effectiveness and cost-utility of dabigatran in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Portugal. A Markov model was used to simulate patients' clinical course, estimating the occurrence of ischemic and hemorrhagic stroke, transient ischemic attack, systemic embolism, myocardial infarction, and intra- and extracranial hemorrhage. The clinical parameters are based on the results of the RE-LY trial, which compared dabigatran with warfarin, and on a meta-analysis that estimated the risk of each event in patients treated with aspirin or with no antithrombotic therapy. Dabigatran provides an increase of 0.331 life years and 0.354 quality-adjusted life years for each patient. From a societal perspective, these clinical gains entail an additional expenditure of 2978 euros. Thus, the incremental cost is 9006 euros per life year gained and 8409 euros per quality-adjusted life year. The results show that dabigatran reduces the number of events, especially the most severe such as ischemic and hemorrhagic stroke, as well as their long-term sequelae. The expense of dabigatran is partially offset by lower event-related costs and by the fact that INR monitoring is unnecessary. It can thus be concluded that the use of dabigatran in clinical practice in Portugal is cost-effective. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review.

PubMed

Lau, Kui Kai; Lovelock, Caroline E; Li, Linxin; Simoni, Michela; Gutnikov, Sergei; Küker, Wilhelm; Mak, Henry Ka Fung; Rothwell, Peter M

2018-06-01

In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke. In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2-4, and ≥5), adjusting for age, sex, and vascular risk factors. Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P <0.0001), but risk associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of major extracranial bleeds was unrelated to microbleed burden ( P trend =0.87), but the 5-year risk of ICH was steeply related ( P trend <0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of ischemic stroke also increased with microbleed burden ( P trend =0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events ( P trend =0.007), the association with ICH was accounted for ( P trend <0.0001) by disabling/fatal events (≥5 microbleeds: 82% disabling/fatal ICH versus 40% disabling/fatal ischemic stroke; P =0.035). In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit thereafter. © 2018 The Authors.

Conceptual modeling for Prospective Health Technology Assessment.

PubMed

Gantner-Bär, Marion; Djanatliev, Anatoli; Prokosch, Hans-Ulrich; Sedlmayr, Martin

2012-01-01

Prospective Health Technology Assessment (ProHTA) is a new and innovative approach to analyze and assess new technologies, methods and procedures in health care. Simulation processes are used to model innovations before the cost-intensive design and development phase. Thus effects on patient care, the health care system as well as health economics aspects can be estimated. To generate simulation models a valid information base is necessary and therefore conceptual modeling is most suitable. Project-specifically improved methods and characteristics of simulation modeling are combined in the ProHTA Conceptual Modeling Process and initially implemented for acute ischemic stroke treatment in Germany. Additionally the project aims at simulation of other diseases and health care systems as well. ProHTA is an interdisciplinary research project within the Cluster of Excellence for Medical Technology - Medical Valley European Metropolitan Region Nuremberg (EMN), which is funded by the German Federal Ministry of Education and Research (BMBF), project grant No. 01EX1013B.

Cardioprotective effect of diadenosine tetraphosphate (AP4A) preservation in hypothermic storage and its relation with mitochondrial ATP-sensitive potassium channels.

PubMed

Ahmet, I; Sawa, Y; Nishimura, M; Kitakaze, M; Matsuda, H

2000-01-15

The preconditioning effect of diadenosine tetraphosphate (AP4A) was reported in ischemia/reperfused hearts, but its effect in heart preservation was unknown. According to the possible role of mitochondrial ATP-sensitive potassium channel (mK(ATP) channel) in the effect of ischemic preconditioning, the contribution of mK(ATP) channel to the effect of AP4A was tested. Isolated rat hearts were arrested and preserved by Eurocollin's (EC) solution at 4 degrees C for 8 hr. AP4A (80 microM) or AP4A with the 5-hydroxydecanoic acid (100 microM), a selective inhibitor of the mK(ATP) channel, was added into the EC solution. The preischemic and postischemic cardiac functions were evaluated on a buffer-perfused Langendorff apparatus before storage and after 20 min of reperfusion. AP4A administration improved the recovery of poststorage cardiac functions (the rate-pressure production, left ventricular systolic pressure, heart rate, coronary flow rate, and derivative of left ventricular systolic pressure; P<0.05) and reduced the leakage of lactate dehydrate and creatine kinase during reperfusion, compared with EC alone. Those effects of AP4A were completely reversed by 5-hydroxydecanoic acid administration in combination subjects. AP4A administration protects the heart through opening of the mK(ATP) channel during hypothermic preservation. Thus, addition of AP4A into cardioplegia may be a novel method of ischemic preconditioning in the transplantation context.

Normal and Pathological NCAT Image and PhantomData Based onPhysiologically Realistic Left Ventricle Finite-Element Models

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

Veress, Alexander I.; Segars, W. Paul; Weiss, Jeffrey A.

2006-08-02

The 4D NURBS-based Cardiac-Torso (NCAT) phantom, whichprovides a realistic model of the normal human anatomy and cardiac andrespiratory motions, is used in medical imaging research to evaluate andimprove imaging devices and techniques, especially dynamic cardiacapplications. One limitation of the phantom is that it lacks the abilityto accurately simulate altered functions of the heart that result fromcardiac pathologies such as coronary artery disease (CAD). The goal ofthis work was to enhance the 4D NCAT phantom by incorporating aphysiologically based, finite-element (FE) mechanical model of the leftventricle (LV) to simulate both normal and abnormal cardiac motions. Thegeometry of the FE mechanical modelmore » was based on gated high-resolutionx-ray multi-slice computed tomography (MSCT) data of a healthy malesubject. The myocardial wall was represented as transversely isotropichyperelastic material, with the fiber angle varying from -90 degrees atthe epicardial surface, through 0 degreesat the mid-wall, to 90 degreesat the endocardial surface. A time varying elastance model was used tosimulate fiber contraction, and physiological intraventricular systolicpressure-time curves were applied to simulate the cardiac motion over theentire cardiac cycle. To demonstrate the ability of the FE mechanicalmodel to accurately simulate the normal cardiac motion as well abnormalmotions indicative of CAD, a normal case and two pathologic cases weresimulated and analyzed. In the first pathologic model, a subendocardialanterior ischemic region was defined. A second model was created with atransmural ischemic region defined in the same location. The FE baseddeformations were incorporated into the 4D NCAT cardiac model through thecontrol points that define the cardiac structures in the phantom whichwere set to move according to the predictions of the mechanical model. Asimulation study was performed using the FE-NCAT combination toinvestigate how the differences in contractile function between thesubendocardial and transmural infarcts manifest themselves in myocardialSPECT images. The normal FE model produced strain distributions that wereconsistent with those reported in the literature and a motion consistentwith that defined in the normal 4D NCAT beating heart model based ontagged MRI data. The addition of a subendocardial ischemic region changedthe average transmural circumferential strain from a contractile value of0.19 to a tensile value of 0.03. The addition of a transmural ischemicregion changed average circumferential strain to a value of 0.16, whichis consistent with data reported in the literature. Model resultsdemonstrated differences in contractile function between subendocardialand transmural infarcts and how these differences in function aredocumented in simulated myocardial SPECT images produced using the 4DNCAT phantom. In comparison to the original NCAT beating heart model, theFE mechanical model produced a more accurate simulation for the cardiacmotion abnormalities. Such a model, when incorporated into the 4D NCATphantom, has great potential for use in cardiac imaging research. Withits enhanced physiologically-based cardiac model, the 4D NCAT phantom canbe used to simulate realistic, predictive imaging data of a patientpopulation with varying whole-body anatomy and with varying healthy anddiseased states of the heart that will provide a known truth from whichto evaluate and improve existing and emerging 4D imaging techniques usedin the diagnosis of cardiac disease.« less

The association between high on-treatment platelet reactivity and early recurrence of ischemic events after minor stroke or TIA.

PubMed

Rao, Zilong; Zheng, Huaguang; Wang, Fei; Wang, Anxin; Liu, Liping; Dong, Kehui; Zhao, Xingquan; Wang, Yilong; Cao, Yibin

2017-08-01

To evaluate the role of HTPR in predicting early recurrence of ischemic events in patients with minor ischemic stroke or high-risk TIA. From January 2014 to September 2014, a single center continuously enrolled patients with minor ischemic stroke or high-risk TIA and gave them antiplatelet therapy consisting of aspirin with clopidogrel. HTPR was assessed by TEG after 7 days of antiplatelet therapy and detected CYP2C19 genotype. The incidence of recurrent ischemic events was assessed 3 months after onset. The incidence of recurrent ischemic events was compared between the HTPR and NTPR groups with the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to determine the risk factors associated with recurrent ischemic events. We enrolled 278 eligible patients with minor ischemic stroke or high-risk TIA. Through TEG testing, patients with HTPR were 22.7%, and carriers were not associated with HTPR to ADP by TEG-ADP(%) (p = 0.193). A total of 265 patients completed 3 months of follow-up, and Kaplan-Meier analysis showed that patients with HTPR had a higher percentage of recurrent ischemic events compared with patients with NTPR (p = 0.002). In multivariate Cox proportional hazards models, history of ischemic stroke or TIA (HR 4.45, 95% CI 1.77-11.16, p = 0.001) and HTPR (HR 3.34, 95% CI 1.41-7.91, p = 0.006) was independently associated with recurrent ischemic events. In patients with minor stroke or TIA, the prevalence of HTPR was 22.7%, and HTPR was independently associated with recurrent ischemic events.

Risk of ischemic stroke after atrial fibrillation diagnosis: A national sample cohort

PubMed Central

Son, Mi Kyoung; Lim, Nam-Kyoo; Kim, Hyung Woo

2017-01-01

Atrial fibrillation (AF) is a major risk factor for ischemic stroke and associated with a 5-fold higher risk of stroke. In this retrospective cohort study, the incidence of and risk factors for ischemic stroke in patients with AF were identified. All patients (≥30 years old) without previous stroke who were diagnosed with AF in 2007–2013 were selected from the National Health Insurance Service-National Sample Cohort. To identify factors that influenced ischemic stroke risk, Cox proportional hazard regression analysis was conducted. During a mean follow-up duration of 3.2 years, 1022 (9.6%) patients were diagnosed with ischemic stroke. The overall incidence rate of ischemic stroke was 30.8/1000 person-years. Of all the ischemic stroke that occurred during the follow-up period, 61.0% occurred within 1-year after AF diagnosis. Of the patients with CHA2DS2-VASc score of ≥2, only 13.6% were receiving warfarin therapy within 30 days after AF diagnosis. Relative to no antithrombotic therapy, warfarin treatment for >90 days before the index event (ischemic stroke in stroke patients and death/study end in non-stroke patients) associated with decreased ischemic stroke risk (Hazard Ratio = 0.41, 95%confidence intervals = 0.32–0.53). Heart failure, hypertension, and diabetes mellitus associated with greater ischemic stroke risk. AF patients in Korea had a higher ischemic stroke incidence rate than patients in other countries and ischemic stroke commonly occurred at early phase after AF diagnosis. Long-term (>90 days) continuous warfarin treatment may be beneficial for AF patients. However, warfarin treatment rates were very low. To prevent stroke, programs that actively detect AF and provide anticoagulation therapy are needed. PMID:28636620

Influence of Bleeding Pattern on Ischemic Lesions After Spontaneous Hypertensive Intracerebral Hemorrhage with Intraventricular Hemorrhage.

PubMed

Rivera-Lara, Lucia; Murthy, Santosh B; Nekoovaght-Tak, Saman; Ali, Hasan; McBee, Nichol; Dlugash, Rachel; Ram, Malathi; Thompson, Richard; Awad, Issam A; Hanley, Daniel F; Ziai, Wendy C

2018-03-27

Concomitant acute ischemic lesions are detected in up to a quarter of patients with spontaneous intracerebral hemorrhage (ICH). Influence of bleeding pattern and intraventricular hemorrhage (IVH) on risk of ischemic lesions has not been investigated. Retrospective study of all 500 patients enrolled in the CLEAR III randomized controlled trial of thrombolytic removal of obstructive IVH using external ventricular drainage. The primary outcome measure was radiologically confirmed ischemic lesions, as reported by the Safety Event Committee and confirmed by two neurologists. We assessed predictors of ischemic lesions including analysis of bleeding patterns (ICH, IVH and subarachnoid hemorrhage) on computed tomography scans (CT). Secondary outcomes were blinded assessment of mortality and modified Rankin scale (mRS) at 30 and 180 days. Ischemic lesions occurred in 23 (4.6%) during first 30 days after ICH. Independent risk factors associated with ischemic lesions in logistic regression models adjusted for confounders were higher IVH volume (p = 0.004) and persistent subarachnoid hemorrhage on CT scan (p = 0.03). Patients with initial IVH volume ≥ 15 ml had five times the odds of concomitant ischemic lesions compared to IVH volume < 15 ml. Patients with ischemic lesions had significantly higher odds of death at 1 and 6 months (but not poor outcome; mRS 4-6) compared to patients without concurrent ischemic lesions. Occurrence of ischemic lesions in the acute phase of IVH is not uncommon and is significantly associated with increased early and late mortality. Extra-parenchymal blood (larger IVH and visible subarachnoid hemorrhage) is a strong predictor for development of concomitant ischemic lesions after ICH.

Computed Tomography-Based Imaging of Voxel-Wise Lesion Water Uptake in Ischemic Brain: Relationship Between Density and Direct Volumetry.

PubMed

Broocks, Gabriel; Flottmann, Fabian; Ernst, Marielle; Faizy, Tobias Djamsched; Minnerup, Jens; Siemonsen, Susanne; Fiehler, Jens; Kemmling, Andre

2018-04-01

Net water uptake per volume of brain tissue may be calculated by computed tomography (CT) density, and this imaging biomarker has recently been investigated as a predictor of lesion age in acute stroke. However, the hypothesis that measurements of CT density may be used to quantify net water uptake per volume of infarct lesion has not been validated by direct volumetric measurements so far. The purpose of this study was to (1) develop a theoretical relationship between CT density reduction and net water uptake per volume of ischemic lesions and (2) confirm this relationship by quantitative in vitro and in vivo CT image analysis using direct volumetric measurements. We developed a theoretical rationale for a linear relationship between net water uptake per volume of ischemic lesions and CT attenuation. The derived relationship between water uptake and CT density was tested in vitro in a set of increasingly diluted iodine solutions with successive CT measurements. Furthermore, the consistency of this relationship was evaluated using human in vivo CT images in a retrospective multicentric cohort. In 50 edematous infarct lesions, net water uptake was determined by direct measurement of the volumetric difference between the ischemic and normal hemisphere and was correlated with net water uptake calculated by ischemic density measurements. With regard to in vitro data, water uptake by density measurement was equivalent to direct volumetric measurement (r = 0.99, P < 0.0001; mean ± SD difference, -0.29% ± 0.39%, not different from 0, P < 0.0001). In the study cohort, the mean ± SD uptake of water within infarct measured by volumetry was 44.7 ± 26.8 mL and the mean percent water uptake per lesion volume was 22.7% ± 7.4%. This was equivalent to percent water uptake obtained from density measurements: 21.4% ± 6.4%. The mean difference between percent water uptake by direct volumetry and percent water uptake by CT density was -1.79% ± 3.40%, which was not significantly different from 0 (P < 0.0001). Volume of water uptake in infarct lesions can be calculated quantitatively by relative CT density measurements. Voxel-wise imaging of water uptake depicts lesion pathophysiology and could serve as a quantitative imaging biomarker of acute infarct lesions.

Gualou Guizhi decoction reverses brain damage with cerebral ischemic stroke, multi-component directed multi-target to screen calcium-overload inhibitors using combination of molecular docking and protein-protein docking.

PubMed

Hu, Juan; Pang, Wen-Sheng; Han, Jing; Zhang, Kuan; Zhang, Ji-Zhou; Chen, Li-Dian

2018-12-01

Stroke is a disease of the leading causes of mortality and disability across the world, but the benefits of drugs curative effects look less compelling, intracellular calcium overload is considered to be a key pathologic factor for ischemic stroke. Gualou Guizhi decoction (GLGZD), a classical Chinese medicine compound prescription, it has been used to human clinical therapy of sequela of cerebral ischemia stroke for 10 years. This work investigated the GLGZD improved prescription against intracellular calcium overload could decreased the concentration of [Ca 2+ ] i in cortex and striatum neurone of MCAO rats. GLGZD contains Trichosanthin and various small molecular that they are the potential active ingredients directed against NR2A, NR2B, FKBP12 and Calnodulin target proteins/enzyme have been screened by computer simulation. "Multicomponent systems" is capable to create pharmacological superposition effects. The Chinese medicine compound prescriptions could be considered as promising sources of candidates for discovery new agents.

Clinical Correlates, Ethnic Differences, and Prognostic Implications of Perivascular Spaces in Transient Ischemic Attack and Ischemic Stroke.

PubMed

Lau, Kui-Kai; Li, Linxin; Lovelock, Caroline E; Zamboni, Giovanna; Chan, Tsz-Tai; Chiang, Man-Fung; Lo, Kin-Ting; Küker, Wilhelm; Mak, Henry Ka-Fung; Rothwell, Peter M

2017-06-01

Perivascular spaces (PVSs) are considered markers of small vessel disease. However, their long-term prognostic implications in transient ischemic attack/ischemic stroke patients are unknown. Ethnic differences in PVS prevalence are also unknown. Two independent prospective studies were conducted, 1 comprising predominantly whites with transient ischemic attack/ischemic stroke (OXVASC [Oxford Vascular] study) and 1 comprising predominantly Chinese with ischemic stroke (University of Hong Kong). Clinical and imaging correlates, prognostic implications for stroke and death, and ethnic differences in basal ganglia (BG) and centrum semiovale (CS) PVSs were studied with adjustment for age, sex, vascular risk factors, and scanner strength. Whites with transient ischemic attack/ischemic stroke (n=1028) had a higher prevalence of both BG and CS-PVSs compared with Chinese (n=974; >20 BG-PVSs: 22.4% versus 7.1%; >20 CS-PVSs: 45.8% versus 10.4%; P <0.0001). More than 20 BG or CS-PVSs were both associated with increasing age and white matter hyperintensity, although associations with BG-PVSs were stronger (all P <0.0001). During 6924 patient-years of follow-up, BG-PVSs were also independently associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio compared with <11 PVSs, 11-20 PVSs: HR, 1.15; 95% confidence interval, 0.78-1.68; >20 PVSs: HR, 1.82; 1.18-2.80; P =0.011) but not intracerebral hemorrhage ( P =0.10) or all-cause mortality ( P =0.16). CS-PVSs were not associated with recurrent stroke ( P =0.57) or mortality ( P =0.072). Prognostic associations were similar in both cohorts. Over and above ethnic differences in frequency of PVSs in transient ischemic attack/ischemic stroke patients, BG and CS-PVSs had similar risk factors, but although >20 BG-PVSs were associated with an increased risk of recurrent ischemic stroke, CS-PVSs were not. © 2017 The Authors.

Clinical Correlates, Ethnic Differences, and Prognostic Implications of Perivascular Spaces in Transient Ischemic Attack and Ischemic Stroke

PubMed Central

Lau, Kui-Kai; Li, Linxin; Lovelock, Caroline E.; Zamboni, Giovanna; Chan, Tsz-Tai; Chiang, Man-Fung; Lo, Kin-Ting; Küker, Wilhelm; Mak, Henry Ka-Fung

2017-01-01

Background and Purpose— Perivascular spaces (PVSs) are considered markers of small vessel disease. However, their long-term prognostic implications in transient ischemic attack/ischemic stroke patients are unknown. Ethnic differences in PVS prevalence are also unknown. Methods— Two independent prospective studies were conducted, 1 comprising predominantly whites with transient ischemic attack/ischemic stroke (OXVASC [Oxford Vascular] study) and 1 comprising predominantly Chinese with ischemic stroke (University of Hong Kong). Clinical and imaging correlates, prognostic implications for stroke and death, and ethnic differences in basal ganglia (BG) and centrum semiovale (CS) PVSs were studied with adjustment for age, sex, vascular risk factors, and scanner strength. Results— Whites with transient ischemic attack/ischemic stroke (n=1028) had a higher prevalence of both BG and CS-PVSs compared with Chinese (n=974; >20 BG-PVSs: 22.4% versus 7.1%; >20 CS-PVSs: 45.8% versus 10.4%; P<0.0001). More than 20 BG or CS-PVSs were both associated with increasing age and white matter hyperintensity, although associations with BG-PVSs were stronger (all P<0.0001). During 6924 patient-years of follow-up, BG-PVSs were also independently associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio compared with <11 PVSs, 11–20 PVSs: HR, 1.15; 95% confidence interval, 0.78–1.68; >20 PVSs: HR, 1.82; 1.18–2.80; P=0.011) but not intracerebral hemorrhage (P=0.10) or all-cause mortality (P=0.16). CS-PVSs were not associated with recurrent stroke (P=0.57) or mortality (P=0.072). Prognostic associations were similar in both cohorts. Conclusions— Over and above ethnic differences in frequency of PVSs in transient ischemic attack/ischemic stroke patients, BG and CS-PVSs had similar risk factors, but although >20 BG-PVSs were associated with an increased risk of recurrent ischemic stroke, CS-PVSs were not. PMID:28495831

Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.

PubMed

Jørgensen, Anders Berg; Frikke-Schmidt, Ruth; Nordestgaard, Børge G; Tybjærg-Hansen, Anne

2014-07-03

High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk of ischemic cardiovascular disease in the general population is unknown. Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7557 of these 10,797 participants. Participants with nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol per liter (350 mg per deciliter) or more (hazard ratio for ischemic vascular disease, 0.43; 95% confidence interval [CI], 0.35 to 0.54; hazard ratio for ischemic heart disease, 0.40; 95% CI, 0.31 to 0.52). Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (P<0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations (P=0.009 and P=0.05, respectively), with corresponding risk reductions of 41% (hazard ratio, 0.59; 95% CI, 0.41 to 0.86; P=0.007) and 36% (hazard ratio, 0.64; 95% CI, 0.41 to 0.99; P=0.04). Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. (Funded by the European Union and others.).

The structure of aqueous sodium hydroxide solutions: a combined solution x-ray diffraction and simulation study.

PubMed

Megyes, Tünde; Bálint, Szabolcs; Grósz, Tamás; Radnai, Tamás; Bakó, Imre; Sipos, Pál

2008-01-28

To determine the structure of aqueous sodium hydroxide solutions, results obtained from x-ray diffraction and computer simulation (molecular dynamics and Car-Parrinello) have been compared. The capabilities and limitations of the methods in describing the solution structure are discussed. For the solutions studied, diffraction methods were found to perform very well in describing the hydration spheres of the sodium ion and yield structural information on the anion's hydration structure. Classical molecular dynamics simulations were not able to correctly describe the bulk structure of these solutions. However, Car-Parrinello simulation proved to be a suitable tool in the detailed interpretation of the hydration sphere of ions and bulk structure of solutions. The results of Car-Parrinello simulations were compared with the findings of diffraction experiments.

Agonist of inward rectifier K+ channels enhances the protection of ischemic postconditioning in isolated rat hearts.

PubMed

Liao, Z; Feng, Z; Long, C

2014-07-01

Selective inhibition of inward rectifier K + channels could abolish the protection mediated by ischemic preconditioning, but the roles of these channels in ischemic postconditioning have not been well characterized. Our study aims to evaluate the effect of inward rectifier K + channels on the protection induced by ischemic postconditioning. Langendorff-perfused rat hearts (n=8 per group) were split into four groups: postconditioning hearts (IPO group); ischemic postconditioning with BaCl 2 hearts (PB group); ischemic postconditioning with zacopride hearts (PZ group); and without ischemic postconditioning (CON group). After suffering 30 minutes of global ischemia, groups IPO, PB and PZ went through 10 seconds of ischemic postconditioning with three different perfusates: respectively, Krebs-Henseleit buffer (IPO group); 20 μmol/L BaCl 2 (antagonist of the channel, PB group); 1 μmol/L zacopride (agonist of the channel, PZ group). At the end of reperfusion, the myocardial performance was better preserved in the PZ group than the other three groups. The PB group showed no significant differences from the CON group. Our study has shown that the I K1 channel agonist zacopride is associated with the enhancement of ischemic postconditioning. © The Author(s) 2014.

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.

Comparison of characteristics and healing course of diabetic foot ulcers by etiological classification: neuropathic, ischemic, and neuro-ischemic type.

PubMed

Yotsu, Rie Roselyne; Pham, Ngoc Minh; Oe, Makoto; Nagase, Takeshi; Sanada, Hiromi; Hara, Hisao; Fukuda, Shoji; Fujitani, Junko; Yamamoto-Honda, Ritsuko; Kajio, Hiroshi; Noda, Mitsuhiko; Tamaki, Takeshi

2014-01-01

To identify differences in the characteristics of patients with diabetic foot ulcers (DFUs) according to their etiological classification and to compare their healing time. Over a 4.5-year period, 73 patients with DFUs were recruited. DFUs were etiologically classified as being of neuropathic, ischemic, or neuro-ischemic origin. Descriptive analyses were performed to characterize study subjects, foot-related factors, and healing outcome and time. Duration of healing was assessed using the Kaplan-Meier method. Healing time among the three types was compared using the log rank test. The number of patients manifesting neuropathic, ischemic, and neuro-ischemic ulcers was 30, 20, and 14, respectively. Differences were identified for age, diabetes duration, body mass index, hypertension, and estimated glomerular filtration rate. Patients with neuro-ischemic ulcers had better ankle-brachial index, skin perfusion pressure (SPP), and transcutaneous oxygen pressure values compared to those with ischemic ulcers. The average time in which 50% of patients had healed wounds was 70, 113, and 233 days for neuropathic, neuro-ischemic, and ischemic ulcers, respectively. Main factors associated with healing were age and SPP values. Based on the etiological ulcer type, DFU healing course and several patient factors differed. Failure to consider the differences in DFU etiology may have led to heterogeneity of results in previous studies on DFUs. Copyright © 2014 Elsevier Inc. All rights reserved.

Aspirin and the risk of cardiovascular events in atherosclerosis patients with and without prior ischemic events.

PubMed

Bavry, Anthony A; Elgendy, Islam Y; Elbez, Yedid; Mahmoud, Ahmed N; Sorbets, Emmanuel; Steg, Philippe Gabriel; Bhatt, Deepak L

2017-09-01

The benefit of aspirin among patients with stable atherosclerosis without a prior ischemic event is not well defined. Aspirin would be of benefit in outpatients with atherosclerosis with prior ischemic events, but not in those without ischemic events. Subjects from the Reduction of Atherothrombosis for Continued Health registry were divided according to prior ischemic event (n =21 724) vs stable atherosclerosis, but no prior ischemic event (n = 11 872). Analyses were propensity score matched. Aspirin use was updated at each clinic visit and considered as a time-varying covariate. The primary outcome was the first occurrence of cardiovascular death, myocardial infarction, or stroke. In the group with a prior ischemic event, aspirin use was associated with a marginally lower risk of the primary outcome at a median of 41 months (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.65-1.01, P = 0.06). In the group without a prior ischemic event, aspirin use was not associated with a lower risk of the primary outcome at a median of 36 months (HR: 1.03, 95% CI: 0.73-1.45, P = 0.86). In this observational analysis of outpatients with stable atherosclerosis, aspirin was marginally beneficial among patients with a prior ischemic event; however, there was no apparent benefit among those with no prior ischemic event. © 2017 Wiley Periodicals, Inc.

Adjunctive Therapy to Improve Functional Recovery after Limb Ischemia Reperfusion Injury

DTIC Science & Technology

2017-10-01

end-point for the operative procedure that reads as follows: “If an animal is observed on preparation for surgery to have an elevated exhaled end...protocol, e.g. the agent is effective even when administered after the leg has become ischemic. Given that small animal studies have been performed and...in a large animal model that better simulates the way the human body responds to treatment of this important injury process. 15. SUBJECT TERMS

Simulation of action potentials from metabolically impaired cardiac myocytes. Role of ATP-sensitive K+ current.

PubMed

Ferrero, J M; Sáiz, J; Ferrero, J M; Thakor, N V

1996-08-01

The role of the ATP-sensitive K+ current (IK-ATP) and its contribution to electrophysiological changes that occur during metabolic impairment in cardiac ventricular myocytes is still being discussed. The aim of this work was to quantitatively study this issue by using computer modeling. A model of IK-ATP is formulated and incorporated into the Luo-Rudy ionic model of the ventricular action potential. Action potentials under different degrees of activation of IK-ATP are simulated. Our results show that in normal ionic concentrations, only approximately 0.6% of the KATP channels, when open, should account for a 50% reduction in action potential duration. However, increased levels of intracellular Mg2+ counteract this shortening. Under conditions of high [K+]0, such as those found in early ischemia, the activation of only approximately 0.4% of the KATP channels could account for a 50% reduction in action potential duration. Thus, our results suggest that opening of IK-ATP channels should play a significant role in action potential shortening during hypoxic/ischemic episodes, with the fraction of open channels involved being very low ( < 1%). However, the results of the model suggest that activation of IK-ATP alone does not quantitatively account for the observed K+ efflux in metabolically impaired cardiac myocytes. Mechanisms other than KATP channel activation should be responsible for a significant part of the K+ efflux measured in hypoxic/ischemic situations.

Electrophysiological properties of computational human ventricular cell action potential models under acute ischemic conditions.

PubMed

Dutta, Sara; Mincholé, Ana; Quinn, T Alexander; Rodriguez, Blanca

2017-10-01

Acute myocardial ischemia is one of the main causes of sudden cardiac death. The mechanisms have been investigated primarily in experimental and computational studies using different animal species, but human studies remain scarce. In this study, we assess the ability of four human ventricular action potential models (ten Tusscher and Panfilov, 2006; Grandi et al., 2010; Carro et al., 2011; O'Hara et al., 2011) to simulate key electrophysiological consequences of acute myocardial ischemia in single cell and tissue simulations. We specifically focus on evaluating the effect of extracellular potassium concentration and activation of the ATP-sensitive inward-rectifying potassium current on action potential duration, post-repolarization refractoriness, and conduction velocity, as the most critical factors in determining reentry vulnerability during ischemia. Our results show that the Grandi and O'Hara models required modifications to reproduce expected ischemic changes, specifically modifying the intracellular potassium concentration in the Grandi model and the sodium current in the O'Hara model. With these modifications, the four human ventricular cell AP models analyzed in this study reproduce the electrophysiological alterations in repolarization, refractoriness, and conduction velocity caused by acute myocardial ischemia. However, quantitative differences are observed between the models and overall, the ten Tusscher and modified O'Hara models show closest agreement to experimental data. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Partial exposure of frog heart to high-potassium solution: an easily reproducible model mimicking ST segment changes.

PubMed

Kon, Nobuaki; Abe, Nozomu; Miyazaki, Masahiro; Mushiake, Hajime; Kazama, Itsuro

2018-04-18

By simply inducing burn injuries on the bullfrog heart, we previously reported a simple model of abnormal ST segment changes observed in human ischemic heart disease. In the present study, instead of inducing burn injuries, we partially exposed the surface of the frog heart to high-potassium (K + ) solution to create a concentration gradient of the extracellular K + within the myocardium. Dual recordings of ECG and the cardiac action potential demonstrated significant elevation of the ST segment and the resting membrane potential, indicating its usefulness as a simple model of heart injury. Additionally, from our results, Na + /K + -ATPase activity was thought to be primarily responsible for generating the K + concentration gradient and inducing the ST segment changes in ECG.

Simulation of water-quality data at selected stream sites in the Missouri River Basin, Montana

USGS Publications Warehouse

Knapton, J.R.; Jacobson, M.A.

1980-01-01

Modification of sampling programs at some water-quality stations in the Missouri River basin in Montana has eliminated the means by which solute loads have been directly obtained in past years. To compensate for this loss, water-quality and streamflow data were statistically analyzed and solute loads were simulated using computer techniques.Functional relationships existing between specific conductance and solute concentration for monthly samples were used to develop linear regression models. The models were then used to simulate daily solute concentrations using daily specific conductance as the independent variable. Once simulated, the solute concentrations, in milligrams per liter, were transformed into daily solute loads, in tons, using mean daily streamflow records.Computer output was formatted into tables listing simulated mean monthly solute concentrations, in milligrams per liter, and the monthly and annual solute loads, in tons, for water years 1975-78.

Oxygen supersaturated fluid using fine micro/nanobubbles

PubMed Central

Matsuki, Noriaki; Ishikawa, Takuji; Ichiba, Shingo; Shiba, Naoki; Ujike, Yoshihito; Yamaguchi, Takami

2014-01-01

Microbubbles show peculiar properties, such as shrinking collapse, long lifetime, high gas solubility, negative electric charge, and free radical production. Fluids supersaturated with various gases can be easily generated using microbubbles. Oxygen microbubble fluid can be very useful for oxygen delivery to hypoxic tissues. However, there have been no reports of comparative investigations into adding fluids containing oxygen fine micro/nanobubbles (OFM-NBs) to common infusion solutions in daily medical care. In this study, it was demonstrated that OFMNBs can generate oxygen-supersaturated fluids, and they may be sufficiently small to infuse safely into blood vessels. It was found that normal saline solution is preferable for generating an oxygen-rich infusion fluid, which is best administered as a 30-minute intravenous infusion. It was also concluded that dextran solution is suitable for drug delivery substances packing oxygen gas over a 1-hour intravenous infusion. In addition, normal saline solution containing OFMNBs was effective for improving blood oxygenation. Thus, the use of OFMNB-containing fluids is a potentially effective novel method for improving blood oxygenation in cases involving hypoxia, ischemic diseases, infection control, and anticancer chemoradiation therapies. PMID:25285003

Oxygen supersaturated fluid using fine micro/nanobubbles.

PubMed

Matsuki, Noriaki; Ishikawa, Takuji; Ichiba, Shingo; Shiba, Naoki; Ujike, Yoshihito; Yamaguchi, Takami

2014-01-01

Microbubbles show peculiar properties, such as shrinking collapse, long lifetime, high gas solubility, negative electric charge, and free radical production. Fluids supersaturated with various gases can be easily generated using microbubbles. Oxygen microbubble fluid can be very useful for oxygen delivery to hypoxic tissues. However, there have been no reports of comparative investigations into adding fluids containing oxygen fine micro/nanobubbles (OFM-NBs) to common infusion solutions in daily medical care. In this study, it was demonstrated that OFMNBs can generate oxygen-supersaturated fluids, and they may be sufficiently small to infuse safely into blood vessels. It was found that normal saline solution is preferable for generating an oxygen-rich infusion fluid, which is best administered as a 30-minute intravenous infusion. It was also concluded that dextran solution is suitable for drug delivery substances packing oxygen gas over a 1-hour intravenous infusion. In addition, normal saline solution containing OFMNBs was effective for improving blood oxygenation. Thus, the use of OFMNB-containing fluids is a potentially effective novel method for improving blood oxygenation in cases involving hypoxia, ischemic diseases, infection control, and anticancer chemoradiation therapies.

Transient ischemic attack

MedlinePlus

... artery surgery - discharge Stroke - discharge Taking warfarin (Coumadin) Images Endarterectomy Transient Ischemic attack (TIA) References Biller J, Ruland S, Schneck MJ. Ischemic cerebrovascular disease. In Daroff ...

Neuroprotective effects of ischemic preconditioning on hippocampal CA1 pyramidal neurons through maintaining calbindin D28k immunoreactivity following subsequent transient cerebral ischemia

PubMed Central

Kim, In Hye; Jeon, Yong Hwan; Lee, Tae-Kyeong; Cho, Jeong Hwi; Lee, Jae-Chul; Park, Joon Ha; Ahn, Ji Hyeon; Shin, Bich-Na; Kim, Yang Hee; Hong, Seongkweon; Yan, Bing Chun; Won, Moo-Ho; Lee, Yun Lyul

2017-01-01

Ischemic preconditioning elicited by a non-fatal brief occlusion of blood flow has been applied for an experimental therapeutic strategy against a subsequent fatal ischemic insult. In this study, we investigated the neuroprotective effects of ischemic preconditioning (2-minute transient cerebral ischemia) on calbindin D28k immunoreactivity in the gerbil hippocampal CA1 area following a subsequent fatal transient ischemic insult (5-minute transient cerebral ischemia). A large number of pyramidal neurons in the hippocampal CA1 area died 4 days after 5-minute transient cerebral ischemia. Ischemic preconditioning reduced the death of pyramidal neurons in the hippocampal CA1 area. Calbindin D28k immunoreactivity was greatly attenuated at 2 days after 5-minute transient cerebral ischemia and it was hardly detected at 5 days post-ischemia. Ischemic preconditioning maintained calbindin D28k immunoreactivity after transient cerebral ischemia. These findings suggest that ischemic preconditioning can attenuate transient cerebral ischemia-caused damage to the pyramidal neurons in the hippocampal CA1 area through maintaining calbindin D28k immunoreactivity. PMID:28761424

Single-Step 3-D Image Reconstruction in Magnetic Induction Tomography: Theoretical Limits of Spatial Resolution and Contrast to Noise Ratio

PubMed Central

Hollaus, Karl; Rosell-Ferrer, Javier; Merwa, Robert

2006-01-01

Magnetic induction tomography (MIT) is a low-resolution imaging modality for reconstructing the changes of the complex conductivity in an object. MIT is based on determining the perturbation of an alternating magnetic field, which is coupled from several excitation coils to the object. The conductivity distribution is reconstructed from the corresponding voltage changes induced in several receiver coils. Potential medical applications comprise the continuous, non-invasive monitoring of tissue alterations which are reflected in the change of the conductivity, e.g. edema, ventilation disorders, wound healing and ischemic processes. MIT requires the solution of an ill-posed inverse eddy current problem. A linearized version of this problem was solved for 16 excitation coils and 32 receiver coils with a model of two spherical perturbations within a cylindrical phantom. The method was tested with simulated measurement data. Images were reconstructed with a regularized single-step Gauss–Newton approach. Theoretical limits for spatial resolution and contrast/noise ratio were calculated and compared with the empirical results from a Monte-Carlo study. The conductivity perturbations inside a homogeneous cylinder were localized for a SNR between 44 and 64 dB. The results prove the feasibility of difference imaging with MIT and give some quantitative data on the limitations of the method. PMID:17031597

Delayed Post-ischemic Conditioning Significantly Improves the Outcome after Retinal Ischemia

PubMed Central

Dreixler, John C.; Poston, Jacqueline N.; Shaikh, Afzhal R.; Alexander, Michael; Tupper, Kelsey Y.; Marcet, Marcus M.; Bernaudin, Myriam; Roth, Steven

2011-01-01

In previous studies, it was shown that post-conditioning, a transient period of brief ischemia following prolonged severe ischemia in the retina, could provide significant improvement in post-ischemic recovery, attenuation of cell loss, and decreased apoptosis. These studies showed that post-conditioning effectively prevented damage after retinal ischemia when it was instituted early (within one hour) in the post-ischemic period. While post-ischemic conditioning holds high promise of clinical translation, patients often present late after the onset of retinal ischemia and therefore immediate application of this anti-ischemic maneuver is generally not feasible. In this study, we examined the hypothesis that application of a post-conditioning stimulus at 24 h or greater following the end of prolonged ischemia would decrease the extent of ischemic injury. Ischemia was induced in rat retina in vivo. Recovery after ischemia followed by 5 minutes of post-conditioning brief ischemia 24 or 48 h after prolonged ischemia was assessed functionally (electroretinography) and histologically at 7 days after ischemia and post-conditioning or sham post-conditioning. We found that the brief ischemic stimulus applied 24, but not 48 h after prolonged ischemia significantly improved functional recovery and decreased histological damage induced by prolonged ischemia. We conclude that within a defined time window, delayed post-ischemic conditioning ameliorated post-ischemic injury in rats. Compared to earlier studies, the present work demonstrates for the first time the novel ability of a significantly delayed ischemic stimulus to provide robust neuroprotection in the retina following ischemia. PMID:21501608

Association of ALOX5AP with ischemic stroke: a population-based case-control study.

PubMed

Kaushal, Ritesh; Pal, Prodipto; Alwell, Kathleen; Haverbusch, Mary; Flaherty, Matthew; Moomaw, Charles; Sekar, Padmini; Kissela, Brett; Kleindorfer, Dawn; Chakraborty, Ranajit; Broderick, Joseph; Deka, Ranjan; Woo, Daniel

2007-06-01

Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However, replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW. Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes, hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P=0.019 and P<10(-4), respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks.

Fasting and non-fasting triglycerides and risk of ischemic cardiovascular disease in Japanese men and women: the Circulatory Risk in Communities Study (CIRCS).

PubMed

Iso, Hiroyasu; Imano, Hironori; Yamagishi, Kazumasa; Ohira, Tetsuya; Cui, Renzhe; Noda, Hiroyuki; Sato, Shinichi; Kiyama, Masahiko; Okada, Takeo; Hitsumoto, Shinichi; Tanigawa, Takeshi; Kitamura, Akihiko

2014-11-01

Non-fasting triglycerides were reported to have a greater impact on risk of ischemic cardiovascular events than fasting triglycerides. However, evidence from Asia, where the prevalence of dyslipidemia is generally lower, has been limited. We used 1975-1986 baseline surveys to investigate cohort data of 10,659 (4264 men and 6395 women) residents aged 40-69 years, initially free from ischemic heart disease and stroke, in four Japanese communities. Serum triglyceride concentrations at baseline were obtained for 2424 fasting (≥8 h after meal) and 8235 non-fasting (<8 h after meal) participants. During the 22-year follow-up, 284 (165 men and 119 women) developed ischemic heart disease and 666 (349 men and 317 women) ischemic stroke. After adjustment for age, sex and known cardiovascular risk factors, multivariable hazard ratios (95%CI) of ischemic cardiovascular disease (ischemic heart disease and ischemic stroke) for the highest versus lowest quartiles of triglycerides were 1.71 (1.14-2.59), P for trend = 0.013, for fasting participants and 1.60 (1.25-2.05), P for trend <0.001, for non-fasting participants. The positive associations did not differ between fasting and non-fasting men, while they were strong for non-fasting women. They were stronger for ischemic heart disease than for ischemic stroke. After further adjustment for HDL-cholesterol, these associations were slightly attenuated, but remained statistically significant. Non-fasting as well as fasting triglycerides are predictive of risk of ischemic cardiovascular disease for Japanese men, as are non-fasting triglycerides for women. Copyright © 2014. Published by Elsevier Ireland Ltd.

C-reactive protein gene C1444T polymorphism and risk of recurrent ischemic events in patients with symptomatic intracranial atherostenoses.

PubMed

Arenillas, Juan F; Massot, Andreu; Alvarez-Sabín, Jose; Fernandez-Cadenas, Israel; del Rio-Espinola, Albert; Chacon, Pilar; Quintana, Manuel; Molina, Carlos A; Rovira, Alex; Montaner, Joan

2009-01-01

High levels of C-reactive protein (CRP) are associated with an increased risk of further ischemic events in patients with symptomatic intracranial atherosclerotic disease (ICAD). It remains unknown to which extent this increased risk might be genetically predetermined. We aimed to investigate the relationship between a common genetic polymorphism of the CRP gene and the risk of recurrent ischemic events in symptomatic ICAD patients. We studied 75 consecutive patients with a first-ever cerebral ischemic event attributable to symptomatic ICAD. Blood samples were drawn 3 months after the qualifying event. Genomic DNA was isolated and the C1444T single nucleotide polymorphism (SNP) of the CRP gene was determined. The blood concentration of CRP was also measured. Patients underwent long-term clinical follow-up to detect the occurrence of further major ischemic events. During a median follow-up time of 23 months, 18 patients (24%) suffered a major ischemic event (10 ischemic strokes, 3 transient ischemic attacks and 5 myocardial infarctions). Raised CRP levels at baseline (p = 0.02) and the presence of the T allele within the CRP C1444T SNP were associated with a higher risk of recurrent ischemic events (p = 0.02). Kaplan-Meier and multivariable Cox regression analyses adjusted for age, sex, vascular risk factors and CRP level identified that the presence of the T allele in the studied polymorphism predicted the occurrence of further ischemic events (hazard ratio 3.6, 95% confidence interval 1.2-11.1; p = 0.025). The presence of the T allele within the CRP gene C1444T polymorphism may be associated with a higher risk of further ischemic events in symptomatic ICAD patients. (c) 2009 S. Karger AG, Basel.

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

PubMed

Bousser, M G; Amarenco, P; Chamorro, A; Fisher, M; Ford, I; Fox, K; Hennerici, M G; Mattle, H P; Rothwell, P M

2009-01-01

Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event. Copyright 2009 S. Karger AG, Basel.

Peripheral Frequency of CD4+ CD28− Cells in Acute Ischemic Stroke

PubMed Central

Tuttolomondo, Antonino; Pecoraro, Rosaria; Casuccio, Alessandra; Di Raimondo, Domenico; Buttà, Carmelo; Clemente, Giuseppe; Corte, Vittoriano della; Guggino, Giuliana; Arnao, Valentina; Maida, Carlo; Simonetta, Irene; Maugeri, Rosario; Squatrito, Rosario; Pinto, Antonio

2015-01-01

Abstract CD4+ CD28− T cells also called CD28 null cells have been reported as increased in the clinical setting of acute coronary syndrome. Only 2 studies previously analyzed peripheral frequency of CD28 null cells in subjects with acute ischemic stroke but, to our knowledge, peripheral frequency of CD28 null cells in each TOAST subtype of ischemic stroke has never been evaluated. We hypothesized that CD4+ cells and, in particular, the CD28 null cell subset could show a different degree of peripheral percentage in subjects with acute ischemic stroke in relation to clinical subtype and severity of ischemic stroke. The aim of our study was to analyze peripheral frequency of CD28 null cells in subjects with acute ischemic stroke in relation to TOAST diagnostic subtype, and to evaluate their relationship with scores of clinical severity of acute ischemic stroke, and their predictive role in the diagnosis of acute ischemic stroke and diagnostic subtype We enrolled 98 consecutive subjects admitted to our recruitment wards with a diagnosis of ischemic stroke. As controls we enrolled 66 hospitalized patients without a diagnosis of acute ischemic stroke. Peripheral frequency of CD4+ and CD28 null cells has been evaluated with a FACS Calibur flow cytometer. Subjects with acute ischemic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to control subjects without acute ischemic stroke. Subjects with cardioembolic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to subjects with other TOAST subtypes. We observed a significant relationship between CD28 null cells peripheral percentage and Scandinavian Stroke Scale and NIHSS scores. ROC curve analysis showed that CD28 null cell percentage may be useful to differentiate between stroke subtypes. These findings seem suggest a possible role for a T-cell component also in acute ischemic stroke clinical setting showing a different peripheral frequency of CD28 null cells in relation of each TOAST subtype of stroke. PMID:25997053

The effects of L-carnitine on spinal cord ischemia/reperfusion injury in rabbits.

PubMed

Tetik, O; Yagdi, T; Islamoglu, F; Calkavur, T; Posacioglu, H; Atay, Y; Ayik, F; Canpolat, L; Yuksel, M

2002-02-01

Paraplegia after distal aortic aneurysm repair remains a persistent clinical problem. We hypothesized that the tolerance of the spinal cord to an ischemic period could be improved with hypothermic Ringer's Lactate containing L-Carnitine. Twenty-eight New Zealand white rabbits were used as spinal cord ischemia models. We separated rabbits into four equal groups and clamped each animal's abdominal aorta distal to the left renal artery. We occluded the aortas above the iliac bifurcation for 30 minutes. In group I, the infrarenal aorta was clamped without infusing any solution. In group II, Ringer's Lactate solution was infused at + 25degrees C for 3 minutes at a rate of 5 ml/min into the isolated aortic segments immediately after cross-clamping and the last 3 minutes of ischemia. In group III, Ringer's Lactate solution at +3 degrees C was given in the same method as that of group II. In group IV, Ringer's Lactate solution at +3 degrees C plus 100 mg/kg of L-carnitine was infused using the same technique. We assessed the neurological status of the hind limbs 24 and 48 hours after operation according to Tarlov's criteria. All animals were sacrificed and spinal cords were harvested for histological analyses. The neurological status in groups III and IV was significantly superior to that of groups I and II. All the animals in group I had complete hind-limb paraplegia. Complete hind-limb paraplegia occurred in 5 rabbits in group II. Two of the 7 animals in group III had spastic paraplegia, and none at all in group IV. Histological analysis of the cross-clamped segments of the rabbits with paraplegia in group I, II and III revealed changes consistent with ischemic injury, while findings were normal for the normal animals in group III and IV. In this model, the infusion of hypothermic Ringer's Lactate contained L-carnitine provided sufficient spinal cord protection against ischemia. Clinically, this may be a useful adjunct for prevention of paraplegia during surgery of the descending aorta.

Mathematical multi-scale model of the cardiovascular system including mitral valve dynamics. Application to ischemic mitral insufficiency

PubMed Central

2011-01-01

Background Valve dysfunction is a common cardiovascular pathology. Despite significant clinical research, there is little formal study of how valve dysfunction affects overall circulatory dynamics. Validated models would offer the ability to better understand these dynamics and thus optimize diagnosis, as well as surgical and other interventions. Methods A cardiovascular and circulatory system (CVS) model has already been validated in silico, and in several animal model studies. It accounts for valve dynamics using Heaviside functions to simulate a physiologically accurate "open on pressure, close on flow" law. However, it does not consider real-time valve opening dynamics and therefore does not fully capture valve dysfunction, particularly where the dysfunction involves partial closure. This research describes an updated version of this previous closed-loop CVS model that includes the progressive opening of the mitral valve, and is defined over the full cardiac cycle. Results Simulations of the cardiovascular system with healthy mitral valve are performed, and, the global hemodynamic behaviour is studied compared with previously validated results. The error between resulting pressure-volume (PV) loops of already validated CVS model and the new CVS model that includes the progressive opening of the mitral valve is assessed and remains within typical measurement error and variability. Simulations of ischemic mitral insufficiency are also performed. Pressure-Volume loops, transmitral flow evolution and mitral valve aperture area evolution follow reported measurements in shape, amplitude and trends. Conclusions The resulting cardiovascular system model including mitral valve dynamics provides a foundation for clinical validation and the study of valvular dysfunction in vivo. The overall models and results could readily be generalised to other cardiac valves. PMID:21942971

A Case for Telestroke in Military Medicine: A Retrospective Analysis of Stroke Cost and Outcomes in U.S. Military Health-Care System.

PubMed

Dave, Ajal; Cagniart, Kendra; Holtkamp, Matthew D

2018-06-07

The development of primary stroke centers has improved outcomes for stroke patients. Telestroke networks have expanded the reach of stroke experts to underserved, geographically remote areas. This study illustrates the outcome and cost differences between neurology and primary care ischemic stroke admissions to demonstrate a need for telestroke networks within the Military Health System (MHS). All adult admissions with a primary diagnosis of ischemic stroke in the MHS Military Mart database from calendar years 2010 to 2015 were reviewed. Neurology, primary care, and intensive care unit (ICU) admissions were compared across primary outcomes of (1) disposition status and (2) intravenous tissue plasminogen activator administration and for secondary outcomes of (1) total cost of hospitalization and (2) length of stay (LOS). A total of 3623 admissions met the study's parameters. The composition was neurology 462 (12.8%), primary care 2324 (64.1%), ICU 677 (18.7%), and other/unknown 160 (4.4%). Almost all neurology admissions (97%) were at the 3 neurology training programs, whereas a strong majority of primary care admissions (80%) were at hospitals without a neurology admitting service. Hospitals without a neurology admitting service had more discharges to rehabilitation facilities and higher rates of in-hospital mortality. LOS was also longer in primary care admissions. Ischemic stroke admissions to neurology had better outcomes and decreased LOS when compared to primary care within the MHS. This demonstrates a possible gap in care. Implementation of a hub and spoke telestroke model is a potential solution. Published by Elsevier Inc.

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

PubMed

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

2018-04-25

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

Limited reliability of computed tomographic perfusion acute infarct volume measurements compared with diffusion-weighted imaging in anterior circulation stroke.

PubMed

Schaefer, Pamela W; Souza, Leticia; Kamalian, Shervin; Hirsch, Joshua A; Yoo, Albert J; Kamalian, Shahmir; Gonzalez, R Gilberto; Lev, Michael H

2015-02-01

Diffusion-weighted imaging (DWI) can reliably identify critically ischemic tissue shortly after stroke onset. We tested whether thresholded computed tomographic cerebral blood flow (CT-CBF) and CT-cerebral blood volume (CT-CBV) maps are sufficiently accurate to substitute for DWI for estimating the critically ischemic tissue volume. Ischemic volumes of 55 patients with acute anterior circulation stroke were assessed on DWI by visual segmentation and on CT-CBF and CT-CBV with segmentation using 15% and 30% thresholds, respectively. The contrast:noise ratios of ischemic regions on the DWI and CT perfusion (CTP) images were measured. Correlation and Bland-Altman analyses were used to assess the reliability of CTP. Mean contrast:noise ratios for DWI, CT-CBF, and CT-CBV were 4.3, 0.9, and 0.4, respectively. CTP and DWI lesion volumes were highly correlated (R(2)=0.87 for CT-CBF; R(2)=0.83 for CT-CBV; P<0.001). Bland-Altman analyses revealed little systemic bias (-2.6 mL) but high measurement variability (95% confidence interval, ±56.7 mL) between mean CT-CBF and DWI lesion volumes, and systemic bias (-26 mL) and high measurement variability (95% confidence interval, ±64.0 mL) between mean CT-CBV and DWI lesion volumes. A simulated treatment study demonstrated that using CTP-CBF instead of DWI for detecting a statistically significant effect would require at least twice as many patients. The poor contrast:noise ratios of CT-CBV and CT-CBF compared with those of DWI result in large measurement error, making it problematic to substitute CTP for DWI in selecting individual acute stroke patients for treatment. CTP could be used for treatment studies of patient groups, but the number of patients needed to identify a significant effect is much higher than the number needed if DWI is used. © 2014 American Heart Association, Inc.

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

PubMed

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

2017-05-15

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

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

Computer simulations of alkali-acetate solutions: Accuracy of the forcefields in difference concentrations

NASA Astrophysics Data System (ADS)

Ahlstrand, Emma; Zukerman Schpector, Julio; Friedman, Ran

2017-11-01

When proteins are solvated in electrolyte solutions that contain alkali ions, the ions interact mostly with carboxylates on the protein surface. Correctly accounting for alkali-carboxylate interactions is thus important for realistic simulations of proteins. Acetates are the simplest carboxylates that are amphipathic, and experimental data for alkali acetate solutions are available and can be compared with observables obtained from simulations. We carried out molecular dynamics simulations of alkali acetate solutions using polarizable and non-polarizable forcefields and examined the ion-acetate interactions. In particular, activity coefficients and association constants were studied in a range of concentrations (0.03, 0.1, and 1M). In addition, quantum-mechanics (QM) based energy decomposition analysis was performed in order to estimate the contribution of polarization, electrostatics, dispersion, and QM (non-classical) effects on the cation-acetate and cation-water interactions. Simulations of Li-acetate solutions in general overestimated the binding of Li+ and acetates. In lower concentrations, the activity coefficients of alkali-acetate solutions were too high, which is suggested to be due to the simulation protocol and not the forcefields. Energy decomposition analysis suggested that improvement of the forcefield parameters to enable accurate simulations of Li-acetate solutions can be achieved but may require the use of a polarizable forcefield. Importantly, simulations with some ion parameters could not reproduce the correct ion-oxygen distances, which calls for caution in the choice of ion parameters when protein simulations are performed in electrolyte solutions.

Direct intraperitoneal resuscitation with lidocaine, methylene blue and pentoxiphylline combination does not decreases inflammation after intestinal ischemia-reperfusion injury in rats.

PubMed

Gandini, Marco; Cerri, Simona; Pregel, Paola; Giusto, Gessica; Vercelli, Cristina; Iussich, Selina; Tursi, Massimiliano; Farca, Anna Maria

2016-05-01

To evaluate the effects of an intraperitoneal solution of methylene blue (MB), lidocaine and pentoxyphylline (PTX) on intestinal ischemic and reperfusion injury. Superior mesenteric artery was isolated and clamped in 36 adult male Sprague Dawley rats. After 60 minutes, clamp was removed and a group received intraperitoneally UNITO solution (PTX 25mg/kg + lidocaine 5mg/kg + MB 2mg/kg), while the other group was treated with warm 0.9% NaCl solution. Rats were euthanized 45 min after drug administration. Lung and bowel were collected for histological evaluation (using Park's score) and determination of myeloperoxidase (MPO) and malondialdehyde (MDA) levels. Control samples showed lymphoplasmocytic infiltrate and crypt necrosis of villi. MPO and MDA measurements shown no differences between treated and control groups. The combination of lidocaine, methylene blue and pentoxyphylline administered intraperitoneally at the studied dose, did not decreased histological lesion scores and biochemical markers levels in intestinal ischemia/reperfusion injury.

Increased primary non-function in transplanted deceased-donor kidneys flushed with histidine-tryptophan-ketoglutarate solution.

PubMed

Stevens, R B; Skorupa, J Y; Rigley, T H; Yannam, G R; Nielsen, K J; Schriner, M E; Skorupa, A J; Murante, A; Holdaway, E; Wrenshall, L E

2009-05-01

Histidine-Tryptophan-Ketoglutarate (HTK) solution is increasingly used to flush and preserve organ donor kidneys, with efficacy claimed equivalent to University of Wisconsin (UW) solution. We observed and reported increased graft pancreatitis in pancreata flushed with HTK solution, which prompted this review of transplanting HTK-flushed kidneys. We analyzed outcomes of deceased-donor kidneys flushed with HTK and UW solutions with a minimum of 12 months follow-up, excluding pediatric and multi-organ recipients. We evaluated patient and graft survival and rejection rates, variables that might constitute hazards to graft survival and renal function. Two-year patient survival, rejection, renal function and graft survival were not different, but early graft loss (<6 months) was worse in HTK-flushed kidneys (p < 0.03). A Cox analysis of donor grade, cold ischemic time, panel reactive antibodies (PRA), donor race, first vs. repeat transplant, rejection and flush solution showed that only HTK use predicted early graft loss (p < 0.04; relative risk = 3.24), almost exclusively attributable to primary non-function (HTK, n = 5 (6.30%); UW, n = 1 (0.65%); p = 0.02). Delayed graft function and early graft loss with HTK occurred only in lesser grade kidneys, suggesting it should be used with caution in marginal donors.

Combined effects of family history of CVD and heart rate on ischemic stroke incidence among Inner Mongolians in China.

PubMed

Zhou, Yipeng; Tian, Yunfan; Zhong, Chongke; Batu, Buren; Xu, Tian; Li, Hongmei; Zhang, Mingzhi; Wang, Aili; Zhang, Yonghong

2016-05-01

This study aimed to evaluate the combined effects of family history of cardiovascular diseases (FHCVD) and heart rate on ischemic stroke incidence among Inner Mongolians in China. A prospective cohort study was conducted among 2589 participants aged 20 years and older from Inner Mongolia, China. The participants were divided into four groups according to status of FHCVD and heart rate and followed up from June 2002 to July 2012. Cox proportional hazards models were used to evaluate the combined effects of FHCVD and heart rate on the incidence of ischemic stroke. A total of 76 ischemic stroke occurred during the follow-up period. The observed ischemic stroke cases tended to be older and male, and had higher prevalence of smoking, drinking, hypertension and FHCVD as well as higher systolic and diastolic blood pressures at baseline compared with those who did not experience ischemic stroke. Age- and gender-adjusted hazard ratio (95% confidence interval) of ischemic stroke in the participants with both FHCVD and heart rate ≥ 80 were 2.89 (1.51-5.53), compared with those without FHCVD and heart rate < 80. After multiple adjustment, the association between ischemic stroke risk and both FHCVD and heart rate ≥ 80 remained statistically significant (hazard ratio, 2.47; 95% confidence interval: 1.22-5.01). Our main finding that participants with both FHCVD and faster heart rate have the highest risk of ischemic stroke suggests that faster heart rate may increase the risk of ischemic stroke among people with FHCVD.

The importance of regulation of blood glucose levels through activation of peripheral 5'-AMP-activated protein kinase on ischemic neuronal damage.

PubMed

Harada, Shinichi; Fujita-Hamabe, Wakako; Tokuyama, Shogo

2010-09-10

5'-AMP-activated protein kinase (AMPK) is a serine/threonine kinase that plays a key role in energy homeostasis. Recently, it was reported that centrally activated AMPK is involved in the development of ischemic neuronal damage, while the effect of peripherally activated AMPK on ischemic neuronal damage is not known. In addition, we have previously reported that the development of post-ischemic glucose intolerance could be one of the triggers for the aggravation of neuronal damage. In this study, we focused on effect of activation of peripheral or central AMPK on the development of ischemic neuronal damage. Male ddY mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histological and behavioral analysis after MCAO. In the liver and skeletal muscle, AMPK activity was not affected by MCAO. But, application of intraperitoneal metformin (250 mg/kg), an AMPK activator, significantly suppressed the development of post-ischemic glucose intolerance and ischemic neuronal damage without alteration of central AMPK activity. On the other hand, application of intracerebroventricular metformin (25, 100 microg/mouse) significantly exacerbated the development of neuronal damage observed on day 1 after MCAO, in a dose-dependent manner. These effects were significantly blocked by compound C, a specific AMPK inhibitor. These results suggest that central AMPK was activated by ischemic stress per se, however, peripheral AMPK was not altered. Furthermore, the regulation of post-ischemic glucose intolerance by activation of peripheral AMPK is of assistance for the suppression of cerebral ischemic neuronal damage. 2010 Elsevier B.V. All rights reserved.

Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial: rationale and design

PubMed Central

Johnston, S. Claiborne; Easton, J. Donald; Farrant, Mary; Barsan, William; Battenhouse, Holly; Conwit, Robin; Dillon, Catherine; Elm, Jordan; Lindblad, Anne; Morgenstern, Lewis; Poisson, Sharon N.; Palesch, Yuko

2015-01-01

Background Ischemic stroke and other vascular outcomes occur in 10–20% of patients in the 3 months following a TIA or minor ischemic stroke, and many are disabling. The highest risk period for these outcomes is the early hours and days immediately following the ischemic event. Aspirin is the most common antithrombotic treatment used for these patients. Aim The aim of POINT is to determine whether clopidogrel plus aspirin taken <12 hours after TIA or minor ischemic stroke symptom onset is more effective in preventing major ischemic vascular events at 90 days in the high-risk, and acceptably safe, compared to aspirin alone. Design POINT is a prospective, randomized, double-blind, multicenter trial in patients with TIA or minor ischemic stroke. Subjects are randomized to clopidogrel (600 mg loading dose followed by 75 mg/day) or matching placebo, and all will receive open-label aspirin 50–325 mg/day, with a dose of 162 mg daily for 5 days followed by 81 mg daily strongly recommended. Study Outcomes The primary efficacy outcome is the composite of new ischemic vascular events: ischemic stroke, myocardial infarction or ischemic vascular death, by 90 days. The primary safety outcome is major hemorrhage, which includes symptomatic intracranial hemorrhage. Discussion Aspirin is the most common antithrombotic given to patients with a stroke or TIA as it reduces the risk subsequent of stroke. This trial expects to determine whether more aggressive antithrombotic therapy with clopidogrel plus aspirin, initiated acutely, is more effective than aspirin alone. PMID:23879752

Acidosis mediates recurrent hypoglycemia-induced increase in ischemic brain injury in treated diabetic rats.

PubMed

Rehni, Ashish K; Shukla, Vibha; Perez-Pinzon, Miguel A; Dave, Kunjan R

2018-03-15

Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats. Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury. Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats. Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Essential role for zinc-triggered p75NTR activation in preconditioning neuroprotection.

PubMed

Lee, Jin-Yeon; Kim, Yu-Jin; Kim, Tae-Youn; Koh, Jae-Young; Kim, Yang-Hee

2008-10-22

Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo, p75(NTR) was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75(NTR) activation in neurons.

Transient ischemic attack and minor stroke are the most common manifestations of acute cerebrovascular disease: a prospective, population-based study--the Aarhus TIA study.

PubMed

von Weitzel-Mudersbach, Paul; Andersen, Grethe; Hundborg, Heidi H; Johnsen, Søren P

2013-01-01

Severity of acute vascular illness may have changed in the last decades due to improvements in primary and secondary prevention. Population-based data on the severity of acute ischemic cerebrovascular disease are sparse. We aimed to examine incidence, characteristics and severity of acute ischemic cerebrovascular disease in a well-defined population. All patients admitted with transient ischemic attack (TIA) or acute ischemic stroke from March 1, 2007, to February 29, 2008, with residence in the Aarhus area, were included. Incidence rates and characteristics of TIA and ischemic stroke were compared. TIA accounted for 30%, TIA and minor stroke combined for 65% of all acute ischemic cerebrovascular events. Age-adjusted incidence rates of TIA and ischemic stroke were 72.2/100,000 and 129.5/100,000 person-years, respectively. TIA patients were younger than stroke patients (66.3 vs. 72.7 years; p < 0.001). Atrial fibrillation, previous myocardial infarction and previous stroke were significantly more frequent in stroke patients; no differences in other baseline characteristics were found. Minor events are the most common in ischemic cerebrovascular disease, and may constitute a larger proportion than previously reported. TIA and stroke patients share many characteristics; however, TIA patients are younger and have fewer manifestations of atherosclerotic diseases, indicating a high potential for secondary prevention. Copyright © 2012 S. Karger AG, Basel.

Risk factors in various subtypes of ischemic stroke according to TOAST criteria.

PubMed

Aquil, Nadia; Begum, Imtiaz; Ahmed, Arshia; Vohra, Ejaz Ahmed; Soomro, Bashir Ahmed

2011-05-01

To identify the frequency of risk factors in various subtypes of acute ischemic stroke according to TOAST criteria. Cross-sectional, observational study. Ziauddin Hospital, Karachi, from January to December 2007. Patients with acute ischemic stroke were enrolled. Studied variables included demographic profile, history of risk factors, physical and neurological examination, and investigations relevant with the objectives of the study. Findings were described as frequency percentages. Proportions of risk factors against subtypes was compared using chi-square test with significance at p < 0.05. Out of the 100 patients with acute ischemic stroke, mean age at presentation was 63.5 years. Risk factor distribution was hypertension in 85%, Diabetes mellitus in 49%, ischemic heart disease in 30%, dyslipedemia in 22%, smoking in 9%, atrial fibrillation in 5%, and previous history of stroke in 29%. The various subtypes of acute ischemic stroke were lacunar infarct in 43%, large artery atherosclerosis in 31%, cardioembolic type in 8%, stroke of other determined etiology in 1% and stroke of undetermined etiology in 18%. Hypertension and Diabetes were the most important risk factors in both large and small artery atherosclerosis. In patients with cardio-embolic stroke significant association was found with ischemic heart disease (p=0.01). Importance and relevance of risk factors evaluated for subtypes rather than ischemic stroke as a whole should be reflected in preventive efforts against the burden of ischemic stroke.

FOXO4-Knockdown Suppresses Oxidative Stress-Induced Apoptosis of Early Pro-Angiogenic Cells and Augments Their Neovascularization Capacities in Ischemic Limbs

PubMed Central

Nakayoshi, Takaharu; Sasaki, Ken-ichiro; Kajimoto, Hidemi; Koiwaya, Hiroshi; Ohtsuka, Masanori; Ueno, Takafumi; Chibana, Hidetoshi; Itaya, Naoki; Sasaki, Masahiro; Yokoyama, Shinji; Fukumoto, Yoshihiro; Imaizumi, Tsutomu

2014-01-01

The effects of therapeutic angiogenesis by intramuscular injection of early pro-angiogenic cells (EPCs) to ischemic limbs are unsatisfactory. Oxidative stress in the ischemic limbs may accelerate apoptosis of injected EPCs, leading to less neovascularization. Forkhead transcription factor 4 (FOXO4) was reported to play a pivotal role in apoptosis signaling of EPCs in response to oxidative stress. Accordingly, we assessed whether FOXO4-knockdown EPCs (FOXO4KD-EPCs) could suppress the oxidative stress-induced apoptosis and augment the neovascularization capacity in ischemic limbs. We transfected small interfering RNA targeted against FOXO4 of human EPCs to generate FOXO4KD-EPCs and confirmed a successful knockdown. FOXO4KD-EPCs gained resistance to apoptosis in response to hydrogen peroxide in vitro. Oxidative stress stained by dihydroethidium was stronger for the immunodeficient rat ischemic limb tissue than for the rat non-ischemic one. Although the number of apoptotic EPCs injected into the rat ischemic limb was greater than that of apoptotic EPCs injected into the rat non-ischemic limb, FOXO4KD-EPCs injected into the rat ischemic limb brought less apoptosis and more neovascularization than EPCs. Taken together, the use of FOXO4KD-EPCs with resistance to oxidative stress-induced apoptosis may be a new strategy to augment the effects of therapeutic angiogenesis by intramuscular injection of EPCs. PMID:24663349

Resistance to Reperfusion Injury Following Short Term Postischemic Administration of Natural Honey in Globally Ischemic Isolated Rat Heart

PubMed Central

Vaez, Haleh; Samadzadeh, Mehrban; Zahednezhad, Fahimeh; Najafi, Moslem

2012-01-01

Purpose: Results of our previous study revealed that preischemic perfusion of honey before zero flow global ischemia had cardioprotective effects in rat. The present study investigated potential resistance to reperfusion injury following short term postischemic administration of natural honey in globally ischemic isolated rat heart. Methods: Male Wistar rats were divided into five groups (n=10-13). The rat hearts were isolated, mounted on a Langendorff apparatus, allowed to equilibrate for 30 min then subjected to 30 min global ischemia. In the control group, the hearts were reperfused with drug free normal Krebs-Henseleit (K/H) solution before ischemia and during 120 min reperfusion. In the treatment groups, reperfusion was initiated with K/H solution containing different concentration of honey (0.25, 0.5, 1 and 2%) for 15 min and was resumed until the end of 120 min with normal K/H solution. Results: In the control group, VEBs number was 784±199, while in honey concentration of 0.25, 0.5, 1 and 2%, it decreased to 83±23 (P<0.001), 138±48 (P<0.01), 142±37 (P<0.001) and 157±40 (P<0.01), respectively. Number and duration of VT and time spent in reversible VF were also reduced by honey. In the control group, the infarct size was 54.1±7.8%, however; honey (0.25, 0.5, 1 and 2%) markedly lowered the value to 12.4±2.4, 12.7±3.3, 11.3±2.6 and 7.9±1.7 (P<0.001), respectively. Conclusion: Postischemic administration of natural honey in global ischemia showed protective effects against ischemia/reperfusion (I/R) injuries in isolated rat heart. Antioxidant and radical scavenging activity, lipoperoxidation inhibition, reduction of necrotized tissue, presence of rich energy sources, various type of vitamins, minerals and enzymes and formation of NO-contain metabolites may probably involve in those cardioprotective effects. PMID:24312792

Targeted delivery of growth factors in ischemic stroke animal models.

PubMed

Rhim, Taiyoun; Lee, Minhyung

2016-01-01

Ischemic stroke is caused by reduced blood supply and leads to loss of brain function. The reduced oxygen and nutrient supply stimulates various physiological responses, including induction of growth factors. Growth factors prevent neuronal cell death, promote neovascularization, and induce cell growth. However, the concentration of growth factors is not sufficient to recover brain function after the ischemic damage, suggesting that delivery of growth factors into the ischemic brain may be a useful treatment for ischemic stroke. In this review, various approaches for the delivery of growth factors to ischemic brain tissue are discussed, including local and targeting delivery systems. To develop growth factor therapy for ischemic stroke, important considerations should be taken into account. First, growth factors may have possible side effects. Thus, concentration of growth factors should be restricted to the ischemic tissues by local administration or targeted delivery. Second, the duration of growth factor therapy should be optimized. Growth factor proteins may be degraded too fast to have a high enough therapeutic effect. Therefore, delivery systems for controlled release or gene delivery may be useful. Third, the delivery systems to the brain should be optimized according to the delivery route.

Predictors of long-term survival among first-ever ischemic and hemorrhagic stroke in a Brazilian stroke cohort.

PubMed

Goulart, Alessandra C; Fernandes, Tiotrefis G; Santos, Itamar S; Alencar, Airlane P; Bensenor, Isabela M; Lotufo, Paulo A

2013-05-24

Few studies have examined both ischemic and hemorrhagic stroke to identify prognostic factors associated to long-term stroke survival. We investigated long-term survival and predictors that could adversely influence ischemic and hemorrhagic first-ever stroke prognosis. We prospectively ascertained 665 consecutive first-ever ischemic and hemorrhagic stroke cases from "The Study of Stroke Mortality and Morbidity" (The EMMA Study) in a community hospital in São Paulo, Brazil. We evaluated cardiovascular risk factors and sociodemographic characteristics (age, gender, race and educational level). We found a lower survival rate among hemorrhagic cases compared to ischemic stroke cases at the end of 4 years of follow-up (52% vs. 44%, p = 0.04). The risk of death was two times higher among people with ischemic stroke without formal education. Also, we found consistently higher risk of death for diabetics with ischemic stroke (HR = 1.45; 95% CI = 1.07-1.97) compared to no diabetics. As expected, age equally influenced on the high risk of poor survival, regardless of stroke subtype. For ischemic stroke, the lack of formal education and diabetes were significant independent predictors of poor long-term survival.

Scanning Electron Microscopy Findings of Machine Perfused Liver Graft After Warm Ischemia Between Hypothermic and Rewarming Machine Perfusion in Pigs.

PubMed

Meng, L; Matsuno, N; Watanabe, K; Furukori, M; Obara, H; Bochimoto, H; Watanabe, T; Fukukawa, H

2016-09-01

The shortage of organ donors is a universal problem. Use of grafts from donors after cardiac death would greatly contribute to the expansion of the donor organ pool. The two major methods of preservation are cold storage and machine perfusion (MP) preservation, and each has its own advantages. Several studies have reported the relative merits of MP for the preservation for grafts from donors after cardiac death. In this study, we used scanning electron microscopy (SEM) to assess the damage to the liver between hypothermic and rewarming preservation conditions. Porcine livers were perfused with a newly developed MP system. The livers were perfused for 4 hours with a modified University of Wisconsin solution-gluconate solution. In group 1, grafts were preserved with warm ischemic time for 60 minutes and hypothermic machine perfusion (HMP) for 4 hours. In group 2, grafts were preserved with warn ischemic time for 60 minutes and had rewarming up to 22°C by MP (RMP) for 4 hours. A significant enlargement of the mitochondria were observed in both the HMP and RMP groups under higher magnification, Additionally, vacuoles appeared occasionally in hepatocytes in the RMP for 4 hours group, but not in the HMP for 4 hours group. An analysis by scanning electron microscope appears to be useful to evaluate the levels of damage of hepatocytes compared with transmission electron microscopy, and further study is needed to analyze the significance of the appearance of swelling of mitochondria and vacuolization during preservation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke.

PubMed

Shichita, Takashi; Ago, Tetsuro; Kamouchi, Masahiro; Kitazono, Takanari; Yoshimura, Akihiko; Ooboshi, Hiroaki

2012-11-01

Post-ischemic inflammation is an essential step in the progression of ischemic stroke. This review focuses on the function of infiltrating immune cells, macrophages, and T cells, in ischemic brain injury. The brain is a sterile organ; however, the activation of Toll-like receptor (TLR) 2 and TLR4 is pivotal in the beginning of post-ischemic inflammation. Some endogenous TLR ligands are released from injured brain cells, including high mobility group box 1 and peroxiredoxin family proteins, and activate the infiltrating macrophages and induce the expression of inflammatory cytokines. Following this step, T cells also infiltrate into the ischemic brain and mediate post-ischemic inflammation in the delayed phase. Various cytokines from helper T cells and γδT cells function as neurotoxic (IL-23/IL-17, IFN-γ) or neuroprotective (IL-10, IL-4) mediators. Novel neuroprotective strategies should therefore be developed through more detailed understanding of this process and the regulation of post-ischemic inflammation. © 2012 The Authors Journal of Neurochemistry © International Society for Neurochemistry.

Transient Ischemic Attack

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Transient Ischemic Attack TIA , or transient ischemic attack, is a "mini stroke" that occurs when a blood ... The only difference between a stroke and TIA is that with TIA the blockage is transient (temporary). ...

Population-based case-control study of white matter changes on brain imaging in transient ischemic attack and ischemic stroke.

PubMed

Li, Linxin; Simoni, Michela; Küker, Wilhelm; Schulz, Ursula G; Christie, Sharon; Wilcock, Gordon K; Rothwell, Peter M

2013-11-01

White matter changes (WMC) are a common finding on brain imaging and are associated with an increased risk of ischemic stroke. They are most frequent in small vessel stroke; however, in the absence of comparisons with normal controls, it is uncertain whether WMC are also more frequent than expected in other stroke subtypes. Therefore, we compared WMC in pathogenic subtypes of ischemic stroke versus controls in a population-based study. We evaluated the presence and severity of WMC on computed tomography and on magnetic resonance brain imaging using modified Blennow/Fazekas scale and age-related white matter changes scale, respectively, in a population-based study of patients with incident transient ischemic attack or ischemic stroke (Oxford Vascular Study) and in a study of local controls (Oxford Project to Investigate Memory and Ageing) without history of transient ischemic attack or ischemic stroke, with stratification by stroke pathogenesis (Trial of Org10172 in Acute Stroke Treatment classification). Among 1601 consecutive eligible patients with first-ever ischemic events, 1453 patients had computed tomography brain imaging, 562 had magnetic resonance imaging, and 414 patients had both. Compared with 313 controls (all with computed tomography and 131 with magnetic resonance imaging) and after adjustment for age, sex, diabetes mellitus, and hypertension, moderate/severe WMC (age-related white matter changes scale) were more frequent in patients with small vessel events (odds ratio, 3.51 [95% confidence interval, 2.13-5.76]; P<0.0001) but not in large artery (odds ratio, 1.03 [95% confidence interval, 0.64-1.67]), cardioembolic (odds ratio, 0.87 [95% confidence interval, 0.56-1.34]), or undetermined (odds ratio, 0.90 [95% confidence interval, 0.62-1.30]) subtypes. Results were consistent for ischemic stroke and transient ischemic attack, for other scales, and for magnetic resonance imaging and computed tomography separately. In contrast to small vessel ischemic events, WMC were not independently associated with other pathogenic subtypes, suggesting that WMC are unlikely to be an independent risk factor for nonsmall vessel events.

Usefulness of cardiometabolic index for the estimation of ischemic stroke risk among general population in rural China.

PubMed

Wang, Haoyu; Chen, Yintao; Guo, Xiaofan; Chang, Ye; Sun, Yingxian

2017-11-01

Cardiometabolic index (CMI) has been recognized as a novel and practical marker for the assessment of cardiometabolic risk as it is independently related to diabetes and atherosclerotic progression. This study tested the hypothesis that CMI represents a risk of ischemic stroke in a general population of rural China. From July 2012 to August 2013, we examined data from a large cross-sectional study of 11,345 participants (mean age 53.8 years; 60.8% females) who underwent biochemical determinations and anthropometric measurements in rural areas of northeast China. Ischemic stroke was documented as a history of cerebrovascular events and verified by medical record review. The prevalence of ischemic stroke was given to 3.1% of females and 3.2% of males. The cardio-metabolic profile was notably more adverse in ischemic stroke groups, irrespective of gender. A dose-response manner was detected for the prevalence of ischemic stroke, exhibiting a significant increase from the lowest to the highest quartiles of CMI (1.2% to 6.4% in females, P for trend<0.001; 2.3% to 4.3% in males, P for trend = 0.017). In multivariable analysis, for every 1 SD increment in CMI, the probability of ischemic stroke increased by 18% in females and 14% in males, respectively. The odds ratios for ischemic stroke comparing the top versus bottom quartiles of CMI were 2.047 (95%CI: 1.168-3.587) for females and 1.722 (95%CI: 1.019-2.910) for males. According to the area under receiver operating characteristic (AUC), the discrimination power of CMI in predicting ischemic stroke was relatively higher for females (AUC: 0.685) than males (AUC: 0.573). The strong and independent association of CMI with ischemic stroke in females, in comparison with the much lesser degree in males, provides further insight to better stratify by sex in investigations of ischemic stroke and solidly corroborates the potential role of ischemic stroke prevention targeted at CMI.

The Central Bright Spot Sign: A Potential New MR Imaging Sign for the Early Diagnosis of Anterior Ischemic Optic Neuropathy due to Giant Cell Arteritis.

PubMed

Remond, P; Attyé, A; Lecler, A; Lamalle, L; Boudiaf, N; Aptel, F; Krainik, A; Chiquet, C

2017-07-01

A rapid identification of the etiology of anterior ischemic optic neuropathy is crucial because it determines therapeutic management. Our aim was to assess MR imaging to study the optic nerve head in patients referred with anterior ischemic optic neuropathy, due to either giant cell arteritis or the nonarteritic form of the disease, compared with healthy subjects. Fifteen patients with giant cell arteritis-related anterior ischemic optic neuropathy and 15 patients with nonarteritic anterior ischemic optic neuropathy from 2 medical centers were prospectively included in our study between August 2015 and May 2016. Fifteen healthy subjects and patients had undergone contrast-enhanced, flow-compensated, 3D T1-weighted MR imaging. The bright spot sign was defined as optic nerve head enhancement with a 3-grade ranking system. Two radiologists and 1 ophthalmologist independently performed blinded evaluations of MR imaging sequences with this scale. Statistical analysis included interobserver agreement. MR imaging scores were significantly higher in patients with giant cell arteritis-related anterior ischemic optic neuropathy than in patients with nonarteritic anterior ischemic optic neuropathy ( P ≤ .05). All patients with giant cell arteritis-related anterior ischemic optic neuropathy (15/15) and 7/15 patients with nonarteritic anterior ischemic optic neuropathy presented with the bright spot sign. No healthy subjects exhibited enhancement of the anterior part of the optic nerve. There was a significant relationship between the side of the bright spot and the side of the anterior ischemic optic neuropathy ( P ≤ .001). Interreader agreement was good for observers (κ = 0.815). Here, we provide evidence of a new MR imaging sign that identifies the acute stage of giant cell arteritis-related anterior ischemic optic neuropathy; patients without this central bright spot sign always had a nonarteritic pathophysiology and therefore did not require emergency corticosteroid therapy. © 2017 by American Journal of Neuroradiology.

One-year atherothrombotic vascular events rates in outpatients with recent non-cardioembolic ischemic stroke: the EVEREST (Effective Vascular Event REduction after STroke) registry.

PubMed

Suzuki, Norihiro; Sato, Motoki; Houkin, Kiyohiro; Terayama, Yasuo; Uchiyama, Shinichiro; Daida, Hiroyuki; Shigematsu, Hiroshi; Goto, Shinya; Tanaka, Kortaro; Origasa, Hideki; Miyamoto, Susumu; Minematsu, Kazuo; Matsumoto, Masayasu; Okada, Yasushi

2012-05-01

Patients with recent ischemic stroke may have higher risk of atherothrombosis than stable patients with established vascular events. Our aims were to investigate 1-year atherothrombotic vascular event rates and to assess the risk factors for recurrent ischemic stroke in this population. This prospective cohort study was conducted between January 2007 and July 2009 at 313 hospitals in Japan. Outpatients who were at least 45 years of age and who had received oral antiplatelet therapy were enrolled within 2 weeks to 6 months from the last onset of noncardioembolic ischemic stroke. At 12 ± 3 months after enrollment, data on presence/absence of atherothrombotic vascular events were collected. The primary endpoint was the occurrence of fatal or nonfatal ischemic stroke. A total of 3452 patients were enrolled, and 3411 patients who had baseline data were included in the analysis. The 1-year event rate was 3.81% (95% confidence interval 3.15-4.48%) for fatal or nonfatal ischemic stroke and 0.84% (95% confidence interval 0.52-1.15%) for all-cause mortality. The annual rate of recurrent ischemic stroke was significantly higher in patients who had ischemic stroke at least twice than in patients who had first-ever ischemic stroke (5.02% vs 3.59%; P = .0313). In the multivariable Cox regression analysis, recurrent ischemic stroke was significantly associated with age (P = .0033), the presence of diabetes (P = .0129), and waist circumference ≥80 cm (P = .0056). Patients with recent ischemic stroke have a higher risk of stroke recurrence than stable patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) registry even though they received antiplatelet therapy. The rigorous management of risk factors is needed. Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.

PPARG gene C161T CT/TT associated with lower blood lipid levels and ischemic stroke from large-artery atherosclerosis in a Han population in Guangdong.

PubMed

Wei, Wei-Min; Wu, Xiao-Yan; Li, Shu-Ting; Shen, QingYu

2016-07-01

Peroxisome proliferator-activated receptor gamma (PPARG) is a transcription factor involved in atherosclerosis and related diseases. In this study, we aimed to investigate whether PPARG C161T was associated with lipid levels and large-artery atherosclerosis (LAA) ischemic stroke in a Han Chinese population in Guangdong province. The genotype PPARG C161T in 149 LAA ischemic stroke patients and 125 healthy controls was examined by polymerase chain reaction-restriction fragment length polymorphism (RFLP) assay. Associations with LAA ischemic stroke were analyzed for PPARG C161T genotype, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), and a logistic regression analysis was performed to identify risk factors for LAA ischemic stroke. The frequency of CC was higher than that of CT + TT and was significantly associated with LAA ischemic stroke. In both the LAA and control groups, TC and LDL-C levels were significantly higher in the CC type than the CT + TT, but TG and HDL-C levels were comparable. The only verified independent risk factors for LAA ischemic stroke were ischemic heart disease (OR: 2.784, 95% CI: 1.377-5.632; p = 0.004) and systolic blood pressure (OR: 1.014, 95% CI: 1.001-1.026; p = 0.029); the PPARG C161T allele was not independently associated with an increased risk of LAA ischemic stroke (OR = 0.697, 95% CI: 0.372-1.305; p = 0.260). In this Han population, PPARG C161T CT/TT was associated with LAA ischemic stroke and lower levels of blood TC and LDL-C, but was not an independent risk factor for LAA ischemic stroke.

Whole Grain Consumption and Risk of Ischemic Stroke: Results From 2 Prospective Cohort Studies.

PubMed

Juan, Juan; Liu, Gang; Willett, Walter C; Hu, Frank B; Rexrode, Kathryn M; Sun, Qi

2017-12-01

Higher intake of whole grains may exert cardiometabolic benefits, although findings on stroke risk are inconclusive. The potentially differential effects of individual whole grain foods on ischemic stroke have not been examined. We analyzed whole grain consumption in relation to ischemic stroke among 71 750 women from the Nurses' Health Study and 42 823 men from the Health Professionals Follow-up Study who were free of cardiovascular disease, diabetes mellitus, and cancer at baseline (1984 and 1986, respectively) through 2010 using a Cox proportional hazards model. Validated semiquantitative food frequency questionnaires were used to assess consumption of whole grain intake, including whole grain cold breakfast cereal, dark bread, oatmeal, brown rice, popcorn, bran, and germ. Self-reported incident cases of ischemic stroke were confirmed through medical record review. During 2 820 128 person-years of follow-up in the 2 cohorts, 2458 cases of ischemic stroke were identified and confirmed. Intake of total whole grains was not associated with risk of ischemic stroke after adjustment for covariates: the pooled hazard ratio (95% confidence interval) comparing extreme intake levels was 1.04 (0.91-1.19). However, intake of whole grain cold breakfast cereal and total bran was inversely associated with ischemic stroke after multivariate adjustment: the pooled hazard ratios (95% confidence intervals) were 0.88 (0.80-0.96; P trend =0.008) and 0.89 (0.79-1.00; P trend =0.004), respectively. Other whole grain foods were not associated with a lower risk of ischemic stroke. Although overall consumption of whole grains was not associated with lower risk of ischemic stroke, greater consumption of whole grain cold breakfast cereal and bran was significantly associated with a lower risk of ischemic stroke. More studies are needed to replicate these associations between individual whole grain foods and risk of ischemic stroke among other populations. © 2017 American Heart Association, Inc.

Neurology Concepts: Young Women and Ischemic Stroke-Evaluation and Management in the Emergency Department.

PubMed

Chang, Bernard P; Wira, Charles; Miller, Joseph; Akhter, Murtaza; Barth, Bradley E; Willey, Joshua; Nentwich, Lauren; Madsen, Tracy

2018-01-01

Ischemic stroke is a leading cause of morbidity and mortality worldwide. While the incidence of ischemic stroke is highest in older populations, incidence of ischemic stroke in adults has been rising particularly rapidly among young (e.g., premenopausal) women. The evaluation and timely diagnosis of ischemic stroke in young women presents a challenging situation in the emergency department, due to a range of sex-specific risk factors and to broad differentials. The goals of this concepts paper are to summarize existing knowledge regarding the evaluation and management of young women with ischemic stroke in the acute setting. A panel of six board-certified emergency physicians, one with fellowship training in stroke and one with training in sex- and sex-based medicine, along with one vascular neurologist were coauthors involved in the paper. Each author used various search strategies (e.g., PubMed, PsycINFO, and Google Scholar) for primary research and reviewed articles related to their section. The references were reviewed and evaluated for relevancy and included based on review by the lead authors. Estimates on the incidence of ischemic stroke in premenopausal women range from 3.65 to 8.9 per 100,000 in the United States. Several risk factors for ischemic stroke exist for young women including oral contraceptive (OCP) use and migraine with aura. Pregnancy and the postpartum period (up to 12 weeks) is also an important transient state during which risks for both ischemic stroke and cerebral hemorrhage are elevated, accounting for 18% of strokes in women under 35. Current evidence regarding the management of acute ischemic stroke in young women is also summarized including use of thrombolytic agents (e.g., tissue plasminogen activator) in both pregnant and nonpregnant individuals. Unique challenges exist in the evaluation and diagnosis of ischemic stroke in young women. There are still many opportunities for future research aimed at improving detection and treatment of this population. © 2017 by the Society for Academic Emergency Medicine.

Left ventricular hypertrophy: a comparison among Kurdish patients with first-ever ischemic versus first-ever hemorrhagic stroke.

PubMed

Amin, Osama Shukir Muhammed

2013-01-01

Left ventricular hypertrophy (LVH) has been proposed to be associated with an increased risk of stroke. We compared the prevalence of LVH among patients with first-ever ischemic versus first-ever hemorrhagic strokes. This observational study, which was conducted at the Sulaimaniya general teaching hospital from November 2009 to March 2012, involved 100 consecutive patients with their first-ever stroke. Fifty patients had ischemic stroke while the rest (n = 50) developed hemorrhagic stroke. The presence of LVH was detected using transthoracic echocardiography and a comparison with respect to its prevalence between the 2 aforementioned groups was made. The mean age of patients in the hemorrhagic group was 61.7 +/- SD 11.2 years while in the ischemic group it was 63.9 +/- SD 6.1 years. Out of 100 patients, 66 (66%) patients were males (31 in the hemorrhagic group and 35 in the ischemic group) while the rest (n = 34; 34%) were females (19 in the hemorrhagic group and 15 in the ischemic one). Ninety one (91%) patients were hypertensive (47 in the hemorrhagic group and 34 in the ischemic group). Fifty three (53%) out of 100 patients demonstrated LVH (31 in the hemorrhagic group and 22 in the ischemic group). A head-to-head comparison between the two groups with respect to gender demonstrated no statistically significant difference in terms of the presence of LVH among patients with hemorrhagic versus ischemic strokes; males (P value < 0.26; 95% CI 3.4-39.3); females (P value < 0.43; 95% CI 16.7-43.8). However, a univariate analysis after correction for age and gender revealed a statistically significant difference between these groups (P-value < 0.001; 95% CI 2.7-46.2). LVH was more common in Kurdish patients with first-ever hemorrhagic stroke than in those who had sustained their first-ever ischemic stroke. Further analytic studies are required to clarify the prevalence of LVH in patients with ischemic 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.

Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study.

PubMed

Saber, Hamidreza; Himali, Jayandra J; Beiser, Alexa S; Shoamanesh, Ashkan; Pikula, Aleksandra; Roubenoff, Ronenn; Romero, Jose R; Kase, Carlos S; Vasan, Ramachandran S; Seshadri, Sudha

2017-07-01

Low insulin-like growth factor 1 (IGF-1) has been associated with increased risk of atherosclerosis and atrial fibrillation in cross-sectional studies. Yet, prospective data linking IGF-1 levels to the development of ischemic stroke remain inconclusive. We examined prospectively the association between serum IGF-1 levels and incident ischemic stroke. We measured serum IGF-1 levels in 757 elderly individuals (mean age 79±5, 62% women), free of prevalent stroke, from the Framingham original cohort participants at the 22nd examination cycle (1990-1994) and were followed up for the development of ischemic stroke. Cox models were used to relate IGF-1 levels to the risk for incident ischemic stroke, adjusted for potential confounders. During a mean follow-up of 10.2 years, 99 individuals developed ischemic stroke. After adjustment for age, sex, and potential confounders, higher IGF-1 levels were associated with a lower risk of incident ischemic stroke, with subjects in the lowest quintile of IGF-1 levels having a 2.3-fold higher risk of incident ischemic stroke (95% confidence interval, 1.09-5.06; P =0.03) as compared with those in the top quintile. We observed an effect modification by diabetes mellitus and waist-hip ratio for the association between IGF-1 and ischemic stroke ( P <0.1). In subgroup analyses, the effects were restricted to subjects with diabetics and those in top waist-hip ratio quartile, in whom each standard deviation increase in IGF-1 was associated with a 61% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P =0.007) and 41% (hazard ratio, 0.59; 95% confidence interval, 0.37-0.95; P =0.031) lower risk of incident ischemic stroke, respectively. IGF-1 levels were inversely associated with ischemic stroke, especially among persons with insulin resistance. © 2017 American Heart Association, Inc.

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

PubMed

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

2017-07-01

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

Long-term outcome of vertebral artery origin stenosis in patients with acute ischemic stroke

PubMed Central

2013-01-01

Background Vertebral artery origin (VAO) stenosis is occasionally observed in patients who have acute ischemic stroke. We investigated the long-term outcomes and clinical significance of VAO stenosis in patients with acute ischemic stroke. Methods We performed a prospective observational study using a single stroke center registry to investigate the risk of recurrent stroke and vascular outcomes in patients with acute ischemic stroke and VAO stenosis. To relate the clinical significance of VAO stenosis to the vascular territory of the index stroke, patients were classified into an asymptomatic VAO stenosis group and a symptomatic VAO stenosis group. Results Of the 774 patients who had acute ischemic stroke, 149 (19.3%) of them had more than 50% stenosis of the VAO. During 309 patient-years of follow-up (mean, 2.3 years), there were 7 ischemic strokes, 6 hemorrhagic strokes, and 2 unknown strokes. The annual event rates were 0.97% for posterior circulation ischemic stroke, 4.86% for all stroke, and 6.80% for the composite cardiovascular outcome. The annual event rate for ischemic stroke in the posterior circulation was significantly higher in patients who had symptomatic VAO stenosis than in patients who had asymptomatic stenosis (1.88% vs. 0%, p = 0.046). In a multivariate analysis, the hazard ratio, per one point increase of the Essen Stroke Risk Score (ESRS) for the composite cardiovascular outcome, was 1.46 (95% CI, 1.02-2.08, p = 0.036). Conclusions Long-term outcomes of more than 50% stenosis of the VAO in patients with acute ischemic stroke were generally favorable. Additionally, ESRS was a predictor for the composite cardiovascular outcome. Asymptomatic VAO stenosis may not be a specific risk factor for recurrent ischemic stroke in the posterior circulation. However, VAO stenosis may require more clinical attention as a potential source of recurrent stroke when VAO stenosis is observed in patients who have concurrent ischemic stroke in the posterior circulation. PMID:24215371

Is the long-term prognosis of transient ischemic attack or minor ischemic stroke affected by the occurrence of nonfocal symptoms?

PubMed

Compter, Annette; van der Worp, H Bart; van Gijn, Jan; Kappelle, L Jaap; Koudstaal, Peter J; Algra, Ale

2014-05-01

In patients with a transient ischemic attack or ischemic stroke, nonfocal neurological symptoms, such as confusion and nonrotatory dizziness, may be associated with a higher risk of vascular events. We assessed the relationship between nonfocal symptoms and the long-term risk of vascular events or death in patients with a transient ischemic attack or minor ischemic stroke. We related initial symptoms with outcome events in 2409 patients with a transient ischemic attack (n=723) or minor ischemic stroke (n=1686), included in the Life Long After Cerebral ischemia cohort. All patients underwent a standardized interview on the occurrence of focal and nonfocal neurological symptoms during the qualifying event. The primary outcome was the composite of any stroke, myocardial infarction, or vascular death. Secondary outcomes were all-cause death, vascular death, cardiac death, myocardial infarction, and stroke. Hazard ratios were calculated with Cox regression. Focal symptoms were accompanied by nonfocal symptoms in 739 (31%) patients. During a mean follow-up of 10.1 years, the primary outcome occurred in 1313 (55%) patients. There was no difference in the risk of the primary outcome between patients with both focal and nonfocal symptoms and patients with focal symptoms alone (adjusted hazard ratio, 0.97; 95% confidence interval, 0.86-1.09; P=0.60). The risk of each of the secondary outcomes was also similar in both groups. About one third of the patients with a transient ischemic attack or minor ischemic stroke has both focal and nonfocal neurological symptoms. Nonfocal symptoms are not associated with an increased long-term risk of vascular events or death. This trial was not registered because enrollment began before July 1, 2005.

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.

Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.

PubMed

Gurbel, Paul A; Antonino, Mark J; Bliden, Kevin P; Dichiara, Joseph; Suarez, Thomas A; Singla, Anand; Tantry, Udaya S

2008-12-01

Platelets play a central role in the genesis of post-percutaneous coronary intervention (PCI) ischemic events. High post-procedural platelet reactivity to adenosine diphosphate (HPR(ADP)) may be a risk factor for ischemic events after PCI. The study was designed to evaluate a cutpoint of platelet reactivity that is associated with the occurrence of ischemic events after PCI. Post-procedural platelet reactivity to ADP was measured by conventional aggregometry in 297 consecutive patients undergoing non-emergent PCI. Patients were prospectively followed for up to 2 years for post-discharge ischemic events. All patients had received clopidogrel and aspirin therapy at the time of aggregation measurements. Eighty-one patients (27%) suffered ischemic events. Patients with ischemic events had higher 5 microM ADP-induced platelet aggregation (46 +/- 14% vs. 30 +/- 17%, p < 0.001) and 20 microM ADP-induced platelet aggregation (60 +/- 13% vs. 43 +/- 19%, p < 0.001) compared to patients without ischemic events. Using a combined receiver operator curve analysis, cutpoints of >46% aggregation following 5 microM ADP stimulation and >59% aggregation following 20 microM ADP stimulation (HPR(ADP)) were associated with 58 and 54% of ischemic events, respectively. Multivariate Cox regression demonstrated a significant relation between event occurrence and post-procedural HPR(ADP) cutpoints (5 microM ADP, OR=3.9, and 20 microM ADP, OR=3.8, p < 0.001 for both). High post-procedural platelet reactivity to ADP is an independent risk factor for ischemic events within 2 years of non-emergent PCI. These data support a potential therapeutic target for antiplatelet therapy based on the results of an ex vivo platelet function test. The study is a step towards a personalized medicine approach to guide the intensity of antiplatelet therapy.

Self-perceived psychological stress and ischemic stroke: a case-control study

PubMed Central

Jood, Katarina; Redfors, Petra; Rosengren, Annika; Blomstrand, Christian; Jern, Christina

2009-01-01

Background A growing body of evidence suggests that psychological stress contributes to coronary artery disease. However, associations between stress and stroke are less clear. In this study, we investigated the possible association between ischemic stroke and self-perceived psychological stress, as measured by a single-item questionnaire, previously reported to be associated with myocardial infarction. Methods In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 consecutive patients with acute ischemic stroke (aged 18 to 69 years) and 600 age-matched and sex-matched population controls were recruited. Ischemic stroke subtype was determined according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Self-perceived psychological stress preceding stroke was assessed retrospectively using a single-item questionnaire. Results Permanent self-perceived psychological stress during the last year or longer was independently associated with overall ischemic stroke (multivariate adjusted odds ratio (OR) 3.49, 95% confidence interval (CI) 2.06 to 5.93). Analyses by stroke subtype showed that this association was present for large vessel disease (OR 3.91, 95% CI 1.58 to 9.67), small vessel disease (OR 3.20, 95% CI 1.64 to 6.24), and cryptogenic stroke (OR 4.03, 95% CI 2.34 to 6.95), but not for cardioembolic stroke (OR 1.48, 95% CI 0.64 to 3.39). Conclusion In this case-control study, we found an independent association between self-perceived psychological stress and ischemic stroke. A novel finding was that this association differed by ischemic stroke subtype. Our results emphasize the need for further prospective studies addressing the potential role for psychological stress as a risk factor for ischemic stroke. In such studies ischemic stroke subtypes should be taken into consideration. PMID:19796376

Hyperglycemia and diabetes have different impacts on outcome of ischemic and hemorrhagic stroke.

PubMed

Snarska, Katarzyna K; Bachórzewska-Gajewska, Hanna; Kapica-Topczewska, Katarzyna; Drozdowski, Wiesław; Chorąży, Monika; Kułakowska, Alina; Małyszko, Jolanta

2017-02-01

Stroke is the second leading cause of long-term disability and death worldwide. Diabetes and hyperglycemia may impact the outcome of stroke. We examined the impact of hyperglycemia and diabetes on in-hospital death among ischemic and hemorrhagic stroke patients. Data from 766 consecutive patients with ischemic (83.15%) and hemorrhagic stroke were analyzed. Patients were classified into four groups: ischemic and diabetic; ischemic and non-diabetic; hemorrhagic and diabetic; and hemorrhagic and non-diabetic. Serum glucose was measured on admission at the emergency department together with biochemical and clinical parameters. Mean admission glucose in ischemic stroke patients with diabetes was higher than in non-diabetic ones ( p < 0.001) and in hemorrhagic stroke patients with diabetes than in those without diabetes ( p < 0.05). Mean admission glucose in all patients who died was significantly higher than in patients who survived. In multivariate analysis, the risk factors for outcome in patients with ischemic stroke and without diabetes were age, admission glucose level and estimated glomerular filtration rate (eGFR), while in diabetics they were female gender, admission glucose level, and eGFR; in patients with hemorrhagic stroke and without diabetes they were age and admission glucose levels. The cut-off value in predicting death in patients with ischemic stroke and without diabetes was above 113.5 mg/dl, while in diabetics it was above 210.5 mg/dl. Hyperglycemia on admission is associated with worsened clinical outcome and increased risk of in-hospital death in ischemic and hemorrhagic stroke patients. Diabetes increased the risk of in-hospital death in hemorrhagic stroke patients, but not in ischemic ones.

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.

Greater Cincinnati/Northern Kentucky Stroke Study: volume of first-ever ischemic stroke among blacks in a population-based study.

PubMed

Kissela, B; Broderick, J; Woo, D; Kothari, R; Miller, R; Khoury, J; Brott, T; Pancioli, A; Jauch, E; Gebel, J; Shukla, R; Alwell, K; Tomsick, T

2001-06-01

The volume of ischemic stroke on CT scans has been studied in a standardized fashion in acute stroke therapy trials with median volumes between 10.5 to 55 cm(3). The volume of first-ever ischemic stroke in the population is not known. The first phase of the population-based Greater Cincinnati/Northern Kentucky Stroke Study identified all ischemic strokes occurring in blacks in the greater Cincinnati region between January and June of 1993. The patients in this phase of the study who had a first-ever ischemic clinical stroke were identified, and the volume of ischemic stroke was measured. There were 257 verified clinical cases of ischemic stroke, of which 181 had a first-ever ischemic infarct. Imaging was available for 150 of these patients, and 79 had an infarct on the CT or MRI study that was definitely or possibly related to the clinical symptoms. For these patients, volumetric measurements were performed by means of the modified ellipsoid method. The median volume of first-ever ischemic stroke for the 79 patients was 2.5 cm(3) (interquartile range, 0.5 to 8.8 cm(3)). There was a significant relation between location of lesion and infarct size (P<0.001) and between volume and mechanism of stroke (P=0.001). The volume of first-ever ischemic stroke among blacks in our population-based study is smaller than has been previously reported in acute stroke therapy trials. The large proportion of small, mild strokes in blacks may be an important reason for the low percentage of patients who meet the inclusion criteria for tissue plasminogen activator. Further study is necessary to see if these results are generalizable to a multiracial population.

Post-Ischemic Bowel Stricture: CT Features in Eight Cases

PubMed Central

Kim, Jin Sil; Hong, Seung-Mo; Park, Seong Ho; Lee, Jong Seok; Kim, Ah Young; Ha, Hyun Kwon

2017-01-01

Objective To investigate the characteristic radiologic features of post-ischemic stricture, which can then be implemented to differentiate that specific disease from other similar bowel diseases, with an emphasis on computed tomography (CT) features. Materials and Methods Eight patients with a diagnosis of ischemic bowel disease, who were also diagnosed with post-ischemic stricture on the basis of clinical or pathologic findings, were included. Detailed clinical data was collected from the available electronic medical records. Two radiologists retrospectively reviewed all CT images. Pathologic findings were also analyzed. Results The mean interval between the diagnosis of ischemic bowel disease and stricture formation was 57 days. The severity of ischemic bowel disease was variable. Most post-ischemic strictures developed in the ileum (n = 5), followed by the colon (n = 2) and then the jejunum (n = 1). All colonic strictures developed in the “watershed zone.” The pathologic features of post-ischemic stricture were deep ulceration, submucosal/subserosal fibrosis and chronic transmural inflammation. The mean length of the post-ischemic stricture was 7.4 cm. All patients in this study possessed one single stricture. On contrast-enhanced CT, most strictures possessed concentric wall thickening (87.5%), with moderate enhancement (87.5%), mucosal enhancement (50%), or higher enhancement in portal phase than arterial phase (66.7%). Conclusion Post-ischemic strictures develop in the ileum, jejunum and colon after an interval of several weeks. In the colonic segment, strictures mainly occur in the “watershed zone.” Typical CT findings include a single area of concentric wall thickening of medium length (mean, 7.4 cm), with moderate and higher enhancement in portal phase and vasa recta prominence. PMID:29089826

TIA (Transient Ischemic Attack)

MedlinePlus

... a TIA . The symptoms are similar to an ischemic stroke, but TIA symptoms usually last less than five ... treated for a blockage-related stroke (called an ischemic stroke), between 7 and 40% report experiencing a TIA ...

Hospital costs of ischemic stroke and TIA in the Netherlands.

PubMed

Buisman, Leander R; Tan, Siok Swan; Nederkoorn, Paul J; Koudstaal, Peter J; Redekop, William K

2015-06-02

There have been no ischemic stroke costing studies since major improvements were implemented in stroke care. We therefore determined hospital resource use and costs of ischemic stroke and TIA in the Netherlands for 2012. We conducted a retrospective cost analysis using individual patient data from a national diagnosis-related group registry. We analyzed 4 subgroups: inpatient ischemic stroke, inpatient TIA, outpatient ischemic stroke, and outpatient TIA. Costs of carotid endarterectomy and costs of an extra follow-up visit were also estimated. Unit costs were based on reference prices from the Dutch Healthcare Insurance Board and tariffs provided by the Dutch Healthcare Authority. Linear regression analysis was used to examine the association between hospital costs and various patient and hospital characteristics. A total of 35,903 ischemic stroke and 21,653 TIA patients were included. Inpatient costs were €5,328 ($6,845) for ischemic stroke and €2,470 ($3,173) for TIA. Outpatient costs were €495 ($636) for ischemic stroke and €587 ($754) for TIA. Costs of carotid endarterectomy were €6,836 ($8,783). Costs of inpatient days were the largest contributor to hospital costs. Age, hospital type, and region were strongly associated with hospital costs. Hospital costs are higher for inpatients and ischemic strokes compared with outpatients and TIAs, with length of stay (LOS) the most important contributor. LOS and hospital costs have substantially declined over the last 10 years, possibly due to improved hospital stroke care and efficient integrated stroke services. © 2015 American Academy of Neurology.

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.

Discrimination of acute ischemic stroke from nonischemic vertigo in patients presenting with only imbalance.

PubMed

Honda, Shoji; Inatomi, Yuichiro; Yonehara, Toshiro; Hashimoto, Yoichiro; Hirano, Teruyuki; Ando, Yukio; Uchino, Makoto

2014-01-01

Some patients who present with an acute feeling of imbalance are experiencing an ischemic stroke that is not evident on computed tomography (CT) scans. The aim of this study was to compare ischemic stroke and nonischemic vertigo patient groups and to investigate independent factors associated with ischemic stroke. We examined 332 consecutive patients with an acute feeling of imbalance who showed no neurologic findings or responsible lesions on CT scan at the hyperacute phase. We examined their clinical backgrounds, physical findings, and laboratory examinations, with ischemic stroke diagnosed by later CT and/or magnetic resonance imaging (MRI). We identified 41 (12.3%) ischemic stroke patients. Atrial fibrillation (odds ratio 4.1; 95% confidence interval 1.4-11.5), white blood cell count (10(3)/μL, 1.4; 1.2-1.6), head and/or neck pain (4.6; 2.1-10.3), first attack of imbalance feeling (3.3; 1.1-12.2), and dizziness (3.7; 1.7-8.3) were significant and independent factors associated with ischemic stroke among patients with an acute feeling of imbalance. We used these factors to calculate an "imbalance score"; 1 point was given for the presence of each factor and a score of 3-5 points was independently associated with ischemic stroke. An awareness of these factors may indicate that further examinations including MRI are necessary to rule out ischemic stroke. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Sensitivity and Specificity of an Adult Stroke Screening Tool in Childhood Ischemic Stroke.

PubMed

Neville, Kerri; Lo, Warren

2016-05-01

There are frequent delays in the diagnosis of acute pediatric ischemic stroke. A screening tool that could increase the suspicion of acute ischemic stroke could aid early recognition and might improve initial care. An earlier study reported that children with acute ischemic stroke have signs that can be recognized with two adult stroke scales. We tested the hypothesis that an adult stroke scale could distinguish children with acute ischemic stroke from children with acute focal neurological deficits not due to stroke. We retrospectively applied an adult stroke scale to the recorded examinations of 53 children with acute symptomatic acute ischemic stroke and 53 age-matched control subjects who presented with focal neurological deficits. We examined the sensitivity and specificity of the stroke scale and the occurrence of acute seizures as predictors of stroke status. The total stroke scale did not differentiate children with acute ischemic stroke from those who had acute deficits from nonstroke causes; however, the presence of arm weakness was significantly associated with stroke cases. Acute seizures were significantly associated with stroke cases. An adult stroke scale is not sensitive or specific to distinguish children with acute ischemic stroke from those with nonstroke focal neurological deficits. The development of a pediatric acute ischemic stroke screening tool should include arm weakness and perhaps acute seizures as core elements. Such a scale must account for the limitations of language in young or intellectually disabled children. Copyright © 2016 Elsevier Inc. All rights reserved.

Ischemic necrosis of the tongue in surgical patients with septic shock: a case report.

PubMed

Cho, Jinbeom; Sung, Kiyoung; Lee, Dosang

2016-07-19

As the tongue is a well-vascularized organ, ischemic necrosis of the tongue is a rare disease entity. Critically ill patients with profound shock may experience end-organ hypoperfusion, which might result in tongue necrosis. However, to our best knowledge, there are no reports regarding ischemic necrosis of the tongue in surgical patients with septic shock. Two patients recently developed ischemic necrosis of the tongue in our surgical intensive care unit. Both patients had undergone emergent surgery for ischemic enteritis and developed postoperative septic shock. The first patient responded to critical treatment with a short period of circulatory shock, and the delivered dose of the vasopressor seemed to be acceptable. In contrast, the second patient developed postoperative refractory shock, and high-dose vasopressor treatment was required to maintain adequate tissue perfusion. Both patients developed ischemic necrosis of the tongue and died shortly after its emergence, despite vigorous resuscitation. We suggest that ischemic necrosis of the tongue is an under-reported manifestation of any type of circulatory shock, which may have a complex pathogenic mechanism. Clinicians should be aware of the possibility of ischemic necrosis of the tongue in patients with circulatory shock, even if the patient exhibits clinical improvement, as this awareness may facilitate estimation of their prognosis and preparation for clinical deterioration.

Autonomic Nervous System and Stress to Predict Secondary Ischemic Events after Transient Ischemic Attack or Minor Stroke: Possible Implications of Heart Rate Variability.

PubMed

Guan, Ling; Collet, Jean-Paul; Mazowita, Garey; Claydon, Victoria E

2018-01-01

Transient ischemic attack (TIA) and minor stroke have high risks of recurrence and deterioration into severe ischemic strokes. Risk stratification of TIA and minor stroke is essential for early effective treatment. Traditional tools have only moderate predictive value, likely due to their inclusion of the limited number of stroke risk factors. Our review follows Hans Selye's fundamental work on stress theory and the progressive shift of the autonomic nervous system (ANS) from adaptation to disease when stress becomes chronic. We will first show that traditional risk factors and acute triggers of ischemic stroke are chronic and acute stress factors or "stressors," respectively. Our first review shows solid evidence of the relationship between chronic stress and stroke occurrence. The stress response is tightly regulated by the ANS whose function can be assessed with heart rate variability (HRV). Our second review demonstrates that stress-related risk factors of ischemic stroke are correlated with ANS dysfunction and impaired HRV. Our conclusions support the idea that HRV parameters may represent the combined effects of all body stressors that are risk factors for ischemic stroke and, thus, may be of important predictive value for the risk of subsequent ischemic events after TIA or minor stroke.

Autonomic Nervous System and Stress to Predict Secondary Ischemic Events after Transient Ischemic Attack or Minor Stroke: Possible Implications of Heart Rate Variability

PubMed Central

Guan, Ling; Collet, Jean-Paul; Mazowita, Garey; Claydon, Victoria E.

2018-01-01

Transient ischemic attack (TIA) and minor stroke have high risks of recurrence and deterioration into severe ischemic strokes. Risk stratification of TIA and minor stroke is essential for early effective treatment. Traditional tools have only moderate predictive value, likely due to their inclusion of the limited number of stroke risk factors. Our review follows Hans Selye’s fundamental work on stress theory and the progressive shift of the autonomic nervous system (ANS) from adaptation to disease when stress becomes chronic. We will first show that traditional risk factors and acute triggers of ischemic stroke are chronic and acute stress factors or “stressors,” respectively. Our first review shows solid evidence of the relationship between chronic stress and stroke occurrence. The stress response is tightly regulated by the ANS whose function can be assessed with heart rate variability (HRV). Our second review demonstrates that stress-related risk factors of ischemic stroke are correlated with ANS dysfunction and impaired HRV. Our conclusions support the idea that HRV parameters may represent the combined effects of all body stressors that are risk factors for ischemic stroke and, thus, may be of important predictive value for the risk of subsequent ischemic events after TIA or minor stroke. PMID:29556209

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

PubMed Central

Brines, Michael; Patel, Nimesh S. A.; Villa, Pia; Brines, Courtenay; Mennini, Tiziana; De Paola, Massimiliano; Erbayraktar, Zubeyde; Erbayraktar, Serhat; Sepodes, Bruno; Thiemermann, Christoph; Ghezzi, Pietro; Yamin, Michael; Hand, Carla C.; Xie, Qiao-wen; Coleman, Thomas; Cerami, Anthony

2008-01-01

Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the β common receptor. In the present work, we have delimited tissue-protective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58–82) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective in vitro and tissue protective in vivo in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia–reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic in vitro or in vivo. Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure. PMID:18676614

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin.

PubMed

Brines, Michael; Patel, Nimesh S A; Villa, Pia; Brines, Courtenay; Mennini, Tiziana; De Paola, Massimiliano; Erbayraktar, Zubeyde; Erbayraktar, Serhat; Sepodes, Bruno; Thiemermann, Christoph; Ghezzi, Pietro; Yamin, Michael; Hand, Carla C; Xie, Qiao-wen; Coleman, Thomas; Cerami, Anthony

2008-08-05

Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the beta common receptor. In the present work, we have delimited tissue-protective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58-82) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective in vitro and tissue protective in vivo in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia-reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic in vitro or in vivo. Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure.

Molecular simulations of diffusion in electrolytes

NASA Astrophysics Data System (ADS)

Wheeler, Dean Richard

This work demonstrates new methodologies for simulating multicomponent diffusion in concentrated solutions using molecular dynamics (MD). Experimental diffusion data for concentrated multicomponent solutions are often lacking, as are accurate methods of predicting diffusion for nonideal solutions. MD can be a viable means of understanding and predicting multicomponent diffusion. While there have been several prior reports of MD simulations of mutual diffusion, no satisfactory expressions for simulating Stefan-Maxwell diffusivities for an arbitrary number of species exist. The approaches developed here allow for the computation of a full diffusion matrix for any number of species in both nonequilibrium and equilibrium MD ensembles. Our nonequilibrium approach is based on the application of constant external fields to drive species diffusion. Our equilibrium approach uses a newly developed Green-Kubo formula for Stefan-Maxwell diffusivities. In addition, as part of this work, we demonstrate a widely applicable means of increasing the computational efficiency of the Ewald sum, a technique for handling long-range Coulombic interactions in simulations. The theoretical development is applicable to any solution which can be simulated using MD; nevertheless, our primary interest is in electrochemical applications. To this end, the methods are tested by simulations of aqueous salt solutions and lithium-battery electrolytes. KCl and NaCl aqueous solutions were simulated over the concentration range 1 to 4 molal. Intermolecular-potential models were parameterized for these transport-based simulations. This work is the first to simulate all three independent diffusion coefficients for aqueous NaCl and KCl solutions. The results show that the nonequilibrium and equilibrium methods are consistent with each other, and in moderate agreement with experiment. We simulate lithium-battery electrolytes containing LiPF6 in propylene carbonate and mixed ethylene carbonate-dimethyl carbonate solvents. As with the aqueous-solution work, potential parameters were generated for these molecules. These nonaqueous electrolytes demonstrate rich transport behavior, which the simulations are able to reproduce qualitatively. In a mixed-solvent simulation we regress all six independent transport coefficients. The simulations show that strong ion pairing is responsible for the increase in viscosity and maximum in conductivity as ion concentrations are increased.

Ischemic Stroke

MedlinePlus

A stroke is a medical emergency. There are two types - ischemic and hemorrhagic. Ischemic stroke is the most common type. It is usually ... are at risk for having a more serious stroke. Symptoms of stroke are Sudden numbness or weakness ...

Effect of alternate energy substrates on mammalian brain metabolism during ischemic events.

PubMed

Koppaka, S S; Puchowicz; LaManna, J C; Gatica, J E

2008-01-01

Regulation of brain metabolism and cerebral blood flow involves complex control systems with several interacting variables at both cellular and organ levels. Quantitative understanding of the spatially and temporally heterogeneous brain control mechanisms during internal and external stimuli requires the development and validation of a computational (mathematical) model of metabolic processes in brain. This paper describes a computational model of cellular metabolism in blood-perfused brain tissue, which considers the astrocyte-neuron lactate-shuttle (ANLS) hypothesis. The model structure consists of neurons, astrocytes, extra-cellular space, and a surrounding capillary network. Each cell is further compartmentalized into cytosol and mitochondria. Inter-compartment interaction is accounted in the form of passive and carrier-mediated transport. Our model was validated against experimental data reported by Crumrine and LaManna, who studied the effect of ischemia and its recovery on various intra-cellular tissue substrates under standard diet conditions. The effect of ketone bodies on brain metabolism was also examined under ischemic conditions following cardiac resuscitation through our model simulations. The influence of ketone bodies on lactate dynamics on mammalian brain following ischemia is studied incorporating experimental data.

Hyperhomocysteinemia in bilateral anterior ischemic optic neuropathy after conventional coronary artery bypass graft: a case report.

PubMed

Niro, A; Sborgia, G; Sborgia, A; Alessio, G

2018-01-17

The incidence of anterior ischemic optic neuropathy after coronary artery bypass graft procedures ranges from 1.3 to 0.25%. The mechanisms of anterior ischemic optic neuropathy after cardiovascular procedures remain undefined but many systemic and related-to-surgery risk factors could underlie anterior ischemic optic neuropathy. In this case, we report a rare presentation of a bilateral anterior ischemic optic neuropathy after coronary artery bypass graft and speculate on the preoperative hyperhomocysteinemia as an independent risk factor for anterior ischemic optic neuropathy. A 56-year-old white man, a tobacco smoker with type 2 diabetes and coronary artery disease, underwent a conventional coronary artery bypass graft with extracorporeal circulation. In spite of ongoing anti-aggregation, antithrombotic, and vasodilator therapy, 10 days after the surgery he complained of severe bilateral visual loss. Funduscopy and fluorescein angiography revealed a bilateral anterior ischemic optic neuropathy. Analysis of preoperative laboratory tests revealed hyperhomocysteinemia. Hyperhomocysteinemia could increase the risk of ocular vascular damage and bilateral ocular involvement in patients who have undergone conventional coronary artery bypass graft.

Toll-like Receptor 2: A Novel Therapeutic Target for Ischemic White Matter Injury and Oligodendrocyte Death

PubMed Central

Choi, Jun Young

2017-01-01

Despite paramount clinical significance of white matter stroke, there is a paucity of researches on the pathomechanism of ischemic white matter damage and accompanying oligodendrocyte (OL) death. Therefore, a large gap exists between clinical needs and laboratory researches in this disease entity. Recent works have started to elucidate cellular and molecular basis of white matter injury under ischemic stress. In this paper, we briefly introduce white matter stroke from a clinical point of view and review pathophysiology of ischemic white matter injury characterized by OL death and demyelination. We present a series of evidence that Toll-like receptor 2 (TLR2), one of the membranous pattern recognition receptors, plays a cell-autonomous protective role in ischemic OL death and ensuing demyelination. Moreover, we also discuss our recent findings that its endogenous ligand, high-mobility group box 1 (HMGB1), is released from dying OLs and exerts autocrine trophic effects on OLs and myelin sheath under ischemic condition. We propose that modulation of TLR2 and its endogenous ligand HMGB1 can be a novel therapeutic target for ischemic white matter disease. PMID:28912641

MRI Features in a Canine Model of Ischemic Stroke: Correlation between Lesion Volume and Neurobehavioral Status during the Subacute Stage

PubMed Central

Kang, Byeong-Teck; Jang, Dong-Pyo; Gu, Su-Hyun; Lee, Jong-Hwan; Jung, Dong-In; Lim, Chae-Young; Kim, Ha-Jung; Kim, Young-Bo; Kim, Hyung-Joong; Woo, Eung-Je; Cho, Zang-Hee; Park, Hee-Myung

2009-01-01

The purpose of this study was to evaluate the diagnostic value of magnetic resonance imaging (MRI) and assess the correlation between the volume of the ischemic lesion and neurobehavioral status during the subacute stage of ischemic stroke. Ischemic stroke was induced in 6 healthy laboratory beagles through permanent occlusion of the middle cerebral artery (MCAO). T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging, diffusion-weighted imaging (DWI), measurement of the apparent diffusion coefficient (ADC) ratio, and neurobehavioral evaluation were performed 3 times serially by using a 1.5-T MR system: before and 3 and 10 d after MCAO. Ischemic lesions demonstrated T2 hyperintensity, FLAIR hyperintensity, and DWI hyperintensity. The ADC ratio was decreased initially but then was increased at 10 d after MCAO. Ischemic lesion volumes on T2-weighted and FLAIR imaging were not significantly different from those on DWI. The lesion volume and neurobehavioral score showed strong correlation. Our results suggest that conventional MRI may be a reliable diagnostic tool during the subacute stage of canine ischemic stroke. PMID:19887030

Therapeutic Angiogenesis via Solar Cell-Facilitated Electrical Stimulation.

PubMed

Jeong, Gun-Jae; Oh, Jin Young; Kim, Yeon-Ju; Bhang, Suk Ho; Jang, Hyeon-Ki; Han, Jin; Yoon, Jeong-Kee; Kwon, Sang-Mo; Lee, Tae Il; Kim, Byung-Soo

2017-11-08

Cell therapy has been suggested as a treatment modality for ischemic diseases, but the poor survival and engraftment of implanted cells limit its therapeutic efficacy. To overcome such limitation, we used electrical stimulation (ES) derived from a wearable solar cell for inducing angiogenesis in ischemic tissue. ES enhanced the secretion of angiogenic growth factors and the migration of mesenchymal stem cells (MSCs), myoblasts, endothelial progenitor cells, and endothelial cells in vitro. In a mouse ischemic hindlimb model, ES generated by a solar cell and applied to the ischemic region promoted migration of MSCs toward the ischemic site and upregulated expression of angiogenic paracrine factors (vascular endothelial, basic fibroblast, and hepatocyte growth factors; and stromal cell-derived factor-1α). Importantly, solar cell-generated ES promoted the formation of capillaries and arterioles at the ischemic region, attenuated muscle necrosis and fibrosis, and eventually prevented loss of the ischemic limb. Solar cell ES therapy showed higher angiogenic efficacy than conventional MSC therapy. This study shows the feasibility of using solar cell ES as a novel treatment for therapeutic angiogenesis.

Ischemic brain injury in cerebral amyloid angiopathy

PubMed Central

van Veluw, Susanne J; Greenberg, Steven M

2016-01-01

Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA. PMID:25944592

Single lung transplantation from a brain-dead donor for a patient with idiopathic pulmonary fibrosis. A breakthrough after new legislation in Japan.

PubMed

Miyoshi, S; Minami, M; Ohta, M; Okumura, M; Takeda, S; Matsuda, H

2001-06-01

Two single lung transplants from a single cadaveric donor were successfully conducted at 2 institutions on March 29, 2000, the first such procedure in Japan under newly introduced legislation. Our patient was a 48-year-old woman with idiopathic pulmonary fibrosis who underwent left single-lung transplantation under cardiopulmonary support. The donor lung was preserved in 4 degrees C modified Euro-Collins solution. Total ischemic time was 5 hours and 37 minutes. The postoperative course was uneventful. The patient was discharged on postoperative day 62 with satisfactory respiratory function.

Dynamics of motion of a clot through an arterial bifurcation: a finite element analysis

NASA Astrophysics Data System (ADS)

Abolfazli, Ehsan; Fatouraee, Nasser; Vahidi, Bahman

2014-10-01

Although arterial embolism is important as a major cause of brain infarction, little information is available about the hemodynamic factors which govern the path emboli tend to follow. A method which predicts the trajectory of emboli in carotid arteries would be of a great value in understanding ischemic attack mechanisms and eventually devising hemodynamically optimal techniques for prevention of strokes. In this paper, computational models are presented to investigate the motion of a blood clot in a human carotid artery bifurcation. The governing equations for blood flow are the Navier-Stokes formulations. To achieve large structural movements, the arbitrary Lagrangian-Eulerian formulation (ALE) with an adaptive mesh method was employed for the fluid domain. The problem was solved by simultaneous solution of the fluid and the structure equations. In this paper, the phenomenon was simulated under laminar and Newtonian flow conditions. The measured stress-strain curve obtained from ultrasound elasticity imaging of the thrombus was set to a Sussman-Bathe material model representing embolus material properties. Shear stress magnitudes in the inner wall of the internal carotid artery (ICA) were measured. High magnitudes of wall shear stress (WSS) occurred in the areas in which the embolus and arterial are in contact with each other. Stress distribution in the embolus was also calculated and areas prone to rapture were identified. Effects of embolus size and embolus density on its motion velocity were investigated and it was observed that an increase in either embolus size or density led to a reduction in movement velocity of the embolus. Embolus trajectory and shear stress from a simulation of embolus movement in a three-dimensional model with patient-specific carotid artery bifurcation geometry are also presented.

Relative Frequencies of Arteritic and Nonarteritic Anterior Ischemic Optic Neuropathy in an Arab Population.

PubMed

Gruener, Anna M; Chang, Jessica R; Bosley, Thomas M; Al-Sadah, Zakeya M; Kum, Clarissa; McCulley, Timothy J

2017-12-01

To evaluate the relative frequencies of arteritic and nonarteritic anterior ischemic optic neuropathy (AION) in an Arab population and to compare and contrast these findings with known epidemiological data from Caucasian populations. A retrospective review of the medical records of all patients diagnosed with AION at the King Khaled Eye Specialist Hospital (KKESH) in Riyadh, Saudi Arabia, between 1997 and 2012. Of 171 patients with AION, 4 had biopsy-proven giant-cell arteritis (GCA). The relative frequencies of arteritic anterior ischemic optic neuropathy (AAION) and nonarteritic anterior ischemic optic neuropathy (NAION) in this Arab cohort were 2.3% and 97.7%, respectively. The relative frequencies of arteritic anterior ischemic optic neuropathy and nonarteritic anterior ischemic optic neuropathy differ between Arab and North American clinic-based populations, with giant-cell arteritis-related ischemia being much less frequent in Saudi Arabia.

εPKC confers acute tolerance to cerebral ischemic reperfusion injury

PubMed Central

Bright, Rachel; Sun, Guo-Hua; Yenari, Midori A.; Steinberg, Gary K.; Mochly-Rosen, Daria

2008-01-01

In response to mild ischemic stress, the brain elicits endogenous survival mechanisms to protect cells against a subsequent lethal ischemic stress, referred to as ischemic tolerance. The molecular signals that mediate this protection are thought to involve the expression and activation of multiple kinases, including protein kinase C (PKC). Here we demonstrate that εPKC mediates cerebral ischemic tolerance in vivo. Systemic delivery of ψεRACK, an εPKC-selective peptide activator, confers neuroprotection against a subsequent cerebral ischemic event when delivered immediately prior to stroke. In addition, activation of εPKC by ψεRACK treatment decreases vascular tone in vivo, as demonstrated by a reduction in microvascular cerebral blood flow. Here we demonstrate the role of acute and transient εPKC in early cerebral tolerance in vivo and suggest that extra-parenchymal mechanisms, such as vasoconstriction, may contribute to the conferred protection. PMID:18586397

Ischemic stroke and select adipose-derived and sex hormones: a review.

PubMed

Meadows, Kristy L

2018-06-06

Ischemic stroke is the fifth leading cause of death in the USA and is the leading cause of serious, long-term disability worldwide. The principle sex hormones (estrogen, progesterone, and testosterone), both endogenous and exogenous, have profound effects on various stroke outcomes and have become the focus of a number of studies evaluating risk factors and treatment options for ischemic stroke. In addition, the expression of other hormones that may influence stroke outcome, including select adipose-derived hormones (adiponectin, leptin, and ghrelin), can be regulated by sex hormones and are also the focus of several ischemic stroke studies. This review aims to summarize some of the preclinical and clinical studies investigating the principle sex hormones, as well as select adipose-derived hormones, as risk factors or potential treatments for ischemic stroke. In addition, the potential for relaxin, a lesser studied sex hormone, as a novel treatment option for ischemic stroke is explored.

Comparison of clinical signs and outcomes between dogs with presumptive ischemic myelopathy and dogs with acute noncompressive nucleus pulposus extrusion.

PubMed

Fenn, Joe; Drees, Randi; Volk, Holger A; De Decker, Steven

2016-10-01

OBJECTIVE To compare clinical signs and outcomes between dogs with presumptive ischemic myelopathy and dogs with presumptive acute noncompressive nucleus pulposus extrusion (ANNPE). DESIGN Retrospective study. ANIMALS 51 dogs with ischemic myelopathy and 42 dogs with ANNPE examined at 1 referral hospital. PROCEDURES Medical records and MRI sequences were reviewed for dogs with a presumptive antemortem diagnosis of ischemic myelopathy or ANNPE. Information regarding signalment, clinical signs at initial examination, and short-term outcome was retrospectively retrieved from patient records. Long-term outcome information was obtained by telephone communication with referring or primary-care veterinarians and owners. RESULTS Compared with the hospital population, English Staffordshire Bull Terriers and Border Collies were overrepresented in the ischemic myelopathy and ANNPE groups, respectively. Dogs with ANNPE were significantly older at disease onset and were more likely to have a history of vocalization at onset of clinical signs, have spinal hyperesthesia during initial examination, have a lesion at C1-C5 spinal cord segments, and be ambulatory at hospital discharge, compared with dogs with ischemic myelopathy. Dogs with ischemic myelopathy were more likely to have a lesion at L4-S3 spinal cord segments and have long-term fecal incontinence, compared with dogs with ANNPE. However, long-term quality of life and outcome did not differ between dogs with ischemic myelopathy and dogs with ANNPE. CONCLUSIONS AND CLINICAL RELEVANCE Results revealed differences in clinical signs at initial examination between dogs with ischemic myelopathy and dogs with ANNPE that may aid clinicians in differentiating the 2 conditions.

Reprint of "Decline in platelet count and long-term post-PCI ischemic events: implication of the intra-aortic balloon pump".

PubMed

Schiariti, Michele; Saladini, Patrizia; Cuturello, Domenico; Iannetta, Loredana; Torromeo, Concetta; Puddu, Paolo Emilio

2014-04-01

Thrombocytopenia (TC) following a percutaneous coronary intervention (PCI) has been associated not only with hemorrhagic, but also with ischemic outcomes. The purpose of this study was to re-examine the relationship of TC with ischemic events at a 1-year follow-up, and investigate the possible associations. We studied a real-world, unselected population of ischemic patients undergoing PCI, totaling 861 patients-year, and divided into two groups: with TC (delta platelet count ≥25% from baseline to post-PCI during the hospital admission) and without TC. Compared with patients without TC, patients with TC had a higher and earlier incidence of both hemorrhagic and ischemic events. In them, the use of intra-aortic balloon pump (IABP) was ten-fold higher. In Kaplan-Meier curves assessing the contribution of both TC and IABP to outcome, IABP was a univariate detrimental factor additive to the role of TC. In a forced Cox model, the relative decline (delta) in platelet count (p=0.05) and the use of IABP (p=0.0001) were both associated with ischemic outcomes. After excluding all patients with IABP, the delta platelet count was no longer significantly associated with ischemic outcomes (p=0.66). After excluding all patients with shock and all those who undergone thrombolysis, there was still a relationship (p=0.0042) between the delta platelet count and ischemic events. In this patient population the use of IABP, but not thrombocytopenia per se, is a possible primary cause of worse ischemic outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

Decline in platelet count and long-term post-PCI ischemic events: implication of the intra-aortic balloon pump.

PubMed

Schiariti, Michele; Saladini, Patrizia; Cuturello, Domenico; Iannetta, Loredana; Torromeo, Concetta; Puddu, Paolo Emilio

2014-01-01

Thrombocytopenia (TC) following a percutaneous coronary intervention (PCI) has been associated not only with hemorrhagic, but also with ischemic outcomes. The purpose of this study was to re-examine the relationship of TC with ischemic events at a 1-year follow-up, and investigate the possible associations. We studied a real-world, unselected population of ischemic patients undergoing PCI, totaling 861 patients-year, and divided into two groups: with TC (delta platelet count ≥25% from baseline to post-PCI during the hospital admission) and without TC. Compared with patients without TC, patients with TC had a higher and earlier incidence of both hemorrhagic and ischemic events. In them, the use of intra-aortic balloon pump (IABP) was ten-fold higher. In Kaplan-Meier curves assessing the contribution of both TC and IABP to outcome, IABP was a univariate detrimental factor additive to the role of TC. In a forced Cox model, the relative decline (delta) in platelet count (p=0.05) and the use of IABP (p=0.0001) were both associated with ischemic outcomes. After excluding all patients with IABP, the delta platelet count was no longer significantly associated with ischemic outcomes (p=0.66). After excluding all patients with shock and all those who undergone thrombolysis, there was still a relationship (p=0.0042) between the delta platelet count and ischemic events. In this patient population the use of IABP, but not thrombocytopenia per se, is a possible primary cause of worse ischemic outcomes. Copyright © 2013 Elsevier Inc. All rights reserved.

Cerebral Microbleeds and the Risk of Incident Ischemic Stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy).

PubMed

Puy, Laurent; De Guio, François; Godin, Ophélia; Duering, Marco; Dichgans, Martin; Chabriat, Hugues; Jouvent, Eric

2017-10-01

Cerebral microbleeds are associated with an increased risk of intracerebral hemorrhage. Recent data suggest that microbleeds may also predict the risk of incident ischemic stroke. However, these results were observed in elderly individuals undertaking various medications and for whom causes of microbleeds and ischemic stroke may differ. We aimed to test the relationship between the presence of microbleeds and incident stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)-a severe monogenic small vessel disease known to be responsible for both highly prevalent microbleeds and a high incidence of ischemic stroke in young patients. We assessed microbleeds on baseline MRI in all 378 patients from the Paris-Munich cohort study. Incident ischemic strokes were recorded during 54 months. Survival analyses were used to test the relationship between microbleeds and incident ischemic stroke. Three hundred sixty-nine patients (mean age, 51.4±11.4 years) were followed-up during a median time of 39 months (interquartile range, 19 months). The risk of incident ischemic stroke was higher in patients with microbleeds than in patients without (35.8% versus 19.6%, hazard ratio, 1.87; 95% confidence interval, 1.16-3.01; P =0.009). These results persisted after adjustment for history of ischemic stroke, age, sex, vascular risk factors, and antiplatelet agents use (hazard ratio, 1.89; 95% confidence interval, 1.10-3.26; P =0.02). The presence of microbleeds is an independent risk marker of incident ischemic stroke in CADASIL, emphasizing the need to carefully interpret MRI data. © 2017 American Heart Association, Inc.

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.

Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12.

PubMed

Kilarski, Laura L; Achterberg, Sefanja; Devan, William J; Traylor, Matthew; Malik, Rainer; Lindgren, Arne; Pare, Guillame; Sharma, Pankaj; Slowik, Agniesczka; Thijs, Vincent; Walters, Matthew; Worrall, Bradford B; Sale, Michele M; Algra, Ale; Kappelle, L Jaap; Wijmenga, Cisca; Norrving, Bo; Sandling, Johanna K; Rönnblom, Lars; Goris, An; Franke, Andre; Sudlow, Cathie; Rothwell, Peter M; Levi, Christopher; Holliday, Elizabeth G; Fornage, Myriam; Psaty, Bruce; Gretarsdottir, Solveig; Thorsteinsdottir, Unnar; Seshadri, Sudha; Mitchell, Braxton D; Kittner, Steven; Clarke, Robert; Hopewell, Jemma C; Bis, Joshua C; Boncoraglio, Giorgio B; Meschia, James; Ikram, M Arfan; Hansen, Bjorn M; Montaner, Joan; Thorleifsson, Gudmar; Stefanson, Kari; Rosand, Jonathan; de Bakker, Paul I W; Farrall, Martin; Dichgans, Martin; Markus, Hugh S; Bevan, Steve

2014-08-19

To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls. In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695). Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage. © 2014 American Academy of Neurology.

Race and sex differences in thrombogenicity: risk of ischemic events following coronary stenting.

PubMed

Gurbel, Paul A; Bliden, Kevin P; Cohen, Eli; Navickas, Irene A; Singla, Anand; Antonino, Mark J; Fissha, Mulugeta; Kreutz, Rolf P; Bassi, Ashwani K; Tantry, Udaya S

2008-06-01

Race and sex affect thrombogenicity. We have demonstrated that platelet-fibrin clot characteristics can be used to stratify patients for risk of ischemic events following percutaneous coronary intervention. We investigated race and sex differences in thrombogenicty and the relation to ischemic risk in 252 consecutive African-American and Caucasian men and women undergoing elective percutaneous coronary intervention. Platelet-fibrin clot characteristics were measured using the Thrombelastograph Hemostasis System. The incidence of adverse ischemic events was assessed over a 6-month follow-up period. Overall, 40 ischemic events (15.9%) occurred. Adverse events were higher in African-Americans than Caucasians (P = 0.14), and in women than men (P = 0.004). The incidence was highest in African-American women (37.5%) and lowest in African-American men (6.5%). Measured Thrombelastograph parameters were significantly different between ischemic and nonischemic patients (P < 0.05). African-American women in the ischemic group exhibited higher thrombogenicity than the other race and sex groups (P < 0.05). Multivariate logistic regression identified platelet-fibrin mediated clot strength (relative risk 2.52, P = 0.017) and sex (relative risk 2.56, P = 0.009) as significant independent predictors of ischemic events 6 months postpercutaneous coronary intervention. Thrombogenicity is a novel measurable cardiovascular risk factor that varies by race and sex, is highest in African-American women, and independently predicts the frequency of ischemic events following percutaneous coronary intervention. Point-of-service measurements of platelet-fibrin clot characteristics may lead to more intensified antithrombotic therapy and reduced mortality in selected patients.

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.

Effects of oxymatrine on sympathoexcitatory reflex induced by myocardial ischemic signaling mediated by P2X₃ receptors in rat SCG and DRG.

PubMed

Li, Guilin; Liu, Shuangmei; Yang, Yang; Xie, Jinyan; Liu, Jun; Kong, Fanjun; Tu, Guihua; Wu, Raoping; Li, Guodong; Liang, Shangdong

2011-04-05

Sympathoexcitatory reflex is characterized by an increase in blood pressure and sympathetic nerve activity. P2X₃ receptors in SCG neurons are involved in increasing sympathoexcitatory reflex after myocardial ischemic (MI) injury. The present study is aimed to explore the effects of oxymatrine (Oxy) on the transmission of myocardial ischemic signaling mediated by P2X₃ receptors in rat superior cervical ganglia (SCG) and cervical dorsal root ganglia (DRG) in the sympathoexcitatory reflex after myocardial ischemic injury. In this study, the expression levels of P2X₃ immunoreactivity, mRNA and protein were analyzed in SCG and DRG neurons by immunohistochemistry, in situ hybridization and Western blotting. The results show that the myocardial ischemic injury induces the increase of the systolic blood pressure and heart rate and upregulates the expression of P2X₃ receptors in SCG and DRG neurons. Upregulated expression of P2X₃ receptors in SCG and DRG neurons subsequently leads to the aggravated sympathoexcitatory reflex. Oxymatrine reduces the systolic blood pressure and heart rate in myocardial ischemic rats. After myocardial ischemic rats are treated with oxymatrine, the expression levels of P2X₃ immunoreactivity, mRNA and protein are lower than those in myocardial ischemic rats. Oxymatrine may decrease the expression of P2X₃ receptor and depress the aggravated sympathoexcitatory reflex induced by the nociceptive transmission of myocardial ischemic injury via P2X₃ receptors of rat SCG and DRG neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

Predictive variables for mortality after acute ischemic stroke.

PubMed

Carter, Angela M; Catto, Andrew J; Mansfield, Michael W; Bamford, John M; Grant, Peter J

2007-06-01

Stroke is a major healthcare issue worldwide with an incidence comparable to coronary events, highlighting the importance of understanding risk factors for stroke and subsequent mortality. In the present study, we determined long-term (all-cause) mortality in 545 patients with ischemic stroke compared with a cohort of 330 age-matched healthy control subjects followed up for a median of 7.4 years. We assessed the effect of selected demographic, clinical, biochemical, hematologic, and hemostatic factors on mortality in patients with ischemic stroke. Stroke subtype was classified according to the Oxfordshire Community Stroke Project criteria. Patients who died 30 days or less after the acute event (n=32) were excluded from analyses because this outcome is considered to be directly attributable to the acute event. Patients with ischemic stroke were at more than 3-fold increased risk of death compared with the age-matched control cohort. In multivariate analyses, age, stroke subtype, atrial fibrillation, and previous stroke/transient ischemic attack were predictive of mortality in patients with ischemic stroke. Albumin and creatinine and the hemostatic factors von Willebrand factor and beta-thromboglobulin were also predictive of mortality in patients with ischemic stroke after accounting for demographic and clinical variables. The results indicate that subjects with acute ischemic stroke are at increased risk of all-cause mortality. Advancing age, large-vessel stroke, atrial fibrillation, and previous stroke/transient ischemic attack predict mortality; and analysis of albumin, creatinine, von Willebrand factor, and beta-thromboglobulin will aid in the identification of patients at increased risk of death after stroke.

Endogenous Agmatine Induced by Ischemic Preconditioning Regulates Ischemic Tolerance Following Cerebral Ischemia

PubMed Central

Kim, Jae Hwan; Kim, Jae Young; Jung, Jin Young; Lee, Yong Woo; Lee, Won Taek; Huh, Seung Kon

2017-01-01

Ischemic preconditioning (IP) is one of the most important endogenous mechanisms that protect the cells against ischemia-reperfusion (I/R) injury. However, the exact molecular mechanisms remain unclear. In this study, we showed that changes in the level of agmatine were correlated with ischemic tolerance. Changes in brain edema, infarct volume, level of agmatine, and expression of arginine decarboxylase (ADC) and nitric oxide synthases (NOS; inducible NOS [iNOS] and neural NOS [nNOS]) were analyzed during I/R injury with or without IP in the rat brain. After cerebral ischemia, brain edema and infarct volume were significantly reduced in the IP group. The level of agmatine was increased before and during ischemic injury and remained elevated in the early reperfusion phase in the IP group compared to the experimental control (EC) group. During IP, the level of plasma agmatine was increased in the early phase of IP, but that of liver agmatine was abruptly decreased. However, the level of agmatine was definitely increased in the ipsilateral and contralateral hemisphere of brain during the IP. IP also increased the expression of ADC—the enzyme responsible for the synthesis of endogenous agmatine—before, during, and after ischemic injury. In addition, ischemic injury increased endogenous ADC expression in the EC group. The expression of nNOS was reduced in the I/R injured brain in the IP group. These results suggest that endogenous increased agmatine may be a component of the ischemic tolerance response that is induced by IP. Agmatine may have a pivotal role in endogenous ischemic tolerance. PMID:29302205

Microbubble signal and trial of org in acute stroke treatment (TOAST) classification in ischemic stroke.

PubMed

Lee, Chan-Hyuk; Kang, Hyun Goo; Lee, Ji Sung; Ryu, Han Uk; Jeong, Seul-Ki

2018-07-15

Right-to-left shunt (RLS) through a patent foramen ovale (PFO) is likely associated with ischemic stroke. Many studies have attempted to demonstrate the association between RLS and ischemic stroke. However, information on the association between the degree of RLS and the subtypes of ischemic stroke categorized by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification is lacking. This was a retrospective study involving 508 patients with ischemic stroke who underwent a transcranial Doppler (TCD) microbubble test between 2013 and 2015. The degree of RLS was divided into 4 grades according to the microbubble signal (MBS) as follows: no MBS, grade 1; MBS < 20, grade 2; MBS > 20, grade 3; curtain sign, grade 4. The degree of RLS and the type of ischemic stroke as classified by TOAST were analyzed and compared with other clinical information and laboratory findings. The higher RLS grade was associated with the cardioembolism (CE) and stroke of undetermined etiology (SUE), and the microbubble signals were inversely related with small vessel disease (SVD). An MBS higher than grade 3 showed a 2.95-fold higher association with SUE than large artery atherosclerosis (LAA), while grade 4 MBS revealed an approximately 8-fold higher association with SUE than LAA. RLS identified by the TCD microbubble test was significantly and independently associated with cryptogenic ischemic stroke (negative evaluation). Subsequent studies are needed to determine the biologic relationship between RLS and ischemic stroke, particularly the cryptogenic subtype of ischemic stroke. Copyright © 2018 Elsevier B.V. All rights reserved.

Non-high-density lipoprotein cholesterol vs low-density lipoprotein cholesterol as a risk factor for ischemic stroke: a result from the Kailuan study.

PubMed

Wu, Jianwei; Chen, Shengyun; Liu, Liping; Gao, Xiang; Zhou, Yong; Wang, Chunxue; Zhang, Qian; Wang, Anxin; Hussain, Mohammed; Sun, Baoying; Wu, Shouling; Zhao, Xingquan

2013-06-01

To compare the predictive value of serum low-density lipoprotein (LDL) cholesterol and non-high-density lipoprotein (non-HDL) cholesterol levels for ischemic stroke in the Chinese population. We performed a four-year cohort study of 95 778 men and women, aged 18-98 years, selected from the Kailuan study (2006-2007). Baseline LDL cholesterol levels were estimated using direct test method. Total cholesterol levels were estimated using endpoint test method. The predictive values of LDL cholesterol and non-HDL cholesterol for ischemic stroke were compared. During the follow-up period, there were 1153 incident cases of ischemic stroke. The hazard ratio (HR) for ischemic stroke in the top quintile of LDL cholesterol was the highest among five quintiles (HR: 1·25; 95% confidence interval (CI), 1·01-1·53). The HR in the top quintile of non-HDL cholesterol for ischemic stroke was also the highest among five quintiles (HR: 1·53; 95% CI, 1·24-1·88). Analysis of trends showed a significant positive relationship between ischemic stroke incidence and serum LDL cholesterol level, and non-HDL cholesterol level, respectively (both P < 0·05). The area under the curve of LDL cholesterol and non-HDL cholesterol for ischemic stroke was 0·51 and 0·56, respectively (P < 0·05 for the difference). Serum Non-HDL cholesterol level is a stronger predictor for the risk of ischemic stroke than serum LDL cholesterol level in the Chinese population.

Ethnic Differences in Ambient Air Pollution and Risk of Acute Ischemic Stroke

PubMed Central

Wing, Jeffrey J.; Adar, Sara D.; Sánchez, Brisa N.; Morgenstern, Lewis B.; Smith, Melinda A.; Lisabeth, Lynda D.

2015-01-01

Objectives To investigate the association between short-term changes in ambient pollution (particulate matter < 2.5μm in aerodynamic diameter (PM2.5) and ozone (O3)) and the risk of ischemic stroke among individuals living in a bi-ethnic community and whether this association is modified by ethnicity. Methods We identified incident ischemic stroke cases from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project between 2000 and 2012. Associations between PM2.5 (mean 24-hour) and O3 (maximal 8-hour) levels, measured on the same-day and lags of 1-3 days, and odds of ischemic stroke were assessed using a time-stratified case-crossover design and modeled using conditional logistic regression. We explored race/ethnicity (Mexican American versus non-Hispanic white) as a modifier by including interaction terms in the models. Results There were 2,948 ischemic strokes with median age 71 years (IQR: 59-80). We observed no overall associations between the air pollutants and odds of ischemic stroke at any lag. When stratified by ethnicity, higher O3 was consistently associated with greater odds of ischemic stroke for non-Hispanic whites, but not for Mexican Americans. Higher PM2.5 was generally associated with lower odds of ischemic stroke for non-Hispanic whites but modestly greater odds for Mexican Americans. Conclusion Ethnic differences in the associations between ischemic stroke and short-term exposures to O3 and PM2.5 were suggested indicating that further study in diverse populations may be warranted. PMID:26451880

No-flow ischemia inhibits insulin signaling in heart by decreasing intracellular pH.

PubMed

Beauloye, C; Bertrand, L; Krause, U; Marsin, A S; Dresselaers, T; Vanstapel, F; Vanoverschelde, J L; Hue, L

2001-03-16

Glucose-insulin-potassium solutions exert beneficial effects on the ischemic heart by reducing infarct size and mortality and improving postischemic left ventricular function. Insulin could be the critical protective component of this mixture, although the insulin response of the ischemic and postischemic myocardium has not been systematically investigated. The aim of this work was to study the insulin response during ischemia by analyzing insulin signaling. This was evaluated by measuring changes in activity and/or phosphorylation state of insulin signaling elements in isolated perfused rat hearts submitted to no-flow ischemia. Intracellular pH (pH(i)) was measured by NMR. No-flow ischemia antagonized insulin signaling including insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, protein kinase B, p70 ribosomal S6 kinase, and glycogen synthase kinase-3. These changes were concomitant with intracellular acidosis. Perfusing hearts with ouabain and amiloride in normoxic conditions decreased pH(i) and insulin signaling, whereas perfusing at pH 8.2 counteracted the drop in pH(i) and the inhibition of insulin signaling by ischemia. Incubation of cardiomyocytes in normoxic conditions, but at pH values below 6.75, mimicked the effect of ischemia and also inhibited insulin-stimulated glucose uptake. Finally, the in vitro insulin receptor tyrosine kinase activity was progressively inhibited at pH values below physiological pH(i), being abolished at pH 6.0. Therefore, ischemic acidosis decreases kinase activity and tyrosine phosphorylation of the insulin receptor thereby preventing activation of the downstream components of the signaling pathway. We conclude that severe ischemia inhibits insulin signaling by decreasing pH(i).

Effect of lidocaine on inflammation in equine jejunum subjected to manipulation only and remote to intestinal segments subjected to ischemia.

PubMed

Bauck, Anje G; Grosche, Astrid; Morton, Alison J; Graham, A Sarah; Vickroy, Thomas W; Freeman, David E

2017-08-01

OBJECTIVE To examine effects of continuous rate infusion of lidocaine on transmural neutrophil infiltration in equine intestine subjected to manipulation only and remote to ischemic intestine. ANIMALS 14 healthy horses. PROCEDURES Ventral midline celiotomy was performed (time 0). Mild ischemia was induced in segments of jejunum and large colon. A 1-m segment of jejunum was manipulated by massaging the jejunal wall 10 times. Horses received lidocaine (n = 7) or saline (0.9% NaCl) solution (7) throughout anesthesia. Biopsy specimens were collected and used to assess tissue injury, neutrophil influx, cyclooxygenase expression, and hypoxia-inducible factor 1α (HIF-1α) expression at 0, 1, and 4 hours after manipulation and ischemia. Transepithelial resistance (TER) and mannitol flux were measured by use of Ussing chambers. RESULTS Lidocaine did not consistently decrease neutrophil infiltration in ischemic, manipulated, or control tissues at 4 hours. Lidocaine significantly reduced circular muscle and overall scores for cyclooxygenase-2 expression in manipulated tissues. Manipulated tissues had significantly less HIF-1α expression at 4 hours than did control tissues. Mucosa from manipulated and control segments obtained at 4 hours had lower TER and greater mannitol flux than did control tissues at 0 hours. Lidocaine did not significantly decrease calprotectin expression. Severity of neutrophil infiltration was similar in control, ischemic, and manipulated tissues at 4 hours. CONCLUSIONS AND CLINICAL RELEVANCE Manipulated jejunum did not have a significantly greater increase in neutrophil infiltration, compared with 4-hour control (nonmanipulated) jejunum remote to sites of manipulation, ischemia, and reperfusion. Lidocaine did not consistently reduce neutrophil infiltration in jejunum.

Protection of ischemic preconditioning on renal neural function in rats with acute renal failure.

PubMed

Wu, Ming-Shiou; Chien, Chiang-Ting; Ma, Ming-Chieh; Chen, Chau-Fong

2009-11-30

We tested whether tolerance induced by ischemic preconditioning (IPC) in kidneys was related to renal nerves. Experimental acute renal failure (ARF) in a rat model was induced for 45 min of left renal arterial occlusion (RAO), followed by 6 or 24 h of reperfusion (ischemic reperfusion (I/R) group). The episode of IPC was four cycles of 4 min of RAO at 11 min intervals and then the I/R injury was treated as above (IPC-I/R group). After 6 h of reperfusion, polyuria was found in the I/R group associated with an enhancement of afferent renal nerve activity (ARNA) and a reflexive decrease in efferent renal nerve activity (ERNA). Changes in nerve responses were related with a reduction in neutral endopeptidase (NEP) activity and an increased release of substance P (SP). After 24 h of reperfusion, the I/R group showed oliguria which was associated with a lower ARNA, hyperactivity of ERNA and a nine-fold increase in SP release due to a further 52% loss in NEP activity. Prior IPC treatment did not affect the changed ischemia-induced excretory and nervous activity patterns during the first 6 h of reperfusion, but normalized both responses in the kidneys 24 h after ischemia. The IPC-mediated protection in oliguric ARF was related to the preservation of NEP activity to only 25% loss that caused an increase of SP amounts of only three-fold and a minor change in neurokinin 1 receptor (NK-1R) activities. Finally, both excretory and sensory responses in oliguric ARF after saline loading were significantly ameliorated by IPC. We conclude that IPC results in preservation of the renal sensory response in postischemic kidneys and has a beneficial effect on controlling efferent renal sympathetic nerve activity and excretion of solutes and water.

Imaging cortical absorption, scattering, and hemodynamic response during ischemic stroke using spatially modulated near-infrared illumination

NASA Astrophysics Data System (ADS)

Abookasis, David; Lay, Christopher C.; Mathews, Marlon S.; Linskey, Mark E.; Frostig, Ron D.; Tromberg, Bruce J.

2009-03-01

We describe a technique that uses spatially modulated near-infrared (NIR) illumination to detect and map changes in both optical properties (absorption and reduced scattering parameters) and tissue composition (oxy- and deoxyhemoglobin, total hemoglobin, and oxygen saturation) during acute ischemic injury in the rat barrel cortex. Cerebral ischemia is induced using an open vascular occlusion technique of the middle cerebral artery (MCA). Diffuse reflected NIR light (680 to 980 nm) from the left parietal somatosensory cortex is detected by a CCD camera before and after MCA occlusion. Monte Carlo simulations are used to analyze the spatial frequency dependence of the reflected light to predict spatiotemporal changes in the distribution of tissue absorption and scattering properties in the brain. Experimental results from seven rats show a 17+/-4.7% increase in tissue concentration of deoxyhemoglobin and a 45+/-3.1, 23+/-5.4, and 21+/-2.2% decrease in oxyhemoglobin, total hemoglobin concentration and cerebral tissue oxygen saturation levels, respectively, 45 min following induction of cerebral ischemia. An ischemic index (Iisch=ctHHb/ctO2Hb) reveals an average of more then twofold contrast after MCAo. The wavelength-dependence of the reduced scattering (i.e., scatter power) decreased by 35+/-10.3% after MCA occlusion. Compared to conventional CCD-based intrinsic signal optical imaging (ISOI), the use of structured illumination and model-based analysis allows for generation of separate maps of light absorption and scattering properties as well as tissue hemoglobin concentration. This potentially provides a powerful approach for quantitative monitoring and imaging of neurophysiology and metabolism with high spatiotemporal resolution.

Neuroprotective Mechanisms of Taurine against Ischemic Stroke.

PubMed

Menzie, Janet; Prentice, Howard; Wu, Jang-Yen

2013-06-03

Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke.

Genetics of ischemic stroke: future clinical applications.

PubMed

Wang, Michael M

2006-11-01

Ischemic stroke has long been thought to have a genetic component that is independent of conventional vascular risk factors. It has been estimated that over one half of stroke risk is determined by inherited genes. However, until recently, strong evidence of genetic influence on ischemic stroke has been subject to criticism because the risk factors for stroke are also inherited and because previous studies suffered from limitations imposed by this highly heterogeneous neurological disorder. Recent advances in molecular genetics have led to the identification of specific genetic loci that impart susceptibility to ischemic stroke. We review the studies of these genes and discuss the future potential applications of genetic markers on the management of ischemic stroke patients.

Remote pre-procedural ischemic stroke as the greatest risk in carotid‑stenting‑associated stroke and death: a single center's experience.

PubMed

Rašiová, Mária; Špak, Ľubomír; Farkašová, Ľudmila; Pataky, Štefan; Koščo, Martin; Hudák, Marek; Moščovič, Matej; Leško, Norbert

2017-08-01

The goal of carotid artery stenting (CAS) is to decrease the stroke risk in patients with carotid stenosis. This procedure carries an immediate risk of stroke and death and many patients do not benefit from it, especially asymptomatic patients. It is crucial to accurately select the patients who would benefit from carotid procedure, and to rule out those for whom the procedure might be hazardous. Remote ischemic stroke is a known risk factor for stroke recurrence during surgery. The aim of our study was to determine the periprocedural complication risk (within 30 days after CAS) associated with carotid stenting (stroke, death) in patients with and without remote pre-procedural ischemic stroke, to analyze periprocedural risk in other specific patient subgroups treated with CAS, and to determine the impact of observed variables on all-cause mortality during long-term follow-up. We conducted a retrospective review of prospectively collected data from all patients treated with protected CAS between June 20, 2008 and December 31, 2015. Patient age, gender, type of carotid stenosis (symptomatic versus asymptomatic), side of stenosis (right or left carotid artery), type of cerebral protection (proximal versus distal), presence of comorbidities (remote ischemic pre-procedural ischemic stroke, coronary artery disease, diabetes mellitus, peripheral artery disease), previous ipsilateral carotid endarterectomy (CEA), contralateral carotid occlusion (CCO) and previous contralateral CAS/CEA were analyzed to identify higher CAS risk and to determine the impact of these variables on all-cause mortality during follow-up. Survival data were obtained from the Health Care Surveillance Authority registry. Mean follow-up was 1054 days (interquartile range 547.3; 1454.8). Remote pre-procedural ischemic stroke was defined as any-territory ischemic stroke >6 months prior to CAS. Primary periprocedural endpoint incidence (stroke/death) in 502 patients was 3.8% (N.=19) of all patients, 5.4% (N.=10) of symptomatic patients and 2.8% (N.=9) of asymptomatic patients. The risk of periprocedural stroke/death was 3.4 times higher in patients with (N.=198) compared to patients without remote ischemic stroke (N.=304) (6.6% versus 2.0% of patients without remote ischemic stroke; P=0.008). Periprocedural stroke/death in symptomatic patients (N.=186) was non-significantly higher in patients with remote ischemic stroke (N.=76) compared with patients without remote ischemic stroke (N.=110) (7.9% versus 3.6%; P=0.206). Asymptomatic patients with remote ischemic stroke (N.=122) had a 5.6-time-higher periprocedural risk of stroke/death compared with asymptomatic patients without remote ischemic stroke (N.=194) (5.7% versus 1.0%; P=0.014). Patients ≥75 years (N.=83) had a 3.0-time-higher periprocedural risk of stroke/death compared with younger patients (N.=419) (8.4% versus 2.9%; P=0.015); a non-significant increase of periprocedural stroke/death was found in both symptomatic (N.=35) and asymptomatic (N.=48) elderly patients (11.4% versus 4.0%, P=0.078; and 6.3% versus 2.4%, P=0.124, respectively). Increased periprocedural risk of stroke/death was not documented in other analyzed patient subgroups. During long-term follow-up, a 1.5-time-higher mortality risk was found in patients with remote ischemic stroke compared with patients without remote ischemic stroke in multivariable analysis; other patient subgroups (except older versus younger patients) did not differ in long-term mortality following carotid stenting. In our experience, all patients with remote pre-procedural any-territory ischemic stroke belong to risky subgroup for periprocedural stroke death after CAS. All asymptomatic patients with remote ischemic stroke should not be treated with CAS. Remote ischemic stroke increases all-cause mortality in long-term follow-up after carotid stenting. Patients aged ≥75 years also have increased risk of periprocedural stroke and death after CAS. These factors should help us to be more selective when planning carotid procedures.

New Treatments for Nonarteritic Anterior Ischemic Optic Neuropathy.

PubMed

Foroozan, Rod

2017-02-01

Despite increasing knowledge about the risk factors and clinical findings of nonarteritic anterior ischemic optic neuropathy (NAION), the treatment of this optic neuropathy has remained limited and without clear evidence-based benefit. Historical treatments of NAION are reviewed, beginning with the Ischemic Optic Neuropathy Decompression Trial. More recent treatments are placed within the historical context and illustrate the need for evidence-based therapy for ischemic optic neuropathy. Copyright © 2016 Elsevier Inc. All rights reserved.

Does non-central nervous system tuberculosis increase the risk of ischemic stroke? A population-based propensity score-matched follow-up study.

PubMed

Wu, Chueh-Hung; Chen, Li-Sheng; Yen, Ming-Fang; Chiu, Yueh-Hsia; Fann, Ching-Yuan; Chen, Hsiu-Hsi; Pan, Shin-Liang

2014-01-01

Previous studies on the association between tuberculosis and the risk of developing ischemic stroke have generated inconsistent results. We therefore performed a population-based, propensity score-matched longitudinal follow-up study to investigate whether contracting non-central nervous system (CNS) tuberculosis leads to an increased risk of ischemic stroke. We used a logistic regression model that includes age, sex, pre-existing comorbidities and socioeconomic status as covariates to compute the propensity score. A total of 5804 persons with at least three ambulatory visits in 2001 with the principal diagnosis of non-CNS tuberculosis were enrolled in the tuberculosis group. The non-tuberculosis group consisted of 5804, propensity score-matched subjects without tuberculosis. The three-year ischemic stroke-free survival rates for these 2 groups were estimated using the Kaplan-Meier method. The stratified Cox proportional hazards regression was used to estimate the effect of tuberculosis on the occurrence of ischemic stroke. During three-year follow-up, 176 subjects in the tuberculosis group (3.0%) and 207 in the non-tuberculosis group (3.6%) had ischemic stroke. The hazard ratio for developing ischemic stroke in the tuberculosis group was 0.92 compared to the non-tuberculosis group (95% confidence interval: 0.73-1.14, P = 0.4299). Non-CNS tuberculosis does not increase the risk of subsequent ischemic stroke.

Relative impact of human leukocyte antigen mismatching and graft ischemic time after lung transplantation.

PubMed

Brugière, Olivier; Thabut, Gabriel; Suberbielle, Caroline; Reynaud-Gaubert, Martine; Thomas, Pascal; Pison, Christophe; Saint Raymond, Christel; Mornex, Jean-François; Bertocchi, Michèle; Dromer, Claire; Velly, Jean-François; Stern, Marc; Philippe, Bruno; Dauriat, Gaëlle; Biondi, Giuseppina; Castier, Yves; Fournier, Michel

2008-06-01

Recent data strongly suggest that human leukocyte antigen (HLA) mismatching has a negative impact on development of bronchiolitis obliterans syndrome (BOS) and survival after lung transplantation (LTx). Because HLA matching is sometimes achieved by extending ischemic time in other solid-organ transplantation models and ischemic time is a risk factor per se for death after LTx, we sought to compare the theoretical benefit of HLA matching with the negative impact of lengthened ischemic time. In this collaborative study we compared the relative impact of HLA mismatching and ischemic time on BOS and survival in 182 LTx recipients. Using multivariate analyses, we observed a lower incidence of BOS (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 1.1 to 2.7, p = 0.03) and enhanced survival (HR = 1.91, 95% CI: 1.24 to 2.92, p = 0.01) in patients with zero or one HLA-A mismatch compared with those having two HLA-A mismatches. This beneficial effect on survival was equivalent to a reduction of ischemic time of 168 minutes. We observed a reduced incidence of BOS and a better survival rate in patients well-matched at the HLA-A locus, associated with an opposite effect of an enhanced ischemic time. This suggests that graft ischemic time should be taken into account in future studies of prospective HLA matching in LTx.

[Broad ischemic stroke revealing infective endocarditis in a young patient: about a case].

PubMed

Ravelosaona, Fanomezantsoa Noella; Razafimahefa, Julien; Randrianasolo, Rahamefy Odilon; Rakotoarimanana, Solofonirina; Tehindrazanarivelo, Djacoba Alain

2016-01-01

Broad ischemic stroke is mainly due to a cardiac embolus or to an atheromatous plaque. In young subjects, one of the main causes of ischemic stroke (broad ischemic stroke in particolar) is embolic heart disease including infective endocarditis. Infective endocarditis is a contraindication against the anticoagulant therapy (which is indicated for the treatment of embolic heart disease complicated by ischemic stroke). One neurologic complications of infective endocarditis is ischemic stroke which often occurs in multiple sites. We here report the case of a 44-year old man with afebrile acute onset of severe left hemiplegia associated with a sistolic mitral murmur, who had fever in hospital on day 5 with no other obvious source of infection present. Brain CT scan showed full broad ischaemic stroke of the right middle cerebral artery territory and doppler ultrasound, performed after stroke onset, showed infective endocarditis affecting the small mitral valve. He was treated with 4 weeks of antibiotic therapy without anticoagulant therapy ; evolution was marked by the disappearance of mitral valve vegetations and by movement sequelae involving the left side of the body. In practical terms, our problem was the onset of the fever which didn't accompany or pre-exist patient's deficit, leading us to the misdiagnosis of ischemic stroke of cardioembolic origin. This case study underlines the importance of doppler ultrasound, in the diagnosis of all broad ischemic strokes, especially superficial, before starting anticoagulant therapy.

Current knowledge on the neuroprotective and neuroregenerative properties of citicoline in acute ischemic stroke

PubMed Central

Martynov, Mikhail Yu; Gusev, Eugeny I

2015-01-01

Ischemic stroke is one of the leading causes of long-lasting disability and death. Two main strategies have been proposed for the treatment of ischemic stroke: restoration of blood flow by thrombolysis or mechanical thrombus extraction during the first few hours of ischemic stroke, which is one of the most effective treatments and leads to a better functional and clinical outcome. The other direction of treatment, which is potentially applicable to most of the patients with ischemic stroke, is neuroprotection. Initially, neuroprotection was mainly targeted at protecting gray matter, but during the past few years there has been a transition from a neuron-oriented approach toward salvaging the whole neurovascular unit using multimodal drugs. Citicoline is a multimodal drug that exhibits neuroprotective and neuroregenerative effects in a variety of experimental and clinical disorders of the central nervous system, including acute and chronic cerebral ischemia, intracerebral hemorrhage, and global cerebral hypoxia. Citicoline has a prolonged therapeutic window and is active at various temporal and biochemical stages of the ischemic cascade. In acute ischemic stroke, citicoline provides neuroprotection by attenuating glutamate exitotoxicity, oxidative stress, apoptosis, and blood–brain barrier dysfunction. In the subacute and chronic phases of ischemic stroke, citicoline exhibits neuroregenerative effects and activates neurogenesis, synaptogenesis, and angiogenesis and enhances neurotransmitter metabolism. Acute and long-term treatment with citicoline is safe and in most clinical studies is effective and improves functional outcome. PMID:27186142

Activation of p38 MAPK participates in brain ischemic tolerance induced by limb ischemic preconditioning by up-regulating HSP 70.

PubMed

Sun, Xiao-Cai; Xian, Xiao-Hui; Li, Wen-Bin; Li, Li; Yan, Cai-Zhen; Li, Qing-Jun; Zhang, Min

2010-08-01

This study investigates whether activation of p38 MAPK by the up-regulation of HSP 70 participates in the induction of brain ischemic tolerance by limb ischemic preconditioning (LIP). Western blot and immunohistochemical assays indicated that p38 MAPK activation occurred earlier than HSP 70 induction in the CA1 region of the hippocampus after LIP. P-p38 MAPK expression was up-regulated at 6h and reached its peak 12h after LIP, while HSP 70 expression was not significantly increased until 1 day and peaked 2 days after LIP. Neuropathological evaluation by thionin staining showed that quercetin (4 ml/kg, 50mg/kg, intraperitoneal injection), an inhibitor of HSP 70, blocked the protective effect of LIP against delayed neuronal death that is normally induced by lethal brain ischemic insult, indicating that HSP 70 participates in the induction of brain ischemic tolerance by LIP. Furthermore, SB 203580, an inhibitor of HSP 70, inhibited HSP 70 activation in the CA1 region of the hippocampus induced by LIP either with or without the presence of subsequent brain ischemic insult. Based on the above results, it can be concluded that activation of p38 MAPK participates in the brain ischemic tolerance induced by LIP at least partly by the up-regulation of HSP 70 expression. (c) 2010 Elsevier Inc. All rights reserved.

Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation-- a nation wide database analysis.

PubMed

Lin, Lian-Yu; Lee, Chang-Hsing; Yu, Chih-Chieh; Tsai, Chia-Ti; Lai, Ling-Pin; Hwang, Juey-Jen; Chen, Pau-Chung; Lin, Jiunn-Lee

2011-07-01

Atrial fibrillation (AF) is a risk factor for ischemic stroke. Stroke-prevention strategies based on risk schemes have been developed but most of the data are from western people. Our goal is to investigate the risk factors of ischemic stroke in Taiwanese with AF in a nation-wide database. A universal national health insurance (NHI) program has been implemented in Taiwan since 1995. We used system sampling database from 1997 to 2008 with a total of 1,000,000 subjects. By using ambulatory and inpatient claim data, we included subjects with AF and were above 20 years old. We excluded those who had ever taken warfarin or aspirin or had valvular heart diseases. A total of 7920 patients (3633 women, 4287 men) were included in the final analyses. Cox regression analysis showed that the risk factors for ischemic stroke were age (OR=1.338 for age 65-74 years vs. age 20-64 years, P=0.014; OR=1.652 for age over 75 years vs. age 20-64 years, P<0.001), hypertension (HTN) (OR=2.656, P<0.001), diabetes mellitus (DM) (OR=1.341, P=0.005), heart failure (OR=1.611, P<0.001), previous ischemic stroke or transient ischemic accident (TIA) (OR=2.752, P<0.001) and peripheral arterial disease (PAD) (OR=1.814, P=0.006). The gender, coronary artery disease, history of myocardial infarction and chronic renal insufficiency were not associated with ischemic stroke. The rate of ischemic stroke was much lower in current cohort as compared with that in whites. Frequent used risk schemes including CHADS₂ and CHA₂DS₂-VASC had comparable but only limited ability to predict ischemic stroke in subjects with AF. Compare with western people, hypertension plays a more important role in ischemic stroke in Taiwanese with AF and the incidence is lower. A substantial number of ischemic strokes cannot be accurately predicted by current risk schemes. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue

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

Magnusson, Lisa U.; Lundqvist, Annika; Asp, Julia

Highlights: Black-Right-Pointing-Pointer We found a 17-fold upregulation of ALOX15 in the ischemic heart. Black-Right-Pointing-Pointer Incubation of human muscle cells in hypoxia showed a 22-fold upregulation of ALOX15. Black-Right-Pointing-Pointer We observed increased levels of proinflammatory markers in ischemic heart tissue. Black-Right-Pointing-Pointer Suggesting a link between ischemia and inflammation in ischemic heart biopsies. -- Abstract: A common feature of the ischemic heart and atherosclerotic plaques is the presence of hypoxia (insufficient levels of oxygen in the tissue). Hypoxia has pronounced effects on almost every aspect of cell physiology, and the nuclear transcription factor hypoxia inducible factor-1{alpha} (HIF-1{alpha}) regulates adaptive responses to lowmore » concentrations of oxygen in mammalian cells. In our recent work, we observed that hypoxia increases the proinflammatory enzyme arachidonate 15-lipoxygenase (ALOX15B) in human carotid plaques. ALOX15 has recently been shown to be present in the human myocardium, but the effect of ischemia on its expression has not been investigated. Here we test the hypothesis that ischemia of the heart leads to increased expression of ALOX15, and found an almost 2-fold increase in HIF-1{alpha} mRNA expression and a 17-fold upregulation of ALOX15 mRNA expression in the ischemic heart biopsies from patients undergoing coronary bypass surgery compared with non ischemic heart tissue. To investigate the effect of low oxygen concentration on ALOX15 we incubated human vascular muscle cells in hypoxia and showed that expression of ALOX15 increased 22-fold compared with cells incubated in normoxic conditions. We also observed increased mRNA levels of proinflammatory markers in ischemic heart tissue compared with non-ischemic controls. In summary, we demonstrate increased ALOX15 in human ischemic heart biopsies. Furthermore we demonstrate that hypoxia increases ALOX15 in human muscle cells. Our results yield important insights into the underlying association between hypoxia and inflammation in the human ischemic heart disease.« less

Involvement of glycogen synthase kinase-3β in liver ischemic conditioning induced cardioprotection against myocardial ischemia and reperfusion injury in rats

PubMed Central

Yang, Shuai; Abbott, Geoffrey W.; Gao, Wei Dong; Liu, Jin; Luo, Chaozhi

2017-01-01

Remote ischemic conditioning has been convincingly shown to render the myocardium resistant to a subsequent more severe sustained episode of ischemia. Compared with other organs, little is known regarding the effect of transient liver ischemic conditioning. We proposed the existence of cardioprotection induced by remote liver conditioning. Male Sprague-Dawley rats were divided into sham-operated control (no further hepatic intervention) and remote liver ischemic conditioning groups. For liver ischemic conditioning, three cycles of 5 min of liver ischemia-reperfusion stimuli were conducted before-(liver preconditioning), post-myocardial ischemia (liver postconditioning), or in combination of both (liver preconditioning + liver postconditioning). Rats were exposed to 45 min of left anterior descending coronary artery occlusion, followed by 3 h of reperfusion thereafter. ECG and hemodynamics were measured throughout the experiment. The coronary artery was reoccluded at the end of reperfusion for infarct size determination. Blood samples were taken for serum lactate dehydrogenase and creatine kinase-MB test. Heart tissues were taken for apoptosis measurements and Western blotting. Our data demonstrate that liver ischemic preconditioning, postconditioning, or a combination of both, offered strong cardioprotection, as evidenced by reduction in infarct size and cardiac tissue damage, recovery of cardiac function, and inhibition of apoptosis after ischemia-reperfusion. Moreover, liver ischemic conditioning increased cardiac (not hepatic) glycogen synthase kinase-3β (GSK-3β) phosphorylation. Accordingly, inhibition of GSK-3β mimicked the cardioprotective action of liver conditioning. These results demonstrate that remote liver ischemic conditioning protected the heart against ischemia and reperfusion injury via GSK-3β-dependent cell-survival signaling pathway. NEW & NOTEWORTHY Remote ischemic conditioning protects hearts against ischemia and reperfusion (I/R) injury. However, it is unclear whether ischemic conditioning of visceral organs such as the liver, the largest metabolic organ in the body, can produce cardioprotection. This is the first study to show the cardioprotective effect of remote liver ischemic conditioning in a rat model of myocardial I/R injury. We also, for the first time, demonstrated these protective properties are associated with glycogen synthase kinase-3β-dependent cell-survival signaling pathway. PMID:28153944

Heparin monotherapy or bivalirudin during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease: results from the Evaluation of Drug-Eluting Stents and Ischemic Events registry.

PubMed

Bangalore, Sripal; Pencina, Michael J; Kleiman, Neal S; Cohen, David J

2014-06-01

The use of bivalirudin versus unfractionated heparin monotherapy in patients without ST-segment-elevation myocardial infarction is not well defined. The study population consisted of patients enrolled in the Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry with either non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease, who underwent percutaneous coronary intervention with either unfractionated heparin or bivalirudin monotherapy. Propensity score matching was used to adjust for baseline characteristics. The primary bleeding (in-hospital composite bleeding-access site bleeding, thrombolysis in myocardial infarction major/minor bleeding, or transfusion) and primary (in-hospital death/myocardial infarction) and secondary ischemic outcomes (death/myocardial infarction/unplanned repeat revascularization at 12 months) were evaluated. Propensity score matching yielded 1036 patients with non-ST-segment-elevation acute coronary syndromes and 2062 patients with stable ischemic heart disease. For the non-ST-segment-elevation acute coronary syndrome cohort, bivalirudin use was associated with lower bleeding (difference, -3.3% [-0.8% to -5.8%]; P=0.01; number need to treat=30) without increase in either primary (difference, 1.2% [4.1% to -1.8%]; P=0.45) or secondary ischemic outcomes, including stent thrombosis (difference, 0.0% [1.3% to -1.3%]; P=1.00). Similarly, in the stable ischemic heart disease cohort, bivalirudin use was associated with lower bleeding (difference, -1.8% [-0.4% to -3.3%]; P=0.01; number need to treat=53) without increase in either primary (difference, 0.4% [2.3% to -1.5%]; P=0.70) or secondary ischemic outcomes, including stent thrombosis (difference, 0.0% [0.7% to -0.7%]; P=1.00) when compared with unfractionated heparin monotherapy. Among patients with non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease undergoing percutaneous coronary intervention, bivalirudin use during percutaneous coronary intervention when compared with unfractionated heparin monotherapy was associated with lower bleeding without significant increase in ischemic outcomes or stent thrombosis. © 2014 American Heart Association, Inc.

Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy.

PubMed

Gao, Yunan; Yang, Hongxiao; Chi, Jing; Xu, Qiannan; Zhao, Luqi; Yang, Weijia; Liu, Weifan; Yang, Wei

2017-01-01

To study the effect of inhaling hydrogen gas on myocardial ischemic/reperfusion(I/R) injury in rats. Seventy male Wistar albino rats were divided into five groups at random as the sham group (Sham). The I/R group (I/R), The ischemic postconditioning group (IPo), The I/R plus hydrogen group (IH2) and the ischemic postconditioning plus hydrogen group (IPoH2). The Sham group was without coronary occlusion. In I/R group, Ischemic/reperfusion injury was induced by coronary occlusion for 1 hour. Followed by 2 hours of reperfusion. In the IPo and IPoH2 group, four cycles of 1 min reperfusion/1 min ischemia was given at the end of 1 hour coronary occlusion. While 2% hydrogen was administered by inhalation 5 min before reperfusion till 2 hours after reperfusion in both the IPoH2 and IH2 group. The heart and blood samples were harvested at the end of the surgical protocol. Then the myocardium cell endoplasmic reticulum(ER) stress and autophagy was observed by electron microscope. In addition, the cardiac ER stress and autophagy related proteins expression were detected by Western blotting analysis. Both inhaling 2% hydrogen and ischemic postconditioning treatment reduced the ischemic size and serum troponin I level in rats with I/R injury, and inhaling hydrogen showed a more curative effect compared with ischemic postconditioning treatment. Meanwhile inhaling hydrogen showed a better protective effect in attenuating tissue reactive oxygen species. Malondialdehyde levels and immunoreactivities against 8-hydroxy-2'-deoxyguanosine and inhibiting cardiac endoplasmic reticulum stress and down-regulating autophagy as compared with ischemic postconditioning treatment. These results revealed a better protective effect of hydrogen on myocardial ischemic/reperfusion injury in rats by attenuating endoplasmic reticulum stress and down-regulating autophagy compared with ischemic postconditioning treatment. © 2017 The Author(s). Published by S. Karger AG, Basel.

Prediction of Early Recurrent Thromboembolic Event and Major Bleeding in Patients With Acute Stroke and Atrial Fibrillation by a Risk Stratification Schema: The ALESSA Score Study.

PubMed

Paciaroni, Maurizio; Agnelli, Giancarlo; Caso, Valeria; Tsivgoulis, Georgios; Furie, Karen L; Tadi, Prasanna; Becattini, Cecilia; Falocci, Nicola; Zedde, Marialuisa; Abdul-Rahim, Azmil H; Lees, Kennedy R; Alberti, Andrea; Venti, Michele; Acciarresi, Monica; D'Amore, Cataldo; Mosconi, Maria Giulia; Cimini, Ludovica Anna; Procopio, Antonio; Bovi, Paolo; Carletti, Monica; Rigatelli, Alberto; Cappellari, Manuel; Putaala, Jukka; Tomppo, Liisa; Tatlisumak, Turgut; Bandini, Fabio; Marcheselli, Simona; Pezzini, Alessandro; Poli, Loris; Padovani, Alessandro; Masotti, Luca; Vannucchi, Vieri; Sohn, Sung-Il; Lorenzini, Gianni; Tassi, Rossana; Guideri, Francesca; Acampa, Maurizio; Martini, Giuseppe; Ntaios, George; Karagkiozi, Efstathia; Athanasakis, George; Makaritsis, Kostantinos; Vadikolias, Kostantinos; Liantinioti, Chrysoula; Chondrogianni, Maria; Mumoli, Nicola; Consoli, Domenico; Galati, Franco; Sacco, Simona; Carolei, Antonio; Tiseo, Cindy; Corea, Francesco; Ageno, Walter; Bellesini, Marta; Colombo, Giovanna; Silvestrelli, Giorgio; Ciccone, Alfonso; Scoditti, Umberto; Denti, Licia; Mancuso, Michelangelo; Maccarrone, Miriam; Orlandi, Giovanni; Giannini, Nicola; Gialdini, Gino; Tassinari, Tiziana; De Lodovici, Maria Luisa; Bono, Giorgio; Rueckert, Christina; Baldi, Antonio; D'Anna, Sebastiano; Toni, Danilo; Letteri, Federica; Giuntini, Martina; Lotti, Enrico Maria; Flomin, Yuriy; Pieroni, Alessio; Kargiotis, Odysseas; Karapanayiotides, Theodore; Monaco, Serena; Baronello, Mario Maimone; Csiba, Laszló; Szabó, Lilla; Chiti, Alberto; Giorli, Elisa; Del Sette, Massimo; Imberti, Davide; Zabzuni, Dorjan; Doronin, Boris; Volodina, Vera; Michel, Patrik; Vanacker, Peter; Barlinn, Kristian; Pallesen, Lars-Peder; Kepplinger, Jessica; Bodechtel, Ulf; Gerber, Johannes; Deleu, Dirk; Melikyan, Gayane; Ibrahim, Faisal; Akhtar, Naveed; Gourbali, Vanessa; Yaghi, Shadi

2017-03-01

This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00-1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08-2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P =0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30-1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632-0.763; P =0.0001) for ischemic outcome events and 0.585 (0.493-0.678; P =0.10) for major bleedings. The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529-0.763; P =0.009) for ischemic outcome events and 0.407 (0.275-0.540; P =0.14) for hemorrhagic outcome events. In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings. © 2017 American Heart Association, Inc.

New perspectives on the pharmacotherapy of ischemic stroke.

PubMed

Bradberry, J Chris; Fagan, Susan C; Gray, David R; Moon, Yong S K

2004-01-01

To provide an overview of the impact of ischemic stroke and the steps that can be taken to reduce its burden through greater awareness of the disease, improved diagnosis and better treatment, with emphasis on the use of antiplatelet agents. Recent (1995-2003) published scientific literature, as identified by the authors through Medline searches, using the terms stroke, transient ischemic attack, cerebrovascular disease, atherothrombosis, risk factors, pharmacotherapy, prevention, and reviews on treatment. Recent systematic English-language review articles and reports of controlled randomized clinical trials were screened for inclusion. Ischemic stroke is generally the result of an atherothrombotic process leading to vessel obstruction or narrowing. Of the two types of ischemic stroke, thrombotic stroke is caused by a thrombus that develops within the cerebral vasculature, while embolic stroke arises from a distant embolus that lodges in a cerebral artery. The neurologic manifestations of stroke depend on the location of injury in the brain and the degree of ischemia or infarction. Symptoms may be reversible or irreversible and range from sensory deficits to hemiplegia. Risk factors for development of ischemic stroke include hypertension, diabetes, dyslipidemia, smoking, atrial fibrillation, prior stroke, and transient ischemic attack. Tissue plasminogen activator is currently the only available drug treatment for acute ischemic stroke. Stroke recurrence rates are high (about 40% over 5 years), and all ischemic stroke patients should receive antithrombotic therapy (unless contraindicated) for secondary prevention. Of the oral antiplatelet therapies, aspirin, clopidogrel (Plavix--Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership), and the extended-release dipyridamole plus aspirin combination are acceptable first-line agents, while anticoagulants (warfarin) are preferred in patients with atrial fibrillation. Lifestyle changes and drug therapy are important components of primary and secondary prevention strategies in ischemic stroke. Risk factors such as elevated blood pressure and high cholesterol should be aggressively treated. Antiplatelet agents, antihypertensive agents, and cholesterol-lowering agents are therapeutic cornerstones for secondary prevention.

Flavanone Intake Is Inversely Associated with Risk of Incident Ischemic Stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study1234

PubMed Central

Goetz, Margarethe E; Judd, Suzanne E; Hartman, Terryl J; McClellan, William; Anderson, Aaron; Vaccarino, Viola

2016-01-01

Background: Flavonoids may have beneficial cerebrovascular effects, but evidence from racially and geographically representative cohorts in comprehensive flavonoid databases is lacking. Given racial and geographic disparities in stroke incidence, representative cohort studies are needed. Objectives: We evaluated the association between flavonoid intake and incident ischemic stroke in a biracial, national cohort using updated flavonoid composition tables and assessed differences in flavonoid intake by sex, race, and region of residence. Methods: We evaluated 20,024 participants in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a biracial prospective study. Participants with stroke history or missing dietary data were excluded. Flavonoid intake was estimated by using a Block98 food frequency questionnaire and the USDA’s Provisional Flavonoid Addendum and Proanthocyanidin Database. Associations between quintiles of flavonoid intake and incident ischemic stroke were evaluated by using Cox proportional hazards models, adjusting for confounders. Results: Over 6.5 y, 524 acute ischemic strokes occurred. Flavanone intake was lower in the Southeastern United States but higher in blacks than in whites. After multivariable adjustment, flavanone intake was inversely associated with incident ischemic stroke (HR: 0.72; 95% CI: 0.55, 0.95; P-trend = 0.03). Consumption of citrus fruits and juices was inversely associated with incident ischemic stroke (HR: 0.69; 95% CI: 0.53, 0.91; P-trend = 0.02). Total flavonoids and other flavonoid subclasses were not associated with incident ischemic stroke. There was no statistical interaction with sex, race, or region for any flavonoid measure. Conclusions: Greater consumption of flavanones, but not total or other flavonoid subclasses, was inversely associated with incident ischemic stroke. Associations did not differ by sex, race, or region for the association; however, regional differences in flavanone intake may contribute to regional disparities in ischemic stroke incidence. Higher flavanone intake in blacks suggests that flavanone intake is not implicated in racial disparities in ischemic stroke incidence. PMID:27655760

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.

Flavanone Intake Is Inversely Associated with Risk of Incident Ischemic Stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

PubMed

Goetz, Margarethe E; Judd, Suzanne E; Hartman, Terryl J; McClellan, William; Anderson, Aaron; Vaccarino, Viola

2016-11-01

Flavonoids may have beneficial cerebrovascular effects, but evidence from racially and geographically representative cohorts in comprehensive flavonoid databases is lacking. Given racial and geographic disparities in stroke incidence, representative cohort studies are needed. We evaluated the association between flavonoid intake and incident ischemic stroke in a biracial, national cohort using updated flavonoid composition tables and assessed differences in flavonoid intake by sex, race, and region of residence. We evaluated 20,024 participants in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a biracial prospective study. Participants with stroke history or missing dietary data were excluded. Flavonoid intake was estimated by using a Block98 food frequency questionnaire and the USDA's Provisional Flavonoid Addendum and Proanthocyanidin Database. Associations between quintiles of flavonoid intake and incident ischemic stroke were evaluated by using Cox proportional hazards models, adjusting for confounders. Over 6.5 y, 524 acute ischemic strokes occurred. Flavanone intake was lower in the Southeastern United States but higher in blacks than in whites. After multivariable adjustment, flavanone intake was inversely associated with incident ischemic stroke (HR: 0.72; 95% CI: 0.55, 0.95; P-trend = 0.03). Consumption of citrus fruits and juices was inversely associated with incident ischemic stroke (HR: 0.69; 95% CI: 0.53, 0.91; P-trend = 0.02). Total flavonoids and other flavonoid subclasses were not associated with incident ischemic stroke. There was no statistical interaction with sex, race, or region for any flavonoid measure. Greater consumption of flavanones, but not total or other flavonoid subclasses, was inversely associated with incident ischemic stroke. Associations did not differ by sex, race, or region for the association; however, regional differences in flavanone intake may contribute to regional disparities in ischemic stroke incidence. Higher flavanone intake in blacks suggests that flavanone intake is not implicated in racial disparities in ischemic stroke incidence. © 2016 American Society for Nutrition.

Matrix Metalloproteinase-9 Mediates the Deleterious Effects of α2-Antiplasmin on Blood-Brain Barrier Breakdown and Ischemic Brain Injury in Experimental Stroke.

PubMed

Singh, Satish; Houng, Aiilyan K; Reed, Guy L

2018-04-15

During acute brain ischemia, α2-antiplasmin markedly enhances brain injury, blood-brain barrier breakdown and matrix metalloproteinase-9 (MMP-9) expression. Although α2-antiplasmin inhibits fibrin thrombus-degradation, and MMP-9 is a collagen-degrading enzyme altering blood-brain barrier, both have similar deleterious effects on the ischemic brain. We examined the hypothesis that MMP-9 is an essential downstream mediator of α2-antiplasmin's deleterious effects during brain ischemia. Middle cerebral artery thromboembolic stroke was induced in a randomized, blinded fashion in mice with increased blood levels of α2-antiplasmin. There was a robust increase in MMP-9 expression (immunofluorescence) in the ischemic vs. the non-ischemic hemisphere of MMP-9 +/+ but not MMP-9 -/- mice, 24 h after stroke. Brain swelling and hemorrhage were significantly increased in the ischemic vs. the non-ischemic hemisphere of MMP-9 +/+ mice. By comparison to MMP-9 +/+ mice, the ischemic hemispheres of MMP-9 -/- mice showed a ∼6-fold reduction in brain swelling (p < 0.001) and a ∼9-fold reduction in brain hemorrhage. Brain infarction (p < 0.0001) and TUNEL-positive cell death (p < 0.001) were significantly diminished in the ischemic hemisphere of MMP-9 -/- mice vs. MMP-9 +/+ mice. Ischemic breakdown of the blood-brain barrier and fibrin deposition were also significantly reduced in MMP-9 -/- mice vs. MMP-9 +/+ mice (p < 0.05), as measured by quantitative immunofluorescence. We conclude that MMP-9 deficiency ablates many of the deleterious effects of high α2-antiplasmin levels, significantly reducing blood-brain barrier breakdown, TUNEL-positive cell death, brain hemorrhage, swelling and infarction. This suggests that the two molecules may be in a shared pathway in which MMP-9 is essential downstream for the deleterious effects of α2-antiplasmin in ischemic stroke. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury

PubMed Central

Lara-Celador, I.; Goñi-de-Cerio, F.; Alvarez, Antonia; Hilario, Enrique

2013-01-01

One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death. Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes. Among them, the endocannabinoid system emerges as a natural system of neuroprotection. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury. PMID:25206720

Ischemic Stroke After Treatment of Intraprocedural Thrombosis During Stent-Assisted Coiling and Flow Diversion.

PubMed

Adeeb, Nimer; Griessenauer, Christoph J; Moore, Justin M; Foreman, Paul M; Shallwani, Hussain; Motiei-Langroudi, Rouzbeh; Gupta, Raghav; Baccin, Carlos E; Alturki, Abdulrahman; Harrigan, Mark R; Siddiqui, Adnan H; Levy, Elad I; Ogilvy, Christopher S; Thomas, Ajith J

2017-04-01

Intraprocedural thrombosis poses a formidable challenge during neuroendovascular procedures because the risks of aggressive thromboembolic treatment must be balanced against the risk of postprocedural hemorrhage. The aim of this study was to identify predictors of ischemic stroke after intraprocedural thrombosis after stent-assisted coiling and pipeline embolization device placement. A retrospective analysis of intracranial aneurysms treated with stent-assisted coiling or pipeline embolization device placement between 2007 and 2016 at 4 major academic institutions was performed to identify procedures that were complicated by intraprocedural thrombosis. Intraprocedural thrombosis occurred in 34 (4.6%) procedures. Postprocedural ischemic stroke and hemorrhage occurred in 20.6% (7/34) and 11.8% (4/34) of procedures complicated by intraprocedural thrombosis, respectively. Current smoking was an independent predictor of ischemic stroke. There was no statistically significant difference in the rate of ischemic stroke or postprocedural hemorrhage with the use of abciximab compared with the use of eptifibatide in treatment of intraprocedural thrombosis. Current protocols for treatment of intraprocedural thrombosis associated with placement of intra-arterial devices were effective in preventing ischemic stroke in ≈80% of cases. Current smoking was the only independent predictor of ischemic stroke. © 2017 American Heart Association, Inc.

[Effect of Chinese drugs for activating blood circulation and removing blood stasis on carotid atherosclerosis and ischemic cerebrovascular events].

PubMed

Lu, Yan; Li, Tao

2014-03-01

To explore the effect of Chinese drugs for activating blood circulation and removing blood stasis (CDABCRBS) on carotid atherosclerotic plaque and long-term ischemic cerebrovascular events. By using open and control method, effect of 4 groups of platelet antagonists, platelet antagonists + CDABCRBS, platelet antagonists +atorvastatin, platelet antagonists +atorvastatin +CDABCRBS on carotid atherosclerotic plaque and long-term ischemic cerebrovascular events of 90 cerebral infarction patients were analyzed. Through survival analysis, there was no statistical difference in the effect of the 4 interventions on the variation of carotid stenosis rates or ischemic cerebrovascular events (P > 0.05). The occurrence of ischemic cerebrovascular events could be postponed by about 4 months in those treated with platelet antagonists + CDABCRBS and platelet antagonists + atorvastatin +CDABCRBS. By multivariate Logistic analysis, age, hypertension, and clopidogrel were associated with stenosis of extracranial carotid arteries (P <0.05). Age, diabetes, aspirin, clopidogrel, CDABCRBS were correlated with cerebrovascular accidents (P < 0.05). Whether or not accompanied with hypertension is an influential factor for carotid stenosis, but it does not affect the occurrence of ischemic cerebrovascular events. CDABCRBS could effectively prolong the occurrence time of ischemic cerebrovascular events.

Protective effect of agmatine on ischemia/reperfusion-induced renal injury in rats.

PubMed

Sugiura, Takahiro; Tsutsui, Hidenobu; Takaoka, Masanori; Kobuchi, Shuhei; Hayashi, Kentaro; Fujii, Toshihide; Matsumura, Yasuo

2008-03-01

Enhanced renal sympathetic nerve activity (RSNA) during ischemic period and the renal venous norepinephrine (NE) overflow after reperfusion play important roles in the development of ischemic/reperfusion (I/R)-induced acute renal failure (ARF) in rats. This study evaluated whether agmatine, which is known to reduce sympathetic nerve activity and NE overflow by electrical stimulation, would prevent the I/R-induced renal dysfunction. Ischemic ARF was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion 2 weeks after the contralateral nephrectomy. Intravenous (IV) injection of agmatine (100 and 300 micromol/kg) to ischemic ARF rats dose-dependently suppressed the enhanced RSNA and attenuated the I/R-induced renal dysfunction and histological damage. Intracerebroventricular (ICV) injection of agmatine (600 nmol/kg) to ischemic ARF rats suppressed the enhanced RSNA during the ischemic period and attenuated the I/R-induced renal injury. Furthermore, both IV and ICV injection of agmatine significantly suppressed the renal venous NE overflow after the reperfusion. These results indicate that agmatine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppression of the enhanced RSNA during ischemic period and NE overflow from renal sympathetic nerve endings.

Consequences of age on ischemic wound healing in rats: altered antioxidant activity and delayed wound closure.

PubMed

Moor, Andrea N; Tummel, Evan; Prather, Jamie L; Jung, Michelle; Lopez, Jonathan J; Connors, Sarah; Gould, Lisa J

2014-04-01

Advertisements targeted at the elderly population suggest that antioxidant therapy will reduce free radicals and promote wound healing, yet few scientific studies substantiate these claims. To better understand the potential utility of supplemental antioxidant therapy for wound healing, we tested the hypothesis that age and tissue ischemia alter the balance of endogenous antioxidant enzymes. Using a bipedicled skin flap model, ischemic and non-ischemic wounds were created on young and aged rats. Wound closure and the balance of the critical antioxidants superoxide dismutase and glutathione in the wound bed were determined. Ischemia delayed wound closure significantly more in aged rats. Lower superoxide dismutase 2 and glutathione in non-ischemic wounds of aged rats indicate a basal deficit due to age alone. Ischemic wounds from aged rats had lower superoxide dismutase 2 protein and activity initially, coupled with decreased ratios of reduced/oxidized glutathione and lower glutathione peroxidase activity. De novo glutathione synthesis, to restore redox balance in aged ischemic wounds, was initiated as evidenced by increased glutamate cysteine ligase. Results demonstrate deficiencies in two antioxidant pathways in aged rats that become exaggerated in ischemic tissue, culminating in profoundly impaired wound healing and prolonged inflammation.

An atomistic simulation scheme for modeling crystal formation from solution.

PubMed

Kawska, Agnieszka; Brickmann, Jürgen; Kniep, Rüdiger; Hochrein, Oliver; Zahn, Dirk

2006-01-14

We present an atomistic simulation scheme for investigating crystal growth from solution. Molecular-dynamics simulation studies of such processes typically suffer from considerable limitations concerning both system size and simulation times. In our method this time-length scale problem is circumvented by an iterative scheme which combines a Monte Carlo-type approach for the identification of ion adsorption sites and, after each growth step, structural optimization of the ion cluster and the solvent by means of molecular-dynamics simulation runs. An important approximation of our method is based on assuming full structural relaxation of the aggregates between each of the growth steps. This concept only holds for compounds of low solubility. To illustrate our method we studied CaF2 aggregate growth from aqueous solution, which may be taken as prototypes for compounds of very low solubility. The limitations of our simulation scheme are illustrated by the example of NaCl aggregation from aqueous solution, which corresponds to a solute/solvent combination of very high salt solubility.

Sensitivity analysis of conservative and reactive stream transient storage models applied to field data from multiple-reach experiments

USGS Publications Warehouse

Gooseff, M.N.; Bencala, K.E.; Scott, D.T.; Runkel, R.L.; McKnight, Diane M.

2005-01-01

The transient storage model (TSM) has been widely used in studies of stream solute transport and fate, with an increasing emphasis on reactive solute transport. In this study we perform sensitivity analyses of a conservative TSM and two different reactive solute transport models (RSTM), one that includes first-order decay in the stream and the storage zone, and a second that considers sorption of a reactive solute on streambed sediments. Two previously analyzed data sets are examined with a focus on the reliability of these RSTMs in characterizing stream and storage zone solute reactions. Sensitivities of simulations to parameters within and among reaches, parameter coefficients of variation, and correlation coefficients are computed and analyzed. Our results indicate that (1) simulated values have the greatest sensitivity to parameters within the same reach, (2) simulated values are also sensitive to parameters in reaches immediately upstream and downstream (inter-reach sensitivity), (3) simulated values have decreasing sensitivity to parameters in reaches farther downstream, and (4) in-stream reactive solute data provide adequate data to resolve effective storage zone reaction parameters, given the model formulations. Simulations of reactive solutes are shown to be equally sensitive to transport parameters and effective reaction parameters of the model, evidence of the control of physical transport on reactive solute dynamics. Similar to conservative transport analysis, reactive solute simulations appear to be most sensitive to data collected during the rising and falling limb of the concentration breakthrough curve. ?? 2005 Elsevier Ltd. All rights reserved.

[Cohort study of ischemic heart disease among 1817 workers in a foundry].

PubMed

Lu, Yang; Zhang, Min

2012-09-01

To determine the risk of ischemic heart disease among foundry workers and the exposure-response relationship between the risk and foundry work and cumulative exposure to silica dust, and to establish a regression model to predict the risk for developing ischemic heart disease by a given length of employment and exposure to silica dust in foundry workers. Cohort study was conducted, following-up workers in an automobile foundry employed for more than one year during January 1, 1980 to December 31, 1996 as cohort members. In total, 30 years were followed to December 31, 2009. In cohort, workers exposed to pouring, sand preparation, cast shakeout and finishing, melting, overhead crane operation, moulding and core-making were in foundry group, and auxiliary workers at the same factory, such as electricians, fitters, and inspectors were in control group. The risk of ischemic heart disease among foundry workers and the exposure-response relationship between the risk and foundry work and cumulative exposure to silica dust were analyzed with cox regression model using SPSS software, and a logistic regression model was established for prediction of risk for developing ischemic heart disease at a given length of employment and exposure to silica dust in foundry workers. Totally, 1817 workers were followed-up for 45 553.05 person-years during 30 years, with 156 cases of ischemic heart disease and incidence of 342.46 per 100 000 person-years. And the average age at onset was 51.46 years and duration of employment at onset was 21.61 years. Results showed that male, smoking, alcohol drinking, age and duration of employment were risk factors for ischemic heart disease. Risk of ischemic heart disease in foundry workers positively correlated with cumulative silica exposure, and the risk of ischemic heart disease increased by 75.8 percent (RR = 1.758, 95% CI 1.221-2.532) with cumulative silica exposure of 1 mg/m3 x year, adjusted for smoking. And risk of ischemic heart disease was significantly higher in the exposed group than that in the control one. Compared with control group workers, risk of ischemic heart disease increased by 1.048 folds, 1.395 folds, 70.4 percent, 97.0 percent and 1.270 folds among workers exposed to sand preparation, cast shakeout and finishing, melting, moulding and core-making, respectively, adjusted for smoking. Based on the predictive of model, risk for developing ischemic heart disease increased with the length of employment and exposure to silica dust in foundry workers. Workers in foundry face high risk of ischemic heart disease. Risk of ischemic heart disease varies by job, which is higher in workers exposed to sand preparation, cast shakeout and finishing, melting, moulding and core-making. Both foundry work and cumulative exposure to silica are risk factors. The model for prediction of risk for developing ischemic heart disease at a given length of employment and exposure to silica dust in foundry workers resulted in a valid exposure-response relationship.

Identifying and managing chest pain in women.

PubMed

Wyant, Andrew R; Collett, DeShana

2015-01-01

Heart disease continues to be the leading cause of death in women in the United States. Sex disparities remain despite research highlighting the unique aspects of managing women with ischemic heart disease. Increased mortality in women may be related to the critical differences in the clinical presentation of ischemic heart disease between the sexes. Sex-related differences in the pathophysiology of ischemic heart disease also influence diagnostic testing and management. This article reviews the differences in diagnosis and management between men and women with ischemic heart disease.

Comparison of Risk Factor Control in the Year After Discharge for Ischemic Stroke Versus Acute Myocardial Infarction.

PubMed

Bravata, Dawn M; Daggy, Joanne; Brosch, Jared; Sico, Jason J; Baye, Fitsum; Myers, Laura J; Roumie, Christianne L; Cheng, Eric; Coffing, Jessica; Arling, Greg

2018-02-01

The Veterans Health Administration has engaged in quality improvement to improve vascular risk factor control. We sought to examine blood pressure (<140/90 mm Hg), lipid (LDL [low-density lipoprotein] cholesterol <100 mg/dL), and glycemic control (hemoglobin A1c <9%), in the year post-hospitalization for acute ischemic stroke or acute myocardial infarction (AMI). We identified patients who were hospitalized (fiscal year 2011) with ischemic stroke, AMI, congestive heart failure, transient ischemic attack, or pneumonia/chronic obstructive pulmonary disease. The primary analysis compared risk factor control after incident ischemic stroke versus AMI. Facilities were included if they cared for ≥25 ischemic stroke and ≥25 AMI patients. A generalized linear mixed model including patient- and facility-level covariates compared risk factor control across diagnoses. Forty thousand two hundred thirty patients were hospitalized (n=75 facilities): 2127 with incident ischemic stroke and 4169 with incident AMI. Fewer stroke patients achieved blood pressure control than AMI patients (64%; 95% confidence interval, 0.62-0.67 versus 77%; 95% confidence interval, 0.75-0.78; P <0.0001). After adjusting for patient and facility covariates, the odds of blood pressure control were still higher for AMI than ischemic stroke patients (odds ratio, 1.39; 95% confidence interval, 1.21-1.51). There were no statistical differences for AMI versus stroke patients in hyperlipidemia ( P =0.534). Among patients with diabetes mellitus, the odds of glycemic control were lower for AMI than ischemic stroke patients (odds ratio, 0.72; 95% confidence interval, 0.54-0.96). Given that hypertension control is a cornerstone of stroke prevention, interventions to improve poststroke hypertension management are needed. © 2017 The Authors.

Dynamic changes in plasma tissue plasminogen activator, plasminogen activator inhibitor-1 and beta-thromboglobulin content in ischemic stroke.

PubMed

Zhuang, Ping; Wo, Da; Xu, Zeng-Guang; Wei, Wei; Mao, Hui-ming

2015-07-01

The aim of this paper is to investigate the corresponding variations of plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activities, and beta-thromboglobulin (β-TG) content in patients during different stages of ischemic stroke. Ischemic stroke is a common disease among aging people and its occurrence is associated with abnormalities in the fibrinolytic system and platelet function. However, few reports focus on the dynamic changes in the plasma fibrinolytic system and β-TG content in patients with ischemic stroke. Patients were divided into three groups: acute, convalescent and chronic. Plasma t-PA and PAI-1 activities were determined by chromogenic substrate analysis and plasma β-TG content was detected by radioimmunoassay. Patients in the acute stage of ischemic stroke had significantly increased levels of t-PA activity and β-TG content, but PAI-1 activity was significantly decreased. Negative correlations were found between plasma t-PA and PAI-1 activities and between plasma t-PA activity and β-TG content in patients with acute ischemic stroke. There were significant differences in plasma t-PA and PAI-1 activities in the aged control group, as well as in the acute, convalescent and chronic groups. It can be speculated that the increased activity of t-PA in patients during the acute stage was the result of compensatory function, and that the increase in plasma β-TG level not only implies the presence of ischemic stroke but is likely a cause of ischemic stroke. During the later stages of ischemic stroke, greater attention is required in monitoring levels of PAI-1. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Results of thrombolyses procedures in acute ischemic cerebral stroke realized in Kraków 2004-2007--Grant Ministry of Science and Information].

PubMed

Popiela, Tadeusz J; Urbanik, Andrzej; Słowik, Agnieszka

2010-01-01

To lower the number of complications of acute cerebral ischemic stroke and to reduce the time of rehabilitation in these patients it is necessary to induce treatment within the first 3 hours of the onset of the stroke. Early intervention however, is possible only in cases with the confirm localized ischemic focus visualized in one of the diagnostic imaging methods. The most widespread is CT, hovewer the first symptoms of ischemic stroke can be seen not beforel2 hours of the onset. The study evaluated the effectiveness of early diagnostics of ischemic stroke using perfusion CT (pCT) with subsequent intravenous or intra-arterial thrombolysis. The patients with ischemic stroke confirmed by pCT and qualified to thrombolysis in the first 3 hours of the onset of the stroke were randomly selected to intravenous or intra-arterial thrmobolysis. Those, who were 3 to 6 hours of the onset of the stroke were qualified to intra-arterial thrombolysis. A study group consisted of 377 patients hospitalized due to ischemic stroke. Of these pCT was performed in 76 cases, intravenous thrombolysis in 4 and intra-arterial thrombolysis in 2. Clinical condition substantially improved in 3 patients. Obtained results indicate the necessity to introduce pCT to the routine diagnostics of the acute ischemic stroke. A small number of patients eligible for thrombolysis does not allow to compare the effectiveness of intra-arterial and intravenous thrombolysis, however the project allowed to work out the efficient system of diagnostics and treatment of the acute ischemic stroke in the area of Krakow based on the standards used in the European countries.

Effect of Socioeconomic Status and Underlying Disease on the Association between Ambient Temperature and Ischemic Stroke.

PubMed

Cho, Seong Kyung; Sohn, Jungwoo; Cho, Jaelim; Noh, Juhwan; Ha, Kyoung Hwa; Choi, Yoon Jung; Pae, Sangjoon; Kim, Changsoo; Shin, Dong Chun

2018-07-01

Inconsistent findings have been reported regarding the effect of ambient temperature on ischemic stroke. Furthermore, little is known about how underlying disease and low socioeconomic status influence the association. We, therefore, investigated the relationship between ambient temperature and emergency department (ED) visits for ischemic stroke, and aimed to identify susceptible populations. Using medical claims data, we identified ED visits for ischemic stroke during 2005-2009 in Seoul, Korea. We conducted piecewise linear regression analyses to find optimum ambient temperature thresholds in summer and winter, and estimated the relative risks (RR) and 95% confidence intervals (CI) per a 1°C increase in temperature above/below the thresholds, adjusting for relative humidity, holidays, day of the week, and air pollutant levels. There were 63564 ED visits for ischemic stroke. In summer, the risk of ED visits for ischemic stroke was not significant, with the threshold at 26.8°C. However, the RRs were 1.055 (95% CI, 1.006-1.106) above 25.0°C in medical aid beneficiaries and 1.044 (1.007-1.082) above 25.8°C in patients with diabetes. In winter, the risk of ED visits for ischemic stroke significantly increased as the temperature decreased above the threshold at 7.2°C. This inverse association was significant also in patients with hypertension and diabetes mellitus above threshold temperatures. Ambient temperature increases above a threshold were positively associated with ED visits for ischemic stroke in patients with diabetes and medical aid beneficiaries in summer. In winter, temperature, to a point, and ischemic stroke visits were inversely associated. © Copyright: Yonsei University College of Medicine 2018.

Substitution of Linoleic Acid for Other Macronutrients and the Risk of Ischemic Stroke.

PubMed

Venø, Stine K; Schmidt, Erik B; Jakobsen, Marianne U; Lundbye-Christensen, Søren; Bach, Flemming W; Overvad, Kim

2017-12-01

Ischemic stroke is a major health problem worldwide, but the influence of dietary factors on stroke risk is not well known. This study aimed to investigate the risk of ischemic stroke and its subtypes with a higher intake from linoleic acid and a concomitant lower intake from saturated fatty acids, monounsaturated fatty acids, or glycemic carbohydrates. In the Danish prospective Diet, Cancer, and Health Study of 57 053 participants aged 50 to 64 years at baseline, information on diet was collected using a validated semiquantitative food frequency questionnaire. Information on ischemic stroke was obtained from the Danish National Patient Register, and cases were all validated and subclassified according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Substitution of linoleic acid for saturated fatty acid, monounsaturated fatty acid, or glycemic carbohydrates was investigated in relation to the risk of ischemic stroke and subtypes. Cox proportional hazards regression was used to estimate the associations with ischemic stroke adjusting for appropriate confounders. During 13.5 years of follow-up 1879 participants developed ischemic stroke. A slightly lower risk of ischemic stroke was found with a 5% higher intake of linoleic acid and a concomitant lower intake of saturated fatty acid (hazard ratio, 0.98; 95% confidence interval, 0.83-1.16), monounsaturated fatty acid (hazard ratio, 0.80; 95% confidence interval, 0.63-1.02), and glycemic carbohydrates (hazard ratio, 0.92; 95% confidence interval, 0.78-1.09), although not statistically significant. Similar patterns of association were found for large-artery atherosclerosis and small-vessel occlusions. This study suggests that replacing saturated fatty acid, glycemic carbohydrate, or monounsaturated fatty acid with linoleic acid may be associated with a lower risk of ischemic stroke. © 2017 American Heart Association, Inc.

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.

B-type natriuretic peptide predicts an ischemic etiology of acute heart failure in patients with stage 4-5 chronic kidney disease.

PubMed

Kim, Sung Eun; Park, Sunghoon; Kim, Jwa-Kyung; Kim, Sung Gyun; Kim, Hyung Jik; Song, Young Rim

2014-04-01

The non-invasive differentiation of ischemic and non-ischemic acute heart failure (AHF) not resulting from acute myocardial infarction is difficult and has therapeutic and prognostic implications. The aim of this study was to assess whether plasma B-type natriuretic peptide (BNP) can identify ischemic etiology in patients with stage 4-5 chronic kidney disease (CKD) presenting with AHF. We prospectively analyzed 61 patients. The diagnosis of ischemic AHF was confirmed by coronary angiography or stress myocardial perfusion imaging. Plasma levels of BNP were measured at admission (BNP1) and 48 h after admission (BNP2). The mean age of the study patients was 67 years. In these patients, 70.5% had diabetes and 47.5% had dialysis-dependent CKD; 28 of these patients (45.9%) had an ischemic etiology with significantly higher concentrations of BNP1 and BNP2 than did patients without ischemia. The area under the receiver operating characteristic curve was 0.755 (P=0.001) for BNP1 and 0.868 (P<0.001) for BNP2 to detect ischemic etiology of AHF. Plasma BNP1 >2907 ng/L (odds ratio [OR], 10.9; 95% confidence interval [CI] 2.5-48.4; P=0.002) and BNP2 >2322 ng/L (OR 93.1, 95% CI 7.0-1238.7; P=0.001) were independently associated with an ischemic etiology of AHF. Plasma BNP may represent a clinically useful non-invasive tool for identification of ischemic etiology of AHF in patients with stage 4-5 CKD. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Low density lipoprotein receptor related protein-1 and 6 gene variants and ischemic stroke risk

PubMed Central

Harriott, Andrea M.; Heckman, Michael G.; Rayaprolu, Sruti; Soto-Ortolaza, Alexandra I.; Diehl, Nancy N.; Kanekiyo, Takahisa; Liu, Chia-Chen; Bu, Guojun; Malik, Rainer; Cole, John W.; Meschia, James F.; Ross, Owen A.

2015-01-01

Background Low density lipoprotein receptor related proteins-1 and 6 have been implicated in cerebral ischemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischemic stroke as part of the Ischemic Stroke Genetics Study (ISGS). Methods We included a Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls). Fourteen LRP6 variants and 3 LRP1 variants were genotyped and assessed for association with ischemic stroke. Results In the Caucasian series, significant associations with ischemic stroke were observed for LRP6 rs2075241 (OR:0.42, P=0.023), rs2302685 (OR:0.44, P=0.049), rs7975614 (OR: 0.07, P=0.017), rs10492120 (OR: 0.62, P=0.036), and rs10743980 (OR: 0.66, P=0.037). Risk of ischemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non-carriers (OR:0.57, P=0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischemic stroke subtypes, while the effects of rs23022685, rs10492120, and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR:1.89, P=0.006). Conclusions The results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischemic stroke. Validation in larger studies is warranted. PMID:26031789

Neuroprotective Mechanisms of Taurine against Ischemic Stroke

PubMed Central

Menzie, Janet; Prentice, Howard; Wu, Jang-Yen

2013-01-01

Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke. PMID:24961429

Overview of Experimental and Clinical Findings regarding the Neuroprotective Effects of Cerebral Ischemic Postconditioning.

PubMed

Ma, Di; Feng, Liangshu; Deng, Fang; Feng, Jia-Chun

2017-01-01

Research on attenuating the structural and functional deficits observed following ischemia-reperfusion has become increasingly focused on the therapeutic potential of ischemic postconditioning. In recent years, various methods and animal models of ischemic postconditioning have been utilized. The results of these numerous studies have indicated that the mechanisms underlying the neuroprotective effects of ischemic postconditioning may involve reductions in the generation of free radicals and inhibition of calcium overload, as well as the release of endogenous active substances, alterations in membrane channel function, and activation of protein kinases. Here we review the novel discovery, mechanism, key factors, and clinical application of ischemic postconditioning and discuss its implications for future research and problem of clinical practice.

Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents

PubMed Central

Khoshnam, Seyed Esmaeil; Winlow, William; Farbood, Yaghoob; Moghaddam, Hadi Fathi; Farzaneh, Maryam

2017-01-01

Stroke is one of the leading causes of death and physical disability worldwide. The consequences of stroke injuries are profound and persistent, causing in considerable burden to both the individual patient and society. Current treatments for ischemic stroke injuries have proved inadequate, partly owing to an incomplete understanding of the cellular and molecular changes that occur following ischemic stroke. MicroRNAs (miRNA) are endogenously expressed RNA molecules that function to inhibit mRNA translation and have key roles in the pathophysiological processes contributing to ischemic stroke injuries. Potential therapeutic areas to compensate these pathogenic processes include promoting angiogenesis, neurogenesis and neuroprotection. Several miRNAs, and their target genes, are recognized to be involved in these recoveries and repair mechanisms. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique importance in ischemic stroke therapeutics. In this Review, we focus on the role of miRNAs as potential diagnostic and prognostic biomarkers, as well as promising therapeutic agents in cerebral ischemic stroke. PMID:28480877

Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage.

PubMed

Yamada, Yoshiji; Kato, Kimihiko; Oguri, Mitsutoshi; Horibe, Hideki; Fujimaki, Tetsuo; Yasukochi, Yoshiki; Takeuchi, Ichiro; Sakuma, Jun

2018-07-01

Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies (GWASs) have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders remain to be identified definitively. We performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in early-onset subjects with these conditions. A total of 6,649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6,224 individuals (450 subjects with ischemic stroke, 5,774 controls) or 6,179 individuals (261 subjects with ICH, 176 subjects with SAH, 5,742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. The association of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The association of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P<0.0004 (0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P<0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous GWASs, we identified HHIPL2, CTNNA3, LOC643770, UTP20 , and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Therefore, to the best of our knowledge, we have newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Rotating black hole solutions in relativistic analogue gravity

NASA Astrophysics Data System (ADS)

Giacomelli, Luca; Liberati, Stefano

2017-09-01

Simulation and experimental realization of acoustic black holes in analogue gravity systems have lead to a novel understanding of relevant phenomena such as Hawking radiation or superradiance. We explore here the possibility of using relativistic systems for simulating rotating black hole solutions and possibly get an acoustic analogue of a Kerr black hole. In doing so, we demonstrate a precise relation between nonrelativistic and relativistic solutions and provide a new class of vortex solutions for relativistic systems. Such solutions might be used in the future as a test bed in numerical simulations as well as concrete experiments.

Angiogenesis and proliferation of bile duct enhances ischemic tolerance in rats with cirrhosis

PubMed Central

Zhang, Zhiqiang; Li, Zhennan; Zou, Chen; Zhang, Jingjing; Zhu, Yi; Miao, Yi

2015-01-01

Background/aims: Primary biliary cirrhosis (PBC), an autoimmune disease of the liver, is marked by slow progressive destruction of bile ducts. These patients with PBC often undergo orthotopic liver transplantation (OLT). Ischemic bile duct lesion (IBDL) is a major source of morbidity and even mortality after OLT. Cirrhosis of the liver has a higher tolerance to ischemia than a normal liver, but the mechanism remains unknown. Angiogenesis and proliferation of bile duct often responses in bile duct ischemia, which may enhance ischemic tolerance in patients with cirrhosis. Methodology: To test the hypothesis, a rat model with cirrhosis was established. Biochemical indexes of ischemic severity were measured including total bilirubin (TBIL) and direct bilirubin (DBIL). Immunohistochemical assay was performed for Ki67 (a biomarker for the proliferation of bile duct) and CD34 (a biomarker of angiogenesis). Results: The levels were lower for TBIL and DBIL in the bile duct from rat model with cirrhosis than that from a normal rat after ischemic surgery (P < 0.05). The levels were higher for Ki67 and CD34 from a rat model with cirrhosis than that from a normal rat after ischemic surgery (P < 0.05). Conclusions: The results suggest that a liver with cirrhosis has a better ischemic tolerance than a normal liver. Angiogenesis and proliferation of bile duct enhances ischemic tolerance in rats with cirrhosis. More research on the pathogenesis of IBDLs is needed for developing more specific preventive or therapeutic strategies. PMID:26550120

Neuroprotective Effects of Peptides during Ischemic Preconditioning.

PubMed

Zarubina, I V; Shabanov, P D

2016-02-01

Experiments on rats showed that neurospecific protein preparations reduce the severity of neurological deficit, restore the structure of individual behavior of the animals with different hypoxia tolerance, and exert antioxidant action during chronic ischemic damage to the brain unfolding during the early and late phases of ischemic preconditioning.

System Simulation by Recursive Feedback: Coupling A Set of Stand-Alone Subsystem Simulations

NASA Technical Reports Server (NTRS)

Nixon, Douglas D.; Hanson, John M. (Technical Monitor)

2002-01-01

Recursive feedback is defined and discussed as a framework for development of specific algorithms and procedures that propagate the time-domain solution for a dynamical system simulation consisting of multiple numerically coupled self-contained stand-alone subsystem simulations. A satellite motion example containing three subsystems (other dynamics, attitude dynamics, and aerodynamics) has been defined and constructed using this approach. Conventional solution methods are used in the subsystem simulations. Centralized and distributed versions of coupling structure have been addressed. Numerical results are evaluated by direct comparison with a standard total-system simultaneous-solution approach.

Methamphetamine colitis: a rare case of ischemic colitis in a young patient.

PubMed

Holubar, Stefan D; Hassinger, James P; Dozois, Eric J; Masuoka, Howard C

2009-08-01

Worldwide, methamphetamine (ie, "crystal meth") abuse is increasing, and is especially prevalent in rural America. However, ischemic colitis secondary to methamphetamine abuse has rarely been reported. We describe the case of a young man who presented with signs and symptoms suggestive of ischemic colitis.

Myricetin and quercetin attenuate ischemic injury in glial cultures by different mechanisms

USDA-ARS?s Scientific Manuscript database

We have demonstrated that polyphenols from cinnamon and green tea reduce cell swelling and mitochondrial dysfunction in C6 glial cultures following ischemic injury. We tested the protective effects of the flavonoid polyphenols, myricetin and quercetin, on key features of ischemic injury. C6 cultures...

New Approach to Identify Ischemic Stroke Patients at Risk to Develop Hemorrhagic Transformation

PubMed Central

MANOLESCU, Bogdan Nicolae; JICKLING, Glen C.

2012-01-01

ABSTRACT Some patients with ischemic stroke are subject to hemorrhagic transformation, a complication leading to increased patient morbidity and mortality. The discovery of biomarkers that can be used to identify ischemic strokes prone to this complication are very important for the clinical practice because therapy could be altered to mitigate the risk. We discuss here the results of a trial that evaluated for the first time tight junction proteins as biomarkers of blood-brain barrier disruption and hemorrhagic transformation in ischemic stroke. PMID:23482691

[NDT-Bobath method used in the rehabilitation of patients with a history of ischemic stroke].

PubMed

Klimkiewicz, Paulina; Kubsik, Anna; Woldańska-Okońska, Marta

2012-01-01

Ischemic stroke is the third leading cause of death and disability in human. The vitally important problem after ischemic stroke is hemiparesis of the body. The most common methods used in improving the mobility of patients after ischemic stroke is a Bobath-NDT (Neuro-Developmental Treatment - Bobath), which initiated the Berta and Karel Bobath for children with cerebral palsy. It is a method designed to neurophysiological recovery of these vital functions that the patient was lost due to illness, and wants it back.

A dual-porosity model for simulating solute transport in oil shale

USGS Publications Warehouse

Glover, K.C.

1987-01-01

A model is described for simulating three-dimensional groundwater flow and solute transport in oil shale and associated geohydrologic units. The model treats oil shale as a dual-porosity medium by simulating flow and transport within fractures using the finite-element method. Diffusion of solute between fractures and the essentially static water of the shale matrix is simulated by including an analytical solution that acts as a source-sink term to the differential equation of solute transport. While knowledge of fracture orientation and spacing is needed to effectively use the model, it is not necessary to map the locations of individual fractures. The computer program listed in the report incorporates many of the features of previous dual-porosity models while retaining a practical approach to solving field problems. As a result the theory of solute transport is not extended in any appreciable way. The emphasis is on bringing together various aspects of solute transport theory in a manner that is particularly suited to the unusual groundwater flow and solute transport characteristics of oil shale systems. (Author 's abstract)

[Preditive clinical factors for epileptic seizures after ischemic stroke].

PubMed

Fukujima, M M; Cardeal, J O; Lima, J G

1996-06-01

Preditive clinical factors for epileptic seizures after ischemic stroke. Clinical features of 35 patients with ischemic stroke who developed epilepsy (Group 1) were compared with those of 35 patients with ischemic stroke without epilepsy (Group 2). The age of the patients did not differ between the groups. There were more men than women and more white than other races in both groups. Diabetes melitus, hypertension, transient ischemic attack, previous stroke, migraine, Chagas disease, cerebral embolism of cardiac origin and use of oral contraceptive did not differ between the groups. Smokers and alcohol users were more frequent in Group 1 (p < 0.05). Most patients of Group 1 presented with hemiparesis; none presented cerebellar or brainstem involvement. Perhaps strokes in smokers have some different aspects, that let them more epileptogenic than in non smokers.

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

Demonstration of the Rat Ischemic Skin Wound Model

PubMed Central

Sherwood, Jacob; Wu, Mack; Gould, Lisa J.

2015-01-01

The propensity for chronic wounds in humans increases with ageing, disease conditions such as diabetes and impaired cardiovascular function, and unrelieved pressure due to immobility. Animal models have been developed that attempt to mimic these conditions for the purpose of furthering our understanding of the complexity of chronic wounds. The model described herein is a rat ischemic skin flap model that permits a prolonged reduction of blood flow resulting in wounds that become ischemic and resemble a chronic wound phenotype (reduced vascularization, increased inflammation and delayed wound closure). It consists of a bipedicled dorsal flap with 2 ischemic wounds placed centrally and 2 non-ischemic wounds lateral to the flap as controls. A novel addition to this ischemic skin flap model is the placement of a silicone sheet beneath the flap that functions as a barrier and a splint to prevent revascularization and reduce contraction as the wounds heal. Despite the debate of using rats for wound healing studies due to their quite distinct anatomic and physiologic differences compared to humans (i.e., the presence of a panniculus carnosus muscle, short life-span, increased number of hair follicles, and their ability to heal infected wounds) the modifications employed in this model make it a valuable alternative to previously developed ischemic skin flap models. PMID:25866964

Demonstration of the rat ischemic skin wound model.

PubMed

Trujillo, Andrea N; Kesl, Shannon L; Sherwood, Jacob; Wu, Mack; Gould, Lisa J

2015-04-01

The propensity for chronic wounds in humans increases with ageing, disease conditions such as diabetes and impaired cardiovascular function, and unrelieved pressure due to immobility. Animal models have been developed that attempt to mimic these conditions for the purpose of furthering our understanding of the complexity of chronic wounds. The model described herein is a rat ischemic skin flap model that permits a prolonged reduction of blood flow resulting in wounds that become ischemic and resemble a chronic wound phenotype (reduced vascularization, increased inflammation and delayed wound closure). It consists of a bipedicled dorsal flap with 2 ischemic wounds placed centrally and 2 non-ischemic wounds lateral to the flap as controls. A novel addition to this ischemic skin flap model is the placement of a silicone sheet beneath the flap that functions as a barrier and a splint to prevent revascularization and reduce contraction as the wounds heal. Despite the debate of using rats for wound healing studies due to their quite distinct anatomic and physiologic differences compared to humans (i.e., the presence of a panniculus carnosus muscle, short life-span, increased number of hair follicles, and their ability to heal infected wounds) the modifications employed in this model make it a valuable alternative to previously developed ischemic skin flap models.

Elevation of Autoantibody in Patients with Ischemic Stroke.

PubMed

Yoshida, Yoichi; Hiwasa, Takaki; Machida, Toshio; Kobayashi, Eiichi; Mine, Seiichiro; Matsushima, Jun; Takiguchi, Masaki; Iwadate, Yasuo

2018-05-31

Recent clinical research has revealed a significant correlation between atherosclerosis, one of the primary etiologies of ischemic stroke, and the immune system. Assuming that "disease-specific autoantibodies are produced in the sera of patients with ischemic stroke," we investigated multiple arteriosclerosis-related antibodies using the serological identification of antigens by recombinant cDNA expression cloning (SEREX), an established method for identifying antigenic proteins. We either screened a human aortic endothelial cell cDNA library or conducted protein array screening using the sera from patients with ischemic stroke, such as carotid artery stenosis or transient ischemic attack (TIA). Next, we measured serum antibody levels using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in patient/healthy donor (HD) cohorts and identified several antigens, the antibody levels of which were significantly higher in patients with ischemic stroke than in HDs. This review introduced the method of identifying antigens by the SEREX and protein microarray and summarized antigenic proteins. In particular, it focused on anti-replication protein A2 antibody and anti-programmed cell death 11 antibody, which are significantly related to atherosclerotic plaque and ischemic brain tissue, respectively, and proposed the mechanism of elevated autoantibody levels against them. Furthermore, this review suggests a possibility of clinical application as an atherosclerotic disease diagnostic marker for TIA or cerebral infarction.

Limb Remote Ischemic Conditioning: Mechanisms, Anesthetics, and the Potential for Expanding Therapeutic Options

PubMed Central

Chen, Gangling; Thakkar, Mrugesh; Robinson, Christopher; Doré, Sylvain

2018-01-01

Novel and innovative approaches are essential in developing new treatments and improving clinical outcomes in patients with ischemic stroke. Remote ischemic conditioning (RIC) is a series of mechanical interruptions in blood flow of a distal organ, following end organ reperfusion, shown to significantly reduce infarct size through inhibition of oxidation and inflammation. Ischemia/reperfusion (I/R) is what ultimately leads to the irreversible brain damage and clinical picture seen in stroke patients. There have been several reports and reviews about the potential of RIC in acute ischemic stroke; however, the focus here is a comprehensive look at the differences in the three types of RIC (remote pre-, per-, and postconditioning). There are some limited uses of preconditioning in acute ischemic stroke due to the unpredictability of the ischemic event; however, it does provide the identification of biomarkers for clinical studies. Remote limb per- and postconditioning offer a more promising treatment during patient care as they can be harnessed during or after the initial ischemic insult. Though further research is needed, it is imperative to discuss the importance of preclinical data in understanding the methods and mechanisms involved in RIC. This understanding will facilitate translation to a clinically feasible paradigm for use in the hospital setting. PMID:29467715

The Role of Extracellular Adenosine Triphosphate in Ischemic Organ Injury.

PubMed

Zhao, Hailin; Kilgas, Susan; Alam, Azeem; Eguchi, Shiori; Ma, Daqing

2016-05-01

Ischemic tissue injury contributes to significant morbidity and mortality and is implicated in a range of pathologic conditions, including but not limited to myocardial infarction, ischemic stroke, and acute kidney injury. The associated reperfusion phase is responsible for the activation of the innate and adaptive immune system, further accentuating inflammation. Adenosine triphosphate molecule has been implicated in various ischemic conditions, including stroke and myocardial infarction. Adenosine triphosphate is a well-defined intracellular energy transfer and is commonly referred to as the body's "energy currency." However, Laboratory studies have demonstrated that extracellular adenosine triphosphate has the ability to initiate inflammation and is therefore referred to as a damage-associated molecular pattern. Purinergic receptors-dependent signaling, proinflammatory cytokine release, increased Ca influx into cells, and subsequent apoptosis have been shown to form a common underlying extracellular adenosine triphosphate molecular mechanism in ischemic organ injury. In this review, we aim to discuss the molecular mechanisms behind adenosine triphosphate-mediated ischemic tissue injury and evaluate the role of extracellular adenosine triphosphate in ischemic injury in specific organs, in order to provide a greater understanding of the pathophysiology of this complex process. We also appraise potential future therapeutic strategies to limit damage in various organs, including the heart, brain, kidneys, and lungs.

Is endothelial microvascular function equally impaired among patients with chronic Chagas and ischemic cardiomyopathy?

PubMed

Borges, Juliana Pereira; Mendes, Fernanda de Souza Nogueira Sardinha; Lopes, Gabriella de Oliveira; Sousa, Andréa Silvestre de; Mediano, Mauro Felippe Felix; Tibiriçá, Eduardo

2018-08-15

Chronic Chagas cardiomyopathy (CCC) and cardiomyopathies due to other etiologies involve differences in pathophysiological pathways that are still unclear. Systemic microvascular abnormalities are associated with the pathogenesis of ischemic heart disease. However, systemic microvascular endothelial function in CCC remains to be elucidated. Thus, we compared the microvascular endothelial function of patients presenting with CCC to those with ischemic cardiomyopathy disease. Microvascular reactivity was assessed in 21 patients with cardiomyopathy secondary to Chagas disease, 21 patients with cardiomyopathy secondary to ischemic disease and 21 healthy controls. Microvascular blood flow was assessed in the skin of the forearm using laser speckle contrast imaging coupled with iontophoresis of acetylcholine (ACh). Peak increase in forearm blood flow with ACh iontophoresis in relation to baseline was greater in healthy controls than in patients with heart disease (controls: 162.7 ± 58.4% vs. ischemic heart disease: 74.1 ± 48.3% and Chagas: 85.1 ± 68.1%; p < 0.0001). Patients with Chagas and ischemic cardiomyopathy presented similar ACh-induced changes from baseline in skin blood flow (p = 0.55). Endothelial microvascular function was equally impaired among patients with CCC and ischemic cardiomyopathy. Copyright © 2018 Elsevier B.V. All rights reserved.

[Malondialdehyde and reduced glutathione increase in patients with chronic stable ischaemic cardiopathy].

PubMed

Cabrera de Bravo, Mayela Carolina; Bermúdez Pirela, Valmore José; Bermúdez Arias, Fernando; Cano Ponce, Clímaco; Mengual Moreno, Edgardo José; Leal González, Elliuz Marina

2005-03-19

Cardiovascular diseases are associated with the ischemia/reperfusion phenomena and therefore to the oxidation/antioxidation balance. The aim of this study was to determine malondialdehyde, nitric oxide, glutathione, ascorbic and dehydroascorbic acid in patients with chronic ischemic heart disease. 32 male patients, with chronic ischemic heart disease, between 40 and 60 years of age were studied. These individuals were divided in two groups: 16 with hypertension and 16 without hypertension. Both groups were compared with 31 healthy male subjects (control group). Significant differences (p < 0.001) was observed in malondialdehyde between no-hypertension ischemic group: 5.3 (1.5) microM and the hypertension ischemic group: 4.8 (1.3) microM in contrast with the healthy group: 2.2 (0.5) microM. Hypertension ischemic group showed significant greater reduced glutation levels: 286.1 (31.4) microg/ml than control group 262.0 (38.8) microg/ml; p < 0.03 and no-hypertension ischemic group: 256.4 (41.5) microg/ml; p < 0.02. No significant difference in the rest of the parameters for all study groups. Oxidation/antioxidation balance during chronic ischemic heart disease can be considered as a good metabolic ischemia indicator, that used in the monitoring and therapeutic evaluation could detect molecular changes that anticipate installation of tissue damage.

A novel Tc-99m and fluorescence labeled peptide as a multimodal imaging agent for targeting angiogenesis in a murine hindlimb ischemia model.

PubMed

Hyoun Kim, Myoung; Kim, Seul-Gi; Guhn Kim, Chang; Kim, Dae-Weung

2017-03-01

The serine-aspartic acid-valine (SDV) peptide binds specifically to integrin αvβ3. We developed a Tc-99m and TAMRA labeled peptide, Tc-99m SDV-ECG-K-TAMRA for multimodal imaging of angiogenesis. Tc-99m SDV-ECG-K-TAMRA was prepared in high yield (>96%) and showed low cytotoxicity. Tc-99m tetrofosmin images 1 week after operation, revealed significantly decreased perfusion of the ischemic hindlimb, and the perfusion recovered gradually for 4 weeks. In contrast, Tc-99m SDV-ECG-K-TAMRA uptake was maximal 1 week after the operation (ischemic-to-non-ischemic uptake ratio =5.03±1.01) and decreased gradually. The ischemic-to-non-ischemic ratio of Tc-99m SDV-ECG-K-TAMRA and Tc-99m tetrofosmin was strongly negatively correlated (r =-0.94). A postmortem analysis revealed increased angiogenesis markers and uptake of Tc-99m SDV-ECG-K-TAMRA by ischemic tissue. Our in vivo and in vitro studies revealed substantial uptake of Tc-99m SDV-ECG-K-TAMRA by ischemic tissue. Tc-99m SDV-ECG-K-TAMRA could be a good candidate dual-modality imaging agent to assess angiogenesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

PubMed Central

Yoshioka, Hideki; Sato, Hiromi; Hatakeyama, Hiroto

2018-01-01

The noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding. PMID:29760204

Carotid artery phantom designment and simulation using field II

NASA Astrophysics Data System (ADS)

Lin, Yuan; Yang, Xin; Ding, Mingyue

2013-10-01

Carotid atherosclerosis is the major cause of ischemic stroke, a leading cause of mortality and disability. Morphology and structure features of carotid plaques are the keys to identify plaques and monitoring the disease. Manually segmentation on the ultrasonic images to get the best-fitted actual size of the carotid plaques based on physicians personal experience, namely "gold standard", is a important step in the study of plaque size. However, it is difficult to qualitatively measure the segmentation error caused by the operator's subjective factors. In order to reduce the subjective factors, and the uncertainty factors of quantification, the experiments in this paper were carried out. In this study, we firstly designed a carotid artery phantom, and then use three different beam-forming algorithms of medical ultrasound to simulate the phantom. Finally obtained plaques areas were analyzed through manual segmentation on simulation images. We could (1) directly evaluate the different beam-forming algorithms for the ultrasound imaging simulation on the effect of carotid artery; (2) also analyze the sensitivity of detection on different size of plaques; (3) indirectly reflect the accuracy of the manual segmentation base on segmentation results the evaluation.

On the first crossing distributions in fractional Brownian motion and the mass function of dark matter haloes

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

Hiotelis, Nicos; Popolo, Antonino Del, E-mail: adelpopolo@oact.inaf.it, E-mail: hiotelis@ipta.demokritos.gr

We construct an integral equation for the first crossing distributions for fractional Brownian motion in the case of a constant barrier and we present an exact analytical solution. Additionally we present first crossing distributions derived by simulating paths from fractional Brownian motion. We compare the results of the analytical solutions with both those of simulations and those of some approximated solutions which have been used in the literature. Finally, we present multiplicity functions for dark matter structures resulting from our analytical approach and we compare with those resulting from N-body simulations. We show that the results of analytical solutions aremore » in good agreement with those of path simulations but differ significantly from those derived from approximated solutions. Additionally, multiplicity functions derived from fractional Brownian motion are poor fits of the those which result from N-body simulations. We also present comparisons with other models which are exist in the literature and we discuss different ways of improving the agreement between analytical results and N-body simulations.« less

External Validation of Risk Scores for Major Bleeding in a Population-Based Cohort of Transient Ischemic Attack and Ischemic Stroke Patients.

PubMed

Hilkens, Nina A; Li, Linxin; Rothwell, Peter M; Algra, Ale; Greving, Jacoba P

2018-03-01

The S 2 TOP-BLEED score may help to identify patients at high risk of bleeding on antiplatelet drugs after a transient ischemic attack or ischemic stroke. The score was derived on trial populations, and its performance in a real-world setting is unknown. We aimed to externally validate the S 2 TOP-BLEED score for major bleeding in a population-based cohort and to compare its performance with other risk scores for bleeding. We studied risk of bleeding in 2072 patients with a transient ischemic attack or ischemic stroke on antiplatelet agents in the population-based OXVASC (Oxford Vascular Study) according to 3 scores: S 2 TOP-BLEED, REACH, and Intracranial-B 2 LEED 3 S. Performance was assessed with C statistics and calibration plots. During 8302 patient-years of follow-up, 117 patients had a major bleed. The S 2 TOP-BLEED score showed a C statistic of 0.69 (95% confidence interval [CI], 0.64-0.73) and accurate calibration for 3-year risk of major bleeding. The S 2 TOP-BLEED score was much more predictive of fatal bleeding than nonmajor bleeding (C statistics 0.77; 95% CI, 0.69-0.85 and 0.50; 95% CI, 0.44-0.58). The REACH score had a C statistic of 0.63 (95% CI, 0.58-0.69) for major bleeding and the Intracranial-B 2 LEED 3 S score a C statistic of 0.60 (95% CI, 0.51-0.70) for intracranial bleeding. The ratio of ischemic events versus bleeds decreased across risk groups of bleeding from 6.6:1 in the low-risk group to 1.8:1 in the high-risk group. The S 2 TOP-BLEED score shows modest performance in a population-based cohort of patients with a transient ischemic attack or ischemic stroke. Although bleeding risks were associated with risks of ischemic events, risk stratification may still be useful to identify a subgroup of patients at particularly high risk of bleeding, in whom preventive measures are indicated. © 2018 The Authors.

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.

Tamoxifen Use Correlates with Increased Risk of the First Episode of Ischemic Cerebrovascular Disease in Older Women with Breast Cancer: A Case-Control Study in Taiwan

PubMed Central

Lai, Shih-Wei; Lin, Cheng-Li; Liao, Kuan-Fu

2017-01-01

Background and Objectives: There are inconsistent results about the association between ischemic cerebrovascular disease and tamoxifen use in women with breast cancer. The study aimed to evaluate the association between the risk of ischemic cerebrovascular disease and tamoxifen use in older women with breast cancer in Taiwan. Methods: We designed a retrospective, nationwide, case-control study using the database of the Taiwan National Health Insurance Program. A total of 800 female subjects with breast cancer aged ≥65 years with the first episode of ischemic cerebrovascular disease from 2000 to 2011 were identified as the cases. Additionally, 2,876 female subjects with breast cancer aged ≥65 years without any type of cerebrovascular diseases were selected as the control subjects. The cases and the control subjects were matched with age and comorbidities. Ever use of tamoxifen was defined as a subject who had at least a prescription for tamoxifen before the index date. Never use of tamoxifen was defined as a subject who never had a prescription for tamoxifen before the index date. We used the multivariable logistic regression model to calculate the odds ratio (OR) and 95% confidence interval (CI) for ischemic cerebrovascular disease associated with tamoxifen use. Results: After adjusting for confounding variables, the adjusted OR of ischemic cerebrovascular disease was 2.5 for subjects with ever use of tamoxifen (95% CI 2.10, 2.97), compared with never use of tamoxifen. In addition, the adjusted OR of ischemic cerebrovascular disease was 1.15 (95% CI 1.10, 1.21) in subjects with ever use of tamoxifen as increase in use duration per 1 year. The adjusted OR of ischemic cerebrovascular disease was 2.54 (95% CI 2.03, 3.17) in subjects with ever use of tamoxifen as increase in dosage per 1 mg. Conclusions: Tamoxifen use is significantly associated with 2.5-fold increased odds of ischemic cerebrovascular disease among older women with breast cancer in Taiwan. There are duration-dependent and dose-dependent effects of tamoxifen use on the risk of ischemic cerebrovascular disease. PMID:29089895

Increased circulating leukocyte-derived microparticles in ischemic cerebrovascular disease.

PubMed

He, Zhangping; Tang, Yanyan; Qin, Chao

2017-06-01

Circulating leukocyte-derived microparticles act as proinflammatory mediators that reflect vascular inflammation. In this study, we examined the hypothesis that the quantity of leukocyte-derived microparticles is increased in patients with ischemic cerebrovascular diseases, and investigated utility of various phenotypes of leukocyte-derived microparticles as specific biomarkers of vascular inflammation injury. Additionally we focused on identifying leukocyte-derived microparticles that may be correlated with stroke severity in acute ischemic stroke patients. The plasma concentration of leukocyte-derived microparticles obtained by a series of centrifugations of 76 consecutive patients with ischemic cerebrovascular diseases and 70 age-, sex-, and race-matched healthy controls were determined by flow cytometry. Significantly elevated numbers of leukocyte (CD45+), monocyte (CD14+), lymphocyte (CD4+), granulocyte (CD15+) derived microparticles were found in the plasma samples of patients ischemic cerebrovascular diseases, compared to healthy controls (p<0.05). Furthermore, the plasma levels of CD14+ microparticles were significantly correlated with stroke severity (r=0.355, p=0.019), cerebral vascular stenosis severity (r=0.255, p=0.025) and stroke subtype (r=0.242, p=0.036). No association with stroke was observed for other leukocyte-derived phenotypes. These results demonstrate that circulating leukocyte-derived microparticles amounts are increased in patients with ischemic cerebrovascular diseases, compared with healthy controls. As proinflammatory mediators, leukocyte-derived microparticles may contribute to vascular inflammatory and the inflammatory process in acute ischemic stroke. Levels of CD14+ microparticles may be a promising biomarker of ischemic severity and outcome of stroke in the clinic. Copyright © 2017 Elsevier Ltd. All rights reserved.

ZNF208 polymorphisms associated with ischemic stroke in a southern Chinese Han population.

PubMed

Yu, Jianzhong; Zhou, Feng; Luo, Dong; Wang, Nianzhen; Zhang, Chong; Jin, Tianbo; Liang, Xiongfei; Yu, Dan

2017-01-01

Ischemic stroke is one of the most common diseases with a high burden of neurological deficits, disability and death. Zinc finger protein 208 (ZNF208) was found to be involved in coronary heart disease, although little information is available about its association with ischemic stroke. We performed the present case-control study to clarify the association between single-nucleotide polymorphisms (SNPs) within ZNF208 and the risk of ischemic stroke in a southern Chinese Han population. A total of 799 subjects (400 cases and 399 healthy controls) were enrolled in the present study. Five SNPs within ZNF208 gene were selected and genotyped using Sequenom MassARRY technology (Sequenom, Inc., San Diego, CA, USA). Data management and statistical analyses were conducted using Sequenom Typer, version 4.0, and a chi-squared test, as well as unconditional logistic regression. Statistical results showed that three variants were associated with the risk of ischemic stroke under allele models (rs2188971, rs2188972, rs8103163 and rs7248488). The variant rs2188972 was also associated with the risk of ischemic stroke in a recessive model after adjustment for age and sex. Haplotype analysis suggested that a significant difference existed between the A rs2188972 T rs2188971 A rs8103163 A rs7248488 haplotype and the risk of ischemic stroke, although this disappeared after adjustment for sex and age. The results obtained in the present study indicate a potential association between ZNF208 variants and the risk of ischemic risk in a southern Chinese Han population. Copyright © 2016 John Wiley & Sons, Ltd.

Short-Term Exposure to Fine Particulate Matter and Risk of Ischemic Stroke.

PubMed

Matsuo, Ryu; Michikawa, Takehiro; Ueda, Kayo; Ago, Tetsuro; Nitta, Hiroshi; Kitazono, Takanari; Kamouchi, Masahiro

2016-12-01

There is a strong association between ambient concentrations of particulate matter (PM) and cardiovascular disease. However, it remains unclear whether acute exposure to fine PM (PM 2.5 ) triggers ischemic stroke events and whether the timing of exposure is associated with stroke risk. We, therefore, examined the association between ambient PM 2.5 and occurrence of ischemic stroke. We analyzed data for 6885 ischemic stroke patients from a multicenter hospital-based stroke registry in Japan who were previously independent and hospitalized within 24 hours of stroke onset. Time of symptom onset was confirmed, and the association between PM (suspended PM and PM 2.5 ) and occurrence of ischemic stroke was analyzed by time-stratified case-crossover analysis. Ambient PM 2.5 and suspended PM at lag days 0 to 1 were associated with subsequent occurrence of ischemic stroke (ambient temperature-adjusted odds ratio [95% confidence interval] per 10 μg/m 3 : suspended PM, 1.02 [1.00-1.05]; PM 2.5 , 1.03 [1.00-1.06]). In contrast, ambient suspended PM and PM 2.5 at lag days 2 to 3 or 4 to 6 showed no significant association with stroke occurrence. The association between PM 2.5 at lag days 0 to 1 and ischemic stroke was maintained after adjusting for other air pollutants (nitrogen dioxide, photochemical oxidants, or sulfur dioxide) or influenza epidemics and was evident in the cold season. These findings suggest that short-term exposure to PM 2.5 within 1 day before onset is associated with the subsequent occurrence of ischemic stroke. © 2016 American Heart Association, Inc.

Psychosocial work environment and risk of ischemic stroke and coronary heart disease: a prospective longitudinal study of 75 236 construction workers.

PubMed

Schiöler, Linus; Söderberg, Mia; Rosengren, Annika; Järvholm, Bengt; Torén, Kjell

2015-05-01

The present study aimed to investigate whether different dimensions of psychosocial stress, as measured by the job demand-control model (JDC), were associated with increased risks of ischemic stroke and coronary heart disease (CHD). A cohort of 75 236 male construction workers was followed from 1989-2004. Exposure to psychosocial stress was determined by a questionnaire answered in 1989-1993. Events of ischemic stroke and CHD were found by linkage to the Swedish Causes of Death and National Patient registers. Hazard ratios (HR) were obtained from Cox regression models, adjusted for age, smoking habits, body mass index and systolic blood pressure. There were 1884 cases of CHD and 739 cases of ischemic stroke. Regarding ischemic stroke, no association was found between job demands [HR 1.12, 95% confidence interval (95% CI) 0.89-1.40, highest versus lowest quintile] or job control (HR 1.04, 95% CI 0.82-1.32, lowest versus highest quintile). Regarding CHD, job demands were associated to CHD (HR 1.18, 95% CI 1.02-1.37, highest vs. lowest quintile), but no consistent trend was seen among quintiles. The results were inconsistent in relation to job control. The division of JDC into four categories showed no significant associations with either ischemic stroke or CHD. This exploratory study showed no significant associations between psychosocial work environment and ischemic stroke, and the associations between job demands and control and CHD were inconsistent and weak. The combination of job control and job demand showed no significant associations with either ischemic stroke or CHD.

Elevated visfatin/pre-B-cell colony-enhancing factor plasma concentration in ischemic stroke.

PubMed

Lu, Li-Fen; Yang, Sheng-Shan; Wang, Chao-Ping; Hung, Wei-Chin; Yu, Teng-Hung; Chiu, Cheng-An; Chung, Fu-Mei; Shin, Shyi-Jang; Lee, Yau-Jiunn

2009-01-01

Visfatin/pre-B-cell colony-enhancing factor is a cytokine that is expressed as a protein in several tissues (e.g., liver, skeletal muscle, immune cells), including adipose tissue, and is reported to stimulate inflammatory cytokine expressions and promote vascular smooth cell maturation. Visfatin may act as a proinflammatory cytokine and be involved in the process of atherosclerosis. In this study, we investigated whether plasma visfatin levels were altered in patients with ischemic stroke. Plasma visfatin concentrations were measured through enzyme immunoassays in patients with ischemic stroke and in control subjects without stroke. The mean plasma concentration of visfatin in the 120 patients with ischemic stroke was significantly higher than that of the 120 control subjects without stroke (51.5 +/- 48.4 v 23.0 +/- 23.9 ng/mL, P < .001). Multiple logistic regression analysis confirmed plasma visfatin to be an independent factor associated with ischemic stroke. Increasing concentrations of visfatin were independently and significantly associated with a higher risk of ischemic stroke when concentrations were analyzed as both a quartile and a continuous variable. The multiple logistic regression analysis-adjusted odds ratios and 95% confidence intervals for ischemic stroke in the second, third, and fourth quartiles were 2.3 (0.7-7.7), 6.9 (2.2-23.3), and 20.1 (4.9-97.7), respectively. Plasma visfatin concentration was positively associated with high-sensitivity C-reactive protein levels and negatively associated with low-density lipoprotein cholesterol. Our results indicate that higher visfatin levels are associated with ischemic stroke in the Chinese population.

Mangiferin Protects Retinal Ganglion Cells in Ischemic Mouse Retina via SIRT1.

PubMed

Kim, Soo-Jin; Sung, Mi-Sun; Heo, Hwan; Lee, Jae-Hyuk; Park, Sang-Woo

2016-06-01

To investigate whether mangiferin can increase the viability of retinal ganglion cells (RGCs) in ischemic mouse retina, and to determine the possible mechanism of neuroprotection. C57BL/6J mice underwent constant elevation of intraocular pressure for 60 min and received saline or mangiferin (30 mg/kg) intraperitoneally once daily until sacrifice. HIF-1α, GFAP and SIRT1 expression was assessed at 1, 4, and 7 days after retinal ischemia. Bax and Bcl-2 expression was also analyzed at 1 and 4 days. RGC survival was assessed by labeling flat-mounted retinas with Brn3a at 2 weeks after retinal ischemia. The effect of co-treatment with mangiferin and sirtinol (SIRT1 inhibitor) was also evaluated. The expression of HIF-1α and GFAP was upregulated in saline-treated retinas within 7 days after ischemia. Mangiferin treatment suppressed this upregulation. The expression of SIRT1 was downregulated in saline-treated ischemic retinas. This downregulation was reversed by mangiferin treatment, resulting in a significant difference from saline-treated ischemic retinas. In mangiferin-treated ischemic retinas, Bax expression was downregulated, whereas Bcl-2 expression was upregulated in comparison with saline-treated ischemic retinas. Mangiferin treatment protected ischemic retinas against RGC loss. Treatment of sirtinol decreased the neuroprotective effect of mangiferin. Our findings suggest that mangiferin has a neuroprotective effect on RGC through downregulation of HIF-1a and GFAP, and upregulation of SIRT1 in ischemic mouse retinas. We suggest that mangiferin might be a potential neuroprotective agent against RGC loss under oxidative stress.

Rationale and Study Design for a Single-Arm Phase IIa Study Investigating Feasibility of Preventing Ischemic Cerebrovascular Events in High-Risk Patients with Acute Non-disabling Ischemic Cerebrovascular Events Using Remote Ischemic Conditioning

PubMed Central

Liu, Shi-Meng; Zhao, Wen-Le; Song, Hai-Qing; Meng, Ran; Li, Si-Jie; Ren, Chang-Hong; Ovbiagele, Bruce; Ji, Xun-Ming; Feng, Wu-Wei

2018-01-01

Background: Acute minor ischemic stroke (AMIS) or transient ischemic attack (TIA) is a common cerebrovascular event with a considerable high recurrence. Prior research demonstrated the effectiveness of regular long-term remote ischemic conditioning (RIC) in secondary stroke prevention in patients with intracranial stenosis. We hypothesized that RIC can serve as an effective adjunctive therapy to pharmacotherapy in preventing ischemic events in patients with AMIS/TIA. This study aimed to investigate the feasibility, safety, and preliminary efficacy of daily RIC in inhibiting cerebrovascular/cardiovascular events after AMIS/TIA. Methods: This is a single-arm, open-label, multicenter Phase IIa futility study with a sample size of 165. Patients with AMIS/TIA receive RIC as an additional therapy to secondary stroke prevention regimen. RIC consists of five cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuffs on bilateral upper limbs twice a day for 90 days. The antiplatelet strategy is based on individual physician's best practice: aspirin alone, clopidogrel alone, or combination of aspirin and clopidogrel. We will assess the recurrence rate of ischemic stroke/TIA within 3 months as the primary outcomes. Conclusions: The data gathered from the study will be used to determine whether a further large-scale, multicenter randomized controlled Phase II trial is warranted in patients with AMIS/TIA. Trial Registration: ClinicalTrials.gov, NCT03004820; https://www.clinicaltrials.gov/ct2/show/NCT03004820. PMID:29363651

The effect of ICD programming on inappropriate and appropriate ICD Therapies in ischemic and nonischemic cardiomyopathy: the MADIT-RIT trial.

PubMed

Sedláček, Kamil; Ruwald, Anne-Christine; Kutyifa, Valentina; McNitt, Scott; Thomsen, Poul Erik Bloch; Klein, Helmut; Stockburger, Martin; Wichterle, Dan; Merkely, Bela; DE LA Concha, Joaquin Fernandez; Swissa, Moshe; Zareba, Wojciech; Moss, Arthur J; Kautzner, Josef; Ruwald, Martin H

2015-04-01

The MADIT-RIT trial demonstrated reduction of inappropriate and appropriate ICD therapies and mortality by high-rate cut-off and 60-second-delayed VT therapy ICD programming in patients with a primary prophylactic ICD indication. The aim of this analysis was to study effects of MADIT-RIT ICD programming in patients with ischemic and nonischemic cardiomyopathy. First and total occurrences of both inappropriate and appropriate ICD therapies were analyzed by multivariate Cox models in 791 (53%) patients with ischemic and 707 (47%) patients with nonischemic cardiomyopathy. Patients with ischemic and nonischemic cardiomyopathy had similar incidence of first inappropriate (9% and 11%, P = 0.21) and first appropriate ICD therapy (11.6% and 14.1%, P = 0.15). Patients with ischemic cardiomyopathy had higher mortality rate (6.1% vs. 3.3%, P = 0.01). MADIT-RIT high-rate cut-off (arm B) and delayed VT therapy ICD programming (arm C) compared with conventional (arm A) ICD programming were associated with a significant risk reduction of first inappropriate and appropriate ICD therapy in patients with ischemic and nonischemic cardiomyopathy (HR range 0.11-0.34, P < 0.001 for all comparisons). Occurrence of total inappropriate and appropriate ICD therapies was significantly reduced by high-rate cut-off ICD programming and delayed VT therapy ICD programming in both ischemic and nonischemic cardiomyopathy patients. High-rate cut-off and delayed VT therapy ICD programming are associated with significant reduction in first and total inappropriate and appropriate ICD therapy in patients with ischemic and nonischemic cardiomyopathy. © 2014 Wiley Periodicals, Inc.

Use of a Diagnostic Score to Prioritize Computed Tomographic (CT) Imaging for Patients Suspected of Ischemic Stroke Who May Benefit from Thrombolytic Therapy

PubMed Central

Bots, Michiel L.; Selvarajah, Sharmini; Kappelle, L. Jaap; Abdul Aziz, Zariah; Sidek, Norsima Nazifah; Vaartjes, Ilonca

2016-01-01

Background A shortage of computed tomographic (CT) machines in low and middle income countries often results in delayed CT imaging for patients suspected of a stroke. Yet, time constraint is one of the most important aspects for patients with an ischemic stroke to benefit from thrombolytic therapy. We set out to assess whether application of the Siriraj Stroke Score is able to assist physicians in prioritizing patients with a high probability of having an ischemic stroke for urgent CT imaging. Methods From the Malaysian National Neurology Registry, we selected patients aged 18 years and over with clinical features suggesting of a stroke, who arrived in the hospital 4.5 hours or less from ictus. The prioritization of receiving CT imaging was left to the discretion of the treating physician. We applied the Siriraj Stroke Score to all patients, refitted the score and defined a cut-off value to best distinguish an ischemic stroke from a hemorrhagic stroke. Results Of the 2176 patients included, 73% had an ischemic stroke. Only 33% of the ischemic stroke patients had CT imaging within 4.5 hours. The median door-to-scan time for these patients was 4 hours (IQR: 1;16). With the recalibrated score, it would have been possible to prioritize 95% (95% CI: 94%–96%) of patients with an ischemic stroke for urgent CT imaging. Conclusions In settings where CT imaging capacity is limited, we propose the use of the Siriraj Stroke Score to prioritize patients with a probable ischemic stroke for urgent CT imaging. PMID:27768752

Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin: A Systematic Review and Meta-Analysis.

PubMed

Lee, Meng; Saver, Jeffrey L; Hong, Keun-Sik; Rao, Neal M; Wu, Yi-Ling; Ovbiagele, Bruce

2017-09-01

Optimal antiplatelet therapy after an ischemic stroke or transient ischemic attack while on aspirin is uncertain. We, therefore, conducted a systematic review and meta-analysis. We searched PubMed (1966 to August 2016) and bibliographies of relevant published original studies to identify randomized trials and cohort studies reporting patients who were on aspirin at the time of an index ischemic stroke or transient ischemic attack and reported hazard ratio for major adverse cardiovascular events or recurrent stroke associated with a switch to or addition of another antiplatelet agent versus maintaining aspirin monotherapy. Estimates were combined using a random effects model. Five studies with 8723 patients with ischemic stroke or transient ischemic attack were identified. Clopidogrel was used in 4 cohorts, and ticagrelor was used in 1 cohort. Pooling results showed that addition of or a switch to another antiplatelet agent, versus aspirin monotherapy, was associated with reduced risks of major adverse cardiovascular events (hazard ratio, 0.68; 95% confidence interval, 0.54-0.85) and recurrent stroke (hazard ratio, 0.70; 95% confidence interval, 0.54-0.92). Each of the strategies of addition of and switching another antiplatelet agent showed benefit versus continued aspirin monotherapy, and studies with regimen initiation in the first days after index event showed more homogenous evidence of benefit. Among patients who experience an ischemic stroke or transient ischemic attack while on aspirin monotherapy, the addition of or a switch to another antiplatelet agent, especially in the first days after index event, is associated with fewer future vascular events, including stroke. © 2017 American Heart Association, Inc.

The Relative Influences of Phosphometabolites and pH on Action Potential Morphology during Myocardial Reperfusion: A Simulation Study

PubMed Central

Roberts, Byron N.; Christini, David J.

2012-01-01

Myocardial ischemia-reperfusion (IR) injury represents a constellation of pathological processes that occur when ischemic myocardium experiences a restoration of perfusion. Reentrant arrhythmias, which represent a particularly lethal manifestation of IR injury, can result when ischemic tissue exhibits decreased excitability and/or changes of action potential duration (APD), conditions that precipitate unidirectional conduction block. Many of the cellular components that are involved with IR injury are modulated by pH and/or phosphometabolites such as ATP and phosphocreatine (PCr), all of which can be manipulated in vivo and potentially in the clinical setting. Using a mathematical model of the cardiomyocyte that we previously developed to study ischemia and reperfusion, we performed a series of simulations with the aim of determining whether pH- or phosphometabolite-related processes play a more significant role in generating changes in excitability and action potential morphology that are associated with the development of reentry. In our simulations, persistent shortening of APD, action potential amplitude (APA), and depolarization of the resting membrane potential were more severe when ATP and PCr availability were suppressed during reperfusion than when extracellular pH recovery was inhibited. Reduced phosphometabolite availability and pH recovery affected multiple ion channels and exchangers. Some of these effects were the result of direct modulation by phosphometabolites and/or acidosis, while others resulted from elevated sodium and calcium loads during reperfusion. In addition, increasing ATP and PCr availability during reperfusion was more beneficial in terms of increasing APD and APA than was increasing the amount of pH recovery. Together, these results suggest that therapies directed at increasing ATP and/or PCr availability during reperfusion may be more beneficial than perturbing pH recovery with regard to mitigating action potential changes that increase the likelihood of reentrant arrhythmias. PMID:23144801

Protective effect of remote ischemic per-conditioning in the ischemia and reperfusion-induce renal injury in rats.

PubMed

Yamaki, Vitor Nagai; Gonçalves, Thiago Barbosa; Coelho, João Vitor Baia; Pontes, Ruy Victor Simões; Costa, Felipe Lobato da Silva; Brito, Marcus Vinicius Henriques

2012-12-01

To evaluate the protective effect of remote ischemic per-conditioning in ischemia and reperfusion-induced renal injury. Fifteen rats (Rattus norvegicus) were randomized into three groups (n = 5): Group Normality (GN), Control Ischemia and Reperfusion (GIR) and Group remote ischemic per-conditioning (GPER). With the exception of the GN group, all others underwent renal ischemia for 30 minutes. In group GPER we performed the ischemic remote per-conditioning, consisting of three cycles of ischemia and reperfusion applied every five minutes during the ischemic period, to the left hindlimb of the rats by means of a tourniquet. To quantify the lesions we measured serum levels of creatinine and urea, as well as analyzed renal histopathology. The GPER group presented with better levels of urea (83.74 ± 14.58%) and creatinine (0.72 ± 26.14%) when compared to GIR group, approaching the GN group. Histopathologically, the lower levels of medullary congestion and hydropic degeneration were found in group GPER. The remote ischemic per-conditioning had a significant protective effect on renal ischemia and reperfusion.

How to minimize ischemic complication related to swollen temporalis muscle following indirect revascularization surgery in moyamoya disease: a technical report.

PubMed

Joo, Sung Pil; Kim, Tae Sun; Moon, Hyung Sik

2014-05-01

There are several reports in the literature of postoperative ischemic events due to swelling of the temporalis muscle after indirect revascularization surgery. Here, we report our surgical technique for preventing ischemic events during the acute postoperative recovery period in moyamoya patients. We used various types of titanium mesh to cover the bony defect area in 8 patients (10 operations) with moyamoya disease. The mesh was cut and manipulated according to the shape of the bony defect. Surgical results were favorable, with no newly developed ischemic event or infarction in the acute recovery period. The mesh formed an outer table of skull, so there was no compressive effect on the temporalis muscle and no cosmetic defects. The titanium mesh appears to be effective and useful for prevention of ischemic insult in the treatment of moyamoya disease. The choice of this procedure depends on both the operative findings of temporalis muscle thickness and the status of ischemic vulnerability of moyamoya brain. Georg Thieme Verlag KG Stuttgart · New York.

Significant Synergistic Effect of Peroxisome Proliferator–Activated Receptor γ C-2821T and Diabetes on the Risk of Ischemic Stroke

PubMed Central

Hsieh, Fang-I; Lo, Wei-Cheng; Lin, Huey-Juan; Hsieh, Yi-Chen; Lien, Li-Ming; Bai, Chyi-Huey; Tseng, Hung-Pin; Chiou, Hung-Yi

2009-01-01

OBJECTIVE To explore the relationship between the genetic polymorphisms of PPARγ (Pro12Ala, C1431T, and C-2821T) and the risk of ischemic stroke and to investigate whether these genetic polymorphisms of PPARγ would modify the risk of ischemic stroke among patients with hypertension or diabetes. RESEARCH DESIGN AND METHODS The case-control study was conducted with 537 ischemic stroke patients and 537 control subjects. A structured questionnaire was used to collect information on conventional cardiovascular risk factors and laboratory results. The genetic polymorphisms of PPARγ were determined by PCR–restriction fragment–length polymorphism. RESULTS A significant interaction was seen between the −2821C allele and diabetes but not between this allele and hypertension. A markedly elevated risk of ischemic stroke (odds ratio 9.7) was found in the subjects with diabetes and the −2821C allele compared with that in those without these two risk factors. CONCLUSIONS The −2821C allele of PPARγ was a strong predictor of ischemic stroke for diabetic patients. PMID:19651920

Novel pathogenetic mechanisms and structural adaptations in ischemic mitral regurgitation.

PubMed

Silbiger, Jeffrey J

2013-10-01

Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed. Copyright © 2013 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

Tetramethylpyrazine-Loaded Hydrogels: Preparation, Penetration Through a Subcutaneous-Mucous-Membrane Model, and a Molecular Dynamics Simulation.

PubMed

Xia, Hongmei; Xu, Yinxiang; Cheng, Zhiqing; Cheng, Yongfeng

2017-07-01

Tetramethylpyrazine (TMP) was extracted from Ligusticum chuanxiong hort. The compound is known to have a variety of medicinal functions; in particular, it is used for the treatment of cerebral ischemic diseases. TMP-loaded hydrogels offer an excellent preparation with the capacity to bypass the blood-brain barrier, allowing treatment of the brain through intranasal administration. We prepared TMP-loaded hydrogels using carbomer 940 and evaluated the release of TMP from the hydrogel. We determined the release rate using Franz-type diffusion cell experiments with a subcutaneous-mucous-membrane model and also by a molecular dynamics (MD) simulation. In general, the former method was more complicated than the latter was. The dynamic behavior of TMP release from the hydrogel was revealed by analysis of the mean square displacement of the trajectory in the MD simulation. The coefficient of TMP diffusion from the hydrogel was calculated at different temperatures (277, 298, and 310 K) by using MD software. The results showed that the coefficient of diffusion increased with an increase in temperature. This trend was observed both experimentally and in the MD simulation. Therefore, the MD simulation was a complementary method to verify the experimental data.

Method and system for fault accommodation of machines

NASA Technical Reports Server (NTRS)

Goebel, Kai Frank (Inventor); Subbu, Rajesh Venkat (Inventor); Rausch, Randal Thomas (Inventor); Frederick, Dean Kimball (Inventor)

2011-01-01

A method for multi-objective fault accommodation using predictive modeling is disclosed. The method includes using a simulated machine that simulates a faulted actual machine, and using a simulated controller that simulates an actual controller. A multi-objective optimization process is performed, based on specified control settings for the simulated controller and specified operational scenarios for the simulated machine controlled by the simulated controller, to generate a Pareto frontier-based solution space relating performance of the simulated machine to settings of the simulated controller, including adjustment to the operational scenarios to represent a fault condition of the simulated machine. Control settings of the actual controller are adjusted, represented by the simulated controller, for controlling the actual machine, represented by the simulated machine, in response to a fault condition of the actual machine, based on the Pareto frontier-based solution space, to maximize desirable operational conditions and minimize undesirable operational conditions while operating the actual machine in a region of the solution space defined by the Pareto frontier.

Lubiprostone induced ischemic colitis.

PubMed

Sherid, Muhammed; Sifuentes, Humberto; Samo, Salih; Deepak, Parakkal; Sridhar, Subbaramiah

2013-01-14

Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding.

Regulatory effect of Dimethyl Sulfoxide (DMSO) on astrocytic reactivity in a murine model of cerebral infarction by arterial embolization

PubMed Central

Rengifo Valbuena, Carlos Augusto; Ávila Rodríguez, Marco Fidel; Céspedes Rubio, Angel

2013-01-01

Introduction: The pathophysiology of cerebral ischemia is essential for early diagnosis, neurologic recovery, the early onset of drug treatment and the prognosis of ischemic events. Experimental models of cerebral ischemia can be used to evaluate the cellular response phenomena and possible neurological protection by drugs. Objective: To characterize the cellular changes in the neuronal population and astrocytic response by the effect of Dimethyl Sulfoxide (DMSO) on a model of ischemia caused by cerebral embolism. Methods: Twenty Wistar rats were divided into four groups (n= 5). The infarct was induced with α-bovine thrombin (40 NIH/Unit.). The treated group received 90 mg (100 μL) of DMSO in saline (1:1 v/v) intraperitoneally for 5 days; ischemic controls received only NaCl (placebo) and two non-ischemic groups (simulated) received NaCl and DMSO respectively. We evaluated the neuronal (anti-NeuN) and astrocytic immune-reactivity (anti-GFAP). The results were analyzed by densitometry (NIH Image J-Fiji 1.45 software) and analysis of variance (ANOVA) with the Graph pad software (Prism 5). Results: Cerebral embolism induced reproducible and reliable lesions in the cortex and hippocampus (CA1)., similar to those of focal models. DMSO did not reverse the loss of post-ischemia neuronal immune-reactivity, but prevented the morphological damage of neurons, and significantly reduced astrocytic hyperactivity in the somato-sensory cortex and CA1 (p <0.001). Conclusions: The regulatory effect of DMSO on astrocyte hyperreactivity and neuronal-astroglial cytoarchitecture , gives it potential neuroprotective properties for the treatment of thromboembolic cerebral ischemia in the acute phase. PMID:24892319

The Role of Simulation in the Design of a Semi-Enclosed Tubular Embolus Retrieval

PubMed Central

Gu, Xuelian; Qi, Yongxiang; Erdman, Arthur; Li, Zhonghua

2017-01-01

A numerical analysis of a semi-enclosed tubular mechanical embolus retrieval device (MERD) for the treatment of acute ischemic stroke (AIS) is presented. In this research, the finite element analysis (FEA) methodology is used to evaluate mechanical performance and provide suggestions for optimizing the geometric design. A MERD fabricated from nickel–titanium alloy (Nitinol) tubing is simulated and analyzed under complex in vivo loading conditions involving shape-setting, crimping, deployment, and embolus retrieval. As a result, the peak strain of the shape-setting procedure is proved to be safe for the device pattern. However, the MERD shows poor mechanical behavior after crimping into a catheter, because the peak crimping strain obtains a value of 12.1%. The delivery and deployment step demonstrates that the artery wall has little risk of serious injuries or rupture. In addition, the process of simulation of embolus retrieval and device system migration inside the cerebral artery lumen provides useful information during the design process. PMID:28690710

Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.

PubMed

Hanscombe, Ken B; Traylor, Matthew; Hysi, Pirro G; Bevan, Stephen; Dichgans, Martin; Rothwell, Peter M; Worrall, Bradford B; Seshadri, Sudha; Sudlow, Cathie; Williams, Frances M K; Markus, Hugh S; Lewis, Cathryn M

2015-08-01

Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes. Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype. © 2015 The Authors.

Lifestyle factors and subsequent ischemic heart disease risk after hematopoietic cell transplantation.

PubMed

Leger, Kasey J; Baker, K Scott; Cushing-Haugen, Kara L; Flowers, Mary E D; Leisenring, Wendy M; Martin, Paul J; Mendoza, Jason A; Reding, Kerryn W; Syrjala, Karen L; Lee, Stephanie J; Chow, Eric J

2018-04-01

The objective of this study was to evaluate whether modifiable cardiovascular risk conditions and lifestyle factors were temporally associated with an increased risk for ischemic heart disease and overall mortality in a cohort of hematopoietic cell transplantation (HCT) survivors. HCT recipients who had survived for ≥1 year, were ≥20 years old, and had undergone transplantation between 1970 and 2010 at a transplant referral center were surveyed in 2010-2011 about cardiovascular health and lifestyle factors (n = 3833). Respondents (n = 2360 [61.6%]) were followed to 2016 for incident ischemic heart disease and overall mortality. Among the 2360 transplant survivors (median age at the baseline survey, 55.9 years; median time since transplantation, 10.8 years), 162 (6.9%) reported ischemic heart disease at the baseline survey. Among those without ischemic heart disease at the baseline survey (n = 2198), the 5-year cumulative incidence of subsequent ischemic heart disease was 4.3%. Obesity, dyslipidemia, diabetes, and physical inactivity at baseline were associated with an increased risk for subsequent ischemic heart disease (hazard ratio [HRs] ≥ 1.8). Greater physical activity and fruit/vegetable intake at baseline were associated with subsequent lower overall mortality (HRs ≤ 0.7). When jointly considered, each additional cardiovascular risk condition and each adverse lifestyle factor were independently associated with subsequent ischemic heart disease (HR for risk conditions, 1.4; 95% confidence interval [CI], 1.0-1.9; HR for lifestyle factors, 1.9; 95% CI, 1.2-2.9), and adverse lifestyle factors remained associated with overall mortality (HR, 1.8; 95% CI, 1.5-2.3). These results support strong efforts to promote healthy lifestyle behaviors and to treat cardiovascular risk factors aggressively in HCT survivors. This may reduce future ischemic heart disease and overall mortality in this high-risk population. Cancer 2018;124:1507-15. © 2018 American Cancer Society. © 2018 American Cancer Society.

NOTCH3 variants and risk of ischemic stroke.

PubMed

Ross, Owen A; Soto-Ortolaza, Alexandra I; Heckman, Michael G; Verbeeck, Christophe; Serie, Daniel J; Rayaprolu, Sruti; Rich, Stephen S; Nalls, Michael A; Singleton, Andrew; Guerreiro, Rita; Kinsella, Emma; Wszolek, Zbigniew K; Brott, Thomas G; Brown, Robert D; Worrall, Bradford B; Meschia, James F

2013-01-01

Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved. All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS). Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series. Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.

Ischemic stroke occurring during intercourse in young women on oral contraceptives.

PubMed

Miller, P Elliott; Brown, Lorrel; Khandheria, Paras; Resar, Jon R

2014-08-01

Ischemic stroke occurring during intercourse in young patients is exceedingly rare. We present 2 cases of young women taking oral contraceptives, each presenting with an ischemic stroke. Transthoracic echocardiography revealed a patent foramen ovale in one patient and an atrial septal defect in the other. The most likely cause of stroke in both patients is embolic. Despite conflicting evidence, young patients presenting with ischemic stroke and found to have a patent foramen ovale or atrial septal defect should be considered for possible device-based closure. Copyright © 2014 Elsevier Inc. All rights reserved.

Spatial nonuniformity of excitation-contraction coupling causes arrhythmogenic Ca2+ waves in rat cardiac muscle.

PubMed

Wakayama, Yuji; Miura, Masahito; Stuyvers, Bruno D; Boyden, Penelope A; ter Keurs, Henk E D J

2005-06-24

Ca2+ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca2+ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation-contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca2+ concentration ([Ca2+]; 0.2 mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca2+]i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 microm) at constant flow. When the jet contained caffeine, BDM, or low [Ca2+], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5 s-2.5 Hz stimulus trains at 23 degrees C; [Ca2+]o=2.0 mmol/L) reproducibly generated Ca2+ waves that arose from the border between shortening and stretched regions. Such Ca2+ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca2+-wave was increased by raising [Ca2+]o. Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca2+ waves underlying TPCs and suggest that Ca2+ dissociated from myofilaments plays an important role in the initiation of Ca2+ waves.

Determinants of Emergency Medical Services Utilization Among Acute Ischemic Stroke Patients in Hubei Province in China.

PubMed

Yin, Xiaoxv; Yang, Tingting; Gong, Yanhong; Zhou, Yanfeng; Li, Wenzhen; Song, Xingyue; Wang, Mengdie; Hu, Bo; Lu, Zuxun

2016-03-01

Emergency medical services (EMS) can effectively shorten the prehospital delay for patients with acute ischemic stroke. This study aimed to investigate EMS utilization and its associated factors in patients with acute ischemic stroke in China. A cross-sectional study was conducted from October 1, 2014, to January 31, 2015, which included 2096 patients admitted for acute ischemic stroke from 66 hospitals in Hubei province in China. A multivariable stepwise logistic regression model was undertaken to identify the factors associated with EMS utilization. Of the 2096 participants, only 323 cases (15.4%) used EMS. Those acute ischemic stroke patients who previously used EMS (odds ratio [OR] =9.8), whose National Institutes of Health Stroke Scale score was ≥10 (OR=3.7), who lived in urban communities (OR=2.5), who had sudden onset of symptoms (OR=2.4), who experienced their first stroke (OR=1.8), and who recognized initial symptom as stroke (OR=1.4) were more likely to use EMS. Additionally, when acute ischemic stroke patients' stroke symptom were noticed first by others (OR=2.1), rather than by the patients, EMS was more likely to be used. A very low proportion of patients with acute ischemic stroke used the EMS in Hubei province in China. Considerable education programs are required regarding knowledge of potential symptoms and the importance of EMS for stroke. © 2016 American Heart Association, Inc.

Isolation and characterization of adult human liver progenitors from ischemic liver tissue derived from therapeutic hepatectomies.

PubMed

Stachelscheid, Harald; Urbaniak, Thomas; Ring, Alexander; Spengler, Berlind; Gerlach, Jörg C; Zeilinger, Katrin

2009-07-01

Recent evidence suggests that progenitor cells in adult tissues and embryonic stem cells share a high resistance to hypoxia and ischemic stress. To study the ischemic resistance of adult liver progenitors, we characterized remaining viable cells in human liver tissue after cold ischemic treatment for 24-168 h, applied to the tissue before cell isolation. In vitro cultures of isolated cells showed a rapid decline of the number of different cell types with increasing ischemia length. After all ischemic periods, liver progenitor-like cells could be observed. The comparably small cells exhibited a low cytoplasm-to-nucleus ratio, formed densely packed colonies, and showed a hepatobiliary marker profile. The cells expressed epithelial cell adhesion molecule, epithelial-specific (CK8/18) and biliary-specific (CK7/19) cytokeratins, albumin, alpha-1-antitrypsin, cytochrome-P450 enzymes, as well as weak levels of hepatocyte nuclear factor-4 and gamma-glutamyl transferase, but not alpha-fetoprotein or Thy-1. In vitro survival and expansion was facilitated by coculture with mouse embryonic fibroblasts. Hepatic progenitor-like cells exhibit a high resistance to ischemic stress and can be isolated from human liver tissue after up to 7 days of ischemia. Ischemic liver tissue from various sources, thought to be unsuitable for cell isolation, may be considered as a prospective source of hepatic progenitor cells.

Comparative risk of ischemic stroke among users of clopidogrel together with individual proton pump inhibitors.

PubMed

Leonard, Charles E; Bilker, Warren B; Brensinger, Colleen M; Flockhart, David A; Freeman, Cristin P; Kasner, Scott E; Kimmel, Stephen E; Hennessy, Sean

2015-03-01

There is controversy and little information about whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We, therefore, aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999 to 2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole, and pantoprazole-with pantoprazole serving as the referent. The end point was hospitalization for acute ischemic stroke, defined by International Classification of Diseases Ninth Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Among 325 559 concomitant users of clopidogrel and a PPI, we identified 1667 ischemic strokes for an annual incidence of 2.4% (95% confidence interval, 2.3-2.5). Adjusted hazard ratios for ischemic stroke versus pantoprazole were 0.98 (0.82-1.17) for esomeprazole; 1.06 (0.92-1.21) for lansoprazole; 0.98 (0.85-1.15) for omeprazole; and 0.85 (0.63-1.13) for rabeprazole. PPIs of interest did not increase the rate of ischemic stroke among clopidogrel users when compared with pantoprazole, a PPI thought to be devoid of the potential to interact with clopidogrel. © 2015 American Heart Association, Inc.

Tissue factor pathway inhibitor, activated protein C resistance, and risk of ischemic stroke due to postmenopausal hormone therapy

PubMed Central

Rossouw, Jacques E; Johnson, Karen C; Pettinger, Mary; Cushman, Mary; Sandset, Per Morten; Kuller, Lewis; Rosendaal, Frits; Rosing, Jan; Wasserthal-Smoller, Sylvia; Martin, Lisa W; Manson, JoAnn E; Lakshminarayan, Kamakshi; Merino, Jose G; Lynch, John

2012-01-01

Background and Purpose To test whether changes in plasma tissue factor pathway inhibitor (TFPI) levels or activated protein C resistance (normalized APC resistance ratio, nAPCsr) modify the increased risk of ischemic stroke due to postmenopausal hormone therapy (PHT). Methods Nested case-control study of 455 cases of ischemic stroke and 565 matched controls in the Women’s Health Initiative trials of PHT. Results Baseline free TFPI was associated with ischemic stroke risk, OR (95% CI) per SD increase = 1.17 (1.01, 1.37, p=0.039, but baseline nAPCsr was not, OR per SD increase = 0.89 (0.75, 1.05), p=0.15. Baseline TFPI levels and nAPCsr did not modify the effect of PHT on ischemic stroke. Treatment-induced mean changes of -28% in free TFPI and +65% in nAPCsr did not change the risk of ischemic stroke (interaction p = 0.452 and 0.971 respectively). In subgroup analyses baseline nAPCsr was inversely associated with lacunar strokes, OR per SD increase = 0.74 (0.57, 0.96), p=0.025, and baseline free TFPI interacted with treatment to increase large vessel atherosclerotic strokes, p=0.008. Conclusions Pro-coagulant changes in TFPI or nAPCsr do not modify the increased ischemic stroke risk due to PHT. PMID:22363056

Secular trends in ischemic stroke subtypes and stroke risk factors.

PubMed

Bogiatzi, Chrysi; Hackam, Daniel G; McLeod, A Ian; Spence, J David

2014-11-01

Early diagnosis and treatment of a stroke improves patient outcomes, and knowledge of the cause of the initial event is crucial to identification of the appropriate therapy to maximally reduce risk of recurrence. Assumptions based on historical frequency of ischemic subtypes may need revision if stroke subtypes are changing as a result of recent changes in therapy, such as increased use of statins. We analyzed secular trends in stroke risk factors and ischemic stroke subtypes among patients with transient ischemic attack or minor or moderate stroke referred to an urgent transient ischemic attack clinic from 2002 to 2012. There was a significant decline in low-density lipoprotein cholesterol and blood pressure, associated with a significant decline in large artery stroke and small vessel stroke. The proportion of cardioembolic stroke increased from 26% in 2002 to 56% in 2012 (P<0.05 for trend). Trends remained significant after adjusting for population change. With more intensive medical management in the community, a significant decrease in atherosclerotic risk factors was observed, with a significant decline in stroke/transient ischemic attack caused by large artery atherosclerosis and small vessel disease. As a result, cardioembolic stroke/transient ischemic attack has increased significantly. Our findings suggest that more intensive investigation for cardiac sources of embolism and greater use of anticoagulation may be warranted. © 2014 American Heart Association, Inc.

Relationship Between Ischemic Heart Disease and Sexual Satisfaction.

PubMed

Ghanbari Afra, Leila; Taghadosi, Mohsen; Gilasi, Hamid Reza

2015-06-10

Ischemic heart disease is a life-threatening condition. Considerable doubts exist over the effects of this disease on patients' sexual activity and satisfaction. The aim of this study was to evaluate the relationship between ischemic heart disease and sexual satisfaction. In a retrospective cohort study, the convenience sample of 150 patients exposure with ischemic heart disease and 150 people without exposure it was drawn from Shahid Beheshti hospital, Kashan, Iran. Sampling was performed from March to September 2014. We employed the Larson's Sexual Satisfaction Questionnaire for gathering the data. Data were analyzed using descriptive statistics and Chi-square, t-test and linear regression analysis. The means of sexual satisfaction in patients exposure with ischemic heart disease and among the subjects without exposure it were 101.47±13.42 and 100.91±16.52, respectively. There was no significant difference between the two groups regarding sexual satisfaction. However, sexual satisfaction was significantly correlated with gender and the use of cardiac medications (P value<0.05). The level of sexual satisfaction in patients with exposure ischemic heart disease is similar to the people without exposure it. Moreover, the men and the patients who do not receive cardiac medications have higher levels of sexual satisfaction. Nurses who are providing care to patients with ischemic heart disease need to pay closer attention to patient education about sexual issues.

Ischemic stroke due to embolic heart diseases and associated factors in Benin hospital setting.

PubMed

Gnonlonfoun, Dieudonné; Adjien, Constant; Gnimavo, Ronald; Goudjinou, Gérard; Hotcho, Corine; Nyangui Mapaga, Jennifer; Sowanou, Arlos; Gnigone, Pupchen; Domingo, Rodrigue; Houinato, Dismand

2018-04-15

Poor access to cardiovascular checkups is a major cause of ignorance of embolic heart diseases as the etiology for ischemic stroke. Study ischemic strokes due to embolic heart diseases and their associated factors. It was a cross-sectional, prospective, descriptive and analytical study conducted from November 1, 2014 to August 31, 2015 on 104 patients with ischemic stroke confirmed through brain imaging. Embolic heart diseases included arrhythmia due to atrial fibrillation (AF), atrial flutter, myocardial infarction (MI), heart valve diseases and atrial septal aneurysm (ASA). The dependent variable was embolic heart disease while independent variables encompassed socio-demographic factors, patients' history, and lifestyle. Data analysis was carried out through SAS 9.3. The rate of embolic heart diseases (EHD) as etiology for ischemic stroke was 26% (28/104). AF accounted for 69% of embolic heart diseases and 22.8% of etiologies for ischemic stroke. Ischemic strokes prevalence was 3.5%, 2.5% and 1.2% respectively for heart valve diseases, MI and ASA. The associated factor was age (p=0.000). The diagnosis of a potential cardiac source of embolism is essential because of therapeutic and prognostic implications. Wherefore, there is need for cardiovascular examination particularly Holter ECG and cardiac ultrasound examination which are not always accessible to our populations. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

Corrosion property of 9Cr-ODS steel in nitric acid solution for spent nuclear fuel reprocessing

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

Takeuchi, M.; Koizumi, T.; Inoue, M.

2013-07-01

Corrosion tests of oxide dispersion strengthened with 9% Cr (9Cr-ODS) steel, which is one of the desirable materials for cladding tube of sodium-cooled fast reactors, in pure nitric acid solution, spent FBR fuel solution, and its simulated solution were performed to understand the corrosion behavior in a spent nuclear fuel reprocessing. In this study, the 9Cr-ODS steel with lower effective chromium content was evaluated to understand the corrosion behavior conservatively. As results, the tube-type specimens of the 9Cr-ODS steels suffered severe weight loss owing to active dissolution at the beginning of the immersion test in pure nitric acid solution inmore » the range from 1 to 3.5 M. In contrast, the weight loss was decreased and they showed a stable corrosion in the higher nitric acid concentration, the dissolved FBR fuel solution, and its simulated solution by passivation. The corrosion rates of the 9Cr-ODS steel in the dissolved FBR fuel solution and its simulated solution were 1-2 mm/y and showed good agreement with each other. The passivation was caused by the shift of corrosion potential to noble side owing to increase in nitric acid concentration or oxidative ions in the dissolved FBR fuel solution and the simulated spent fuel solution. (authors)« less

Steady and Unsteady Nozzle Simulations Using the Conservation Element and Solution Element Method

NASA Technical Reports Server (NTRS)

Friedlander, David Joshua; Wang, Xiao-Yen J.

2014-01-01

This paper presents results from computational fluid dynamic (CFD) simulations of a three-stream plug nozzle. Time-accurate, Euler, quasi-1D and 2D-axisymmetric simulations were performed as part of an effort to provide a CFD-based approach to modeling nozzle dynamics. The CFD code used for the simulations is based on the space-time Conservation Element and Solution Element (CESE) method. Steady-state results were validated using the Wind-US code and a code utilizing the MacCormack method while the unsteady results were partially validated via an aeroacoustic benchmark problem. The CESE steady-state flow field solutions showed excellent agreement with solutions derived from the other methods and codes while preliminary unsteady results for the three-stream plug nozzle are also shown. Additionally, a study was performed to explore the sensitivity of gross thrust computations to the control surface definition. The results showed that most of the sensitivity while computing the gross thrust is attributed to the control surface stencil resolution and choice of stencil end points and not to the control surface definition itself.Finally, comparisons between the quasi-1D and 2D-axisymetric solutions were performed in order to gain insight on whether a quasi-1D solution can capture the steady and unsteady nozzle phenomena without the cost of a 2D-axisymmetric simulation. Initial results show that while the quasi-1D solutions are similar to the 2D-axisymmetric solutions, the inability of the quasi-1D simulations to predict two dimensional phenomena limits its accuracy.

Cellulose Nanofibrils and Mechanism of their Mineralization in Biomimetic Synthesis of Hydroxyapatite/Native Bacterial Cellulose Nanocomposites: Molecular Dynamics Simulations.

PubMed

Lukasheva, N V; Tolmachev, D A

2016-01-12

Molecular dynamics (MD) simulation of a nanofibril of native bacterial cellulose (BC) in solutions of mineral ions is presented. The supersaturated calcium-phosphate (CP) solution with the ionic composition of hydroxyapatite and CaCl2 solutions with the concentrations below, equal to, and above the solubility limits are simulated. The influence of solvation models (TIP3P and TIP4P-ew water models) on structural characteristics of the simulated nanofibril and on the crystal nucleation process is assessed. The structural characteristics of cellulose nanofibrils (in particular, of the surface layer) are found to be nearly independent of the solvation models used in the simulation and on the presence of ions in the solutions. It is shown that ionic clusters are formed in the solution rather than on the fibril surface. The cluster sizes are slightly different for the two water models. The effect of the ion-ion interaction parameters on the results is discussed. The main conclusion is that the activity of hydroxyl groups on the BC fibril surface is not high enough to cause adsorption of Ca(2+) ions from the solution. Therefore, the nucleation of CP crystals takes place initially in solution, and then the crystallites formed can be adsorbed on BC nanofibril surfaces.

ENHANCED GENE DELIVERY IN PORCINE VASCULATURE TISSUE FOLLOWING INCORPORATION OF ADENO-ASSOCIATED VIRUS NANOPARTICLES INTO POROUS SILICON MICROPARTICLES

PubMed Central

McConnell, Kellie I.; Rhudy, Jessica; Yokoi, Kenji; Gu, Jianhua; Mack, Aaron; Suh, Junghae; La Francesca, Saverio; Sakamoto, Jason; Serda, Rita E.

2014-01-01

There is an unmet clinical need to increase lung transplant successes, patient satisfaction and to improve mortality rates. We offer the development of a nanovector-based solution that will reduce the incidence of lung ischemic reperfusion injury (IRI) leading to graft organ failure through the successful ex vivo treatment of the lung prior to transplantation. The innovation is in the integrated application of our novel porous silicon (pSi) microparticles carrying adeno-associated virus (AAV) nanoparticles, and the use of our ex vivo lung perfusion/ventilation system for the modulation of pro-inflammatory cytokines initiated by ischemic pulmonary conditions prior to organ transplant that often lead to complications. Gene delivery of anti-inflammatory agents to combat the inflammatory cascade may be a promising approach to prevent IRI following lung transplantation. The rationale for the device is that the microparticle will deliver a large payload of virus to cells and serve to protect the AAV from immune recognition. The microparticle-nanoparticle hybrid device was tested both in vitro on cell monolayers and ex vivo using either porcine venous tissue or a pig lung transplantation model, which recapitulates pulmonary IRI that occurs clinically post-transplantation. Remarkably, loading AAV vectors into pSi microparticles increases gene delivery to otherwise non-permissive endothelial cells. PMID:25180449

RNA interference therapy: a new solution for intracranial atherosclerosis?

PubMed Central

Tang, Tao; Wong, Ka-Sing

2014-01-01

Intracranial atherosclerotic stenosis (ICAS) of a major intracranial artery, especially middle cerebral artery (MCA), is reported to be one leading cause of ischemic stroke throughout the world. Compared with other stroke subtypes, ICAS is associated with a higher risk of recurrent stroke despite aggressive medical therapy. Increased understanding of the pathophysiology of ICAS has highlighted several possible targets for therapeutic interventions. Both luminal stenosis and plaque components of ICAS have been found to be associated with ischemic stroke based a post-mortem study. Recent application of high-resolution magnetic resonance imaging (HRMRI) in evaluating ICAS provides new insight into the vascular biology of plaque morphology and component. High signal on T1-weighted fat-suppressed images (HST1) within MCA plaque of HRMRI, highly suggested of fresh or recent intraplaque hemorrhage, has been found to be associated with ipsilateral brain infarction. Thus, the higher prevalence of intraplaque hemorrhage and neovasculature in symptomatic patients with MCA stenosis may provide a potential target for plaque stabilization. We hypothesize that RNA interference (RNAi) therapy delivered by modified nanoparticles may achieve in vivo biomedical imaging and targeted therapy. With the rapid developments in studies about therapeutic and diagnostic nanomaterials, future studies further exploring the molecular biology of atherosclerosis may provide more drug targets for plaque stabilization. PMID:25333054

Accelerating Convergence in Molecular Dynamics Simulations of Solutes in Lipid Membranes by Conducting a Random Walk along the Bilayer Normal.

PubMed

Neale, Chris; Madill, Chris; Rauscher, Sarah; Pomès, Régis

2013-08-13

All molecular dynamics simulations are susceptible to sampling errors, which degrade the accuracy and precision of observed values. The statistical convergence of simulations containing atomistic lipid bilayers is limited by the slow relaxation of the lipid phase, which can exceed hundreds of nanoseconds. These long conformational autocorrelation times are exacerbated in the presence of charged solutes, which can induce significant distortions of the bilayer structure. Such long relaxation times represent hidden barriers that induce systematic sampling errors in simulations of solute insertion. To identify optimal methods for enhancing sampling efficiency, we quantitatively evaluate convergence rates using generalized ensemble sampling algorithms in calculations of the potential of mean force for the insertion of the ionic side chain analog of arginine in a lipid bilayer. Umbrella sampling (US) is used to restrain solute insertion depth along the bilayer normal, the order parameter commonly used in simulations of molecular solutes in lipid bilayers. When US simulations are modified to conduct random walks along the bilayer normal using a Hamiltonian exchange algorithm, systematic sampling errors are eliminated more rapidly and the rate of statistical convergence of the standard free energy of binding of the solute to the lipid bilayer is increased 3-fold. We compute the ratio of the replica flux transmitted across a defined region of the order parameter to the replica flux that entered that region in Hamiltonian exchange simulations. We show that this quantity, the transmission factor, identifies sampling barriers in degrees of freedom orthogonal to the order parameter. The transmission factor is used to estimate the depth-dependent conformational autocorrelation times of the simulation system, some of which exceed the simulation time, and thereby identify solute insertion depths that are prone to systematic sampling errors and estimate the lower bound of the amount of sampling that is required to resolve these sampling errors. Finally, we extend our simulations and verify that the conformational autocorrelation times estimated by the transmission factor accurately predict correlation times that exceed the simulation time scale-something that, to our knowledge, has never before been achieved.

Exploring a multi-scale method for molecular simulation in continuum solvent model: Explicit simulation of continuum solvent as an incompressible fluid.

PubMed

Xiao, Li; Luo, Ray

2017-12-07

We explored a multi-scale algorithm for the Poisson-Boltzmann continuum solvent model for more robust simulations of biomolecules. In this method, the continuum solvent/solute interface is explicitly simulated with a numerical fluid dynamics procedure, which is tightly coupled to the solute molecular dynamics simulation. There are multiple benefits to adopt such a strategy as presented below. At this stage of the development, only nonelectrostatic interactions, i.e., van der Waals and hydrophobic interactions, are included in the algorithm to assess the quality of the solvent-solute interface generated by the new method. Nevertheless, numerical challenges exist in accurately interpolating the highly nonlinear van der Waals term when solving the finite-difference fluid dynamics equations. We were able to bypass the challenge rigorously by merging the van der Waals potential and pressure together when solving the fluid dynamics equations and by considering its contribution in the free-boundary condition analytically. The multi-scale simulation method was first validated by reproducing the solute-solvent interface of a single atom with analytical solution. Next, we performed the relaxation simulation of a restrained symmetrical monomer and observed a symmetrical solvent interface at equilibrium with detailed surface features resembling those found on the solvent excluded surface. Four typical small molecular complexes were then tested, both volume and force balancing analyses showing that these simple complexes can reach equilibrium within the simulation time window. Finally, we studied the quality of the multi-scale solute-solvent interfaces for the four tested dimer complexes and found that they agree well with the boundaries as sampled in the explicit water simulations.

Association of Childhood Body Mass Index and Change in Body Mass Index With First Adult Ischemic Stroke.

PubMed

Gjærde, Line K; Gamborg, Michael; Ängquist, Lars; Truelsen, Thomas C; Sørensen, Thorkild I A; Baker, Jennifer L

2017-11-01

The incidence of ischemic stroke among young adults is rising and is potentially due to an increase in stroke risk factors occurring at younger ages, such as obesity. To investigate whether childhood body mass index (BMI) and change in BMI are associated with adult ischemic stroke and to assess whether the associations are age dependent or influenced by birth weight. This investigation was a population-based cohort study of schoolchildren born from 1930 to 1987, with follow-up through national health registers from 1977 to 2012 in Denmark. Participants were 307 677 individuals (8899 ischemic stroke cases) with measured weight and height at ages 7 to 13 years. The dates of the analysis were September 1, 2015, to May 27, 2016. Childhood BMI, change in BMI, and birth weight. Ischemic stroke events were divided into early (≤55 years) or late (>55 years) age at diagnosis. The study cohort comprised 307 677 participants (approximately 49% female and 51% male). During the study period, 3529 women and 5370 men experienced an ischemic stroke. At all ages from 7 to 13 years, an above-average BMI z score was positively associated with early ischemic stroke. At age 13 years, a BMI z score of 1 was associated with hazard ratios (HRs) of 1.26 (95% CI, 1.11-1.43) in women and 1.21 (95% CI, 1.10-1.33) in men. No significant associations were found for below-average BMI z scores. Among children with above-average BMI z scores at age 7 years, a score increase of 0.5 from ages 7 to 13 years was positively associated with early ischemic stroke in women (HR, 1.10; 95% CI, 1.01-1.20) and in men (HR, 1.08; 95% CI, 1.00-1.16). Similarly, among children with below-average BMI z scores at age 7 years, a score increase of 0.5 from ages 7 to 13 years was positively associated with early ischemic stroke in women (HR, 1.14; 95% CI, 1.06-1.23) and in men (HR, 1.10; 95% CI, 1.04-1.18). Adjusting for birth weight minimally affected the associations. Independent of birth weight, above-average childhood BMI and increases in BMI during childhood are positively associated with early adult ischemic stroke. To avoid the occurrence of early ischemic stroke associated with childhood overweight and obesity, these results suggest that all children should be helped to attain and maintain healthy weights.

Cost-Effectiveness of Endovascular Stroke Therapy: A Patient Subgroup Analysis From a US Healthcare Perspective.

PubMed

Kunz, Wolfgang G; Hunink, M G Myriam; Sommer, Wieland H; Beyer, Sebastian E; Meinel, Felix G; Dorn, Franziska; Wirth, Stefan; Reiser, Maximilian F; Ertl-Wagner, Birgit; Thierfelder, Kolja M

2016-11-01

Endovascular therapy in addition to standard care (EVT+SC) has been demonstrated to be more effective than SC in acute ischemic large vessel occlusion stroke. Our aim was to determine the cost-effectiveness of EVT+SC depending on patients' initial National Institutes of Health Stroke Scale (NIHSS) score, time from symptom onset, Alberta Stroke Program Early CT Score (ASPECTS), and occlusion location. A decision model based on Markov simulations estimated lifetime costs and quality-adjusted life years (QALYs) associated with both strategies applied in a US setting. Model input parameters were obtained from the literature, including recently pooled outcome data of 5 randomized controlled trials (ESCAPE [Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke], EXTEND-IA [Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial], MR CLEAN [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], REVASCAT [Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset], and SWIFT PRIME [Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment]). Probabilistic sensitivity analysis was performed to estimate uncertainty of the model results. Net monetary benefits, incremental costs, incremental effectiveness, and incremental cost-effectiveness ratios were derived from the probabilistic sensitivity analysis. The willingness-to-pay was set to $50 000/QALY. Overall, EVT+SC was cost-effective compared with SC (incremental cost: $4938, incremental effectiveness: 1.59 QALYs, and incremental cost-effectiveness ratio: $3110/QALY) in 100% of simulations. In all patient subgroups, EVT+SC led to gained QALYs (range: 0.47-2.12), and mean incremental cost-effectiveness ratios were considered cost-effective. However, subgroups with ASPECTS ≤5 or with M2 occlusions showed considerably higher incremental cost-effectiveness ratios ($14 273/QALY and $28 812/QALY, respectively) and only reached suboptimal acceptability in the probabilistic sensitivity analysis (75.5% and 59.4%, respectively). All other subgroups had acceptability rates of 90% to 100%. EVT+SC is cost-effective in most subgroups. In patients with ASPECTS ≤5 or with M2 occlusions, cost-effectiveness remains uncertain based on current data. © 2016 American Heart Association, Inc.

Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury

PubMed Central

Chakravarti, Bandana; Mabe, Nathaniel W.; Seeley, Sarah L.; Bui, Albert D.; Yang, Jianqi; Watts, Stephanie W.; Neubig, Richard R.; Fisher, Rory A.

2017-01-01

Gαi-coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In this study, we investigated the effect of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6−/−) and RGS6 wild-type (RGS6+/+) mice were subjected to 30 minutes of ischemia and 2 hours of reperfusion on a Langendorff heart apparatus. Infarcts in RGS6−/− hearts were significantly larger than infarcts in RGS6+/+ hearts. RGS6−/− hearts also exhibited increased phosphorylation of β2-adrenergic receptors and G protein–coupled receptor kinase 2 (GRK2). Mitochondrial GRK2 as well as caspase-3 cleavage were increased significantly in RGS6−/− hearts compared with RGS6+/+ hearts after ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and the GRK2 phosphorylation observed in RGS6−/− hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to prodeath signaling through a β2AR-GRK2–dependent signaling mechanism, and they provide evidence for a protective role of RGS6 in the ischemic heart. Individuals expressing genetic polymorphisms that suppress the activity of RGS6 may be at increased risk of cardiac ischemic injury. Furthermore, the development of agents that increase RGS6 expression or activity might provide a novel strategy for the treatment of ischemic heart disease. PMID:28035008

Ischemic Heart Disease and Stroke in Relation to Blood DNA Methylation

PubMed Central

Baccarelli, Andrea; Wright, Robert; Bollati, Valentina; Litonjua, Augusto; Zanobetti, Antonella; Tarantini, Letizia; Sparrow, David; Vokonas, Pantel; Schwartz, Joel

2013-01-01

Background Epigenetic features such as DNA hypomethylation have been associated with conditions related to cardiovascular risk. We evaluated whether lower blood DNA methylation in heavily methylated repetitive sequences predicts the risk of ischemic heart disease and stroke. Methods We quantified blood DNA methylation of LINE-1 repetitive elements through PCR-pyrosequencing in 712 elderly individuals from the Boston-area Normative Aging Study. We estimated risk-factor adjusted relative risks (RRs) for ischemic heart disease and stroke at baseline (242 prevalent cases); as well as in incidence (44 new cases; median follow-up, 63 months); and subsequent mortality from ischemic heart disease (86 deaths; median follow-up, 75 months). Results Blood LINE-1 hypomethylation was associated with baseline ischemic heart disease (RR=2.1 [95% confidence interval = 1.2 to 4.0] for lowest vs. highest methylation quartile) and for stroke (2.5 [0.9 to 7.5]). Among participants free of baseline disease, individuals with methylation below the median also had higher risk of developing ischemic heart disease (4.0 [1.8 to 8.9]) or stroke (5.7 [0.8 to 39.5]). In the entire cohort, persons with methylation below the median had higher mortality from ischemic heart disease (3.3 [1.3 to 8.4]) and stroke (2.8 [0.6 to 14.3]). Total mortality was also increased (2.0 [1.2 to 3.3]). These results were confirmed in additional regression models using LINE-1 methylation as a continuous variable. Conclusions Subjects with prevalent IHD and stroke exhibited lower LINE-1 methylation. In longitudinal analyses, persons with lower LINE-1 methylation were at higher risk for incident ischemic heart disease and stroke, and for total mortality. PMID:20805753

Lipid and Lipoprotein Biomarkers and the Risk of Ischemic Stroke in Postmenopausal Women

PubMed Central

Berger, Jeffrey S.; McGinn, Aileen P.; Howard, Barbara V.; Kuller, Lewis; Manson, JoAnn E.; Otvos, Jim; Curb, J. David; Eaton, Charles B; Kaplan, Robert C.; Lynch, John K.; Rosenbaum, Daniel M.; Wassertheil-Smoller, Sylvia

2012-01-01

Background Few studies simultaneously investigated lipids and lipoprotein biomarkers as predictors of ischemic stroke. The value of these biomarkers as independent predictors of ischemic stroke remains controversial. Methods We conducted a prospective nested case-control study among postmenopausal women from the Women’s Health Initiative Observational Study to assess the relationship between fasting lipids (total cholesterol, LDL-C, HDL-C, and triglycerides), lipoproteins (LDL, HDL and VLDL particle number and size, IDL particle number, and lipoprotein [a]) and risk of ischemic stroke. Among women free of stroke at baseline, 774 ischemic stroke patients were matched according to age and race to controls using a 1:1 ratio. Results In bivariate analysis, baseline triglycerides (P<0.001), IDL particles (P<0.01), LDL particles (P<0.01), VLDL triglyceride (P<0.001), VLDL particles (P<0.01), VLDL size (P<0.001), LDL size (P=0.03), and total/HDL cholesterol ratio (P<0.01) were significantly higher among women with incident ischemic stroke, while levels of HDL-C (P<0.01) and HDL size (P<0.01) were lower. No significant baseline difference for total cholesterol (P=0.15), LDL-C (P=0.47), and lipoprotein (a) (P=0.11) was observed. In multivariable analysis, triglycerides, (OR for the highest vs lowest quartile, 1.56; 95% CI, 1.13-2.17, P for trend =0.02), VLDL size (OR 1.59, 95% CI, 1.10-2.28, P for trend =0.03) and IDL particle number (OR 1.46, 95% CI, 1.04-2.04, P for trend =0.02) were significantly associated with ischemic stroke. Conclusion Among a panel of lipid and lipoprotein biomarkers, baseline triglycerides, VLDL size and IDL particle number were significantly associated with incident ischemic stroke in postmenopausal women. PMID:22308251

Differences in stroke and ischemic heart disease mortality by occupation and industry among Japanese working-aged men.

PubMed

Wada, Koji; Eguchi, Hisashi; Prieto-Merino, David

2016-12-01

Occupation- and industry-based risks for stroke and ischemic heart disease may vary among Japanese working-aged men. We examined the differences in mortality rates between stroke and ischemic heart disease by occupation and industry among employed Japanese men aged 25-59 years. In 2010, we obtained occupation- and industry-specific vital statistics data from the Japanese Ministry of Health, Labour, and Welfare dataset. We analyzed data for Japanese men who were aged 25-59 years in 2010, grouped in 5-year age intervals. We estimated the mortality rates of stroke and ischemic heart disease in each age group for occupation and industry categories as defined in the national census. We did not have detailed individual-level variables. We used the number of employees in 2010 as the denominator and the number of events as the numerator, assuming a Poisson distribution. We conducted separate regression models to estimate the incident relative risk for stroke and ischemic heart disease for each category compared with the reference categories "sales" (occupation) and "wholesale and retail" (industry). When compared with the reference groups, we found that occupations and industries with a relatively higher risk of stroke and ischemic heart disease were: service, administrative and managerial, agriculture and fisheries, construction and mining, electricity and gas, transport, and professional and engineering. This suggests there are occupation- and industry-based mortality risk differences of stroke and ischemic heart disease for Japanese working-aged men. These differences in risk might be explained to factors associated with specific occupations or industries, such as lifestyles or work styles, which should be explored in further research. The mortality risk differences of stroke and ischemic heart disease shown in the present study may reflect an excessive risk of Karoshi (death from overwork).

A Modified Collagen Gel Dressing Promotes Angiogenesis in a Pre-Clinical Swine Model of Chronic Ischemic Wounds

PubMed Central

Elgharably, Haytham; Ganesh, Kasturi; Dickerson, Jennifer; Khanna, Savita; Abas, Motaz; Ghatak, Piya Das; Dixit, Sriteja; Bergdall, Valerie; Roy, Sashwati; Sen, Chandan K.

2015-01-01

We recently performed proteomic characterization of a modified collagen gel (MCG) dressing and reported promising effects of the gel in healing full-thickness excisional wounds. In this work, we test the translational relevance of our aforesaid findings by testing the dressing in a swine model of chronic ischemic wounds recently reported by our laboratory. Full thickness excisional wounds were established in the center of bi- pedicle ischemic skin flaps on the backs of animals. Ischemia was verified by Laser Doppler imaging and MCG was applied to the test group of wounds. Seven days post- wounding, macrophage recruitment to the wound was significantly higher in MCG- treated ischemic wounds. In vitro, MCG up-regulated expression of Mrc-1 (a reparative M2 macrophage marker) and induced the expression of anti-inflammatory cytokine IL-10 and of β-FGF. An increased expression of CCR2, a M2 macrophage marker, was noted in the macrophages from MCG treated wounds. Furthermore, analyses of wound tissues 7 days post wounding showed up-regulation of TGF-β, VEGF, vWF, and collagen type I expression in MCG-treated ischemic wounds. At 21 days post-wounding, MCG-treated ischemic wounds displayed higher abundance of proliferating endothelial cells that formed mature vascular structures and increased blood flow to the wound. Fibroblast count was markedly higher in MCG-treated ischemic wound-edge tissue. In addition, MCG-treated wound-edge tissues displayed higher abundance of mature collagen with increased collagen type I:III deposition. Taken together, MCG helped mount a more robust inflammatory response which resolved in a timely manner, followed by an enhanced proliferative phase, angiogenic outcome and post-wound tissue remodeling. Findings of the current study warrant clinical testing of MCG in a setting of ischemic chronic wounds. PMID:25224310

Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone.

PubMed

Hong, Keun-Sik; Lee, Seung-Hoon; Kim, Eung Gyu; Cho, Ki-Hyun; Chang, Dae Il; Rha, Joung-Ho; Bae, Hee-Joon; Lee, Kyung Bok; Kim, Dong Eog; Park, Jong-Moo; Kim, Hahn-Young; Cha, Jae-Kwan; Yu, Kyung-Ho; Lee, Yong-Seok; Lee, Soo Joo; Choi, Jay Chol; Cho, Yong-Jin; Kwon, Sun U; Kim, Gyeong-Moon; Sohn, Sung-Il; Park, Kwang-Yeol; Kang, Dong-Wha; Sohn, Chul-Ho; Lee, Jun; Yoon, Byung-Woo

2016-09-01

In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268. © 2016 American Heart Association, Inc.

Increased Vascular Disease Mortality Risk in Prediabetic Korean Adults Is Mainly Attributable to Ischemic Stroke.

PubMed

Kim, Nam Hoon; Kwon, Tae Yeon; Yu, Sungwook; Kim, Nan Hee; Choi, Kyung Mook; Baik, Sei Hyun; Park, Yousung; Kim, Sin Gon

2017-04-01

Prediabetes is a known risk factor for vascular diseases; however, its differential contribution to mortality risk from various vascular disease subtypes is not known. The subjects of the National Health Insurance Service in Korea (2002-2013) nationwide cohort were stratified into normal glucose tolerance (fasting glucose <100 mg/dL), impaired fasting glucose (IFG) stage 1 (100-109 mg/dL), IFG stage 2 (110-125 mg/dL), and diabetes mellitus groups based on the fasting glucose level. A Cox regression analysis with counting process formulation was used to assess the mortality risk for vascular disease and its subtypes-ischemic heart disease, ischemic stroke, and hemorrhagic stroke. When adjusted for age, sex, and body mass index, IFG stage 2, but not stage 1, was associated with significantly higher all-cause mortality (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.18-1.34) and vascular disease mortality (HR, 1.27; 95% CI, 1.08-1.49) compared with normal glucose tolerance. Among the vascular disease subtypes, mortality from ischemic stroke was significantly higher (HR, 1.60; 95% CI, 1.18-2.18) in subjects with IFG stage 2 but not from ischemic heart disease and hemorrhagic stroke. The ischemic stroke mortality associated with IFG stage 2 remained significantly high when adjusted other modifiable vascular disease risk factors (HR, 1.51; 95% CI: 1.10-2.09) and medical treatments (HR, 1.75; 95% CI, 1.19-2.57). Higher IFG degree (fasting glucose, 110-125 mg/dL) was associated with increased all-cause and vascular disease mortality. The increased vascular disease mortality in IFG stage 2 was attributable to ischemic stroke, but not ischemic heart disease or hemorrhagic stroke in Korean adults. © 2017 American Heart Association, Inc.

Value of Computed Tomographic Perfusion-Based Patient Selection for Intra-Arterial Acute Ischemic Stroke Treatment.

PubMed

Borst, Jordi; Berkhemer, Olvert A; Roos, Yvo B W E M; van Bavel, Ed; van Zwam, Wim H; van Oostenbrugge, Robert J; van Walderveen, Marianne A A; Lingsma, Hester F; van der Lugt, Aad; Dippel, Diederik W J; Yoo, Albert J; Marquering, Henk A; Majoie, Charles B L M

2015-12-01

The utility of computed tomographic perfusion (CTP)-based patient selection for intra-arterial treatment of acute ischemic stroke has not been proven in randomized trials and requires further study in a cohort that was not selected based on CTP. Our objective was to study the relationship between CTP-derived parameters and outcome and treatment effect in patients with acute ischemic stroke because of a proximal intracranial arterial occlusion. We included 175 patients who underwent CTP in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN). Association of CTP-derived parameters (ischemic-core volume, penumbra volume, and percentage ischemic core) with outcome was estimated with multivariable ordinal logistic regression as an adjusted odds ratio for a shift in the direction of a better outcome on the modified Rankin Scale. Interaction between CTP-derived parameters and treatment effect was determined using multivariable ordinal logistic regression. Interaction with treatment effect was also tested for mismatch (core <70 mL; penumbra core >1.2; penumbra core >10 mL). The adjusted odds ratio for improved functional outcome for ischemic core, percentage ischemic core, and penumbra were 0.79 per 10 mL (95% confidence interval: 0.71-0.89; P<0.001), 0.82 per 10% (95% confidence interval: 0.66-0.90; P=0.002), and 0.97 per 10 mL (96% confidence interval: 0.92-1.01; P=0.15), respectively. No significant interaction between any of the CTP-derived parameters and treatment effect was observed. We observed no significant interaction between mismatch and treatment effect. CTP seems useful for predicting functional outcome, but cannot reliably identify patients who will not benefit from intra-arterial therapy. © 2015 American Heart Association, Inc.

Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack.

PubMed

Brookes, Rebecca L; Crichton, Siobhan; Wolfe, Charles D A; Yi, Qilong; Li, Linxin; Hankey, Graeme J; Rothwell, Peter M; Markus, Hugh S

2018-01-01

A variant in the histone deacetylase 9 ( HDAC9 ) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P =0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3-0.7; P =0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; P =0.003). These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke. © 2017 The Authors.

Adenosine Diphosphate-Induced Platelet-Fibrin Clot Strength: A New Thrombelastographic Indicator of Long-Term Post-Stenting Ischemic Events

PubMed Central

Gurbel, Paul A.; Bliden, Kevin P.; Navickas, Irene A.; Mahla, Elizabeth; Dichiara, Joseph; Suarez, Thomas A.; Antonino, Mark J.; Tantry, Udaya S.; Cohen, Eli

2010-01-01

Background Post-stenting ischemic events occur despite dual antiplatelet therapy suggesting that a “one size fits all” antithrombotic strategy has significant limitations. Ex vivo platelet function measurements may facilitate risk stratification and personalized antiplatelet therapy. Methods We investigated the prognostic utility of the strength of ADP-induced (MAADP) and thrombin-induced (MATHROMBIN) platelet-fibrin clots measured by thrombelastography and ADP-induced light transmittance aggregation (LTAADP) in 225 serial patients following elective stenting treated with aspirin and clopidogrel. Ischemic and bleeding events were assessed over three-years. Results Overall, 59 (26 %) first ischemic events occurred. Patients with ischemic events had higher MAADP, MATHROMBIN, and LTAADP (p<0.0001 for all comparisons). By receiver operating characteristic curve analysis, MAADP > 47mm had the best predictive value of long-term ischemic events compared to other measurements (p<0.0001) with an area under the curve = 0.84 [95% CI 0.78 – 0.89, p < 0.0001]. The univariate Cox proportional hazards model identified MAADP >47mm, MATHROMBIN >69mm, and LTA ADP >34% as significant independent predictors of first ischemic events at the three-year time point, with hazard ratios of 10.3 (p<0.0001), 3.8 (p<0.0001), and 4.8 (p<0.0001) respectively. Fifteen bleeding events occurred. Receiver operator characteristic curve and quartile analysis suggest MAADP ≤ 31 as a predictive value for bleeding. Conclusion This study is the first demonstration of the prognostic utility of MAADP in predicting long term event occurrence following stenting. The quantitative assessment of ADP-stimulated platelet-fibrin clot strength measured by thrombelastography can serve as a future tool in investigations of personalized antiplatelet treatment designed to reduce ischemic events and bleeding. PMID:20691842

Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events.

PubMed

Gurbel, Paul A; Bliden, Kevin P; Navickas, Irene A; Mahla, Elizabeth; Dichiara, Joseph; Suarez, Thomas A; Antonino, Mark J; Tantry, Udaya S; Cohen, Eli

2010-08-01

Poststenting ischemic events occur despite dual-antiplatelet therapy, suggesting that a "one size fits all" antithrombotic strategy has significant limitations. Ex vivo platelet function measurements may facilitate risk stratification and personalized antiplatelet therapy. We investigated the prognostic utility of the strength of adenosine diphosphate (ADP)-induced (MA(ADP)) and thrombin-induced (MA(THROMBIN)) platelet-fibrin clots measured by thrombelastography and ADP-induced light transmittance aggregation (LTA(ADP)) in 225 serial patients after elective stenting treated with aspirin and clopidogrel. Ischemic and bleeding events were assessed over 3 years. Overall, 59 (26%) first ischemic events occurred. Patients with ischemic events had higher MA(ADP), MA(THROMBIN), and LTA(ADP) (P < .0001 for all comparisons). By receiver operating characteristic curve analysis, MA(ADP) >47 mm had the best predictive value of long-term ischemic events compared with other measurements (P < .0001), with an area under the curve = 0.84 (95% CI 0.78-0.89, P < .0001). The univariate Cox proportional hazards model identified MA(ADP) >47 mm, MA(THROMBIN) >69 mm, and LTA(ADP) >34% as significant independent predictors of first ischemic events at the 3-year time point, with hazard ratios of 10.3 (P < .0001), 3.8 (P < .0001), and 4.8 (P < .0001), respectively. Fifteen bleeding events occurred. Receiver operating characteristic curve and quartile analysis suggests MA(ADP)

Epistasis Analysis for Estrogen Metabolic and Signaling Pathway Genes on Young Ischemic Stroke Patients

PubMed Central

Hsieh, Yi-Chen; Jeng, Jiann-Shing; Lin, Huey-Juan; Hu, Chaur-Jong; Yu, Chia-Chen; Lien, Li-Ming; Peng, Giia-Sheun; Chen, Chin-I; Tang, Sung-Chun; Chi, Nai-Fang; Tseng, Hung-Pin; Chern, Chang-Ming; Hsieh, Fang-I; Bai, Chyi-Huey; Chen, Yi-Rhu; Chiou, Hung-Yi; Jeng, Jiann-Shing; Tang, Sung-Chun; Yeh, Shin-Joe; Tsai, Li-Kai; Kong, Shin; Lien, Li-Ming; Chiu, Hou-Chang; Chen, Wei-Hung; Bai, Chyi-Huey; Huang, Tzu-Hsuan; Chi-Ieong, Lau; Wu, Ya-Ying; Yuan, Rey-Yue; Hu, Chaur-Jong; Sheu, Jau- Jiuan; Yu, Jia-Ming; Ho, Chun-Sum; Chen, Chin-I; Sung, Jia-Ying; Weng, Hsing-Yu; Han, Yu-Hsuan; Huang, Chun-Ping; Chung, Wen-Ting; Ke, Der-Shin; Lin, Huey-Juan; Chang, Chia-Yu; Yeh, Poh-Shiow; Lin, Kao-Chang; Cheng, Tain-Junn; Chou, Chih-Ho; Yang, Chun-Ming; Peng, Giia-Sheun; Lin, Jiann-Chyun; Hsu, Yaw-Don; Denq, Jong-Chyou; Lee, Jiunn-Tay; Hsu, Chang-Hung; Lin, Chun-Chieh; Yen, Che-Hung; Cheng, Chun-An; Sung, Yueh-Feng; Chen, Yuan-Liang; Lien, Ming-Tung; Chou, Chung-Hsing; Liu, Chia-Chen; Yang, Fu-Chi; Wu, Yi-Chung; Tso, An-Chen; Lai, Yu- Hua; Chiang, Chun-I; Tsai, Chia-Kuang; Liu, Meng-Ta; Lin, Ying-Che; Hsu, Yu-Chuan; Chen, Chih-Hung; Sung, Pi-Shan; Chern, Chang-Ming; Hu, Han-Hwa; Wong, Wen-Jang; Luk, Yun-On; Hsu, Li-Chi; Chung, Chih-Ping; Tseng, Hung-Pin; Liu, Chin-Hsiung; Lin, Chun-Liang; Lin, Hung-Chih; Hu, Chaur-Jong

2012-01-01

Background Endogenous estrogens play an important role in the overall cardiocirculatory system. However, there are no studies exploring the hormone metabolism and signaling pathway genes together on ischemic stroke, including sulfotransferase family 1E (SULT1E1), catechol-O-methyl-transferase (COMT), and estrogen receptor α (ESR1). Methods A case-control study was conducted on 305 young ischemic stroke subjects aged ≦ 50 years and 309 age-matched healthy controls. SULT1E1 -64G/A, COMT Val158Met, ESR1 c.454−397 T/C and c.454−351 A/G genes were genotyped and compared between cases and controls to identify single nucleotide polymorphisms associated with ischemic stroke susceptibility. Gene-gene interaction effects were analyzed using entropy-based multifactor dimensionality reduction (MDR), classification and regression tree (CART), and traditional multiple regression models. Results COMT Val158Met polymorphism showed a significant association with susceptibility of young ischemic stroke among females. There was a two-way interaction between SULT1E1 -64G/A and COMT Val158Met in both MDR and CART analysis. The logistic regression model also showed there was a significant interaction effect between SULT1E1 -64G/A and COMT Val158Met on ischemic stroke of the young (P for interaction = 0.0171). We further found that lower estradiol level could increase the risk of young ischemic stroke for those who carry either SULT1E1 or COMT risk genotypes, showing a significant interaction effect (P for interaction = 0.0174). Conclusions Our findings support that a significant epistasis effect exists among estrogen metabolic and signaling pathway genes and gene-environment interactions on young ischemic stroke subjects. PMID:23112845

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

Acute Ischemic Stroke Infarct Topology: Association with Lesion Volume and Severity of Symptoms at Admission and Discharge.

PubMed

Payabvash, S; Taleb, S; Benson, J C; McKinney, A M

2017-01-01

Acute stroke presentation and outcome depend on both ischemic infarct volume and location. We aimed to determine the association between acute ischemic infarct topology and lesion volume and stroke severity at presentation and discharge. Patients with acute ischemic stroke who underwent MR imaging within 24 hours of symptom onset or last seen well were included. Infarcts were segmented and coregistered on the Montreal Neurological Institute-152 brain map. Voxel-based analyses were performed to determine the distribution of infarct lesions associated with larger volumes, higher NIHSS scores at admission and discharge, and greater NIHSS/volume ratios. A total of 238 patients were included. Ischemic infarcts involving the bilateral lentiform nuclei, insular ribbons, middle corona radiata, and right precentral gyrus were associated with larger infarct volumes (average, 76.7 ± 125.6 mL versus 16.4 ± 24.0 mL, P < .001) and higher admission NIHSS scores. Meanwhile, brain stem and thalami infarctions were associated with higher admission NIHSS/volume ratios. The discharge NIHSS scores were available in 218 patients, in whom voxel-based analysis demonstrated that ischemic infarcts of the bilateral posterior insular ribbons, middle corona radiata, and right precentral gyrus were associated with more severe symptoms at discharge, whereas ischemic lesions of the brain stem, bilateral thalami, and, to a lesser extent, the middle corona radiata were associated with higher ratios of discharge NIHSS score/infarct volume. Acute ischemic infarcts of the insulae, lentiform nuclei, and middle corona radiata tend to have larger volumes, more severe presentations, and worse outcomes, whereas brain stem and thalamic infarcts have greater symptom severity relative to smaller lesion volumes. © 2017 by American Journal of Neuroradiology.

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.

Incidence, recurrence, and long-term survival of ischemic stroke subtypes: A population-based study in the Middle East.

PubMed

Saber, Hamidreza; Thrift, Amanda G; Kapral, Moira K; Shoamanesh, Ashkan; Amiri, Amin; Farzadfard, Mohammad T; Behrouz, Réza; Azarpazhooh, Mahmoud Reza

2017-10-01

Background Incidence, risk factors, case fatality and survival rates of ischemic stroke subtypes are unknown in the Middle East due to the lack of community-based incidence stroke studies in this region. Aim To characterize ischemic stroke subtypes in a Middle Eastern population. Methods The Mashad Stroke Incidence Study is a community-based study that prospectively ascertained all cases of stroke among the 450,229 inhabitants of Mashhad, Iran between 2006 and 2007. We identified 512 cases of first-ever ischemic stroke [264 men (mean age 65.5 ± 14.4) and 248 women (mean age 64.14 ± 14.5)]. Subtypes of ischemic stroke were classified according to the TOAST criteria. Incidence rates were age standardized to the WHO and European populations. Results The proportion of stroke subtypes was distributed as follows: 14.1% large artery disease, 15% cardioembolic, 22.5% small artery disease, 43.9% undetermined and 4.5% other. The greatest overall incidence rates were attributed to undetermined infarction (49.97/100,000) followed by small artery disease (25.54/100,000). Prevalence of hypertension, diabetes and atrial fibrillation differed among ischemic stroke subtypes. Overall, there were 268 (52.34%) deaths and 73 (14.25%) recurrent strokes at five years after incident ischemic stroke, with the greatest risk of recurrence seen in the large artery disease (35.6%) and cardioembolic (35.5%) subgroups. Survival was similar in men and women for each stroke subtype. Conclusions We observed markedly greater incidence rates of ischemic stroke subtypes than in other countries within the Mashad Stroke Incidence Study after age standardization. Our findings should be considered when planning prevention and stroke care services in this region.

Secular trends in the incidence of and risk factors for ischemic stroke and its subtypes in Japanese population.

PubMed

Kubo, Michiaki; Hata, Jun; Doi, Yasufumi; Tanizaki, Yumihiro; Iida, Mitsuo; Kiyohara, Yutaka

2008-12-16

The study of long-term trends in the incidence of and risk factors for ischemic stroke subtypes could offer insights into primary and secondary prevention. We established 3 cohorts of residents >/=40 years of age in 1961, 1974, and 1988 in the Japanese community of Hisayama. Morphological examinations by autopsy or brain imaging were performed on most of the ischemic stroke cases developed in these cohorts. When 13-year follow-up data were compared, the age-adjusted incidence of ischemic stroke and lacunar infarction declined significantly from the first to the third cohort for both sexes, whereas the incidences of atherothrombotic and cardioembolic infarction did not change during this period. Hypertension was a powerful risk factor for the development of ischemic stroke, and improvement of hypertension control would have largely influenced this declining trend: The age- and sex-adjusted hazard ratio of hypertension decreased from 3.25 (95% CI 2.17 to 4.86) in the first cohort to 1.83 (1.29 to 2.58) in the third cohort. A rapid increase in the prevalence of metabolic disorders may have offset the impact of improvements in hypertension control and resulted in a slowdown of the decline in the incidence of ischemic stroke in the cohorts in the present study; however, hypertension still makes a large contribution to the development of ischemic stroke. These findings suggest that in the Japanese population, the incidence of ischemic stroke has declined significantly over the past 40 years, probably owing to better management of hypertension. There is a need for greater primary prevention efforts in the treatment of hypertension and metabolic disorders.

The time dependence of the effect of ischemic preconditioning on successive sprint swimming performance.

PubMed

Lisbôa, Felipe D; Turnes, Tiago; Cruz, Rogério S O; Raimundo, João A G; Pereira, Gustavo S; Caputo, Fabrizio

2017-05-01

The present study aimed to determine the effects of ischemic preconditioning on performance in three successive 50-m swimming trials and to measure stroke rate, stroke length and blood lactate accumulation. Counterbalanced, repeated-measures cross-over study. On two separate days, eleven competitive male swimmers (20±3 years, 182±5cm, 77±5kg) performed three successive 50-m trials in a 50-m swimming pool, preceded by intermittent bilateral cuff inflation (4× 5-min of blood flow restriction+5-min of cuff deflation) at either 220 for thighs and 180mmHg for arms (ischemic preconditioning) or 20mmHg for both limbs (control-treatment). The 50-m trials were conducted 1-, 2-, and 8-h after the procedure. While no ergogenic effect of ischemic preconditioning was observed for 1-h (0.4%, 95% confidence limits of ±0.6%, p=0.215), there were clear beneficial effects of ischemic preconditioning on 2- and 8-h (1.0% and 1.2%, respectively; 95% confidence limits of ±0.6% in both cases, p≤0.002). Furthermore, ischemic preconditioning increased blood lactate accumulation in 2-(p<0.001) and 8-h (p=0.010) and stroke rate for 2- and 8-h in specific 10-m segments (p<0.05). These findings suggest a time-dependent effect of ischemic preconditioning on 50-m swimming performance for competitive athletes, with the time window of the beneficial effect starting after about 2-h and lasting for at least 8-h after ischemic preconditioning. This change in performance was accompanied by an increase in blood lactate accumulation and faster strokes in front crawl. Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Fractal analysis of the ischemic transition region in chronic ischemic heart disease using magnetic resonance imaging.

PubMed

Michallek, Florian; Dewey, Marc

2017-04-01

To introduce a novel hypothesis and method to characterise pathomechanisms underlying myocardial ischemia in chronic ischemic heart disease by local fractal analysis (FA) of the ischemic myocardial transition region in perfusion imaging. Vascular mechanisms to compensate ischemia are regulated at various vascular scales with their superimposed perfusion pattern being hypothetically self-similar. Dedicated FA software ("FraktalWandler") has been developed. Fractal dimensions during first-pass (FD first-pass ) and recirculation (FD recirculation ) are hypothesised to indicate the predominating pathomechanism and ischemic severity, respectively. Twenty-six patients with evidence of myocardial ischemia in 108 ischemic myocardial segments on magnetic resonance imaging (MRI) were analysed. The 40th and 60th percentiles of FD first-pass were used for pathomechanical classification, assigning lesions with FD first-pass  ≤ 2.335 to predominating coronary microvascular dysfunction (CMD) and ≥2.387 to predominating coronary artery disease (CAD). Optimal classification point in ROC analysis was FD first-pass  = 2.358. FD recirculation correlated moderately with per cent diameter stenosis in invasive coronary angiography in lesions classified CAD (r = 0.472, p = 0.001) but not CMD (r = 0.082, p = 0.600). The ischemic transition region may provide information on pathomechanical composition and severity of myocardial ischemia. FA of this region is feasible and may improve diagnosis compared to traditional noninvasive myocardial perfusion analysis. • A novel hypothesis and method is introduced to pathophysiologically characterise myocardial ischemia. • The ischemic transition region appears a meaningful diagnostic target in perfusion imaging. • Fractal analysis may characterise pathomechanical composition and severity of myocardial ischemia.

Advanced interatrial block and ischemic stroke: The Atherosclerosis Risk in Communities Study.

PubMed

O'Neal, Wesley T; Kamel, Hooman; Zhang, Zhu-Ming; Chen, Lin Y; Alonso, Alvaro; Soliman, Elsayed Z

2016-07-26

Given that recent reports have suggested left atrial disease to be an independent risk factor for ischemic stroke, we sought to examine if advanced interatrial block (aIAB) is an independent stroke risk factor. We examined the association between aIAB and incident ischemic stroke in 14,716 participants (mean age 54 ± 5.8 years; 55% female; 26% black) from the Atherosclerosis Risk in Communities Study (ARIC). Cases of aIAB were identified from digital ECGs recorded during the baseline ARIC visit (1987-1989) and the first 3 follow-up study visits (1990-1992, 1993-1995, and 1996-1998). Adjudicated ischemic stroke events were ascertained through December 31, 2010. There were 266 (1.8%) participants who had evidence of aIAB. Over a median follow-up of 22 years, 916 (6.2%) ischemic stroke events were detected. The incidence rate (per 1,000 person-years) of ischemic stroke among those with aIAB (incidence rate 8.05, 95% confidence interval [CI] 5.7, 11.4) was more than twice the rate in those without aIAB (incidence rate 3.14, 95% CI 2.94, 3.35). In a multivariable Cox regression analysis adjusted for stroke risk factors and potential confounders, aIAB was associated with an increased risk of ischemic stroke (hazard ratio 1.63, 95% CI 1.13, 2.34). The results were consistent across subgroups of participants stratified by age, sex, and race. In the ARIC, aIAB was associated with incident ischemic stroke, which strengthens the hypothesis that left atrial disease should be considered an independent stroke risk factor. © 2016 American Academy of Neurology.

Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study.

PubMed

White, Halina; Boden-Albala, Bernadette; Wang, Cuiling; Elkind, Mitchell S V; Rundek, Tanja; Wright, Clinton B; Sacco, Ralph L

2005-03-15

Stroke incidence is greater in blacks than in whites; data on Hispanics are limited. Comparing subtype-specific ischemic stroke incidence rates may help to explain race-ethnic differences in stroke risk. The aim of this population-based study was to determine ischemic stroke subtype incidence rates for whites, blacks, and Hispanics living in one community. A comprehensive stroke surveillance system incorporating multiple overlapping strategies was used to identify all cases of first ischemic stroke occurring between July 1, 1993, and June 30, 1997, in northern Manhattan. Ischemic stroke subtypes were determined according to a modified NINDS scheme, and age-adjusted, race-specific incidence rates calculated. The annual age-adjusted incidence of first ischemic stroke per 100,000 was 88 (95% CI, 75 to 101) in whites, 149 (95% CI, 132 to 165) in Hispanics, and 191 (95% CI, 160 to 221) in blacks. Among blacks compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.85 (95% CI, 1.82 to 18.73); extracranial atherosclerotic stroke, 3.18 (95% CI, 1.42 to 7.13); lacunar stroke, 3.09 (95% CI, 1.86 to 5.11); and cardioembolic stroke, 1.58 (95% CI, 0.99 to 2.52). Among Hispanics compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.00 (95% CI, 1.69 to 14.76); extracranial atherosclerotic stroke, 1.71 (95% CI, 0.80 to 3.63); lacunar stroke, 2.32 (95% CI, 1.48 to 3.63); and cardioembolic stroke, 1.42 (95% CI, 0.97 to 2.09). The high ischemic stroke incidence among blacks and Hispanics compared with whites is due to higher rates of all ischemic stroke subtypes.

Statins reduce appropriate implantable cardioverter-defibrillator shocks in ischemic cardiomyopathy with no benefit in nonischemic cardiomyopathy.

PubMed

Contractor, Tahmeed; Beri, Abhimanyu; Gardiner, Joseph; Ardhanari, Sivakumar; Thakur, Ranjan

2012-11-01

Statins have been hypothesized to decrease ventricular arrhythmias through a direct antiarrhythmic effect. Clinical studies have demonstrated a clear reduction only in populations with underlying ischemic heart disease. This study was designed to compare the effect of statins on appropriate shocks between ischemic and nonischemic cardiomyopathy. Patients with an ejection fraction 35% or less who received an implantable cardioverter-defibrillator and had follow-up for at least 1 month were included. The ischemic and nonischemic groups were divided into statin treatment and control subgroups and the occurrence of appropriate shocks was compared. The frequency of shocks was analyzed using negative binomial models to account for overdispersion of the "count" data (number of appropriate shocks) and an adjusted intensity rate ratio was calculated for statin use. A total of 676 patients were included, of which statins were used by 65% (329 of 506) of the ischemic and 42% (72 of 170) of the nonischemic groups. Occurrence of appropriate shocks was significantly reduced with statins in ischemic (13.4% vs 20.9%; relative risk 0.64, P = 0.028), but not in the patients with nonischemic cardiomyopathy. Similarly, although use of statins lowered the intensity rate of appropriate shocks in ischemic patients (intensity rate ratio, 0.23; 95% confidence interval, 0.12-0.47), no such benefit was noted in the nonischemic group (intensity rate ratio, 1.27; 95% confidence interval, 0.37-4.40). In conclusion, statins reduced the occurrence and frequency of appropriate shocks for ventricular arrhythmias in ischemic but not in nonischemic cardiomyopathy. Larger, randomized controlled trials are needed to confirm these findings.

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

PubMed

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

2016-01-01

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

Application of an interactive water simulation model in urban water management: a case study in Amsterdam.

PubMed

Leskens, J G; Brugnach, M; Hoekstra, A Y

2014-01-01

Water simulation models are available to support decision-makers in urban water management. To use current water simulation models, special expertise is required. Therefore, model information is prepared prior to work sessions, in which decision-makers weigh different solutions. However, this model information quickly becomes outdated when new suggestions for solutions arise and are therefore limited in use. We suggest that new model techniques, i.e. fast and flexible computation algorithms and realistic visualizations, allow this problem to be solved by using simulation models during work sessions. A new Interactive Water Simulation Model was applied for two case study areas in Amsterdam and was used in two workshops. In these workshops, the Interactive Water Simulation Model was positively received. It included non-specialist participants in the process of suggesting and selecting possible solutions and made them part of the accompanying discussions and negotiations. It also provided the opportunity to evaluate and enhance possible solutions more often within the time horizon of a decision-making process. Several preconditions proved to be important for successfully applying the Interactive Water Simulation Model, such as the willingness of the stakeholders to participate and the preparation of different general main solutions that can be used for further iterations during a work session.

The Migraine-Ischemic Stroke Relation in Young Adults

PubMed Central

Pezzini, Alessandro; Del Zotto, Elisabetta; Giossi, Alessia; Volonghi, Irene; Costa, Paolo; Dalla Volta, Giorgio; Padovani, Alessandro

2011-01-01

In spite of the strong epidemiologic evidence linking migraine and ischemic stroke in young adults, the mechanisms explaining this association remain poorly understood. The observation that stroke occurs more frequently during the interictal phase of migraine prompts to speculation that an indirect relation between the two diseases might exist. In this regard, four major issues might be considered which may be summarized as follows: (1) the migraine-ischemic stroke relation is influenced by specific risk factors such as patent foramen ovale or endothelial dysfunction and more frequent in particular conditions like spontaneous cervical artery dissection; (2) migraine is associated with an increased prevalence of cardiovascular risk factors; (3) the link is caused by migraine-specific drugs; (4) migraine and ischemic vascular events are linked via a genetic component. In the present paper, we will review epidemiological studies, discuss potential mechanisms of migraine-induced stroke and comorbid ischemic stroke, and pose new research questions. PMID:21197470

Massive cortico-subcortical ischemic stroke with a consecutive hemorrhagic event: a case report.

PubMed

Pirici, D; Ion, Daniela Adriana; Mogoantă, L; Mărgăritescu, Otilia; Pirici, Ionica; Foarfă, Camelia; Tudorică, Valerica; Panduru, N M; Coconu, Marieta; Checheriţă, I A

2011-01-01

We report a case of a 78-year-old woman with a large cerebral infarction probably due to athermanous embolism following atrial fibrillation. The patient, known with atrial fibrillation, high blood pressure and heart failure, complained of headache and motor impairment on the left side of the body. CT imaging revealed a subacute ischemic lesion in the right fronto-occipital lobes, and an old ischemic lesion in the right fronto-parietal lobes. Anticoagulant treatment was conducted with careful monitoring of the coagulability status. After almost three weeks, suddenly the patient became comatose and died shortly after. Macroscopic and microscopic examination confirmed the cortico-subcortical ischemic lesions, but also identified a fresh hemorrhagic site in pons, distant from the initial lesion sites. An immunohistochemical study identified blood vessels in the ischemic sites completely isolated from any glial support. This is a rare case of a large cerebral infarction with a pontine hemorrhagic event.

[Free radicals and hepatic ischemia-reperfusion].

PubMed

Szijártó, Attila

2015-11-22

The critical importance of the ischemic-reperfusive injury is well documented with regards to numerous organs and clinical conditions. Oxygen free radicals play a central role in the mediation of the injury, which dominantly influences the prevalence of postoperative complications, (long term) organ damage, and the potential manifestation of systemic reactions. The both anatomically and pathophysiologically unique ischemic-reperfusive injury of the liver, which is expressively vulnerable to free radicals, is of utmost importance in liver surgery. Several techniques (adaptive maneuvers, chemical agents) are known to ameliorate the reperfusive injury. Based on the prior research of the workgroup of the author, the aim of the current article is to overview the set of measures capable of attenuating ischemic-reperfusive injury (ischemic preconditioning, -perconditioning, administration of adenosine, -inosine, -levosimendan, and -poly-ADP-ribose-polymerase inhibitor), with special attention to the ischemic-reperfusive injury of the liver, as well as the special pathophysiological role of free radicals in mediating hepatic damage.

Role of inflammation and its mediators in acute ischemic stroke

PubMed Central

Jin, Rong; Liu, Lin; Zhang, Shihao; Nanda, Anil; Li, Guohong

2013-01-01

Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Increasing evidence suggests that inflammatory response is a double-edged sword, as it not only exacerbates secondary brain injury in the acute stage of stroke but also beneficially contributes to brain recovery after stroke. In this article, we provide an overview on the role of inflammation and its mediators in acute ischemic stroke. We discuss various pro-inflammatory and anti-inflammatory responses in different phases after ischemic stroke and the possible reasons for their failures in clinical trials. Undoubtedly, there is still much to be done in order to translate promising pre-clinical findings into clinical practice. A better understanding of the dynamic balance between pro- and anti-inflammatory responses and identifying the discrepancies between pre-clinical studies and clinical trials may serve as a basis for designing effective therapies. PMID:24006091

[Primary emergencies: management of acute ischemic stroke].

PubMed

Leys, Didier; Goldstein, Patrick

2012-01-01

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

Lubiprostone induced ischemic colitis

PubMed Central

Sherid, Muhammed; Sifuentes, Humberto; Samo, Salih; Deepak, Parakkal; Sridhar, Subbaramiah

2013-01-01

Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding. PMID:23345954

[Association Between SNP rs6007897 of CELSR1 and Acute Ischemic Stroke in Western China Han Population: a Case-control Study].

PubMed

Qin, Feng-qin; Yu, Li-hua; Hu, Wen-ting; Guo, Jian; Chen, Ning; Guo, Jiang; Fang, Jing-huan; He, Li

2015-07-01

To investigate the relationship between single nucleotide polymorphism (SNP) rs6007897 of CELSR1 and acute ischemic stroke in Western China Han population. All subjects (759 acute ischemic stroke patients and 786 controls) were genotyped using ligation detection reaction (LDR). We analyzed the differences between SNP rs6007897 genotypes and allele frequencies between two groups. Two genotypes (AA, AG) of rs6007897 were found in both stroke and control group. There was no statistically significance between two groups about genotype and allele frequency. After adjusting for risk factors, we found there was no significant association between rs6007897 and ischemic stroke CP = 0.797, odds ratio (OR) = 0.886, 95% confidence interval (CI) = 0.352-2.227). SNP rs6007897 of CELSR1 was not significantly associated with ischemic stroke in Western China Han population.

Niche astrocytes promote the survival, proliferation and neuronal differentiation of co-transplanted neural stem cells following ischemic stroke in rats

PubMed Central

Luo, Li; Guo, Kaihua; Fan, Wenguo; Lu, Yinghong; Chen, Lizhi; Wang, Yang; Shao, Yijia; Wu, Gongxiong; Xu, Jie; Lü, Lanhai

2017-01-01

Niche astrocytes have been reported to promote neuronal differentiation through juxtacrine signaling. However, the effects of astrocytes on neuronal differentiation following ischemic stroke are not fully understood. In the present study, transplanted astrocytes and neural stem cells (NSCs) were transplanted into the ischemic striatum of transient middle cerebral artery occlusion (MCAO) model rats 48 h following surgery. It was observed that the co-transplantation of astrocytes and NSCs resulted in a higher ratio of survival and proliferation of the transplanted NSCs, and neuronal differentiation, in MCAO rats compared with NSC transplantation alone. These results demonstrate that the co-administration of astrocytes promotes the survival and neuronal differentiation of NSCs in the ischemic brain. These results suggest that the co-transplantation of astrocytes and NSCs is more effective than NSCs alone in the production of neurons following ischemic stroke in rats. PMID:28352345

Single nucleotide polymorphisms associated with coronary heart disease predict incident ischemic stroke in the atherosclerosis risk in communities study.

PubMed

Morrison, Alanna C; Bare, Lance A; Luke, May M; Pankow, James S; Mosley, Thomas H; Devlin, James J; Willerson, James T; Boerwinkle, Eric

2008-01-01

Ischemic stroke and coronary heart disease (CHD) may share genetic factors contributing to a common etiology. This study investigates whether 51 single nucleotide polymorphisms (SNPs) associated with CHD in multiple antecedent studies are associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. From the multiethnic ARIC cohort of 14,215 individuals, 495 validated ischemic strokes were identified. Cox proportional hazards models, adjusted for age and gender, identified three SNPs in Whites and two SNPs in Blacks associated with incident stroke (p

A modified dynamical model of drying process of polymer blend solution coated on a flat substrate

NASA Astrophysics Data System (ADS)

Kagami, Hiroyuki

2008-05-01

We have proposed and modified a model of drying process of polymer solution coated on a flat substrate for flat polymer film fabrication. And for example numerical simulation of the model reproduces a typical thickness profile of the polymer film formed after drying. Then we have clarified dependence of distribution of polymer molecules on a flat substrate on a various parameters based on analysis of numerical simulations. Then we drove nonlinear equations of drying process from the dynamical model and the fruits were reported. The subject of above studies was limited to solution having one kind of solute though the model could essentially deal with solution having some kinds of solutes. But nowadays discussion of drying process of a solution having some kinds of solutes is needed because drying process of solution having some kinds of solutes appears in many industrial scenes. Polymer blend solution is one instance. And typical resist consists of a few kinds of polymers. Then we introduced a dynamical model of drying process of polymer blend solution coated on a flat substrate and results of numerical simulations of the dynamical model. But above model was the simplest one. In this study, we modify above dynamical model of drying process of polymer blend solution adding effects that some parameters change with time as functions of some variables to it. Then we consider essence of drying process of polymer blend solution through comparison between results of numerical simulations of the modified model and those of the former model.

Super-rogue waves in simulations based on weakly nonlinear and fully nonlinear hydrodynamic equations.

PubMed

Slunyaev, A; Pelinovsky, E; Sergeeva, A; Chabchoub, A; Hoffmann, N; Onorato, M; Akhmediev, N

2013-07-01

The rogue wave solutions (rational multibreathers) of the nonlinear Schrödinger equation (NLS) are tested in numerical simulations of weakly nonlinear and fully nonlinear hydrodynamic equations. Only the lowest order solutions from 1 to 5 are considered. A higher accuracy of wave propagation in space is reached using the modified NLS equation, also known as the Dysthe equation. This numerical modeling allowed us to directly compare simulations with recent results of laboratory measurements in Chabchoub et al. [Phys. Rev. E 86, 056601 (2012)]. In order to achieve even higher physical accuracy, we employed fully nonlinear simulations of potential Euler equations. These simulations provided us with basic characteristics of long time evolution of rational solutions of the NLS equation in the case of near-breaking conditions. The analytic NLS solutions are found to describe the actual wave dynamics of steep waves reasonably well.

Fragmentation-based QM/MM simulations: length dependence of chain dynamics and hydrogen bonding of polyethylene oxide and polyethylene in aqueous solutions.

PubMed

Li, Hui; Li, Wei; Li, Shuhua; Ma, Jing

2008-06-12

Molecular fragmentation quantum mechanics (QM) calculations have been combined with molecular mechanics (MM) to construct the fragmentation QM/MM method for simulations of dilute solutions of macromolecules. We adopt the electrostatics embedding QM/MM model, where the low-cost generalized energy-based fragmentation calculations are employed for the QM part. Conformation energy calculations, geometry optimizations, and Born-Oppenheimer molecular dynamics simulations of poly(ethylene oxide), PEO(n) (n = 6-20), and polyethylene, PE(n) ( n = 9-30), in aqueous solution have been performed within the framework of both fragmentation and conventional QM/MM methods. The intermolecular hydrogen bonding and chain configurations obtained from the fragmentation QM/MM simulations are consistent with the conventional QM/MM method. The length dependence of chain conformations and dynamics of PEO and PE oligomers in aqueous solutions is also investigated through the fragmentation QM/MM molecular dynamics simulations.

The Five Ps of Acute Ischemic Stroke Treatment: Parenchyma, Pipes, Perfusion, Penumbra, and Prevention of Complications

PubMed Central

Felberg, Robert A.; Naidech, Andrew

2003-01-01

Stroke is a treatable disease. Despite the therapeutic nihilism of the past, the advent of thrombolysis has changed the way stroke treatment is approached. Acute ischemic stroke is a challenging and heterogeneous disease, and treatment must be based on an understanding of the underlying pathophysiology of ischemia. Interventions are designed to improve neuronal salvage and outcome. The underlying tenets of stroke therapy focus on the brain parenchyma, arterial flow (pipes), perfusion, the ischemic milieu or penumbra, and prevention of complications. This article focuses on the practical issues of ischemic stroke care with a brief review of supporting literature. PMID:22470250

[The relationship between ischemic preconditioning-induced infarction size limitation and duration of test myocardial ischemia].

PubMed

Blokhin, I O; Galagudza, M M; Vlasov, T D; Nifontov, E M; Petrishchev, N N

2008-07-01

Traditionally infarction size reduction by ischemic preconditioning is estimated in duration of test ischemia. This approach limits the understanding of real antiischemic efficacy of ischemic preconditioning. Present study was performed in the in vivo rat model of regional myocardial ischemia-reperfusion and showed that protective effect afforded by ischemic preconditioning progressively decreased with prolongation of test ischemia. There were no statistically significant differences in infarction size between control and preconditioned animals when the duration of test ischemia was increased up to 1 hour. Preconditioning ensured maximal infarction-limiting effect in duration of test ischemia varying from 20 to 40 minutes.

Stroke: advances in medical therapy and acute stroke intervention.

PubMed

Barrett, Kevin M; Lal, Brajesh K; Meschia, James F

2015-10-01

Evidence-based therapeutic options for stroke continue to emerge based on results from well-designed clinical studies. Ischemic stroke far exceeds hemorrhagic stroke in terms of prevalence and incidence, both in the USA and worldwide. The public health effect of reducing death and disability related to ischemic stroke justifies the resources that have been invested in identifying safe and effective treatments. The emergence of novel oral anticoagulants for ischemic stroke prevention in atrial fibrillation has introduced complexity to clinical decision making for patients with this common cardiac arrhythmia. Some accepted ischemic stroke preventative strategies, such as carotid revascularization for asymptomatic carotid stenosis, require reassessment, given advances in risk factor management, antithrombotic therapy, and surgical techniques. Intra-arterial therapy, particularly with stent retrievers after intravenous tissue plasminogen activator, has recently been demonstrated to improve functional outcomes and will require investment in system-based care models to ensure that effective treatments are received by patients in a timely fashion. The purpose of this review is to describe recent advances in medical and surgical approaches to ischemic stroke prevention and acute treatment. Results from recently published clinical trials will be highlighted along with ongoing clinical trials addressing key questions in ischemic stroke management and prevention where equipoise remains.

CCL11 (Eotaxin-1) Levels Predict Long-Term Functional Outcomes in Patients Following Ischemic Stroke.

PubMed

Roy-O'Reilly, Meaghan; Ritzel, Rodney M; Conway, Sarah E; Staff, Ilene; Fortunato, Gilbert; McCullough, Louise D

2017-12-01

Circulating levels of the pro-inflammatory cytokine C-C motif chemokine 11 (CCL11, also known as eotaxin-1) are increased in several animal models of neuroinflammation, including traumatic brain injury and Alzheimer's disease. Increased levels of CCL11 have also been linked to decreased neurogenesis in mice. We hypothesized that circulating CCL11 levels would increase following ischemic stroke in mice and humans, and that higher CCL11 levels would correlate with poor long-term recovery in patients. As predicted, circulating levels of CCL11 in both young and aged mice increased significantly 24 h after experimental stroke. However, ischemic stroke patients showed decreased CCL11 levels compared to controls 24 h after stroke. Interestingly, lower post-stroke CCL11 levels were predictive of increased stroke severity and independently predictive of poorer functional outcomes in patients 12 months after ischemic stroke. These results illustrate important differences in the peripheral inflammatory response to ischemic stroke between mice and human patients. In addition, it suggests CCL11 as a candidate biomarker for the prediction of acute and long-term functional outcomes in ischemic stroke patients.

[CHANGING OF ISCHEMIC M. SOLEUS TETANIC CONTRACTION PARAMETERS IN RATS WITH CHRONIC ALCOHOL INTOXICATION].

PubMed

Melnychuk, O A; Motuziuk, O P; Shvayko, S Ye

2015-01-01

This article deals with the changes of isolated ischemic m. soleus tetanus parameters in rats with chronic alcohol intoxication. The experiments were carried out on 15 male Wistar rats that were divided into three groups for 5 animals in each: group I (control) and two groups in which was induced hind limbs acute muscles ischemia: group II - rats without alcoholic intoxication, group III - rats with chronic alcoholic intoxication. Strain measurement muscle mechanical activity were conducted in isometric mode under conditions of direct electrical muscular preparation stimulation. It is proved that ischemic m. soleus tetanic force in rats with chronic alcoholic intoxication in comparison with rats without alcoholic intoxication does not significant changes. But signifycantly increases the reaching tetanus peak time. It is shown that in rats without alcoholic intoxication and with chronic alcoholic intoxication in comparison with intact animals, significantly decreases the duration of ischemic m. soleus stabile force level. It is shoved significant changes of individual muscles contraction time course of ischemic m. soleus tetanus in this rats group in comparison to intact animal. It is shown that these changes influence on successive muscular contraction efficiency of frequency summation in ischemic m. soleus tetanus and their speed-power characteristics.

Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation.

PubMed

Yang, Tuo; Sun, Yang; Mao, Leilei; Zhang, Meijuan; Li, Qianqian; Zhang, Lili; Shi, Yejie; Leak, Rehana K; Chen, Jun; Zhang, Feng

2018-05-06

Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Computed microtomography visualization and quantification of mouse ischemic brain lesion by nonionic radio contrast agents

PubMed Central

Dobrivojević, Marina; Bohaček, Ivan; Erjavec, Igor; Gorup, Dunja; Gajović, Srećko

2013-01-01

Aim To explore the possibility of brain imaging by microcomputed tomography (microCT) using x-ray contrasting methods to visualize mouse brain ischemic lesions after middle cerebral artery occlusion (MCAO). Methods Isolated brains were immersed in ionic or nonionic radio contrast agent (RCA) for 5 days and subsequently scanned using microCT scanner. To verify whether ex-vivo microCT brain images can be used to characterize ischemic lesions, they were compared to Nissl stained serial histological sections of the same brains. To verify if brains immersed in RCA may be used afterwards for other methods, subsequent immunofluorescent labeling with anti-NeuN was performed. Results Nonionic RCA showed better gray to white matter contrast in the brain, and therefore was selected for further studies. MicroCT measurement of ischemic lesion size and cerebral edema significantly correlated with the values determined by Nissl staining (ischemic lesion size: P=0.0005; cerebral edema: P=0.0002). Brain immersion in nonionic RCA did not affect subsequent immunofluorescent analysis and NeuN immunoreactivity. Conclusion MicroCT method was proven to be suitable for delineation of the ischemic lesion from the non-infarcted tissue, and quantification of lesion volume and cerebral edema. PMID:23444240

Computed microtomography visualization and quantification of mouse ischemic brain lesion by nonionic radio contrast agents.

PubMed

Dobrivojević, Marina; Bohaček, Ivan; Erjavec, Igor; Gorup, Dunja; Gajović, Srećko

2013-02-01

To explore the possibility of brain imaging by microcomputed tomography (microCT) using x-ray contrasting methods to visualize mouse brain ischemic lesions after middle cerebral artery occlusion (MCAO). Isolated brains were immersed in ionic or nonionic radio contrast agent (RCA) for 5 days and subsequently scanned using microCT scanner. To verify whether ex-vivo microCT brain images can be used to characterize ischemic lesions, they were compared to Nissl stained serial histological sections of the same brains. To verify if brains immersed in RCA may be used afterwards for other methods, subsequent immunofluorescent labeling with anti-NeuN was performed. Nonionic RCA showed better gray to white matter contrast in the brain, and therefore was selected for further studies. MicroCT measurement of ischemic lesion size and cerebral edema significantly correlated with the values determined by Nissl staining (ischemic lesion size: P=0.0005; cerebral edema: P=0.0002). Brain immersion in nonionic RCA did not affect subsequent immunofluorescent analysis and NeuN immunoreactivity. MicroCT method was proven to be suitable for delineation of the ischemic lesion from the non-infarcted tissue, and quantification of lesion volume and cerebral edema.

Estimation of cesium ion exchange distribution coefficients for concentrated electrolytic solutions when using crystalline silicotitanates

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

Zheng, Z.; Gu, D.; Anthony, R.G.

1995-06-01

Polzer et al.`s method combined with Bromley`s method for estimating activity coefficients and a Langmuir isotherm for cesium in a simple simulated waste solution containing 5.1 M NaNO{sub 3} and 0.6 M NaOH was used to estimate distribution coefficients for cesium in a complex simulated waste solution characteristic of the radioactive tank wastes at Hanford and other US Department of energy sites. The ion exchange material was a hydrous sodium crystalline silicotitanate, labeled TAM-5, which is being developed by Texas A and M University, Sandia National Laboratories, and UOP Associates. Cesium distribution coefficients collected by Bray et al. on amore » NCAW simulated waste solution were predicted with deviations of less than 25% for solutions containing 1 M, 3 M, and 5 M Na{sup +} and Na:Cs ratios of 10{sup 3}--10{sup 8}. The deviations were less than 5% for the solutions with 1 M Na{sup +}. Cesium distribution coefficients were also predicted and compared with values measured by Egan et al. for TAM-5 and for a storage tank supernate and a newly generated waste solution. Excellent results were obtained for the newly generated waste simulated solution, which did not contain potassium or rubidium.The predictions for the other simulated waste solution were significantly greater than the measured values, because of the presence of large concentrations of potassium or rubidium. The effect of competitive ion exchange between Cs, Rb, and K was not included in the theory. However, the effect of competitive ion exchange between Cs, Rb, and K was not included in the theory. However, the effect of competitive exchange of Cs, Rb, and K appears to be greater for the Oak Ridge simulated waste solution than for the NCAW waste.« less

Evaluation of unsaturated-zone solute-transport models for studies of agricultural chemicals

USGS Publications Warehouse

Nolan, Bernard T.; Bayless, E. Randall; Green, Christopher T.; Garg, Sheena; Voss, Frank D.; Lampe, David C.; Barbash, Jack E.; Capel, Paul D.; Bekins, Barbara A.

2005-01-01

Of the models tested, RZWQM, HYDRUS2D, VS2DT, GLEAMS and PRZM had graphical user interfaces. Extensive documentation was available for RZWQM, HYDRUS2D, and VS2DT. RZWQM can explicitly simulate water and solute flux in macropores, and both HYDRUS2D and VS2DT can simulate water and solute flux in two dimensions. The version of RZWQM tested had a maximum simulation depth of 3 meters. The complex models simulate the formation, transport, and fate of degradates of up to three to five compounds including the parent, with the exception of VS2DT, which simulates the transport and fate of a single compound.

Nonisothermal Analysis of Solution Kinetics by Spreadsheet Simulation

ERIC Educational Resources Information Center

de Levie, Robert

2012-01-01

A fast and generally applicable alternative solution to the problem of determining the useful shelf life of medicinal solutions is described. It illustrates the power and convenience of the combination of numerical simulation and nonlinear least squares with a practical pharmaceutical application of chemical kinetics and thermodynamics, validated…

Posterior communicating artery hypoplasia as a risk factor for acute ischemic stroke in the absence of carotid artery occlusion.

PubMed

Chuang, Yu-Ming; Liu, Chih-Yang; Pan, Po-Jung; Lin, Ching-Po

2008-12-01

Posterior communicating artery (PCoA) hypoplasia is a fetal variant of the Circle of Willis. According to angiograms and autopsy reports, this congenital variation is found in 6-21% of the general population. PCoA hypoplasia only becomes a risk factor for ischemic stroke in the presence of ipsilateral internal carotid artery (ICA) occlusion. The aim of our study was to determine the role of PCoA hypoplasia in acute ischemic stroke in the absence of ICA occlusion. We examined 310 acute ischemic stroke patients (mean age+/-standard deviation; 68.9+/-15.6 years). Cerebral magnetic resonance angiography was performed within 72 hours of ischemic stroke onset. For comparison, a risk factor-matched control group was recruited. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) to estimate the independent effect of potential risk factors. The overall incidence of PCoA hypoplasia in our experimental group was 19.35% (n=60), which was significantly higher than in the control group (8.20%, n=22, p=0.036, OR, 3.21; 95% CI, 1.43-9.62). The most common ischemic event was ipsilateral thalamic lacunar infarctions with or without occipital lobe involvement. Based on our results, PCoA hypoplasia appears to be a contributor to the risk of ischemic stroke, even in the absence of ICA occlusion. This risk is especially pronounced for strokes involving arteries that penetrate the thalamus.

Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart

PubMed Central

Seeley, Sarah L.; Stoops, Thorne S.; D’Souza, Manoranjan S.

2017-01-01

Background We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Methods Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Results Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Conclusions Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse. PMID:28575091

The economic impact of enoxaparin versus unfractionated heparin for prevention of venous thromboembolism in acute ischemic stroke patients

PubMed Central

Pineo, Graham F; Lin, Jay; Annemans, Lieven

2012-01-01

Venous thromboembolism (VTE) is a common complication after acute ischemic stroke that can be prevented by the use of anticoagulants. Current guidelines from the American College of Chest Physicians recommend that patients with acute ischemic stroke and restricted mobility receive prophylactic low-dose unfractionated heparin or a low-molecular-weight heparin. Results from clinical studies, most recently from PREVAIL (PREvention of Venous Thromboembolism After Acute Ischemic Stroke with LMWH and unfractionated heparin), suggest that the low-molecular-weight heparin, enoxaparin, is preferable to unfractionated heparin for VTE prophylaxis in patients with acute ischemic stroke and restricted mobility. This is due to a better clinical benefit-to-risk ratio, with the added convenience of once-daily administration. In line with findings from modeling studies and real-world data in acutely ill medical patients, recent economic data indicate that the higher drug cost of enoxaparin is offset by the reduction in clinical events as compared with the use of unfractionated heparin for the prevention of VTE after acute ischemic stroke, particularly in patients with severe stroke. With national performance measures highlighting the need for hospitals to examine their VTE practices, the relative costs of different regimens are of particular importance to health care decision-makers. The data reviewed here suggest that preferential use of enoxaparin over unfractionated heparin for the prevention of VTE after acute ischemic stroke may lead to reduced VTE rates and concomitant cost savings in clinical practice. PMID:22570556

Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart.

PubMed

Rorabaugh, Boyd R; Seeley, Sarah L; Stoops, Thorne S; D'Souza, Manoranjan S

2017-01-01

We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

Behavior outcome after ischemic and hemorrhagic stroke, with similar brain damage, in rats.

PubMed

Mestriner, Régis Gemerasca; Miguel, Patrícia Maidana; Bagatini, Pamela Brambilla; Saur, Lisiani; Boisserand, Lígia Simões Braga; Baptista, Pedro Porto Alegre; Xavier, Léder Leal; Netto, Carlos Alexandre

2013-05-01

Stroke causes disability and mortality worldwide and is divided into ischemic and hemorrhagic subtypes. Although clinical trials suggest distinct recovery profiles for ischemic and hemorrhagic events, this is not conclusive due to stroke heterogeneity. The aim of this study was to produce similar brain damage, using experimental models of ischemic (IS) and hemorrhagic (HS) stroke and evaluate the motor spontaneous recovery profile. We used 31 Wistar rats divided into the following groups: Sham (n=7), ischemic (IS) (n=12) or hemorrhagic (HS) (n=12). Brain ischemia or hemorrhage was induced by endotelin-1 (ET-1) and collagenase type IV-S (collagenase) microinjections, respectively. All groups were evaluated in the open field, cylinder and ladder walk behavioral tests at distinct time points as from baseline to 30 days post-surgery (30 PS). Histological and morphometric analyses were used to assess the volume of lost tissue and lesion length. Present results reveal that both forms of experimental stroke had a comparable long-term pattern of damage, since no differences were found in volume of tissue lost or lesion size 30 days after surgery. However, behavioral data showed that hemorrhagic rats were less impaired at skilled walking than ischemic ones at 15 and 30 days post-surgery. We suggest that experimentally comparable stroke design is useful because it reduces heterogeneity and facilitates the assessment of neurobiological differences related to stroke subtypes; and that spontaneous skilled walking recovery differs between experimental ischemic and hemorrhagic insults. Copyright © 2013 Elsevier B.V. All rights reserved.

Association between red blood cell distribution width (RDW) and carotid artery atherosclerosis (CAS) in patients with primary ischemic stroke.

PubMed

Jia, He; Li, Huimian; Zhang, Yan; Li, Che; Hu, Yingyun; Xia, Chunfang

2015-01-01

The present study aimed to explore the association between RDW and CAS in patients with ischemic stroke, expecting to find a new and significant diagnosis index for clinical practice. This cross-sectional study involves 432 consecutive patients with primary ischemic stroke (within 72 h). All subjects were confirmed by magnetic resonance imaging, and underwent physical examination, laboratory tests and carotid ultrasonography check. Finally, 392 patients were included according to the exclusion criteria. The odds ratios of independent variables were calculated using stepwise multiple logistic regression. Carotid intimal-medial thickness (IMT) and RDW are both significantly different between CAS group and control group. Univariate analyses show that high-sensitive C-reactive protein (Hs-CRP) and RDW (r=0.436) are both in significantly positive association with IMT. Stepwise multiple logistic regression shows that RDW is an independent protective factor of CAS in patients with ischemic stroke. Compared with the lowest quartile, the second to fourth quartiles are 1.13 (95% CI: 1.13-3.05), 2.02 (95% CI: 1.66-4.67), and 3.10 (95% CI: 2.46-7.65), respectively. The present study suggested that RDW level were higher than non-CAS in patients with primary ischemic stroke. Our results facilitated a bridge to connect RDW with ischemic stroke and further confirmed the role of RDW in the progression of the ischemic stroke. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparative risk of ischemic stroke among users of clopidogrel together with individual proton pump inhibitors

PubMed Central

Bilker, Warren B.; Brensinger, Colleen M.; Flockhart, David A.; Freeman, Cristin P.; Kasner, Scott E.; Kimmel, Stephen E.; Hennessy, Sean

2015-01-01

Background and Purpose There is controversy and little information concerning whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We therefore aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. Methods We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999–2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole and pantoprazole—with pantoprazole serving as the referent. The endpoint was hospitalization for acute ischemic stroke, defined by International Classification of Diseases 9th Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Results Among 325,559 concomitant users of clopidogrel and a PPI, we identified 1,667 ischemic strokes for an annual incidence of 2.4% (95% confidence interval: 2.3–2.5). Adjusted hazard ratios for ischemic stroke vs. pantoprazole were: 0.98 (0.82–1.17) for esomeprazole; 1.06 (0.92–1.21) for lansoprazole; 0.98 (0.85–1.15) for omeprazole; and 0.85 (0.63–1.13) for rabeprazole. Conclusions PPIs of interest did not increase the rate of ischemic stroke among clopidogrel users when compared to pantoprazole, a PPI thought to be devoid of the potential to interact with clopidogrel. PMID:25657176

Internet-based information-seeking behavior for transient ischemic attack.

PubMed

Abedi, Vida; Mbaye, Marieme; Tsivgoulis, Georgios; Male, Shailesh; Goyal, Nitin; Alexandrov, Andrei V; Zand, Ramin

2015-12-01

In recent years, Internet became an increasingly important tool for accessing health information and is being used more frequently to promote public health. To use Google search data to explore information seeking behavior for transient ischemic attack. We selected two groups of keywords related to transient ischemic attack: 'Transient Ischemic Attack' and 'Mini Stroke'. We obtained all available online search data performed in the United States from the Google search engine for a 10-year span--January 2004 to December 2013. The monthly and daily search data for the selected keywords were analyzed--using moving average--to explore the trends, peaks, and declining effects. There were three significant concurrent peaks in the Google search data for the selected keywords. Each peak was directly associated with media coverage and news headlines related to the incident of transient ischemic attack in a public figure. Following each event, it took three- to seven-days for the search trend to return to its respective average value. Furthermore, the trend was steady for 'Transient Ischemic Attack'; however, the search interest for the keyword 'Mini Stroke' shows a steady increase. The overall search interest for the selected keywords was significantly higher in the southeastern United States. Our study shows that changes in online search behavior can be associated with media coverage of key events (in our case transient ischemic attack) in public figures. These findings suggest that multimedia health promotion campaigns might be more effective, if increased promptly after similar media coverage. © 2015 World Stroke Organization.

Premature Atrial Contractions on the Screening Electrocardiogram and Risk of Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study.

PubMed

O'Neal, Wesley T; Kamel, Hooman; Kleindorfer, Dawn; Judd, Suzanne E; Howard, George; Howard, Virginia J; Soliman, Elsayed Z

2016-01-01

It is currently unknown if premature atrial contractions (PACs) detected on the routine screening electrocardiogram are associated with an increased risk of ischemic stroke. We examined the association between PACs and ischemic stroke in 22,975 (mean age 64 ± 9.2; 56% women; 40% black) participants from the Reasons for Geographic and Racial Differences in Stroke study. Participants who were free of stroke at baseline were included. PACs were detected from centrally read electrocardiograms at baseline. Cox regression was used to examine the association between PACs and ischemic stroke events through March 31, 2014. PACs were present in 1,687 (7.3%) participants at baseline. In a Cox regression model adjusted for stroke risk factors and potential confounders, PACs were associated with an increased risk of ischemic stroke (hazards ratio (HR) 1.34, 95% CI 1.04-1.74). The relationship was limited to non-lacunar infarcts (HR 1.42, 95% CI 1.08-1.87), and not lacunar strokes (HR 1.01, 95% CI 0.51-2.03). An interaction by sex was detected, with the association between PACs and ischemic stroke being stronger among women (HR 1.82, 95% CI 1.29-2.56) than men (HR 1.03, 95% CI 0.69-1.52; p-interaction = 0.0095). PACs detected on the routine electrocardiogram are associated with an increased risk for non-lacunar ischemic strokes, especially in women. © 2016 S. Karger AG, Basel.

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

Temporal trends in stroke incidence in South Asian, Chinese and white patients: A population based analysis.

PubMed

Khan, Nadia A; McAlister, Finlay A; Pilote, Louise; Palepu, Anita; Quan, Hude; Hill, Michael D; Fang, Jiming; Kapral, Moira K

2017-01-01

Little is known about potential ethnic differences in stroke incidence. We compared incidence and time trends of ischemic stroke and primary intracerebral hemorrhage in South Asian, Chinese and white persons in a population-based study. Population based census and administrative data analysis in the provinces of Ontario and British Columbia, Canada using validated ICD 9/ICD 10 coding for acute ischemic and hemorrhagic stroke (1997-2010). There were 3290 South Asians, 4444 Chinese and 160944 white patients with acute ischemic stroke and 535 South Asian, 1376 Chinese and 21842 white patients with intracerebral hemorrhage. South Asians were younger than whites at onset of stroke (70 vs. 74 years for ischemic and 67 vs. 71 years for hemorrhagic stroke). Age and sex adjusted ischemic stroke incidence in 2010 was 43% lower in Chinese and 63% lower in South Asian than in White patients. Age and sex adjusted intracerebral hemorrhage incidence was 18% higher in Chinese patients, and 66% lower in South Asian relative to white patients. Stroke incidence declined in all ethnic groups (relative reduction 69% in South Asians, 25% in Chinese, and 34% in white patients for ischemic stroke and for intracerebral hemorrhage, 79% for South Asians, 51% for Chinese and 30% in white patients). Although stroke rates declined across all ethnic groups, these rates differed significantly by ethnicity. Further study is needed to understand mechanisms underlying the higher ischemic stroke incidence in white patients and intracerebral hemorrhage in Chinese patients.

Delayed treatment with ADAMTS13 ameliorates cerebral ischemic injury without hemorrhagic complication.

PubMed

Nakano, Takafumi; Irie, Keiichi; Hayakawa, Kazuhide; Sano, Kazunori; Nakamura, Yoshihiko; Tanaka, Masayoshi; Yamashita, Yuta; Satho, Tomomitsu; Fujioka, Masayuki; Muroi, Carl; Matsuo, Koichi; Ishikura, Hiroyasu; Futagami, Kojiro; Mishima, Kenichi

2015-10-22

Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, delayed tPA treatment increases the risk of cerebral hemorrhage and can result in exacerbation of nerve injury. ADAMTS13, a von Willebrand factor (VWF) cleaving protease, has a protective effect against ischemic brain injury and may reduce bleeding risk by cleaving VWF. We examined whether ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA in mice subjected to middle cerebral artery occlusion (MCAO). ADAMTS13 (0.1mg/kg) or tPA (10mg/kg) was administered i.v., immediately after reperfusion of after 2-h or 4-h MCAO for comparison of the therapeutic time windows in ischemic stroke. Infarct volume, hemorrhagic volume, plasma high-mobility group box1 (HMGB1) levels and cerebral blood flow were measured 24h after MCAO. Both ADAMTS13 and tPA improved the infarct volume without hemorrhagic complications in 2-h MCAO mice. On the other hand, ADAMTS13 reduced the infarct volume and plasma HMGB1 levels, and improved cerebral blood flow without hemorrhagic complications in 4-h MCAO mice, but tPA was not effective and these animals showed massive intracerebral hemorrhage. These results indicated that ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA, and ADAMTS13 may be useful as a new therapeutic agent for ischemic stroke. Copyright © 2015 Elsevier B.V. All rights reserved.

Theory and Simulation of Multicomponent Osmotic Systems

PubMed Central

Karunaweera, Sadish; Gee, Moon Bae; Weerasinghe, Samantha; Smith, Paul E.

2012-01-01

Most cellular processes occur in systems containing a variety of components many of which are open to material exchange. However, computer simulations of biological systems are almost exclusively performed in systems closed to material exchange. In principle, the behavior of biomolecules in open and closed systems will be different. Here, we provide a rigorous framework for the analysis of experimental and simulation data concerning open and closed multicomponent systems using the Kirkwood-Buff (KB) theory of solutions. The results are illustrated using computer simulations for various concentrations of the solutes Gly, Gly2 and Gly3 in both open and closed systems, and in the absence or presence of NaCl as a cosolvent. In addition, KB theory is used to help rationalize the aggregation properties of the solutes. Here one observes that the picture of solute association described by the KB integrals, which are directly related to the solution thermodynamics, and that provided by more physical clustering approaches are different. It is argued that the combination of KB theory and simulation data provides a simple and powerful tool for the analysis of complex multicomponent open and closed systems. PMID:23329894

Melittin Aggregation in Aqueous Solutions: Insight from Molecular Dynamics Simulations.

PubMed

Liao, Chenyi; Esai Selvan, Myvizhi; Zhao, Jun; Slimovitch, Jonathan L; Schneebeli, Severin T; Shelley, Mee; Shelley, John C; Li, Jianing

2015-08-20

Melittin is a natural peptide that aggregates in aqueous solutions with paradigmatic monomer-to-tetramer and coil-to-helix transitions. Since little is known about the molecular mechanisms of melittin aggregation in solution, we simulated its self-aggregation process under various conditions. After confirming the stability of a melittin tetramer in solution, we observed—for the first time in atomistic detail—that four separated melittin monomers aggregate into a tetramer. Our simulated dependence of melittin aggregation on peptide concentration, temperature, and ionic strength is in good agreement with prior experiments. We propose that melittin mainly self-aggregates via a mechanism involving the sequential addition of monomers, which is supported by both qualitative and quantitative evidence obtained from unbiased and metadynamics simulations. Moreover, by combining computer simulations and a theory of the electrical double layer, we provide evidence to suggest why melittin aggregation in solution likely stops at the tetramer, rather than forming higher-order oligomers. Overall, our study not only explains prior experimental results at the molecular level but also provides quantitative mechanistic information that may guide the engineering of melittin for higher efficacy and safety.

White Matter Hyperintensities Improve Ischemic Stroke Recurrence Prediction.

PubMed

Andersen, Søren Due; Larsen, Torben Bjerregaard; Gorst-Rasmussen, Anders; Yavarian, Yousef; Lip, Gregory Y H; Bach, Flemming W

2017-01-01

Nearly one in 5 patients with ischemic stroke will invariably experience a second stroke within 5 years. Stroke risk stratification schemes based solely on clinical variables perform only modestly in non-atrial fibrillation (AF) patients and improvement of these schemes will enhance their clinical utility. Cerebral white matter hyperintensities are associated with an increased risk of incident ischemic stroke in the general population, whereas their association with the risk of ischemic stroke recurrence is more ambiguous. In a non-AF stroke cohort, we investigated the association between cerebral white matter hyperintensities and the risk of recurrent ischemic stroke, and we evaluated the predictive performance of the CHA2DS2VASc score and the Essen Stroke Risk Score (clinical scores) when augmented with information on white matter hyperintensities. In a registry-based, observational cohort study, we included 832 patients (mean age 59.6 (SD 13.9); 42.0% females) with incident ischemic stroke and no AF. We assessed the severity of white matter hyperintensities using MRI. Hazard ratios stratified by the white matter hyperintensities score and adjusted for the components of the CHA2DS2VASc score were calculated based on the Cox proportional hazards analysis. Recalibrated clinical scores were calculated by adding one point to the score for the presence of moderate to severe white matter hyperintensities. The discriminatory performance of the scores was assessed with the C-statistic. White matter hyperintensities were significantly associated with the risk of recurrent ischemic stroke after adjusting for clinical risk factors. The hazard ratios ranged from 1.65 (95% CI 0.70-3.86) for mild changes to 5.28 (95% CI 1.98-14.07) for the most severe changes. C-statistics for the prediction of recurrent ischemic stroke were 0.59 (95% CI 0.51-0.65) for the CHA2DS2VASc score and 0.60 (95% CI 0.53-0.68) for the Essen Stroke Risk Score. The recalibrated clinical scores showed improved C-statistics: the recalibrated CHA2DS2VASc score 0.62 (95% CI 0.54-0.70; p = 0.024) and the recalibrated Essen Stroke Risk Score 0.63 (95% CI 0.56-0.71; p = 0.031). C-statistics of the white matter hyperintensities score were 0.62 (95% CI 0.52-0.68) to 0.65 (95% CI 0.58-0.73). An increasing burden of white matter hyperintensities was independently associated with recurrent ischemic stroke in a cohort of non-AF ischemic stroke patients. Recalibration of the CHA2DS2VASc score and the Essen Stroke Risk Score with one point for the presence of moderate to severe white matter hyperintensities led to improved discriminatory performance in ischemic stroke recurrence prediction. Risk scores based on white matter hyperintensities alone were at least as accurate as the established clinical risk scores in the prediction of ischemic stroke recurrence. © 2016 S. Karger AG, Basel.

Modeling crystal growth from solution with molecular dynamics simulations: approaches to transition rate constants.

PubMed

Reilly, Anthony M; Briesen, Heiko

2012-01-21

The feasibility of using the molecular dynamics (MD) simulation technique to study crystal growth from solution quantitatively, as well as to obtain transition rate constants, has been studied. The dynamics of an interface between a solution of Lennard-Jones particles and the (100) face of an fcc lattice comprised of solute particles have been studied using MD simulations, showing that MD is, in principle, capable of following growth behavior over large supersaturation and temperature ranges. Using transition state theory, and a nearest-neighbor approximation growth and dissolution rate constants have been extracted from equilibrium MD simulations at a variety of temperatures. The temperature dependence of the rates agrees well with the expected transition state theory behavior. © 2012 American Institute of Physics

Ambulatory Care Data Base (ACDB) Data Dictionary Sequential Files of Phase 2.

DTIC Science & Technology

1992-04-01

ARTERIES 4340 CEREBRAL THROMBOSIS 43491 STROKE , ISCHEMIC 435 TRANSIENT CEREBRAL ISCHEMIA 4359 TRANSIENT ISCHEMIC ATTACK (TIA) 43591 TRANS ISCHEMIC ATTACK W...CRISIS 4373 ANEURYSM, CEREBRAL , NONRUPTURED 4374 ARTERITIS, CEREBRAL 4378 CEREBROVASCULAR DISEASE, OTHER ILL-DEFINED 43781 STROKE , LACUNAR 438 LATE...FOR LOCALIZATION OF CEREBRAL SEIZURE FOC 95999 OTHER NEUROLOGICAL DIAGNOSTIC PROCEDURES 96500 CHEMO INJ, SINGLE, PRE-MIX, PUSH 96501 CHEMO INJ, SINGLE

Journey During Acute Ischemic Stroke: A Physician’s Experience

PubMed Central

Hoong, Low Chen; Sharma, Vijay K.

2010-01-01

Acute ischemic stroke is a potentially devastating condition. What follows is a true narration of the experience of a doctor-patient during his treatment for acute ischemic stroke and how the experience changed him. Described is the temporal sequence of events, starting from home to infusion of tissue plasminogen activator, which, when coupled with a multimodal therapeutic approach, resulted in an excellent clinical recovery. PMID:20458112

Is Migraine a Risk Factor for Pediatric Stroke?

PubMed Central

Gelfand, Amy A.; Fullerton, Heather J.; Jacobson, Alice; Sidney, Stephen; Goadsby, Peter J.; Kurth, Tobias; Pressman, Alice

2015-01-01

Importance Our understanding of risk factors for childhood stroke is incomplete. In adults, migraine with aura is associated with a two-fold increase in ischemic stroke risk. Objective In this cohort study we examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC). Design, Setting, and Participants Children ages 2-17 years who were members of KPNC for ≥6 months between1997-2007 were included. Migraine cohort members had one or more of: an ICD-9 code for migraine, migraine listed as a significant health problem, or a prescription for a migraine-specific medication. The comparison group was children with no evidence of headache. Main outcome measures stroke incidence rates and incidence rate ratios (IR). Results Among the 1,566,952 children within KPNC during the study period, 88,164 had migraine, and 1,323,142 had no evidence of headache. Eight migraineurs had a stroke (3 [38%] hemorrhagic; 5 [63%]ischemic). Eighty strokes occurred in children without headache, (53 [66%]hemorrhagic;27 [34%] ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8-5.2). A post-hoc analysis of adolescents (12-17 years) showed an increased risk of ischemic stroke among those with migraine; IR 3.4(95% CI 1.2-9.5). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2-2.0). Conclusions There was no statistically significant increase in hemorrhagic or ischemic stroke risk in pediatric migraineurs in this cohort study. A post-hoc analysis found that ischemic stroke risk was significantly elevated in adolescents with migraine. Future studies should focus on identifying risk factors for ischemic stroke among adolescent migraineurs. Based on adult data, we recommend that migraine aura status should be studied as a possible risk factor for ischemic stroke among adolescent migraineurs. PMID:25754176

Is migraine a risk factor for pediatric stroke?

PubMed

Gelfand, Amy A; Fullerton, Heather J; Jacobson, Alice; Sidney, Stephen; Goadsby, Peter J; Kurth, Tobias; Pressman, Alice

2015-12-01

Our understanding of risk factors for childhood stroke is incomplete. In adults, migraine with aura is associated with a two-fold increase in ischemic stroke risk. In this cohort study we examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC). Children ages 2-17 years who were members of KPNC for ≥6 months between 1997 and 2007 were included. Migraine cohort members had one or more of: an ICD-9 code for migraine, migraine listed as a significant health problem, or a prescription for a migraine-specific medication. The comparison group was children with no evidence of headache. Main outcome measures included stroke incidence rates and incidence rate ratios (IR). Among the 1,566,952 children within KPNC during the study period, 88,164 had migraine, and 1,323,142 had no evidence of headache. Eight migraineurs had a stroke (three (38%) hemorrhagic; five (63%) ischemic). Eighty strokes occurred in children without headache (53 (66%) hemorrhagic; 27 (34%) ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8-5.2). A post-hoc analysis of adolescents (12-17 years) showed an increased risk of ischemic stroke among those with migraine; IR 3.4 (95% CI 1.2-9.5). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2-2.0). There was no statistically significant increase in hemorrhagic or ischemic stroke risk in pediatric migraineurs in this cohort study. A post-hoc analysis found that ischemic stroke risk was significantly elevated in adolescents with migraine. Future studies should focus on identifying risk factors for ischemic stroke among adolescent migraineurs. Based on adult data, we recommend that migraine aura status should be studied as a possible risk factor for ischemic stroke among adolescent migraineurs. © International Headache Society 2015.

A lower baseline glomerular filtration rate predicts high mortality and newly cerebrovascular accidents in acute ischemic stroke patients.

PubMed

Dong, Kai; Huang, Xiaoqin; Zhang, Qian; Yu, Zhipeng; Ding, Jianping; Song, Haiqing

2017-02-01

Chronic kidney disease (CKD) is gradually recognized as an independent risk factor for cardiovascular and cardio-/cerebrovascular disease. This study aimed to examine the association of the estimated glomerular filtration rate (eGFR) and clinical outcomes at 3 months after the onset of ischemic stroke in a hospitalized Chinese population.Totally, 972 patients with acute ischemic stroke were enrolled into this study. Modified of Diet in Renal Disease (MDRD) equations were used to calculate eGFR and define CKD. The site and degree of the stenosis were examined. Patients were followed-up for 3 months. Endpoint events included all-cause death and newly ischemic events. The multivariate logistic model was used to determine the association between renal dysfunction and patients' outcomes.Of all patients, 130 patients (13.4%) had reduced eGFR (<60 mL/min/1.73 m), and 556 patients had a normal eGFR (≥90 mL/min/1.73 m). A total of 694 patients suffered from cerebral artery stenosis, in which 293 patients only had intracranial artery stenosis (ICAS), 110 only with extracranial carotid atherosclerotic stenosis (ECAS), and 301 with both ICAS and ECAS. The patients with eGFR <60 mL/min/1.73m had a higher proportion of death and newly ischemic events compared with those with a relatively normal eGFR. Multivariate analysis revealed that a baseline eGFR <60 mL/min/1.73 m increased the risk of mortality by 3.089-fold and newly ischemic events by 4.067-fold. In further analysis, a reduced eGFR was associated with increased rates of mortality and newly events both in ICAS patients and ECAS patients. However, only an increased risk of newly events was found as the degree of renal function deteriorated in ICAS patients (odds ratio = 8.169, 95% confidence interval = 2.445-14.127).A low baseline eGFR predicted a high mortality and newly ischemic events at 3 months in ischemic stroke patients. A low baseline eGFR was also a strong independent predictor for newly ischemic events in ICAS patients.

C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease.

PubMed

Arenillas, Juan F; Alvarez-Sabín, José; Molina, Carlos A; Chacón, Pilar; Montaner, Joan; Rovira, Alex; Ibarra, Bernardo; Quintana, Manuel

2003-10-01

The role of inflammation in intracranial large-artery occlusive disease is unclear. We sought to investigate the relationship between high-sensitivity C-reactive protein (CRP) levels and the risk of further ischemic events in first-ever transient ischemic attack (TIA) or stroke patients with intracranial large-artery occlusive disease. Of a total of 127 consecutive first-ever TIA or ischemic stroke patients with intracranial stenoses detected by transcranial Doppler ultrasonography, 71 fulfilled all inclusion criteria, which included angiographic confirmation. Serum high-sensitivity CRP level was determined a minimum of 3 months after the qualifying event. Patients were followed up during 1 year after blood sampling. Thirteen patients (18.3%) with intracranial large-artery occlusive disease experienced an end point event: 9 cerebral ischemic events, 7 of which were attributable to intracranial large-artery occlusive disease, and 4 myocardial infarctions. Patients in the highest quintile of high-sensitivity CRP level had a significantly higher adjusted odds ratio for new events compared with those in the first quintile (odds ratio, 8.66; 95% CI, 1.39 to 53.84; P=0.01). A high-sensitivity CRP level above the receiver operating characteristic curve cutoff value of 1.41 mg/dL emerged as an independent predictor of new end point events (hazard ratio, 7.14; 95% CI, 1.77 to 28.73; P=0.005) and of further intracranial large-artery occlusive disease-related ischemic events (hazard ratio, 30.67; 95% CI, 3.6 to 255.5; P=0.0015), after adjustment for age, sex, and risk factors. Kaplan-Meier curves showed that a significantly lower proportion of patients with a high-sensitivity CRP >1.41 mg/dL remained free of a new ischemic event (P<0.0001). High-sensitivity CRP serum level predicts further intracranial large-artery occlusive disease-related and any major ischemic events in patients with first-ever TIA or stroke with intracranial large-artery occlusive disease. These findings are consistent with the hypothesis that inflammation may be involved in the progression and complication of intracranial large-artery occlusive disease.

Troponin elevation in acute ischemic stroke (TRELAS) - protocol of a prospective observational trial

PubMed Central

2011-01-01

Background Levels of the cardiac muscle regulatory protein troponin T (cTnT) are frequently elevated in patients with acute ischemic stroke and elevated cTnT predicts poor outcome and mortality. The pathomechanism of troponin release may relate to co-morbid coronary artery disease and myocardial ischemia or, alternatively, to neurogenic cardiac damage due to autonomic activation after acute ischemic stroke. Therefore, there is uncertainty about how acute ischemic stroke patients with increased cTnT levels should be managed regarding diagnostic and therapeutic workup. Methods/Design The primary objective of the prospective observational trial TRELAS (TRoponin ELevation in Acute ischemic Stroke) is to investigate the frequency and underlying pathomechanism of cTnT elevation in acute ischemic stroke patients in order to give guidance for clinical practice. All consecutive patients with acute ischemic stroke admitted within 72 hours after symptom onset to the Department of Neurology at the Campus Benjamin Franklin of the University Hospital Charité will be screened for cTnT elevations (i.e. >= 0.05 μg/l) on admission and again on the following day. Patients with increased cTnT will undergo coronary angiography within 72 hours. Diagnostic findings of coronary angiograms will be compared with age- and gender-matched patients presenting with Non-ST-Elevation myocardial infarction to the Department of Cardiology. The primary endpoint of the study will be the occurrence of culprit lesions in the coronary angiogram indicating underlying co-morbid obstructive coronary artery disease. Secondary endpoints will be the localization of stroke in the cerebral imaging and left ventriculographic findings of wall motion abnormalities suggestive of stroke-induced global cardiac dysfunction. Discussion TRELAS will prospectively determine the frequency and possible etiology of troponin elevation in a large cohort of ischemic stroke patients. The findings are expected to contribute to clarify pathophysiologic concepts of co-morbid cardiac damage in ischemic stroke patients and also to provide a basis for clinical recommendations for cardiac workup of such patients. Trial registration clinicaltrials.gov NCT01263964 PMID:21824425

A comparison of solute-transport solution techniques based on inverse modelling results

USGS Publications Warehouse

Mehl, S.; Hill, M.C.

2000-01-01

Five common numerical techniques (finite difference, predictor-corrector, total-variation-diminishing, method-of-characteristics, and modified-method-of-characteristics) were tested using simulations of a controlled conservative tracer-test experiment through a heterogeneous, two-dimensional sand tank. The experimental facility was constructed using randomly distributed homogeneous blocks of five sand types. This experimental model provides an outstanding opportunity to compare the solution techniques because of the heterogeneous hydraulic conductivity distribution of known structure, and the availability of detailed measurements with which to compare simulated concentrations. The present work uses this opportunity to investigate how three common types of results-simulated breakthrough curves, sensitivity analysis, and calibrated parameter values-change in this heterogeneous situation, given the different methods of simulating solute transport. The results show that simulated peak concentrations, even at very fine grid spacings, varied because of different amounts of numerical dispersion. Sensitivity analysis results were robust in that they were independent of the solution technique. They revealed extreme correlation between hydraulic conductivity and porosity, and that the breakthrough curve data did not provide enough information about the dispersivities to estimate individual values for the five sands. However, estimated hydraulic conductivity values are significantly influenced by both the large possible variations in model dispersion and the amount of numerical dispersion present in the solution technique.Five common numerical techniques (finite difference, predictor-corrector, total-variation-diminishing, method-of-characteristics, and modified-method-of-characteristics) were tested using simulations of a controlled conservative tracer-test experiment through a heterogeneous, two-dimensional sand tank. The experimental facility was constructed using randomly distributed homogeneous blocks of five sand types. This experimental model provides an outstanding opportunity to compare the solution techniques because of the heterogeneous hydraulic conductivity distribution of known structure, and the availability of detailed measurements with which to compare simulated concentrations. The present work uses this opportunity to investigate how three common types of results - simulated breakthrough curves, sensitivity analysis, and calibrated parameter values - change in this heterogeneous situation, given the different methods of simulating solute transport. The results show that simulated peak concentrations, even at very fine grid spacings, varied because of different amounts of numerical dispersion. Sensitivity analysis results were robust in that they were independent of the solution technique. They revealed extreme correlation between hydraulic conductivity and porosity, and that the breakthrough curve data did not provide enough information about the dispersivities to estimate individual values for the five sands. However, estimated hydraulic conductivity values are significantly influenced by both the large possible variations in model dispersion and the amount of numerical dispersion present in the solution technique.

A low-rank control variate for multilevel Monte Carlo simulation of high-dimensional uncertain systems

NASA Astrophysics Data System (ADS)

Fairbanks, Hillary R.; Doostan, Alireza; Ketelsen, Christian; Iaccarino, Gianluca

2017-07-01

Multilevel Monte Carlo (MLMC) is a recently proposed variation of Monte Carlo (MC) simulation that achieves variance reduction by simulating the governing equations on a series of spatial (or temporal) grids with increasing resolution. Instead of directly employing the fine grid solutions, MLMC estimates the expectation of the quantity of interest from the coarsest grid solutions as well as differences between each two consecutive grid solutions. When the differences corresponding to finer grids become smaller, hence less variable, fewer MC realizations of finer grid solutions are needed to compute the difference expectations, thus leading to a reduction in the overall work. This paper presents an extension of MLMC, referred to as multilevel control variates (MLCV), where a low-rank approximation to the solution on each grid, obtained primarily based on coarser grid solutions, is used as a control variate for estimating the expectations involved in MLMC. Cost estimates as well as numerical examples are presented to demonstrate the advantage of this new MLCV approach over the standard MLMC when the solution of interest admits a low-rank approximation and the cost of simulating finer grids grows fast.

Direct Coexistence Methods to Determine the Solubility of Salts in Water from Numerical Simulations. Test Case NaCl.

PubMed

Manzanilla-Granados, Héctor M; Saint-Martín, Humberto; Fuentes-Azcatl, Raúl; Alejandre, José

2015-07-02

The solubility of NaCl, an equilibrium between a saturated solution of ions and a solid with a crystalline structure, was obtained from molecular dynamics simulations using the SPC/E and TIP4P-Ew water models. Four initial setups on supersaturated systems were tested on sodium chloride (NaCl) solutions to determine the equilibrium conditions and computational performance: (1) an ionic solution confined between two crystal plates of periodic NaCl, (2) a solution with all the ions initially distributed randomly, (3) a nanocrystal immersed in pure water, and (4) a nanocrystal immersed in an ionic solution. In some cases, the equilibration of the system can take several microseconds. The results from this work showed that the solubility of NaCl was the same, within simulation error, for the four setups, and in agreement with previously reported values from simulations with the setup (1). The system of a nanocrystal immersed in supersaturated solution was found to equilibrate faster than others. In agreement with laser-Doppler droplet measurements, at equilibrium with the solution the crystals in all the setups had a slight positive charge.

COUPLING OF CORONAL AND HELIOSPHERIC MAGNETOHYDRODYNAMIC MODELS: SOLUTION COMPARISONS AND VERIFICATION

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

Merkin, V. G.; Lionello, R.; Linker, J.

2016-11-01

Two well-established magnetohydrodynamic (MHD) codes are coupled to model the solar corona and the inner heliosphere. The corona is simulated using the MHD algorithm outside a sphere (MAS) model. The Lyon–Fedder–Mobarry (LFM) model is used in the heliosphere. The interface between the models is placed in a spherical shell above the critical point and allows both models to work in either a rotating or an inertial frame. Numerical tests are presented examining the coupled model solutions from 20 to 50 solar radii. The heliospheric simulations are run with both LFM and the MAS extension into the heliosphere, and use themore » same polytropic coronal MAS solutions as the inner boundary condition. The coronal simulations are performed for idealized magnetic configurations, with an out-of-equilibrium flux rope inserted into an axisymmetric background, with and without including the solar rotation. The temporal evolution at the inner boundary of the LFM and MAS solutions is shown to be nearly identical, as are the steady-state background solutions, prior to the insertion of the flux rope. However, after the coronal mass ejection has propagated through the significant portion of the simulation domain, the heliospheric solutions diverge. Additional simulations with different resolution are then performed and show that the MAS heliospheric solutions approach those of LFM when run with progressively higher resolution. Following these detailed tests, a more realistic simulation driven by the thermodynamic coronal MAS is presented, which includes solar rotation and an azimuthally asymmetric background and extends to the Earth’s orbit.« less

Intercomparison of 3D pore-scale flow and solute transport simulation methods

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

Yang, Xiaofan; Mehmani, Yashar; Perkins, William A.

2016-09-01

Multiple numerical approaches have been developed to simulate porous media fluid flow and solute transport at the pore scale. These include methods that 1) explicitly model the three-dimensional geometry of pore spaces and 2) those that conceptualize the pore space as a topologically consistent set of stylized pore bodies and pore throats. In previous work we validated a model of class 1, based on direct numerical simulation using computational fluid dynamics (CFD) codes, against magnetic resonance velocimetry (MRV) measurements of pore-scale velocities. Here we expand that validation to include additional models of class 1 based on the immersed-boundary method (IMB),more » lattice Boltzmann method (LBM), smoothed particle hydrodynamics (SPH), as well as a model of class 2 (a pore-network model or PNM). The PNM approach used in the current study was recently improved and demonstrated to accurately simulate solute transport in a two-dimensional experiment. While the PNM approach is computationally much less demanding than direct numerical simulation methods, the effect of conceptualizing complex three-dimensional pore geometries on solute transport in the manner of PNMs has not been fully determined. We apply all four approaches (CFD, LBM, SPH and PNM) to simulate pore-scale velocity distributions and nonreactive solute transport, and intercompare the model results with previously reported experimental observations. Experimental observations are limited to measured pore-scale velocities, so solute transport comparisons are made only among the various models. Comparisons are drawn both in terms of macroscopic variables (e.g., permeability, solute breakthrough curves) and microscopic variables (e.g., local velocities and concentrations).« less

Brownian dynamics simulation of protein diffusion in crowded environments

NASA Astrophysics Data System (ADS)

Mereghetti, Paolo; Wade, Rebecca C.

2013-02-01

High macromolecular concentrations are a distinguishing feature of living organisms. Understanding how the high concentration of solutes affects the dynamic properties of biological macromolecules is fundamental for the comprehension of biological processes in living systems. We first describe the development of a Brownian dynamics simulation methodology to investigate the dynamic and structural properties of protein solutions using atomic-detail protein structures. We then discuss insights obtained from applying this approach to simulation of solutions of a range of types of proteins.

System Simulation by Recursive Feedback: Coupling a Set of Stand-Alone Subsystem Simulations

NASA Technical Reports Server (NTRS)

Nixon, D. D.

2001-01-01

Conventional construction of digital dynamic system simulations often involves collecting differential equations that model each subsystem, arran g them to a standard form, and obtaining their numerical gin solution as a single coupled, total-system simultaneous set. Simulation by numerical coupling of independent stand-alone subsimulations is a fundamentally different approach that is attractive because, among other things, the architecture naturally facilitates high fidelity, broad scope, and discipline independence. Recursive feedback is defined and discussed as a candidate approach to multidiscipline dynamic system simulation by numerical coupling of self-contained, single-discipline subsystem simulations. A satellite motion example containing three subsystems (orbit dynamics, attitude dynamics, and aerodynamics) has been defined and constructed using this approach. Conventional solution methods are used in the subsystem simulations. Distributed and centralized implementations of coupling have been considered. Numerical results are evaluated by direct comparison with a standard total-system, simultaneous-solution approach.

A new equilibrium torus solution and GRMHD initial conditions

NASA Astrophysics Data System (ADS)

Penna, Robert F.; Kulkarni, Akshay; Narayan, Ramesh

2013-11-01

Context. General relativistic magnetohydrodynamic (GRMHD) simulations are providing influential models for black hole spin measurements, gamma ray bursts, and supermassive black hole feedback. Many of these simulations use the same initial condition: a rotating torus of fluid in hydrostatic equilibrium. A persistent concern is that simulation results sometimes depend on arbitrary features of the initial torus. For example, the Bernoulli parameter (which is related to outflows), appears to be controlled by the Bernoulli parameter of the initial torus. Aims: In this paper, we give a new equilibrium torus solution and describe two applications for the future. First, it can be used as a more physical initial condition for GRMHD simulations than earlier torus solutions. Second, it can be used in conjunction with earlier torus solutions to isolate the simulation results that depend on initial conditions. Methods: We assume axisymmetry, an ideal gas equation of state, constant entropy, and ignore self-gravity. We fix an angular momentum distribution and solve the relativistic Euler equations in the Kerr metric. Results: The Bernoulli parameter, rotation rate, and geometrical thickness of the torus can be adjusted independently. Our torus tends to be more bound and have a larger radial extent than earlier torus solutions. Conclusions: While this paper was in preparation, several GRMHD simulations appeared based on our equilibrium torus. We believe it will continue to provide a more realistic starting point for future simulations.

[Effect of "Xingnao Kaiqiao Zhenfa" (Acupuncture Technique for Restoring Consciousness) Combined with Rehabilitation Training on Nerve Repair and Expression of Growth-associated Protein-43 of Peri-ischemic Cortex in Ischemic Stroke Rats].

PubMed

Xu, Lei; Yan, Xing-Zhou; Li, Zhen-Yu; Cao, Xiao-Fang; Wang, Min

2017-06-25

To observe the effect of "Xingnao Kaiqiao Zhenfa" (acupuncture technique for restoring consciousness) combined with enriched rehabilitation training on motor function and expression of growth-associated protein-43 (GAP-43) of peri-ischemic cortex in ischemic stroke rats, so as to investigate its mechanism underlying improvement of ischemic stroke. SD rats were randomly divided into sham operation, model, rehabilitation and comprehensive rehabilitation groups, which were further divided into 3 time-points:7, 14 and 21 d ( n =6 in each). Cerebral ischemia(CI) model was established by occlusion of the middle cerebral artery with heat-coagulation. The rehabilitation group was treated by enriched rehabilitation training, once a day. The comprehensive rehabilitation group was treated by acupuncture combined with enriched rehabilitation training. Acupuncture was applied to bilateral "Neiguan"(PC 6) and "Shuigou"(GV 26) for 30 min, once a day. The neurological function score, balance-beam walking test and rotating-rod walking test were evaluated at the end of the corresponding treatment time. The expression of GAP-43 in peri-ischemic cortex was detected by immunohistochemistry. In comparison with the sham operation group, the scores of neurological function, beam walking test and rotating-rod walking test were significantly higher in the model group ( P <0.01). There were no significant changes in the scores of balance-beam walking and rotating-rod walking tests in the rehabilitation group compared with the model group on day 7 ( P >0.05). Compared with the model group at the other time points, the scores of neurological function, balance-beam walking test and rotating-rod walking test were significantly lower in the rehabilitation and comprehensive rehabilitation groups ( P <0.05). Compared with the rehabilitation group, the scores of neurological function, balance-beam walking test and rotating-rod walking test were significantly lower in the comprehensive rehabilitation group ( P <0.05). In comparison with the sham operation group, the number of GAP-43 positive cells of peri-ischemic cortex was significantly higher in the model group ( P <0.01). Compared with the model group, the numbers of GAP-43 positive cells of peri-ischemic cortex were significantly increased in the rehabilitation and comprehensive rehabilitation groups ( P <0.01). The number of GAP-43 positive cells of peri-ischemic cortex in the comprehensive rehabilitation group was significantly higher than that in the rehabilitation group ( P <0.01). "Xingnao Kaiqiao Zhenfa" combined with enriched rehabilitation training can promote the recovery of nerve function in ischemic stroke rats, which may be associated with its effect in up-regulating the expression of GAP-43 in the peri-ischemic cortex.

A texture-based framework for improving CFD data visualization in a virtual environment

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

Bivins, Gerrick O'Ron

2005-01-01

In the field of computational fluid dynamics (CFD) accurate representations of fluid phenomena can be simulated hut require large amounts of data to represent the flow domain. Most datasets generated from a CFD simulation can be coarse, ~10,000 nodes or cells, or very fine with node counts on the order of 1,000,000. A typical dataset solution can also contain multiple solutions for each node, pertaining to various properties of the flow at a particular node. Scalar properties such as density, temperature, pressure, and velocity magnitude are properties that are typically calculated and stored in a dataset solution. Solutions are notmore » limited to just scalar properties. Vector quantities, such as velocity, are also often calculated and stored for a CFD simulation. Accessing all of this data efficiently during runtime is a key problem for visualization in an interactive application. Understanding simulation solutions requires a post-processing tool to convert the data into something more meaningful. Ideally, the application would present an interactive visual representation of the numerical data for any dataset that was simulated while maintaining the accuracy of the calculated solution. Most CFD applications currently sacrifice interactivity for accuracy, yielding highly detailed flow descriptions hut limiting interaction for investigating the field.« less

A texture-based frameowrk for improving CFD data visualization in a virtual environment

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

Bivins, Gerrick O'Ron

2005-01-01

In the field of computational fluid dynamics (CFD) accurate representations of fluid phenomena can be simulated but require large amounts of data to represent the flow domain. Most datasets generated from a CFD simulation can be coarse, ~ 10,000 nodes or cells, or very fine with node counts on the order of 1,000,000. A typical dataset solution can also contain multiple solutions for each node, pertaining to various properties of the flow at a particular node. Scalar properties such as density, temperature, pressure, and velocity magnitude are properties that are typically calculated and stored in a dataset solution. Solutions aremore » not limited to just scalar properties. Vector quantities, such as velocity, are also often calculated and stored for a CFD simulation. Accessing all of this data efficiently during runtime is a key problem for visualization in an interactive application. Understanding simulation solutions requires a post-processing tool to convert the data into something more meaningful. Ideally, the application would present an interactive visual representation of the numerical data for any dataset that was simulated while maintaining the accuracy of the calculated solution. Most CFD applications currently sacrifice interactivity for accuracy, yielding highly detailed flow descriptions but limiting interaction for investigating the field.« less

Molecular dynamics simulation study of the early stages of nucleation of iron oxyhydroxide nanoparticles in aqueous solutions

DOE PAGES

Zhang, Hengzhong; Waychunas, Glenn A.; Banfield, Jillian F.

2015-07-29

Nucleation is a fundamental step in crystal growth. Of environmental and materials relevance are reactions that lead to nucleation of iron oxyhydroxides in aqueous solutions. These reactions are difficult to study experimentally due to their rapid kinetics. Here, we used classical molecular dynamics simulations to investigate nucleation of iron hydroxide/oxyhydroxide nanoparticles in aqueous solutions. Results show that in a solution containing ferric ions and hydroxyl groups, iron–hydroxyl molecular clusters form by merging ferric monomers, dimers, and other oligomers, driven by strong affinity of ferric ions to hydroxyls. When deprotonation reactions are not considered in the simulations, these clusters aggregate tomore » form small iron hydroxide nanocrystals with a six-membered ring-like layered structure allomeric to gibbsite. By comparison, in a solution containing iron chloride and sodium hydroxide, the presence of chlorine drives cluster assembly along a different direction to form long molecular chains (rather than rings) composed of Fe–O octahedra linked by edge sharing. Further, in chlorine-free solutions, when deprotonation reactions are considered, the simulations predict ultimate formation of amorphous iron oxyhydroxide nanoparticles with local atomic structure similar to that of ferrihydrite nanoparticles. Overall, our simulation results reveal that nucleation of iron oxyhydroxide nanoparticles proceeds via a cluster aggregation-based nonclassical pathway.« less

Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke.

PubMed

Cui, Xu; Chen, Jieli; Zacharek, Alex; Roberts, Cynthia; Yang, Yuping; Chopp, Michael

2009-01-01

We tested the hypothesis that a nitric oxide donor, DETA-NONOate, up-regulates stromal cell-derived factor-1 (SDF1) and angiopoietin 1 (Ang1) in the ischemic brain and their respective receptors chemokine CXC motif receptor 4 (CXCR4) and Tie2 in the subventricular zone (SVZ) and thereby promote SVZ neuroblast cell migration after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo), and 24 hr later DETA-NONOate (0.4 mg/kg) or phosphate-buffered solution was intravenously administered. Mice were sacrificed at 14 days for histological assessment or sacrificed at 3 days for analysis by real-time polymerase chain reaction and migration after MCAo. To elucidate whether SDF1/CXCR4 and Ang1/Tie2 pathways mediate DETA-NONOate-induced SVZ migration after stroke, SDF1alpha, Ang1 peptide, a specific antagonist of CXCR4 (AMD3100), and a neutralizing antibody of Tie2 (anti-Tie2) were used in vitro. DETA-NONOate significantly increased the percentage area of doublecortin (DCX, a marker of migrating neuroblasts)-immunoreactive cells in the SVZ and ischemic boundary zone. DETA-NONOate significantly increased the expression of SDF1 and Ang1 in the ischemic border and up-regulated CXCR4 and Tie2 in the SVZ compared with MCAo control. DCX-positive cell migration from SVZ explants was significantly increased in the DETA-NONOate treatment group compared with MCAo-alone animals. In vitro, SDF1alpha and Ang1 significantly increased SVZ explants cell migration. In addition, inhibition of CXCR4 or Tie2 significantly attenuated DETA-NONOate-induced SVZ cell migration. Our data indicate that treatment of stroke with a nitric oxide donor up-regulates SDF1/CXCR4 and Ang1/Tie2 pathways and thereby likely increases SVZ neuroblast cell migration. 2008 Wiley-Liss, Inc.

Nitric Oxide Donor Upregulation of SDF1/CXCR4 and Ang1/Tie2 Promotes Neuroblast Cell Migration After Stroke

PubMed Central

Cui, Xu; Chen, Jieli; Zacharek, Alex; Roberts, Cynthia; Yang, Yuping; Chopp, Michael

2008-01-01

We tested the hypothesis that a nitric oxide donor, DETA-NONOate upregulates Stromal cell-Derived Factor-1 (SDF1) and Angiopoietin 1 (Ang1) in the ischemic brain and their, respective, receptors chemokine CXC motif receptor 4 (CXCR4) and Tie2 in the subventricular zone (SVZ) and thereby promote SVZ neuroblast cell migration after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and 24 hours later DETA-NONOate (0.4 mg/kg) or phosphate buffered solution were intravenously administered. Mice were sacrificed at 14 days for histological assessment or sacrificed at 3 days for analysis real-time polymerase chain reaction and migration after MCAo. To elucidate whether SDF1/CXCR4 and Ang1/Tie2 pathways mediate DETA-NONOate induced SVZ migration after stroke, SDF1α, Ang1 peptide and a specific antagonist of CXCR4 (AMD3100) and a neutralizing antibody of Tie2 (anti-Tie2) were used in vitro. DETA-NONOate significantly increased the percent area of doublecortin (a marker of migrating neuroblasts) immunoreactive-cells in the SVZ and ischemic boundary zone. DETA-NONOate significantly increased the expression of SDF1 and Ang1 in the ischemic border and upregulated CXCR4 and Tie2 in the SVZ compared with MCAo control. DCX-positive cell migration from SVZ explants was significantly increased in the DETA-NONOate treatment group compared with MCAo alone animals. In vitro, SDF1α and Ang1 significantly increased SVZ explants cell migration. In addition, inhibition of CXCR4 or Tie2 significantly attenuated DETA-NONOate induced SVZ cell migration. Our data indicated that treatment of stroke with a nitric oxide donor upregulates SDF1/CXCR4 and Ang1/Tie2 pathways and thereby likely increases SVZ neuroblast cell migration. PMID:18711749

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

PubMed Central

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

2013-01-01

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

Assessment of platelet function in acute ischemic stroke patients previously treated with aspirin.

PubMed

Lago, Aida; Parkhutik, Vera; Tembl, Jose Ignacio; Vallés, Juana; Santos, Maria Teresa; Moscardó, Antonio

2014-01-01

Platelet inhibition measured by platelet function tests could be critical to understand the reasons for early recurrence and to guide therapeutic recommendations. We assess the platelet function during the acute phase of ischemic stroke in patients pretreated with aspirin who continue their treatment with aspirin only, are started on clopidogrel only, or add clopidogrel to aspirin. Sixty-four patients were taking aspirin before the stroke. Depending on the administered antiplatelet, 3 groups were defined: ASA: patients who continued on aspirin orally or intravenous acetylsalicylate of lysine, n = 30; CLO: patients who discontinued aspirin and were started on clopidogrel, n = 16; and ASA + CLO: patients who were prescribed both aspirin and clopidogrel, n = 10. Collagen-induced thromboxane A2 (TXA2) synthesis, ADP (adenosine diphosphate)-induced aggregation, and occlusion time (PF-100) were measured. CLO group only had a marked elevation of TXA2 (17.44 ± 15.62 ng/mL, P = .000) and a shortening of the platelet function analyzer (PFA)-100 closure time (157.13 ± 88 seconds, P = .047) compared with the other 2 groups (ASA: TXA2, .62 ± 1.59 ng/mL; ASA + CLO: TXA2 1.79 ± 4.59 ng/mL). They achieved a small (13%) but significant reduction of ADP-induced aggregation (87.00 ± 23.06 mm, P = .008) compared with the ASA group (102.82 ± 22.38 seconds). Stopping aspirin intake within the first 72 hours of the acute stroke drastically increases TXA2 synthesis. During the same time window, the freshly prescribed clopidogrel manages to reduce the ADP-induced aggregation only slightly (13%). This study offers analytic proof that the common practice of replacing aspirin with clopidogrel does not leave stroke patients fully protected during the first days after an ischemic stroke. Possible solutions could be to preserve aspirin during a few days or to use loading doses of clopidogrel at hospital admission. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

State-of the-art review on the renal and visceral protection during open thoracoabdominal aortic aneurysm repair.

PubMed

Waked, Karl; Schepens, Marc

2018-01-01

During open thoracoabdominal aortic aneurysm repair (OTAAAR), there is an inevitable organ ischemic period that occurs when the abdominal arteries are being reattached to the aortic graft. Despite various protective techniques, the incidence of renal and visceral complications remains substantial. This state-of-the-art review gives an overview of the current and most evidence-based organ protection methods during OTAAAR, based on the most recent publications and personal experience. An electronic search was performed in four medical databases, using the following MeSH terms: thoracoabdominal aneurysm, TAAAR, visceral protection, renal protection, kidney, perfusion, and intestines. Every publication type was considered. The literature search was ended on August 31st, 2017. The left heart bypass (LHB) is currently the most frequent adjunct to provide distal aortic perfusion (DAP) during aortic clamping. Together with systemic hypothermia, it forms the cornerstone in organ protection during aortic clamping. Further renal protection can be obtained by selective renal perfusion (SRP) with cold blood or cold crystalloid solution, the latter enriched with mannitol. The perfusion should be administered in a volume- and pressure-controlled way and, if possible, by use of a pulsatile pump. Selective visceral perfusion (SVP) is not routinely used, as it does not provide adequate blood flow for visceral protection. The best way to protect the intestines is by minimizing the ischemic time. The preservation of renal and visceral function after OTAAAR can only be obtained with specific strategies before, during, and after the operation. This involves a series of measures, including selective digestive decontamination (SDD), avoidance of nephrotoxic drugs, minimizing the renal and intestinal ischemic time, systemic cooling, avoidance of hemodynamic instability, and regional protective perfusion of the kidneys. Future innovations in catheters, cardiac bypass flow types, mechanical components, hybrid vascular grafts, and pharmaceutical protection measures will hopefully further reduce organ complications.

Structural, thermodynamic, and electrical properties of polar fluids and ionic solutions on a hypersphere: Results of simulations

NASA Astrophysics Data System (ADS)

Caillol, J. M.; Levesque, D.

1992-01-01

The reliability and the efficiency of a new method suitable for the simulations of dielectric fluids and ionic solutions is established by numerical computations. The efficiency depends on the use of a simulation cell which is the surface of a four-dimensional sphere. The reliability originates from a charge-charge potential solution of the Poisson equation in this confining volume. The computation time, for systems of a few hundred molecules, is reduced by a factor of 2 or 3 compared to this of a simulation performed in a cubic volume with periodic boundary conditions and the Ewald charge-charge potential.

Reactive astrocytes and therapeutic potential in focal ischemic stroke

PubMed Central

Choudhury, Gourav Roy; Ding, Shinghua

2015-01-01

Astrocytes are specialized and the most abundant cell type in the central nervous system (CNS). They play important roles in the physiology of the brain. Astrocytes are also critically involved in many CNS disorders including focal ischemic stroke, the leading cause of brain injury and death in patients. One of the prominent pathological features of a focal ischemic stroke is reactive astrogliosis and glial scar formation. Reactive astrogliosis is accompanied with changes in morphology, proliferation and gene expression in the reactive astrocytes. This study provides an overview of the most recent advances in astrocytic Ca2+ signaling, spatial and temporal dynamics of the morphology and proliferation of reactive astrocytes as well as signaling pathways involved in the reactive astrogliosis after ischemic stroke based on results from experimental studies performed in various animal models. This review also discusses the therapeutic potential of reactive astrocytes in a focal ischemic stroke. As reactive astrocytes exhibit high plasticity, we suggest that modulation of local reactive astrocytes is a promising strategy for cell-based stroke therapy. PMID:25982835

The Yin and Yang of innate immunity in stroke.

PubMed

Xu, Xiaomeng; Jiang, Yongjun

2014-01-01

Immune system plays an elementary role in the pathophysiological progress of ischemic stroke. It consists of innate and adaptive immune system. Activated within minutes after ischemic onset, innate immunity is responsible for the elimination of necrotic cells and tissue repair, while it is critically involved in the initiation and amplification of poststroke inflammation that amplifies ischemic damage to the brain tissue. Innate immune response requires days to be fully developed, providing a considerable time window for therapeutic intervention, suggesting prospect of novel immunomodulatory therapies against poststroke inflammation-induced brain injury. However, obstacles still exist and a comprehensive understanding of ischemic stroke and innate immune reaction is essential. In this review, we highlighted the current experimental and clinical data depicting the innate immune response following ischemic stroke, mainly focusing on the recognition of damage-associated molecular patterns, activation and recruitment of innate immune cells, and involvement of various cytokines. In addition, clinical trials targeting innate immunity were also documented regardless of the outcome, stressing the requirements for further investigation.

Ischemic Colitis

PubMed Central

Montessori, Gino; Liepa, Egils V.

1970-01-01

Twenty cases of ischemic colitis are reviewed; 19 were obtained from autopsy files and the diagnosis in one was made from a surgical specimen. The majority of the patients were elderly with generalized arteriosclerosis. In approximately two-thirds of the patients the ischemic colitis was precipitated by preceding trauma, operation or congestive heart failure. Clinically, ischemic colitis is characterized by abdominal pain, distension and bleeding per rectum. Perforation of large bowel may occur. The lesions tend to be localized around the splenic flexure and junction of the descending and sigmoid colon, and in cases following aortic graft surgery the rectum is involved. Microscopically, there is necrosis, hemorrhage and ulceration. In less severe cases the mucosa only is affected. Cases with perforation show necrosis of all layers. It is considered that ischemic colitis is comparatively frequent and should be distinguished from other inflammatory conditions of the colon. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5FIG. 6FIG. 7FIG. 8FIG. 9 PMID:5308923

Neuroprotective Effect of a New Synthetic Aspirin-decursinol Adduct in Experimental Animal Models of Ischemic Stroke

PubMed Central

Shin, Bich Na; Ahn, Ji Hyeon; Kim, In Hye; Lee, Jae-Chul; Yoo, Ki-Yeon; Hwang, In Koo; Choi, Jung Hoon; Park, Jeong Ho; Lee, Yun Lyul; Suh, Hong-Won; Jun, Jong-Gab; Kwon, Young-Guen; Kim, Young-Myeong; Kwon, Seung-Hae; Her, Song; Kim, Jin Su; Hyun, Byung-Hwa; Kim, Chul-Kyu; Cho, Jun Hwi; Lee, Choong Hyun; Won, Moo-Ho

2013-01-01

Stroke is the second leading cause of death. Experimental animal models of cerebral ischemia are widely used for researching mechanisms of ischemic damage and developing new drugs for the prevention and treatment of stroke. The present study aimed to comparatively investigate neuroprotective effects of aspirin (ASA), decursinol (DA) and new synthetic aspirin-decursinol adduct (ASA-DA) against transient focal and global cerebral ischemic damage. We found that treatment with 20 mg/kg, not 10 mg/kg, ASA-DA protected against ischemia-induced neuronal death after transient focal and global ischemic damage, and its neuroprotective effect was much better than that of ASA or DA alone. In addition, 20 mg/kg ASA-DA treatment reduced the ischemia-induced gliosis and maintained antioxidants levels in the corresponding injury regions. In brief, ASA-DA, a new synthetic drug, dramatically protected neurons from ischemic damage, and neuroprotective effects of ASA-DA may be closely related to the attenuation of ischemia-induced gliosis and maintenance of antioxidants. PMID:24073226

Neuroprotective effect of a new synthetic aspirin-decursinol adduct in experimental animal models of ischemic stroke.

PubMed

Yan, Bing Chun; Park, Joon Ha; Shin, Bich Na; Ahn, Ji Hyeon; Kim, In Hye; Lee, Jae-Chul; Yoo, Ki-Yeon; Hwang, In Koo; Choi, Jung Hoon; Park, Jeong Ho; Lee, Yun Lyul; Suh, Hong-Won; Jun, Jong-Gab; Kwon, Young-Guen; Kim, Young-Myeong; Kwon, Seung-Hae; Her, Song; Kim, Jin Su; Hyun, Byung-Hwa; Kim, Chul-Kyu; Cho, Jun Hwi; Lee, Choong Hyun; Won, Moo-Ho

2013-01-01

Stroke is the second leading cause of death. Experimental animal models of cerebral ischemia are widely used for researching mechanisms of ischemic damage and developing new drugs for the prevention and treatment of stroke. The present study aimed to comparatively investigate neuroprotective effects of aspirin (ASA), decursinol (DA) and new synthetic aspirin-decursinol adduct (ASA-DA) against transient focal and global cerebral ischemic damage. We found that treatment with 20 mg/kg, not 10 mg/kg, ASA-DA protected against ischemia-induced neuronal death after transient focal and global ischemic damage, and its neuroprotective effect was much better than that of ASA or DA alone. In addition, 20 mg/kg ASA-DA treatment reduced the ischemia-induced gliosis and maintained antioxidants levels in the corresponding injury regions. In brief, ASA-DA, a new synthetic drug, dramatically protected neurons from ischemic damage, and neuroprotective effects of ASA-DA may be closely related to the attenuation of ischemia-induced gliosis and maintenance of antioxidants.

Ultrasound imaging of propagation of myocardial contraction for non-invasive identification of myocardial ischemia

NASA Astrophysics Data System (ADS)

Matsuno, Yuya; Taki, Hirofumi; Yamamoto, Hiroaki; Hirano, Michinori; Morosawa, Susumu; Shimokawa, Hiroaki; Kanai, Hiroshi

2017-07-01

Non-invasive identification of ischemic regions is important for diagnosis and treatment of myocardial infarction. In the present study, ultrasound measurement was applied to the interventricular septum of three open-chest swine hearts. The properties of the myocardial contraction response of the septum were compared between normal and acute ischemic conditions, where the acute ischemic condition of the septum originated from direct avascularization of the left anterior descending (LAD) coronary artery. The result showed that the contraction response propagated from the basal side to the apical side along the septum. The estimated propagation velocities in the normal and acute ischemic conditions were 3.6 and 1.9 m/s, respectively. This finding indicates that acute ischemia which occurred 5 s after the avascularization of the LAD promptly suppressed the propagation velocity through the ventricular septum to about half the normal velocity. It was suggested that the myocardial ischemic region could be identified using the difference in the propagation velocity of the myocardial response to contraction.

Ischemic colitis induced by the newly reformulated multicomponent weight-loss supplement Hydroxycut®

PubMed Central

Sherid, Muhammed; Samo, Salih; Sulaiman, Samian; Gaziano, Joseph H

2013-01-01

Ischemic colitis accounts for 6%-18% of causes of acute lower gastrointestinal bleeding. It is more often multifactorial and more common in elderly. Drugs are considered important causative agents of this disease with different mechanisms. In this paper, we describe a 37-year-old otherwise healthy female presented with sudden onset diffuse abdominal pain and bloody stool. Radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her only suspected factor was hydroxycut which she had been taking for a period of 1 mo prior to her presentation. Her condition improved uneventfully after cessation of hydroxycut, bowel rest, intravenous hydration, and antibiotics. This is a first case of ischemic colitis with clear relationship with hydroxycut use (Naranjo score of 7). Our case demonstrates the importance of questioning patients regarding the usage of dietary supplements; especially since many patients consider them safe and do not disclose their use voluntarily to their physicians. Hydroxycut has to be considered as a potential trigger for otherwise unexplained ischemic colitis. PMID:23596542

Visualization of in vivo metabolic flows reveals accelerated utilization of glucose and lactate in penumbra of ischemic heart

PubMed Central

Sugiura, Yuki; Katsumata, Yoshinori; Sano, Motoaki; Honda, Kurara; Kajimura, Mayumi; Fukuda, Keiichi; Suematsu, Makoto

2016-01-01

Acute ischemia produces dynamic changes in labile metabolites. To capture snapshots of such acute metabolic changes, we utilized focused microwave treatment to fix metabolic flow in vivo in hearts of mice 10 min after ligation of the left anterior descending artery. The left ventricle was subdivided into short-axis serial slices and the metabolites were analyzed by capillary electrophoresis mass spectrometry and matrix-assisted laser desorption/ionization imaging mass spectrometry. These techniques allowed us to determine the fate of exogenously administered 13C6-glucose and 13C3-lactate. The penumbra regions, which are adjacent to the ischemic core, exhibited the greatest adenine nucleotide energy charge and an adenosine overflow extending from the ischemic core, which can cause ischemic hyperemia. Imaging analysis of metabolic pathway flows revealed that the penumbra executes accelerated glucose oxidation, with remaining lactate utilization for tricarboxylic acid cycle for energy compensation, suggesting unexpected metabolic interplays of the penumbra with the ischemic core and normoxic regions. PMID:27581923

Interobserver variability and feasibility of polymerase chain reaction-based assay in distinguishing ischemic colitis from Clostridium difficile colitis in endoscopic mucosal biopsies.

PubMed

Wiland, Homer O; Procop, Gary W; Goldblum, John R; Tuohy, Marion; Rybicki, Lisa; Patil, Deepa T

2013-06-01

Polymerase chain reaction (PCR)-based assays using stool samples are currently the most effective method of detecting Clostridium difficile. This study examines the feasibility of this assay using mucosal biopsy samples and evaluates the interobserver reproducibility in diagnosing and distinguishing ischemic colitis from C difficile colitis. Thirty-eight biopsy specimens were reviewed and classified by 3 observers into C difficile and ischemic colitis. The findings were correlated with clinical data. PCR was performed on 34 cases using BD GeneOhm C difficile assay. The histologic interobserver agreement was excellent (κ= 0.86) and the agreement between histologic and clinical diagnosis was good (κ = 0.84). All 19 ischemic colitis cases tested negative (100% specificity) and 3 of 15 cases of C difficile colitis tested positive (20% sensitivity). C difficile colitis can be reliably distinguished from ischemic colitis using histologic criteria. The C difficile PCR test on endoscopic biopsy specimens has excellent specificity but limited sensitivity.

Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats.

PubMed

Oliveira, Rita de Cássia Silva de; Brito, Marcus Vinicius Henriques; Ribeiro, Rubens Fernando Gonçalves; Oliveira, Leonam Oliver Durval; Monteiro, Andrew Moraes; Brandão, Fernando Mateus Viegas; Cavalcante, Lainy Carollyne da Costa; Gouveia, Eduardo Henrique Herbster; Henriques, Higor Yuri Bezerra

2017-03-01

To evaluate the effects of tramadol hydrochloride associated to remote ischemic perconditioning on oxidative stress. Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Tramadol group (T) treated with tramadol hydrochloride (40mg/kg); remote ischemic perconditioning + Tramadol group (Per+T) with both treatments. Oxidative stress was assessed after 24 hours of reperfusion. Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was difference between Tramadol with Sham, Per and Per+T groups (p<0.05), both in plasma and renal tissue. Remote ischemic perconditioning was more effective reducing renal ischemia-reperfusion injury than administration of tramadol or association of both treatments.

ISCHEMIC CENTRAL RETINAL VEIN OCCLUSION IN THE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR ERA.

PubMed

Tam, Emily K; Golchet, Pamela; Yung, Madeline; DeCroos, Francis C; Spirn, Marc; Lehmann-Clarke, Lydia; Ambresin, Aude; Tsui, Irena

2018-02-01

Anti-vascular endothelial growth factor therapy has improved the prognosis for patients with central retinal vein occlusion (CRVO). However, most studies published to date exclude ischemic CRVO. The purpose of this study was to describe the outcome in eyes with ischemic CRVO treated with anti-vascular endothelial growth factor therapy. Thirty-seven patients with ischemic CRVO from 3 centers were followed for at least 6 months. Data on patient demographic, vision status, and anti-vascular endothelial growth factor treatments were collected. Average number of injections during the study period was 5. Younger age was associated with improved vision (P = 0.006). Patients with improved visual outcomes tended to have macular edema as the primary indication for treatment, whereas patients with worse outcomes tended to have neovascularization as the primary indication for treatment. This study highlights significant variability in the use of anti-vascular endothelial growth factor therapy for ischemic CRVO and underscores that eyes with neovascularization tend to have worse visual outcomes.

Application of Molecular Dynamics Simulations in Molecular Property Prediction II: Diffusion Coefficient

PubMed Central

Wang, Junmei; Hou, Tingjun

2011-01-01

In this work, we have evaluated how well the General AMBER force field (GAFF) performs in studying the dynamic properties of liquids. Diffusion coefficients (D) have been predicted for 17 solvents, 5 organic compounds in aqueous solutions, 4 proteins in aqueous solutions, and 9 organic compounds in non-aqueous solutions. An efficient sampling strategy has been proposed and tested in the calculation of the diffusion coefficients of solutes in solutions. There are two major findings of this study. First of all, the diffusion coefficients of organic solutes in aqueous solution can be well predicted: the average unsigned error (AUE) and the root-mean-square error (RMSE) are 0.137 and 0.171 ×10−5 cm−2s−1, respectively. Second, although the absolute values of D cannot be predicted, good correlations have been achieved for 8 organic solvents with experimental data (R2 = 0.784), 4 proteins in aqueous solutions (R2 = 0.996) and 9 organic compounds in non-aqueous solutions (R2 = 0.834). The temperature dependent behaviors of three solvents, namely, TIP3P water, dimethyl sulfoxide (DMSO) and cyclohexane have been studied. The major MD settings, such as the sizes of simulation boxes and with/without wrapping the coordinates of MD snapshots into the primary simulation boxes have been explored. We have concluded that our sampling strategy that averaging the mean square displacement (MSD) collected in multiple short-MD simulations is efficient in predicting diffusion coefficients of solutes at infinite dilution. PMID:21953689

Simulating the injection of micellar solutions to recover diesel in a sand column.

PubMed

Bernardez, Letícia A; Therrien, René; Lefebvre, René; Martel, Richard

2009-01-26

This paper presents numerical simulations of laboratory experiments where diesel, initially present at 18% residual saturation in a sand column, was recovered by injecting a micellar solution containing the surfactant Hostapur SAS-60 (SAS), and two alcohols, n-butanol (n-BuOH), and n-pentanol (n-PeOH). The micellar solution was developed and optimized for diesel recovery using phase diagrams and soil column experiments. Numerical simulations with the compositional simulator UTCHEM agree with the experimental results and show that the entire residual diesel in the sand column was recovered after the downward injection of 5 pore volumes of the micellar solution. Recovery of diesel occurs by enhanced solubility in the microemulsion phase and by mobilization. An additional series of simulations investigated the effects of phase transfer, alcohol partitioning, and component segregation on diesel recovery. These simulations indicate that diesel can be accurately represented in the model by a single component, but that the pseudo-component approach for active matter and the assumption of local phase equilibrium leads to an underestimation of diesel mobilization.

Simulating the injection of micellar solutions to recover diesel in a sand column

NASA Astrophysics Data System (ADS)

Bernardez, Letícia A.; Therrien, René; Lefebvre, René; Martel, Richard

2009-01-01

This paper presents numerical simulations of laboratory experiments where diesel, initially present at 18% residual saturation in a sand column, was recovered by injecting a micellar solution containing the surfactant Hostapur SAS-60 (SAS), and two alcohols, n-butanol ( n-BuOH), and n-pentanol ( n-PeOH). The micellar solution was developed and optimized for diesel recovery using phase diagrams and soil column experiments. Numerical simulations with the compositional simulator UTCHEM agree with the experimental results and show that the entire residual diesel in the sand column was recovered after the downward injection of 5 pore volumes of the micellar solution. Recovery of diesel occurs by enhanced solubility in the microemulsion phase and by mobilization. An additional series of simulations investigated the effects of phase transfer, alcohol partitioning, and component segregation on diesel recovery. These simulations indicate that diesel can be accurately represented in the model by a single component, but that the pseudo-component approach for active matter and the assumption of local phase equilibrium leads to an underestimation of diesel mobilization.

Effect of first myocardial ischemic event on renal function.

PubMed

Eijkelkamp, Wouter B A; de Graeff, Pieter A; van Veldhuisen, Dirk J; van Dokkum, Richard P E; Gansevoort, Ronald T; de Jong, Paul E; de Zeeuw, Dick; Hillege, Hans L

2007-07-01

Effects of cardiovascular dysfunction on renal function have been poorly characterized. Therefore, we investigated the relation between a first ischemic cardiac event and long-term renal function changes in the general population from the PREVEND study. We studied 6,360 subjects with a total follow-up duration of 27.017 subject-years. The estimated mean proportional increase in serum creatinine after a first ischemic cardiac event was 3.1% compared with 0.4% per year of follow-up in subjects without such an event (p = 0.005). This represented a significantly larger decrease in estimated glomerular filtration rate after the event in subjects with an event versus the decrease in subjects without a first ischemic cardiac event (2.2 vs 0.5 ml/min/1.73 m(2)/year of follow-up, p = 0.006). In multivariate analysis with adjustment for renal risk factors, this event showed an independent association with serum creatinine change. In conclusion, a first ischemic cardiac event appears to enhance the natural decrease in renal function. Because even mild renal dysfunction should be considered a major cardiovascular risk factor after myocardial infarction, increased renal function loss after an ischemic cardiac event could add to the risk for subsequent cardiovascular morbidity, thus closing a vicious circle.

Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet–Fed Mice

PubMed Central

Ryan, Terence E.; Schmidt, Cameron A.; Green, Thomas D.; Spangenburg, Espen E.; Neufer, P. Darrell

2016-01-01

Patients with type 2 diabetes respond poorly to treatments for peripheral arterial disease (PAD) and are more likely to present with the most severe manifestation of the disease, critical limb ischemia. The underlying mechanisms linking type 2 diabetes and the severity of PAD manifestation are not well understood. We sought to test whether diet-induced mitochondrial dysfunction and oxidative stress would increase the susceptibility of the peripheral limb to hindlimb ischemia (HLI). Six weeks of high-fat diet (HFD) in C57BL/6 mice was insufficient to alter skeletal muscle mitochondrial content and respiratory function or the size of ischemic lesion after HLI, despite reducing blood flow. However, 16 weeks of HFD similarly decreased ischemic limb blood flow, but also exacerbated limb tissue necrosis, increased the myopathic lesion size, reduced muscle regeneration, attenuated muscle function, and exacerbated ischemic mitochondrial dysfunction. Mechanistically, mitochondrial-targeted overexpression of catalase prevented the HFD-induced ischemic limb necrosis, myopathy, and mitochondrial dysfunction, despite no improvement in limb blood flow. These findings demonstrate that skeletal muscle mitochondria are a critical pathological link between type 2 diabetes and PAD. Furthermore, therapeutically targeting mitochondria and oxidant burden is an effective strategy to alleviate tissue loss and ischemic myopathy during PAD. PMID:27284110

Ischemic postconditioning: from receptor to end-effector.

PubMed

Cohen, Michael V; Downey, James M

2011-03-01

Ischemic preconditioning, a robust cardioprotective intervention, has limited clinical efficacy because it must be initiated before myocardial ischemia. Conversely, ischemic postconditioning, repeated brief reocclusions of a coronary artery after release of prolonged coronary occlusion, provides cardioprotection in clinically feasible settings, that is, coronary angioplasty. Ischemic postconditioning's signaling is being investigated to identify pharmacological triggers that could be used without angioplasty. In initial minutes of reperfusion H(+) washes out of previously ischemic cells. pH rises enabling mitochondrial permeability transition pores (MPTPs) to form leading to cessation of ATP production and cell necrosis. Coronary reocclusions maintain sufficient acidosis to keep MPTP closed while signaling is initiated that can generate endogenous antagonists of MPTP formation even after cellular pH normalizes. Reintroduction of oxygen generates reactive oxygen species that activate protein kinase C to increase sensitivity of adenosine A(2b) receptors allowing adenosine released from ischemic cells to bind leading to activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2. Phosphatidylinositol 3-kinase activation results in phosphorylation of Akt promoting activation of nitric oxide synthase and nitric oxide production, which inhibits glycogen synthase kinase-3β, perhaps the final cytosolic signaling step before inhibition of MPTP formation. Interference with MPTP may be the final step that determines cell salvage.

Hypothermia therapy for newborns with hypoxic ischemic encephalopathy.

PubMed

Silveira, Rita C; Procianoy, Renato S

2015-01-01

Therapeutic hypothermia reduces cerebral injury and improves the neurological outcome secondary to hypoxic ischemic encephalopathy in newborns. It has been indicated for asphyxiated full-term or near-term newborn infants with clinical signs of hypoxic-ischemic encephalopathy (HIE). A search was performed for articles on therapeutic hypothermia in newborns with perinatal asphyxia in PubMed; the authors chose those considered most significant. There are two therapeutic hypothermia methods: selective head cooling and total body cooling. The target body temperature is 34.5 °C for selective head cooling and 33.5 °C for total body cooling. Temperatures lower than 32 °C are less neuroprotective, and temperatures below 30 °C are very dangerous, with severe complications. Therapeutic hypothermia must start within the first 6h after birth, as studies have shown that this represents the therapeutic window for the hypoxic-ischemic event. Therapy must be maintained for 72 h, with very strict control of the newborn's body temperature. It has been shown that therapeutic hypothermia is effective in reducing neurologic impairment, especially in full-term or near-term newborns with moderate hypoxic-ischemic encephalopathy. Therapeutic hypothermia is a neuroprotective technique indicated for newborn infants with perinatal asphyxia and hypoxic-ischemic encephalopathy. Copyright © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

The Usefulness of the TOAST Classification and Prognostic Significance of Pyramidal Symptoms During the Acute Phase of Cerebellar Ischemic Stroke.

PubMed

Dziadkowiak, Edyta; Chojdak-Łukasiewicz, Justyna; Guziński, Maciej; Noga, Leszek; Paradowski, Bogusław

2016-04-01

Cerebellar stroke is a rare condition with very nonspecific clinical features. The symptoms in the acute phase could imitate acute peripheral vestibular disorders or a brainstem lesion. The aim of this study was to assess the usefulness of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification in cerebellar stroke and the impact of clinical features on the prognosis. We retrospectively analyzed 107 patients with diagnosed ischemic cerebellar infarction. We studied the clinical features and compared them based on the location of the ischemic lesion and its distribution in the posterior interior cerebellar artery (PICA), superior cerebellar artery (SCA), and anterior inferior cerebellar artery (AICA) territories. According to the TOAST classification, stroke was more prevalent in atrial fibrillation (26/107) and when the lesion was in the PICA territory (39/107). Pyramidal signs occurred in 29/107 of patients and were more prevalent when the lesion was distributed in more than two vascular regions (p = 0.00640). Mortality was higher among patients with ischemic lesion caused by cardiac sources (p = 0.00094) and with pyramidal signs (p = 0.00640). The TOAST classification is less useful in assessing supratentorial ischemic infarcts. Cardioembolic etiology, location of the ischemic lesion, and pyramidal signs support a negative prognosis.

The Role of Neuroimaging in the Latent Period of Blunt Traumatic Cerebrovascular Injury

PubMed Central

Karamchandani, Rahul; Rajajee, Venkatakrishna; Pandey, Aditya

2011-01-01

Introduction: Blunt cerebrovascular injury (BCVI) is found in 1-2.7% of all blunt trauma when appropriate screening criteria are employed. A significant number of patients with BCVI have a latent, or asymptomatic period, in which therapeutic intervention based on the appropriate use of angiographic imaging may decrease the risk of an ischemic stroke. Methods: Case report and review of literature. Results: A 42 year old woman suffered a fall off a motorcycle and was neurologically intact in the emergency room. Fractures involving the transverse foramen of cervical vertebrae were found on non-contrast Computed Tomography (CT) but screening for BCVI with angiographic imaging not performed. She subsequently suffered an ischemic stroke resulting in significant disability. Published studies that address the use of screening criteria for BCVI and subsequent management are reviewed. Conclusion: BCVI results in significant morbidity and mortality attributable to ischemic stroke. There is often a latent period between BCVI and occurrence of ischemic stroke. Specific risk factors can be used to identify patients requiring screening with catheter or CT angiography. Treatment with antithrombotic agents is the mainstay of treatment of BCVI and may reduce the rate of ischemic stroke. Identification and treatment of asymptomatic BCVI in blunt trauma patients may prevent ischemic stroke in a predominantly young population. PMID:22253664

Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection.

PubMed

Kolb, Alexander L; Corridon, Peter R; Zhang, Shijun; Xu, Weimin; Witzmann, Frank A; Collett, Jason A; Rhodes, George J; Winfree, Seth; Bready, Devin; Pfeffenberger, Zechariah J; Pomerantz, Jeremy M; Hato, Takashi; Nagami, Glenn T; Molitoris, Bruce A; Basile, David P; Atkinson, Simon J; Bacallao, Robert L

2018-04-01

Ischemic preconditioning confers organ-wide protection against subsequent ischemic stress. A substantial body of evidence underscores the importance of mitochondria adaptation as a critical component of cell protection from ischemia. To identify changes in mitochondria protein expression in response to ischemic preconditioning, we isolated mitochondria from ischemic preconditioned kidneys and sham-treated kidneys as a basis for comparison. The proteomic screen identified highly upregulated proteins, including NADP+-dependent isocitrate dehydrogenase 2 (IDH2), and we confirmed the ability of this protein to confer cellular protection from injury in murine S3 proximal tubule cells subjected to hypoxia. To further evaluate the role of IDH2 in cell protection, we performed detailed analysis of the effects of Idh2 gene delivery on kidney susceptibility to ischemia-reperfusion injury. Gene delivery of IDH2 before injury attenuated the injury-induced rise in serum creatinine ( P <0.05) observed in controls and increased the mitochondria membrane potential ( P <0.05), maximal respiratory capacity ( P <0.05), and intracellular ATP levels ( P <0.05) above those in controls. This communication shows that gene delivery of Idh2 can confer organ-wide protection against subsequent ischemia-reperfusion injury and mimics ischemic preconditioning. Copyright © 2018 by the American Society of Nephrology.

Genistein Promotes Endothelial Colony-Forming Cell (ECFC) Bioactivities and Cardiac Regeneration in Myocardial Infarction

PubMed Central

Lee, Sang Hun; Lee, Jun Hee; Asahara, Takayuki; Kim, Yong Sook; Jeong, Hae Chang; Ahn, Youngkeun; Jung, Jin Sup; Kwon, Sang-Mo

2014-01-01

Although stem cell-mediated treatment of ischemic diseases offers significant therapeutic promise, the limitation in the therapeutic efficacy of transplanted stem cells in vivo because of poor engraftment remains a challenge. Several strategies aimed at improving survival and engraftment of stem cells in the ischemic myocardium have been developed, such as cell transplantation in combination with growth factor delivery, genetic modification of stem cells, and/or cell therapy using scaffolds. To improve therapeutic efficacy, we investigated the effects of genistein on the engraftment of transplanted ECFCs in an acute myocardial ischemia model. Results: We found that genistein treatment enhanced ECFCs' migration and proliferation, which was accompanied by increases in the expression of ILK, α-parvin, F-actin, and phospholylation of ERK 1/2 signaling. Transplantation of genistein-stimulates ECFCs (GS-ECFCs) into myocardial ischemic sites in vivo induced cellular proliferation and secretion of angiogenic cytokines at the ischemic sites and thereby enhanced neovascularization and decreased myocardial fibrosis as well as improved cardiac function, as shown by echocardiography. Taken together, these data suggest that pretreatment of ECFCs with genistein prior to transplantation can improve the regenerative potential in ischemic tissues, providing a novel strategy in adult stem cell therapy for ischemic diseases. PMID:24830850

Integrity of Cerebellar Fastigial Nucleus Intrinsic Neurons Is Critical for the Global Ischemic Preconditioning

PubMed Central

Regnier-Golanov, Angelique S.; Britz, Gavin W.

2017-01-01

Excitation of intrinsic neurons of cerebellar fastigial nucleus (FN) renders brain tolerant to local and global ischemia. This effect reaches a maximum 72 h after the stimulation and lasts over 10 days. Comparable neuroprotection is observed following sublethal global brain ischemia, a phenomenon known as preconditioning. We hypothesized that FN may participate in the mechanisms of ischemic preconditioning as a part of the intrinsic neuroprotective mechanism. To explore potential significance of FN neurons in brain ischemic tolerance we lesioned intrinsic FN neurons with excitotoxin ibotenic acid five days before exposure to 20 min four-vessel occlusion (4-VO) global ischemia while analyzing neuronal damage in Cornu Ammoni area 1 (CA1) hippocampal area one week later. In FN-lesioned animals, loss of CA1 cells was higher by 22% compared to control (phosphate buffered saline (PBS)-injected) animals. Moreover, lesion of FN neurons increased morbidity following global ischemia by 50%. Ablation of FN neurons also reversed salvaging effects of five-minute ischemic preconditioning on CA1 neurons and morbidity, while ablation of cerebellar dentate nucleus neurons did not change effect of ischemic preconditioning. We conclude that FN is an important part of intrinsic neuroprotective system, which participates in ischemic preconditioning and may participate in naturally occurring neuroprotection, such as “diving response”. PMID:28934119

Clinical characteristics of patients with ischemic stroke following the 2016 Kumamoto earthquake.

PubMed

Inatomi, Yuichiro; Nakajima, Makoto; Yonehara, Toshiro; Ando, Yukio

2017-12-01

To investigate the clinical characteristics of patients with ischemic stroke following the 2016 Kumamoto earthquake. We retrospectively studied patients with ischemic stroke admitted to our hospital for 12weeks following the earthquake. We compared the clinical backgrounds and characteristics of the patients: before (the same period from the previous 3years) and after the earthquake; and the early (first 2weeks) and late (subsequent 10weeks) phases. A total of 194 patients with ischemic stroke were admitted to our hospital after the earthquake; 496 (165.3/year) patients were admitted before the earthquake. No differences between the two groups were noted for the clinical backgrounds, characteristics, or biomarkers. Past history of sleeping in a shelter or small vehicle was found in 13% and 28% of patients, respectively. Sleeping in a shelter (27% vs. 10%, p=0.013) was found more frequently in patients during the early phase than during the late phase after the earthquake. Admission of patients with ischemic stroke increased after the earthquake; however no differences between before and after the earthquake were noted for their clinical characteristics. To prevent ischemic stroke following earthquakes, mental stress and physical status of evacuees must be assessed. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Quest for Arterial Recanalization in Acute Ischemic Stroke-The Past, Present and the Future

PubMed Central

L.L.Yeo, Leonard; Sharma, Vijay K

2013-01-01

Ischemic stroke is one of the major causes of mortality and long-term disability. In the recent past, only very few treatment options were available and a considerable proportion of stroke survivors remained permanently disabled. However, over the last 2 decades rapid advances in acute stroke care have resulted in a corresponding improvement in mortality rates and functional outcomes. In this review, we describe the evolution of systemic thrombolytic agents and various interventional devices, their current status as well as some of the future prospects. We reviewed literature pertaining to acute ischemic stroke reperfusion treatment. We explored the current accepted treatment strategies to attain cerebral reperfusion via intravenous modalities and compare and contrast them within the boundaries of their clinical trials. Subsequently we reviewed the trials for interventional devices for acute ischemic stroke, categorizing them into thrombectomy devices, aspiration devices, clot disruption devices and thrombus entrapment devices. Finally we surveyed several of the alternative reperfusion strategies available. We also shed some light on the controversies surrounding the current strategies of treatment of acute ischemic stroke. Acute invasive interventional strategies continue to improve along with the noninvasive modalities. Both approaches appear promising. We conducted a comprehensive chronological review of the existing treatments as well as upcoming remedies for acute ischemic stroke. PMID:23864913

Neuroprotection and reduced gliosis by pre- and post-treatments of hydroquinone in a gerbil model of transient cerebral ischemia.

PubMed

Park, Joon Ha; Park, Chan Woo; Ahn, Ji Hyeon; Choi, Soo Young; Shin, Myoung Cheol; Cho, Jun Hwi; Lee, Tae-Kyeong; Kim, In Hye; Cho, Jeong Hwi; Lee, Jae-Chul; Kim, Yang Hee; Kim, Young-Myeong; Kim, Jong-Dai; Tae, Hyun-Jin; Shin, Bich Na; Bae, Eun Joo; Chen, Bai Hui; Won, Moo-Ho; Kang, Il Jun

2017-12-25

Hydroquinone (HQ), a major metabolite of benzene, exists in many plant-derived food and products. Although many studies have addressed biological properties of HQ including the regulation of immune responses and antioxidant activity, neuroprotective effects of HQ following ischemic insults have not yet been considered. Therefore, in this study, we examined neuroprotective effects of HQ against ischemic damage in the gerbil hippocampal cornu ammonis 1 (CA1) region following 5 min of transient cerebral ischemia. We found that pre- and post-treatments with 50 and 100 mg/kg of HQ protected CA1 pyramidal neurons from ischemic insult. Especially, pre- and post-treatments with 100 mg/kg of HQ showed strong neuroprotective effects against ischemic damage. In addition, pre- and post-treatments with 100 mg/kg of HQ significantly attenuated activations of astrocytes and microglia in the ischemic CA1 region compared to the vehicle-treated-ischemia-operated group. Briefly, these results show that pre- and post-treatments with HQ can protect neurons from transient cerebral ischemia and strongly attenuate ischemia-induced glial activation in the hippocampal CA1 region, and indicate that HQ can be used for both prevention and therapy of ischemic injury. Copyright © 2017 Elsevier B.V. All rights reserved.

Sickle cell trait and incident ischemic stroke in the Atherosclerosis Risk in Communities study.

PubMed

Caughey, Melissa C; Loehr, Laura R; Key, Nigel S; Derebail, Vimal K; Gottesman, Rebecca F; Kshirsagar, Abhijit V; Grove, Megan L; Heiss, Gerardo

2014-10-01

Numerous case reports describe stroke in individuals with sickle cell trait (SCT) in the absence of traditional risk factors for cerebrovascular disease. To date, no prospective epidemiological studies have investigated this association. A population-based sample of blacks (n=3497; mean age=54 years; female=62%) was followed from 1987 to 2011 in the Atherosclerosis Risk in Communities (ARIC) study, contributing a total of 65 371 person-years. Hazard ratios and incidence rate differences for ischemic stroke were estimated, contrasting SCT to homozygous hemoglobin A. Models were adjusted for age, sex, smoking, diabetes mellitus, hypertension, total cholesterol, atrial fibrillation, and coronary heart disease. SCT was identified in 223 (6.4%) participants. During a median follow-up of 22 years, 401 subjects experienced incident stroke (89% ischemic). Incident ischemic stroke was more frequent among those with SCT (13%) than those with homozygous hemoglobin A (10%). SCT was associated with an ischemic stroke hazard ratio of 1.4 (1.0-2.0) and an incidence rate difference amounting to 1.9 (0.4-3.8) extra strokes per 1000 person-years. We observed an increased risk of ischemic stroke in blacks with SCT. Further investigation of the incidence and pathophysiology of stroke in patients with SCT is warranted. © 2014 American Heart Association, Inc.

Premature Ventricular Complexes on Screening Electrocardiogram and Risk of Ischemic Stroke

PubMed Central

Agarwal, Sunil K.; Chao, Jennifer; Peace, Frederick; Judd, Suzanne E.; Kissela, Brett; Kleindorfer, Dawn; Howard, Virginia J.; Howard, George; Soliman, Elsayed Z.

2015-01-01

Background and Purpose Premature ventricular complexes (PVCs) detected from long-term electrocardiogram (ECG) recordings have been associated with an increased risk of ischemic stroke. Whether PVCs seen on routine ECG, commonly used in clinical practice, are associated with an increased risk of ischemic stroke remains unstudied. Methods This analysis included 24,460 participants (age 64.5+9.3 years, 55.1% Female, 40.0% African Americans) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of stroke at the time of enrollment. PVCs were ascertained from baseline ECG (2003-2007), and incident stroke cases through 2011 were confirmed by an adjudication committee. Results A total of 1,415 (5.8%) participants had at least one PVC at baseline, and 591 developed incident ischemic stroke during an average (SD) follow-up of 6.0 (2.0) years. In a Cox Proportional hazards model adjusted for age, sex, race, geographic region, education, prior heart disease, systolic blood pressure, blood pressure lowering medications, current smoking, diabetes, left ventricular hypertrophy by ECG, aspirin use and warfarin use, presence of PVCs was associated with 38% increased risk of ischemic stroke (HR (95% CI): 1.38 (1.05, 1.81)). Conclusions PVCs are common on routine screening ECGs, and are associated with an increased risk of ischemic stroke. PMID:25873602

Carotid Bulb Webs as a Cause of "Cryptogenic" Ischemic Stroke.

PubMed

Sajedi, P I; Gonzalez, J N; Cronin, C A; Kouo, T; Steven, A; Zhuo, J; Thompson, O; Castellani, R; Kittner, S J; Gandhi, D; Raghavan, P

2017-07-01

Carotid webs are intraluminal shelf-like filling defects at the carotid bulb with recently recognized implications in patients with recurrent ischemic stroke. We sought to determine whether carotid webs are an under-recognized cause of "cryptogenic" ischemic stroke and to estimate their prevalence in the general population. A retrospective review of neck CTA studies in young patients with cryptogenic stroke over the past 6 years ( n = 33) was performed to determine the prevalence of carotid webs compared with a control group of patients who received neck CTA studies for reasons other than ischemic stroke ( n = 63). The prevalence of carotid webs in the cryptogenic stroke population was 21.2% (95% CI, 8.9%-38.9%). Patients with symptomatic carotid webs had a mean age of 38.9 years (range, 30-48 years) and were mostly African American (86%) and women (86%). In contrast, only 1.6% (95% CI, 0%-8.5%) of patients in the control group demonstrated a web. Our findings demonstrate a statistically significant association between carotid webs and ischemic stroke (OR = 16.7; 95% CI, 2.78-320.3; P = .01). Carotid webs exhibit a strong association with ischemic stroke, and their presence should be suspected in patients lacking other risk factors, particularly African American women. © 2017 by American Journal of Neuroradiology.

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

PubMed Central

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

2010-01-01

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

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

PubMed

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

2015-01-01

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

Protective effects of incensole acetate on cerebral ischemic injury.

PubMed

Moussaieff, Arieh; Yu, Jin; Zhu, Hong; Gattoni-Celli, Sebastiano; Shohami, Esther; Kindy, Mark S

2012-03-14

The resin of Boswellia species is a major anti-inflammatory agent that has been used for centuries to treat various conditions including injuries and inflammatory conditions. Incensole acetate (IA), a major constituent of this resin, has been shown to inhibit NF-κB activation and concomitant inflammation, as well as the neurological deficit following head trauma. Here, we show that IA protects against ischemic neuronal damage and reperfusion injury in mice, attenuating the inflammatory nature of ischemic damage. IA given post-ischemia, reduced infarct volumes and improved neurological activities in the mouse model of ischemic injury in a dose dependent fashion. The protection from damage was accompanied by inhibition of TNF-α, IL-1β and TGF-β expression, as well as NF-κB activation following injury. In addition, IA is shown to have a therapeutic window of treatment up to 6h after ischemic injury. Finally, the protective effects of IA were partially mediated by TRPV3 channels as determined by the TRPV3 deficient mice and channel blocker studies. This study suggests that the anti-inflammatory and neuroprotective activities of IA may serve as a novel therapeutic treatment for ischemic and reperfusion injury, and as a tool in the ongoing research of mechanisms for neurological damage. Published by Elsevier B.V.

Molecular Simulation Uncovers the Conformational Space of the λ Cro Dimer in Solution

PubMed Central

Ahlstrom, Logan S.; Miyashita, Osamu

2011-01-01

The significant variation among solved structures of the λ Cro dimer suggests its flexibility. However, contacts in the crystal lattice could have stabilized a conformation which is unrepresentative of its dominant solution form. Here we report on the conformational space of the Cro dimer in solution using replica exchange molecular dynamics in explicit solvent. The simulated ensemble shows remarkable correlation with available x-ray structures. Network analysis and a free energy surface reveal the predominance of closed and semi-open dimers, with a modest barrier separating these two states. The fully open conformation lies higher in free energy, indicating that it requires stabilization by DNA or crystal contacts. Most NMR models are found to be unstable conformations in solution. Intersubunit salt bridging between Arg4 and Glu53 during simulation stabilizes closed conformations. Because a semi-open state is among the low-energy conformations sampled in simulation, we propose that Cro-DNA binding may not entail a large conformational change relative to the dominant dimer forms in solution. PMID:22098751

3-D simulation of nanopore structure for DNA sequencing.

PubMed

Park, Jun-Mo; Pak, Y Eugene; Chun, Honggu; Lee, Jong-Ho

2012-07-01

In this paper, we propose a method for simulating nanopore structure by using conventional 3-D simulation tool to mimic the I-V behavior of the nanopore structure. In the simulation, we use lightly doped silicon for ionic solution where some parameters like electron affinity and dielectric constant are fitted to consider the ionic solution. By using this method, we can simulate the I-V behavior of nanopore structure depending on the location and the size of the sphere shaped silicon oxide which is considered to be an indicator of a DNA base. In addition, we simulate an Ionic Field Effect Transistor (IFET) which has basically the nanopore structure, and show that the simulated curves follow sufficiently the I-V behavior of the measurement data. Therefore, we think it is reasonable to apply parameter modeling mentioned above to simulate nanopore structure. The key idea is to modify electron affinity of silicon which is used to mimic the KCl solution to avoid band bending and depletion inside the nanopore. We could efficiently utilize conventional 3-D simulation tool to simulate the I-V behavior of nanopore structures.

Correlation between brain injury and dysphagia in adult patients with stroke

PubMed Central

Nunes, Maria Cristina de Alencar; Jurkiewicz, Ari Leon; Santos, Rosane Sampaio; Furkim, Ana Maria; Massi, Giselle; Pinto, Gisele Sant Ana; Lange, Marcos Christiano

2012-01-01

Summary Introduction: In the literature, the incidence of oropharyngeal dysphagia in patients with cerebrovascular accident (AVE) ranges 20–90%. Some studies correlate the location of a stroke with dysphagia, while others do not. Objective: To correlate brain injury with dysphagia in patients with stroke in relation to the type and location of stroke. Method: A prospective study conducted at the Hospital de Clinicas with 30 stroke patients: 18 women and 12 men. All patients underwent clinical evaluation and swallowing nasolaryngofibroscopy (FEES®), and were divided based on the location of the injury: cerebral cortex, cerebellar cortex, subcortical areas, and type: hemorrhagic or transient ischemic. Results: Of the 30 patients, 18 had ischemic stroke, 10 had hemorrhagic stroke, and 2 had transient stroke. Regarding the location, 10 lesions were in the cerebral cortex, 3 were in the cerebral and cerebellar cortices, 3 were in the cerebral cortex and subcortical areas, and 3 were in the cerebral and cerebellar cortices and subcortical areas. Cerebral cortex and subcortical area ischemic strokes predominated in the clinical evaluation of dysphagia. In FEES®, decreased laryngeal sensitivity persisted following cerebral cortex and ischemic strokes. Waste in the pharyngeal recesses associated with epiglottic valleculae predominated in the piriform cortex in all lesion areas and in ischemic stroke. A patient with damage to the cerebral and cerebellar cortices from an ischemic stroke exhibited laryngeal penetration and tracheal aspiration of liquid and honey. Conclusion: Dysphagia was prevalent when a lesion was located in the cerebral cortex and was of the ischemic type. PMID:25991951

[The impact of non-thrombolytic management of acute ischemic stroke in older individuals: the experience of the Federal District, Brazil].

PubMed

Moura, Mirian; Casulari, Luiz Augusto

2015-07-01

To analyze the impact of a non-specific, decentralized treatment protocol for ischemic stroke in older individuals on the quality of the care provided in the public health care system (SUS, Sistema Único de Saúde) in the Federal District. This retrospective historical control study employed data from the SUS Hospital Information System (SIH/SUS). Two time periods were compared: before and after the adoption of a protocol based on non-specific measures (medical therapy without alteplase) and decentralized care. A set of 2 369 admissions of patients older than 60 years with ischemic stroke was analyzed for the period of 2006/2007, and 5 207 admissions for 2010/2011. The variables were frequency, length of stay, mortality, lethality of ischemic stroke, intensive care unit (ICU) admission, and hospital reimbursement for ischemic stroke admissions. Effectiveness was evaluated based on mortality and lethality rates and efficiency was evaluated based on length of stay, use of ICU, and reimbursed amounts. In the second time period, there was an increase of 119.8% in the number of ischemic stroke admissions (P = 0.0001), increase of 27.3% in absolute mortality, decrease of 5.0% in lethality rate (P = 0.02), and increase of 130.6% in ICU utilization rate (P = 0.0001). There was no difference between the periods regarding mean number of inpatient days and reimbursed amounts. The indicators used in the present study showed improved effectiveness of acute ischemic stroke treatment with the use of a non-specific, decentralized protocol. However, no impact was observed on efficiency.

Preconditioning, postconditioning and their application to clinical cardiology.

PubMed

Kloner, Robert A; Rezkalla, Shereif H

2006-05-01

Ischemic preconditioning is a well-established phenomenon first described in experimental preparations in which brief episodes of ischemia/reperfusion applied prior to a longer coronary artery occlusion reduce myocardial infarct size. There are ample correlates of ischemic preconditioning in the clinical realm. Preconditioning mimetic agents that stimulate the biochemical pathways of ischemic preconditioning and protect the heart without inducing ischemia have been examined in numerous experimental studies. However, despite the effectiveness of ischemic preconditioning and preconditioning mimetics for protecting ischemic myocardium, there are no preconditioning-based therapies that are routinely used in clinical medicine at the current time. Part of the problem is the need to administer therapy prior to the known ischemic event. Other issues are that percutaneous coronary intervention technology has advanced so far (with the development of stents and drug-eluting stents) that ischemic preconditioning or preconditioning mimetics have not been needed in most interventional cases. Recent clinical trials such as AMISTAD I and II (Acute Myocardial Infarction STudy of ADenosine) suggest that some preconditioning mimetics may reduce myocardial infarct size when given along with reperfusion or, as in the IONA trial, have benefit on clinical events when administered chronically in patients with known coronary artery disease. It is possible that some of the benefit described for adenosine in the AMISTAD 1 and 2 trials represents a manifestation of the recently described postconditioning phenomenon. It is probable that postconditioning--in which reperfusion is interrupted with brief coronary occlusions and reperfusion sequences--is more likely than preconditioning to be feasible as a clinical application to patients undergoing percutaneous coronary intervention for acute myocardial infarction.

Ischemic Optic Neuropathy in Cardiac Surgery: Incidence and Risk Factors in the United States from the National Inpatient Sample 1998 to 2013.

PubMed

Rubin, Daniel S; Matsumoto, Monica M; Moss, Heather E; Joslin, Charlotte E; Tung, Avery; Roth, Steven

2017-05-01

Ischemic optic neuropathy is the most common form of perioperative visual loss, with highest incidence in cardiac and spinal fusion surgery. To date, potential risk factors have been identified in cardiac surgery by only small, single-institution studies. To determine the preoperative risk factors for ischemic optic neuropathy, the authors used the National Inpatient Sample, a database of inpatient discharges for nonfederal hospitals in the United States. Adults aged 18 yr or older admitted for coronary artery bypass grafting, heart valve repair or replacement surgery, or left ventricular assist device insertion in National Inpatient Sample from 1998 to 2013 were included. Risk of ischemic optic neuropathy was evaluated by multivariable logistic regression. A total of 5,559,395 discharges met inclusion criteria with 794 (0.014%) cases of ischemic optic neuropathy. The average yearly incidence was 1.43 of 10,000 cardiac procedures, with no change during the study period (P = 0.57). Conditions increasing risk were carotid artery stenosis (odds ratio, 2.70), stroke (odds ratio, 3.43), diabetic retinopathy (odds ratio, 3.83), hypertensive retinopathy (odds ratio, 30.09), macular degeneration (odds ratio, 4.50), glaucoma (odds ratio, 2.68), and cataract (odds ratio, 5.62). Female sex (odds ratio, 0.59) and uncomplicated diabetes mellitus type 2 (odds ratio, 0.51) decreased risk. The incidence of ischemic optic neuropathy in cardiac surgery did not change during the study period. Development of ischemic optic neuropathy after cardiac surgery is associated with carotid artery stenosis, stroke, and degenerative eye conditions.

Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with factor V Leiden.

PubMed

Margaglione, M; D'Andrea, G; Giuliani, N; Brancaccio, V; De Lucia, D; Grandone, E; De Stefano, V; Tonali, P A; Di Minno, G

1999-07-01

At a young age, ischemic stroke is an uncommon event in which prothrombotic factors are likely to play an important role. In 202 referred cases, 105 men and 97 women, median age 39 years (range, 3 to 50), with a history of ischemic stroke and in 1036 age frequency-matched apparently healthy individuals from the same ethnic background, we have investigated whether inherited prothrombotic conditions increase the risk of ischemic stroke. Neither abnormal plasma levels of natural anticoagulants and fibrinogen nor significant increase of the prothrombin A20210 allele was found in stroke cases compared with controls. Hypertension (odds ratio [OR], 22.61), male sex (OR, 2.30), smoking (OR, 2.78) and alcohol habits (OR, 0.14), a personal history of venous thromboembolism (OR, 4.53), a family history of stroke (OR, 1.93), high circulating levels of fibrinogen (P=0.0190), and total cholesterol (P=0.101) were all independently associated with ischemic stroke. Compared with noncarriers, carriers of the factor V (FV) Leiden mutation (OR, 2.56), and to a lesser extent, of the methylenetetrahydrofolate reductase (MTHFR) TT genotype (OR, 1.60), had an independent higher estimated risk of having a history of ischemic stroke. The relationship with the FV Leiden mutation was greater in women (OR, 3.95). Thus, in addition to established determinants, FV Leiden mutation is independently associated with the occurrence of ischemic stroke in this setting. The greater association in women suggests the possibility of an interaction of this genotype with female hormones.

Association Between Dehydration and Short-Term Risk of Ischemic Stroke in Patients with Atrial Fibrillation.

PubMed

Swerdel, Joel N; Janevic, Teresa M; Kostis, William J; Faiz, Ambarina; Cosgrove, Nora M; Kostis, John B

2017-04-01

Previous cross-sectional studies have demonstrated a higher incidence of dehydration in patients admitted for stroke suggesting a possible association. However, the temporality of the association has not been well established. We examined whether dehydration increases the risk of ischemic stroke in patients with a recent hospitalization for atrial fibrillation (AF). Data was from 1994 to 2012 from the Myocardial Infarction Data Acquisition System (MIDAS), a repository of in-patient records New Jersey hospitals, for AF hospitalizations (n = 1,282,787). Estimates for the association between AF hospitalization with/without dehydration and ischemic stroke within 30 days post-AF discharge were determined using log-linear multivariable modeling adjusting for socio-demographic factors and comorbid conditions. Within 10 days of discharge for AF, patients 18-80 years old (YO) with comorbid dehydration had a 60 % higher risk of ischemic stroke compared to AF patients without comorbid dehydration (adjusted risk ratio (ARR) 1.60, 95 % confidence interval (CI) 1.28-2.00). Eighteen- to 80-YO patients had a 34 % higher risk of ischemic stroke in days 11-20 post-AF discharge (ARR 1.34, 95 % CI 1.04, 1.74). There was no difference in the risk of stroke in 18-80-YO patients with or without prior dehydration during days 21-30 post-AF discharge. We also found no difference in the risk of ischemic stroke during any time period in patients over 80 YO. Dehydration may be a significant risk factor for ischemic stroke in patients 18-80 YO with AF.

Endothelial dysfunction and arterial stiffness in ischemic stroke: the role of sleep-disordered breathing.

PubMed

Cereda, Carlo W; Tamisier, Renaud; Manconi, Mauro; Andreotti, Jennifer; Frangi, Jane; Pifferini, Valeria; Bassetti, Claudio L

2013-04-01

Sleep-disordered breathing (SDB) represents a risk factor for cardiovascular morbidity after a cerebral ischemic event (acute ischemic event, ischemic stroke, or transient ischemic attack). In the present study, endothelial function and arterial stiffness were analyzed in patients who experienced a postacute ischemic event with relation to SDB, sleep disruption, and nocturnal oxygenation parameters. SDB was assessed by full polysomnography in patients with acute ischemic event 3 months after the admission at our stroke unit. Moderate-severe SDB was defined according to the apnea-hypopnea index as apnea-hypopnea index ≥ 20. Endothelial function and arterial stiffness were assessed by peripheral arterial tonometry using Endo-PAT 2000. Thirty-seven patients were included. The augmentation index was significantly different between patients with apnea-hypopnea index <20 and apnea-hypopnea index ≥ 20 (22.4 ± 15.6% versus 34.6 ± 21.6%; P=0.042), whereas reactive hyperemia index level was not (2.02 ± 0.65 versus 2.31 ± 0.61; P=0.127). Patients with apnea-hypopnea index ≥ 20 showed an increased risk for arterial stiffness (odds ratio, 5.98 [95% CI, 1.11-41.72]) even when controlling for age, sex, body mass index, hypertension, and diabetes mellitus. The augmentation index was correlated with the arousal index (P=0.010) and with mean O2 saturation (P = 0.043). Poststroke patients with moderate-severe SDB were more prone to have increased arterial stiffness, although we did not find significant differences in endothelial function. Arterial stiffness also correlated with sleep disruption (arousal index) and mean O2 saturation.

Association of Leukoaraiosis With Convalescent Rehabilitation Outcome in Patients With Ischemic Stroke.

PubMed

Senda, Joe; Ito, Keiichi; Kotake, Tomomitsu; Kanamori, Masahiko; Kishimoto, Hideo; Kadono, Izumi; Suzuki, Yoshiro; Katsuno, Masahisa; Nishida, Yoshihiro; Ishiguro, Naoki; Sobue, Gen

2016-01-01

We investigated the factors influencing inpatient convalescent rehabilitation outcomes in patients with ischemic stroke, particularly severity of leukoaraiosis on magnetic resonance imaging. Participants included 520 patients with ischemic stroke (317 men and 203 women; mean age, 72.8±8.4 years) who were transferred from acute care hospitals for inpatient convalescent rehabilitation. Ischemic stroke subtypes included lacunar infarction (n=41), atherothrombosis (n=223), artery-to-artery embolism (n=67), cardiogenic embolism (n=97), undetermined embolism (n=76), and uncategorized ischemic stroke (n=16). Leukoaraiosis was graded according to periventricular hyperintensity (PVH) and deep white matter hyperintensity on magnetic resonance imaging. Functional Independence Measure scores were assessed on admission and at discharge. Multiple regression analysis revealed that rehabilitation outcomes, measured as total Functional Independence Measure scores, were significantly associated with leukoaraiosis estimated by PVH grade. This association was observed after adjustment for factors such as severity, age, and poststroke history. In all patients, PVH grades were associated with Functional Independence Measure motor scores (P<0.001), whereas in patients with artery-to-artery embolism or cardiogenic embolism and deep white matter hyperintensity grades were associated with Functional Independence Measure cognitive scores (P<0.05). Our study revealed that the degree of leukoaraiosis was associated with inpatient convalescent rehabilitation outcome in patients with ischemic stroke. Furthermore, the PVH grade was associated with motor function outcome, whereas the deep white matter hyperintensity grade correlated with cognitive function outcome, likely because the progression patterns and anatomic backgrounds of PVH and deep white matter hyperintensity differ according to ischemic stroke subtype. © 2015 American Heart Association, Inc.

Arsenic Exposure in Relation to Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study.

PubMed

Tsinovoi, Cari L; Xun, Pengcheng; McClure, Leslie A; Carioni, Vivian M O; Brockman, John D; Cai, Jianwen; Guallar, Eliseo; Cushman, Mary; Unverzagt, Frederick W; Howard, Virginia J; He, Ka

2018-01-01

The purpose of this case-cohort study was to examine urinary arsenic levels in relation to incident ischemic stroke in the United States. We performed a case-cohort study nested within the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort. A subcohort (n=2486) of controls was randomly sampled within region-race-sex strata while all incident ischemic stroke cases from the full REGARDS cohort (n=671) were included. Baseline urinary arsenic was measured by inductively coupled plasma-mass spectrometry. Arsenic species, including urinary inorganic arsenic and its metabolites monomethylarsonic acid and dimethylarsinic acid, were measured in a random subset (n=199). Weighted Cox's proportional hazards models were used to calculate hazard ratios and 95% confidence intervals of ischemic stroke by arsenic and its species. The average follow-up was 6.7 years. Although incident ischemic stroke showed no association with total arsenic or total inorganic arsenic, for each unit higher level of urinary monomethylarsonic acid on a log-scale, after adjustment for potential confounders, ischemic stroke risk increased ≈2-fold (hazard ratio=1.98; 95% confidence interval: 1.12-3.50). Effect modification by age, race, sex, or geographic region was not evident. A metabolite of arsenic was positively associated with incident ischemic stroke in this case-cohort study of the US general population, a low-to-moderate exposure area. Overall, these findings suggest a potential role for arsenic methylation in the pathogenesis of stroke, having important implications for future cerebrovascular research. © 2017 American Heart Association, Inc.

Cerebral ischemic lesions detected with diffusion-weighted magnetic resonance imaging after carotid artery stenting: Comparison of several anti-embolic protection devices.

PubMed

Taha, Mahmoud M; Maeda, Masayuki; Sakaida, Hiroshi; Kawaguchi, Kenji; Toma, Naoki; Yamamoto, Akitaka; Hirose, Tomofumi; Miura, Youichi; Fujimoto, Masashi; Matsushima, Satoshi; Taki, Waro

2009-09-01

Distal embolism is an important periprocedural technical complication with carotid angioplasty and carotid artery stenting (CAS). We evaluated the safety and efficacy of protection devices used during CAS by detecting new cerebral ischemic lesions using diffusion-weighted magnetic resonance imaging in 95 patients who underwent 98 CAS procedures: 34 using single PercuSurge GuardWire, 31 using double balloon protection, 15 using proximal flow reverse protection devices, 14 using Naviballoon, and 4 using filter anti-embolic devices. Diffusion-weighted imaging was performed preoperatively and postoperatively to evaluate the presence of any new embolic cerebral lesions. Postoperative diffusion-weighted imaging revealed 117 new ischemic lesions. Three patients had new ischemic stroke, two minor and one major, all ipsilateral to the treated carotid artery. The remaining patients had clinically silent ischemia. The incidence of new embolic lesions was lower using the proximal flow reverse protection device than with the double balloon protection (33% vs. 48.4%), but the volume of ipsilateral new ischemic lesions per patient was 136.6 mm(3) vs. 86.9 mm(3), respectively. Neuroprotection with Naviballoon yielded ipsilateral lesions of large volume (86.6 mm(3)) and higher number (5.7 lesions per patient) than using the filter anti-embolic device (34.8 mm(3) and 1 lesion per patient). New cerebral ischemic lesions after neuroprotected CAS are usually silent. The lower incidence of distal ischemia using proximal flow reverse and double balloon protection devices is limited by the larger volume and higher number of ischemic lesions.

Drug Delivery to the Ischemic Brain

PubMed Central

Thompson, Brandon J.; Ronaldson, Patrick T.

2014-01-01

Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events inneurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for acute ischemic stroke treatment, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is re-established. Therefore, there is a critical need for novel therapeutic approaches that can “rescue” salvageable brain tissue and/or protect BBB integrity during ischemic stroke. One class of drugs that may enable neural cell rescue following cerebral ischemia/reperfusion injury is the HMG-CoA reductase inhibitors (i.e., statins). Understanding potential CNS drug delivery pathways for statins is critical to their utility in ischemic stroke. Here, we review molecular pathways associated with cerebral ischemia and novel approaches for delivering drugs to treat ischemic disease. Specifically, we discuss utility of endogenous BBB drug uptake transporters such as organic anion transporting polypeptides (OATPs/Oatps) and nanotechnology-based carriers for optimization of CNS drug delivery. Overall, this chapter highlights state-of-the-art technologies that may improve pharmacotherapy of cerebral ischemia. PMID:25307217

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.

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

Top-100 Highest-Cited Original Articles in Ischemic Stroke: A Bibliometric Analysis.

PubMed

Malhotra, Konark; Saeed, Omar; Goyal, Nitin; Katsanos, Aristeidis H; Tsivgoulis, Georgios

2018-03-01

The total number of citations of a research article can be used to determine its impact on the scientific community. We aimed to identify the top-100 articles published on ischemic stroke and evaluate their characteristics. Based on the database of Journal Citation Reports, 934 journals were selected that published original ischemic stroke articles. We used Web of Science citation search tool to identify top-100 citation classics, i.e., articles with more than 400 citations, in the field of ischemic stroke. All original articles were evaluated for publication year, journal category, journal and its impact factor, number of total and annual citations, research topic, publishing country, and institutional affiliation. The top-100 citation classics in ischemic stroke were published from 1970 to 2015, with the decade of 1990-1999 contributing 47 articles of historical significance. Median of total citations and annual citations in our analysis were 625.0 (interquartile range [IQR] 851.3-494.5) and 35.7 (IQR 79.9-25.9), respectively. The majority of the articles originated from the United States (n = 57), focused over the medical management (n = 26), and were published in the New England Journal of Medicine or Stroke (n = 25 each) journals. The median impact factor for the journals that published top-100 ischemic stroke citation classics was 9.11 (IQR 21.49-6.11). Our list of top-100 citation classics specific to ischemic stroke provide a detailed insight into academic achievements, historical perspective and serves as a guide for the scientific progress in stroke. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel Biomarker for Evaluating Ischemic Stress Using an Electrogram Derived Phase Space

PubMed Central

Good, Wilson W.; Erem, Burak; Coll-Font, Jaume; Brooks, Dana H.; MacLeod, Rob S.

2017-01-01

The underlying pathophysiology of ischemia is poorly understood, resulting in unreliable clinical diagnosis of this disease. This limited knowledge of underlying mechanisms suggested a data driven approach, which seeks to identify patterns in the ECG data that can be linked statistically to underlying behavior and conditions of ischemic tissue. Previous studies have suggested that an approach known as Laplacian eigenmaps (LE) can identify trajectories, or manifolds, that are sensitive to different spatiotemporal consequences of ischemic stress, and thus serve as potential clinically relevant biomarkers. We applied the LE approach to measured transmural potentials in several canine preparations, recorded during control and ischemic conditions, and discovered regions on an approximated QRS-derived manifold that were sensitive to ischemia. By identifying a vector pointing to ischemia-associated changes to the manifold and measuring the shift in trajectories along that vector during ischemia, which we denote as Mshift, it was possible to also pull that vector back into signal space and determine which electrodes were responsible for driving the observed changes in the manifold. We refer to the signal space change as the manifold differential (Mdiff). Both the Mdiff and Mshift metrics show a similar degree of sensitivity to ischemic changes as standard metrics applied during the ST segment in detecting ischemic regions. The new metrics also were able to distinguish between sub-types of ischemia. Thus our results indicate that it may be possible to use the Mshift and Mdiff metrics along with ST derived metrics to determine whether tissue within the myocardium is ischemic or not. PMID:28451594

Combined morphine and limb remote ischemic perconditioning provides an enhanced protection against myocardial ischemia/reperfusion injury by antiapoptosis.

PubMed

Wang, Shi-Yu; Cui, Xin-Long; Xue, Fu-Shan; Duan, Ran; Li, Rui-Ping; Liu, Gao-Pu; Yang, Gui-Zhen; Sun, Chao

2016-05-01

Both morphine and limb remote ischemic perconditioning (RIPer) can protect against myocardial ischemia/reperfusion injury (IRI). This experiment was designed to assess whether combined morphine and limb RIPer could provide and enhanced protection against myocardial IRI in an in vivo rat model. One hundred male Sprague-Dawley rats were randomly allocated to six groups: sham, ischemia/reperfusion (IR), ischemic preconditioning, RIPer, morphine (M), and combined morphine and remote ischemic perconditioning (M + RIPer). Ventricular arrhythmias that occurred during ischemia and early reperfusion were scored, and serum creatine kinase isoenzyme and cardiac troponin I levels were assayed. The infarct size was determined by Evans blue and triphenyl tetrazolium chloride staining. The apoptosis in the myocardial ischemic core, ischemic border, and nonischemic areas was assessed through real-time polymerase chain reaction for Bax and Bcl-2 and with the transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay. The infarct size, serum cardiac troponin I level, incidence, and score of the arrhythmias during the initial reperfusion were significantly reduced in the M + RIPer group compared with the IR group but did not differ significantly between the ischemic preconditioning and M + RIPer groups. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling-positive cells were significantly decreased, and the Bcl-2/Bax ratio was significantly increased in the M + RIPer group compared with the IR group. This experiment demonstrates that combined morphine and limb RIPer provides an enhanced protection against myocardial IRI by the Bcl-2-linked apoptotic signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Serum Sodium and Potassium Levels in Cerebro-vascular Accident Patients.

PubMed

Farahmand, Farahmand; Choobi Anzali, Babak; Heshmat, Ramin; Ghafouri, Hamed-Basir; Hamedanchi, Sepehr

2013-05-01

We aim to assess serum sodium and potassium levels in patients with different types of cerebro-vascular accidents (CVA) in comparison to control group. A comparative cross-sectional study conducted on patients admitted to the emergency department from January to August 2012. Control group consisted of patients admitted to emergency department due to common cold, urinary tract infection, low back pain, cluster, and tension headache or migraine. Serum sodium and potassium levels were measured via standard laboratory methods. There were 77 patients in control group and 78 in CVA group. Forty nine patients from the CVA group had ischemic CVA, 11 had hemorrhagic CVA and 18 suffered a transient ischemic attack (TIA). Serum sodium level in control group was significantly lower than in patients with TIA, ischemic CVA, and hemorrhagic CVA (P < 0.001). Serum potassium level in control group was higher than patients with TIA, ischemic CVA, and hemorrhagic CVA (P < 0.001). Patients with hemorrhagic CVA showed significantly lower serum potassium level than patients with TIA and ischemic CVA (P < 0.001). Correspondingly, it was observed that serum sodium to potassium ratio was higher in patients with TIA, ischemic CVA, and hemorrhagic CVA (P < 0.001). In patients with hemorrhagic CVA serum sodium to potassium ratio was higher when compared to patients with TIA and ischemic CVA (P < 0.001). This study shows that higher serum sodium and lower serum potassium level may be associated with higher incidence of CVA. Further studies are paramount to elucidate the role of serum electrolyte levels in vascular events.

Inducible Glutamate Oxaloacetate Transaminase as a Therapeutic Target Against Ischemic Stroke

PubMed Central

Khanna, Savita; Briggs, Zachary

2015-01-01

Abstract Significance: Glutamate serves multi-faceted (patho)physiological functions in the central nervous system as the most abundant excitatory neurotransmitter and under pathological conditions as a potent neurotoxin. Regarding the latter, elevated extracellular glutamate is known to play a central role in ischemic stroke brain injury. Recent Advances: Glutamate oxaloacetate transaminase (GOT) has emerged as a new therapeutic target in protecting against ischemic stroke injury. Oxygen-sensitive induction of GOT expression and activity during ischemic stroke lowers glutamate levels at the stroke site while sustaining adenosine triphosphate levels in brain. The energy demands of the brain are among the highest of all organs underscoring the need to quickly mobilize alternative carbon skeletons for metabolism in the absence of glucose during ischemic stroke. Recent work builds on the important observation of Hans Krebs that GOT-mediated metabolism of glutamate generates tri-carboxylic acid (TCA) cycle intermediates in brain tissue. Taken together, outcomes suggest GOT may enable the transformative switch of otherwise excitotoxic glutamate into life-sustaining TCA cycle intermediates during ischemic stroke. Critical Issues: Neuroprotective strategies that focus solely on blocking mechanisms of glutamate-mediated excitotoxicity have historically failed in clinical trials. That GOT can enable glutamate to assume the role of a survival factor represents a paradigm shift necessary to develop the overall significance of glutamate in stroke biology. Future Directions: Ongoing efforts are focused to develop the therapeutic significance of GOT in stroke-affected brain. Small molecules that target induction of GOT expression and activity in the ischemic penumbra are the focus of ongoing studies. Antioxid. Redox Signal. 22, 175–186. PMID:25343301

Association between arterial calcifications and nonlacunar and lacunar ischemic strokes.

PubMed

van Dijk, Anouk C; Fonville, Susanne; Zadi, Taihra; van Hattem, Antonius M G; Saiedie, Ghesrouw; Koudstaal, Peter J; van der Lugt, Aad

2014-03-01

Nonlacunar cerebral infarcts are presumed to be caused by thromboembolism from the heart or extracranial arteries, whereas lacunar infarcts are thought to be caused by small vessel disease. We investigated to what extent arterial calcifications differ between nonlacunar and lacunar ischemic strokes. We studied 820 consecutive patients with transient ischemic attack or ischemic stroke in the anterior circulation who underwent multidetector computed tomography angiography and had no rare cause of stroke. The presence of likely cardioembolic pathogenesis was determined according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The remaining 708 patients were categorized as nonlacunar or lacunar strokes, either transient ischemic attacks or strokes, based on clinical symptoms corrected by brain imaging results. We measured volume of calcifications in the aortic arch, symptomatic extracranial and intracranial carotid artery using multidetector computed tomography angiography. The difference in calcifications between nonlacunar and lacunar strokes was assessed with a multivariable logistic regression analysis. We adjusted for degree of symptomatic carotid artery stenosis and cardiovascular risk factors. We found an independent association between volume of aortic arch calcifications and nonlacunar ischemic strokes (adjusted odds ratio [95% confidence interval], 1.11 [1.02-1.21]). No independent associations between extracranial and intracranial carotid artery calcifications and nonlacunar strokes were present. The only difference we found between nonlacunar and lacunar strokes was a higher calcification volume in the aortic arch in nonlacunar strokes. Our findings only partially confirm the notion of distinct etiologies and suggest that the potential role of other plaque components, plaque morphology, and aortic arch calcifications in ischemic stroke subtypes awaits further evaluation.

Novel Biomarker for Evaluating Ischemic Stress Using an Electrogram Derived Phase Space.

PubMed

Good, Wilson W; Erem, Burak; Coll-Font, Jaume; Brooks, Dana H; MacLeod, Rob S

2016-09-01

The underlying pathophysiology of ischemia is poorly understood, resulting in unreliable clinical diagnosis of this disease. This limited knowledge of underlying mechanisms suggested a data driven approach, which seeks to identify patterns in the ECG data that can be linked statistically to underlying behavior and conditions of ischemic tissue. Previous studies have suggested that an approach known as Laplacian eigenmaps (LE) can identify trajectories, or manifolds, that are sensitive to different spatiotemporal consequences of ischemic stress, and thus serve as potential clinically relevant biomarkers. We applied the LE approach to measured transmural potentials in several canine preparations, recorded during control and ischemic conditions, and discovered regions on an approximated QRS-derived manifold that were sensitive to ischemia. By identifying a vector pointing to ischemia-associated changes to the manifold and measuring the shift in trajectories along that vector during ischemia, which we denote as Mshift, it was possible to also pull that vector back into signal space and determine which electrodes were responsible for driving the observed changes in the manifold. We refer to the signal space change as the manifold differential (Mdiff). Both the Mdiff and Mshift metrics show a similar degree of sensitivity to ischemic changes as standard metrics applied during the ST segment in detecting ischemic regions. The new metrics also were able to distinguish between sub-types of ischemia. Thus our results indicate that it may be possible to use the Mshift and Mdiff metrics along with ST derived metrics to determine whether tissue within the myocardium is ischemic or not.

The Siblings With Ischemic Stroke Study (SWISS) Protocol

PubMed Central

Meschia, James F; Brown, Robert D; Brott, Thomas G; Chukwudelunzu, Felix E; Hardy, John; Rich, Stephen S

2002-01-01

Background Family history and twins studies suggest an inherited component to ischemic stroke risk. Candidate gene association studies have been performed but have limited capacity to identify novel risk factor genes. The Siblings With Ischemic Stroke Study (SWISS) aims to conduct a genome-wide scan in sibling pairs concordant or discordant for ischemic stroke to identify novel genetic risk factors through linkage analysis. Methods Screening at multiple clinical centers identifies patients (probands) with radiographically confirmed ischemic stroke and a family history of at least 1 living full sibling with stroke. After giving informed consent, without violating privacy among other family members, the proband invites siblings concordant and discordant for stroke to participate. Siblings then contact the study coordinating center. The diagnosis of ischemic stroke in potentially concordant siblings is confirmed by systematic centralized review of medical records. The stroke-free status of potentially discordant siblings is confirmed by validated structured telephone interview. Blood samples for DNA analysis are taken from concordant sibling pairs and, if applicable, from 1 discordant sibling. Epstein-Barr virus-transformed lymphoblastoid cell lines are created, and a scan of the human genome is planned. Discussion Conducting adequately powered genomics studies of stroke in humans is challenging because of the heterogeneity of the stroke phenotype and the difficulty of obtaining DNA samples from clinically well-characterized members of a cohort of stroke pedigrees. The multicentered design of this study is intended to efficiently assemble a cohort of ischemic stroke pedigrees without invoking community consent or using cold-calling of pedigree members. PMID:11882254

A simulation study of homogeneous ice nucleation in supercooled salty water

NASA Astrophysics Data System (ADS)

Soria, Guiomar D.; Espinosa, Jorge R.; Ramirez, Jorge; Valeriani, Chantal; Vega, Carlos; Sanz, Eduardo

2018-06-01

We use computer simulations to investigate the effect of salt on homogeneous ice nucleation. The melting point of the employed solution model was obtained both by direct coexistence simulations and by thermodynamic integration from previous calculations of the water chemical potential. Using a seeding approach, in which we simulate ice seeds embedded in a supercooled aqueous solution, we compute the nucleation rate as a function of temperature for a 1.85 NaCl mol per water kilogram solution at 1 bar. To improve the accuracy and reliability of our calculations, we combine seeding with the direct computation of the ice-solution interfacial free energy at coexistence using the Mold Integration method. We compare the results with previous simulation work on pure water to understand the effect caused by the solute. The model captures the experimental trend that the nucleation rate at a given supercooling decreases when adding salt. Despite the fact that the thermodynamic driving force for ice nucleation is higher for salty water for a given supercooling, the nucleation rate slows down with salt due to a significant increase of the ice-fluid interfacial free energy. The salty water model predicts an ice nucleation rate that is in good agreement with experimental measurements, bringing confidence in the predictive ability of the model. We expect that the combination of state-of-the-art simulation methods here employed to study ice nucleation from solution will be of much use in forthcoming numerical investigations of crystallization in mixtures.

A simulation study of homogeneous ice nucleation in supercooled salty water.

PubMed

Soria, Guiomar D; Espinosa, Jorge R; Ramirez, Jorge; Valeriani, Chantal; Vega, Carlos; Sanz, Eduardo

2018-06-14

We use computer simulations to investigate the effect of salt on homogeneous ice nucleation. The melting point of the employed solution model was obtained both by direct coexistence simulations and by thermodynamic integration from previous calculations of the water chemical potential. Using a seeding approach, in which we simulate ice seeds embedded in a supercooled aqueous solution, we compute the nucleation rate as a function of temperature for a 1.85 NaCl mol per water kilogram solution at 1 bar. To improve the accuracy and reliability of our calculations, we combine seeding with the direct computation of the ice-solution interfacial free energy at coexistence using the Mold Integration method. We compare the results with previous simulation work on pure water to understand the effect caused by the solute. The model captures the experimental trend that the nucleation rate at a given supercooling decreases when adding salt. Despite the fact that the thermodynamic driving force for ice nucleation is higher for salty water for a given supercooling, the nucleation rate slows down with salt due to a significant increase of the ice-fluid interfacial free energy. The salty water model predicts an ice nucleation rate that is in good agreement with experimental measurements, bringing confidence in the predictive ability of the model. We expect that the combination of state-of-the-art simulation methods here employed to study ice nucleation from solution will be of much use in forthcoming numerical investigations of crystallization in mixtures.

Stroke and Cerebrovascular Diseases Registry

ClinicalTrials.gov

2017-09-11

Stroke; Acute Stroke; Acute Brain Injury; Ischemic Stroke; Hemorrhagic Stroke; Transient Ischemic Attack; Subarachnoid Hemorrhage; Cerebral Ischemia; Cerebral Infarction; Cerebral Stroke; Venous Sinus Thrombosis, Cranial

[Identification of early irreversible damage area in a rat model of cerebral ischemia and reperfusion].

PubMed

Liu, S; Guo, Y

2000-02-01

To observe the early neuron ischemic damage in focal cerebral ischemia/reperfusion with histostaining methods of argyrophil III (AG III), Toludine blue(TB), and H&E, and to make out the 'separating line' between the areas of reversible and irreversible early ischemic damage. Forty-two male Wistar rats were randomly divided into the following groups: pseudo-surgical, blank-control, O2R0(occluded for 2 hours and reperfused for 0 hour), O2R0.5, O2R2, O2R4, O2R24. There were 6 rats in each group. Rats in experimental groups were suffered focal cerebral ischemia/reperfusion through a nylon suture method. After a special processor for tissue manage, the brain were coronal sectioned and stained with H&E, TB, and AG III. The area where dark neurons dwell in (ischemic core) were calculated with image analysis system. The success rate of ischemic model for this experiment is 90%. After being stained with argyrophil III method, normal neurons appear yellow or pale brown, which is hardly distinguished from the pale brown background. The ischemic neuron stained black, and has collapsed body and "corkscrew-like" axon or dentries, which were broken to some extent. The neuropil in the dark neurons dwelt area appears gray or pale black, which is apparently different from the pale brown neighborhood area. The distribution of dark neurons in cortex varies according to different layers, and has a character of columnar form. The dark neurons present as early as 2 hours ischemia without reperfusion with AG III method. AG III stain could selectively display early ischemic neurons, the area dwelt by dark neurons represent early ischemic core. Dark neuron is possibly the irreversibly damaged neuron. Identification of dark neurons could be helpful in the discrimination between early ischemic center and penumbra.

Association between atherogenic dyslipidemia and recurrent stroke risk in patients with different subtypes of ischemic stroke.

PubMed

Zhao, Lu; Wang, Ruihao; Song, Bo; Tan, Song; Gao, Yuan; Fang, Hui; Lu, Jie; Xu, Yuming

2015-07-01

The association between atherogenic dyslipidemia and stroke recurrence remains unclear, and may be influenced by different subtypes of ischemic stroke. We aimed to investigate whether atherogenic dyslipidemia contributed to stroke recurrence in ischemic stroke patients and in those with certain subtypes of ischemic stroke. We conducted a prospective hospital-based study enrolling patients with acute ischemic stroke. Atherogenic dyslipidemia was defined as high-density lipoprotein cholesterol <40 mg/dl and triglycerides ≥200 mg/dl. Ischemic stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The patients were followed up at 3, 6, 12 and 24 months after stroke onset. The association between atherogenic dyslipidemia and stroke recurrence was analyzed by using multivariable Cox regression model. In the 510 ischemic stroke patients, 64 patients (12·5%) had atherogenic dyslipidemia, and 66 patients (12·9%) experienced stroke recurrence events within 24 months. Kaplan-Meier analysis revealed that stroke recurrence rate was significantly higher in patients with atherogenic dyslipidemia than those without in all the stroke patients (20·3% vs. 11·9%; P = 0·048), and more evident in those of large-artery atherosclerosis subtype (31·0% vs. 14·1%; P = 0·014), but not in the other subtypes. Multivariable Cox regression analysis revealed that atherogenic dyslipidemia was associated with higher stroke recurrence risk among stroke patients of large-artery atherosclerosis subtype (hazard ratio, 2·79; 95% confidence interval, 1·24-6·28), but not significant in all the stroke patients (hazard ratio, 1·69; 95% confidence interval, 0·85-3·37). Atherogenic dyslipidemia is associated with higher risk of stroke recurrence in ischemic stroke patients. Such association might be more pronounced in large-artery atherosclerosis subtype and needs further investigation to establish such relationship. © 2015 World Stroke Organization.

Hemorrhagic versus ischemic stroke: Who can best benefit from blended conventional physiotherapy with robotic-assisted gait therapy?

PubMed

Dierick, Frédéric; Dehas, Mélanie; Isambert, Jean-Luc; Injeyan, Soizic; Bouché, Anne-France; Bleyenheuft, Yannick; Portnoy, Sigal

2017-01-01

Contrary to common belief of clinicians that hemorrhagic stroke survivors have better functional prognoses than ischemic, recent studies show that ischemic survivors could experience similar or even better functional improvements. However, the influence of stroke subtype on gait and posture outcomes following an intervention blending conventional physiotherapy with robotic-assisted gait therapy is missing. This study compared gait and posture outcome measures between ambulatory hemorrhagic patients and ischemic patients, who received a similar 4 weeks' intervention blending a conventional bottom-up physiotherapy approach and an exoskeleton top-down robotic-assisted gait training (RAGT) approach with Lokomat. Forty adult hemiparetic stroke inpatient subjects were recruited: 20 hemorrhagic and 20 ischemic, matched by age, gender, side of hemisphere lesion, stroke severity, and locomotor impairments. Functional Ambulation Category, Postural Assessment Scale for Stroke, Tinetti Performance Oriented Mobility Assessment, 6 Minutes Walk Test, Timed Up and Go and 10-Meter Walk Test were performed before and after a 4-week long intervention. Functional gains were calculated for all tests. Hemorrhagic and ischemic subjects showed significant improvements in Functional Ambulation Category (P<0.001 and P = 0.008, respectively), Postural Assessment Scale for Stroke (P<0.001 and P = 0.003), 6 Minutes Walk Test (P = 0.003 and P = 0.015) and 10-Meter Walk Test (P = 0.001 and P = 0.024). Ischemic patients also showed significant improvements in Timed Up and Go. Significantly greater mean Functional Ambulation Category and Tinetti Performance Oriented Mobility Assessment gains were observed for hemorrhagic compared to ischemic, with large (dz = 0.81) and medium (dz = 0.66) effect sizes, respectively. Overall, both groups exhibited quasi similar functional improvements and benefits from the same type, length and frequency of blended conventional physiotherapy and RAGT protocol. The use of intensive treatment plans blending top-down physiotherapy and bottom-up robotic approaches is promising for post-stroke rehabilitation.

Hemorrhagic versus ischemic stroke: Who can best benefit from blended conventional physiotherapy with robotic-assisted gait therapy?

PubMed Central

Dehas, Mélanie; Isambert, Jean-Luc; Injeyan, Soizic; Bouché, Anne-France; Bleyenheuft, Yannick; Portnoy, Sigal

2017-01-01

Background Contrary to common belief of clinicians that hemorrhagic stroke survivors have better functional prognoses than ischemic, recent studies show that ischemic survivors could experience similar or even better functional improvements. However, the influence of stroke subtype on gait and posture outcomes following an intervention blending conventional physiotherapy with robotic-assisted gait therapy is missing. Objective This study compared gait and posture outcome measures between ambulatory hemorrhagic patients and ischemic patients, who received a similar 4 weeks’ intervention blending a conventional bottom-up physiotherapy approach and an exoskeleton top-down robotic-assisted gait training (RAGT) approach with Lokomat. Methods Forty adult hemiparetic stroke inpatient subjects were recruited: 20 hemorrhagic and 20 ischemic, matched by age, gender, side of hemisphere lesion, stroke severity, and locomotor impairments. Functional Ambulation Category, Postural Assessment Scale for Stroke, Tinetti Performance Oriented Mobility Assessment, 6 Minutes Walk Test, Timed Up and Go and 10-Meter Walk Test were performed before and after a 4-week long intervention. Functional gains were calculated for all tests. Results Hemorrhagic and ischemic subjects showed significant improvements in Functional Ambulation Category (P<0.001 and P = 0.008, respectively), Postural Assessment Scale for Stroke (P<0.001 and P = 0.003), 6 Minutes Walk Test (P = 0.003 and P = 0.015) and 10-Meter Walk Test (P = 0.001 and P = 0.024). Ischemic patients also showed significant improvements in Timed Up and Go. Significantly greater mean Functional Ambulation Category and Tinetti Performance Oriented Mobility Assessment gains were observed for hemorrhagic compared to ischemic, with large (dz = 0.81) and medium (dz = 0.66) effect sizes, respectively. Conclusion Overall, both groups exhibited quasi similar functional improvements and benefits from the same type, length and frequency of blended conventional physiotherapy and RAGT protocol. The use of intensive treatment plans blending top-down physiotherapy and bottom-up robotic approaches is promising for post-stroke rehabilitation. PMID:28575054

Ischemic Volume and Neurological Deficit: Correlation of Computed Tomography Perfusion with the National Institutes of Health Stroke Scale Score in Acute Ischemic Stroke.

PubMed

Furlanis, Giovanni; Ajčević, Miloš; Stragapede, Lara; Lugnan, Carlo; Ridolfi, Mariana; Caruso, Paola; Naccarato, Marcello; Ukmar, Maja; Manganotti, Paolo

2018-04-30

The National Institutes of Health Stroke Scale (NIHSS) is the most adopted stroke patients' evaluation tool in emergency settings to assess the severity of stroke and to determine the patients' eligibility for specific treatments. Computed tomography perfusion (CTP) is crucial to identify salvageable tissue that can benefit from the reperfusion treatment. The aim of this study is to identify the relation between the NIHSS scores and the hypoperfused volumes evaluated by CTP in patients with hyperacute ischemic stroke. This retrospective study was conducted on 105 patients with ischemic stroke who underwent NIHSS assessment and CTP in the hyperacute phase. Hypoperfused volume was evaluated by CTP maps processed with semi-automatic algorithm. An analysis was conducted to determine the degree of correlation between the NIHSS scores and the ischemic lesion volumes and to investigate the relation between the anterior and the posterior circulation strokes, as well as between the right and the left hemispheric strokes. A significant correlation was found between ischemic volume and NIHSS score at baseline (r = .82; P < .0001) in the entire cohort. A high NIHSS-volume correlation was identified in the anterior circulation stroke (r = .76; P < .0001); whereas, it was nonsignificant in the posterior circulation stroke. NIHSS score and volume correlated for the left and the right hemispheric strokes (r = .83 and .81; P < .0001), showing a slightly higher slope in the left. This study showed a strong correlation between the baseline NIHSS score and the ischemic volume estimated by CTP. We confirmed that NIHSS is a reliable predictor of perfusion deficits in acute ischemic stroke. CTP allows fast imaging assessment in the hyperacute phase. The results highlight the importance of these diagnostic tools in the assessment of stroke severity and in acute decision-making. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack

PubMed Central

Brookes, Rebecca L.; Crichton, Siobhan; Wolfe, Charles D.A.; Yi, Qilong; Li, Linxin; Hankey, Graeme J.; Rothwell, Peter M.

2018-01-01

Background and Purpose— A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. Methods— Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. Results— A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3–0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29–0.77; P=0.003). Conclusions— These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke. PMID:29247141

A modified collagen gel dressing promotes angiogenesis in a preclinical swine model of chronic ischemic wounds.

PubMed

Elgharably, Haytham; Ganesh, Kasturi; Dickerson, Jennifer; Khanna, Savita; Abas, Motaz; Ghatak, Piya Das; Dixit, Sriteja; Bergdall, Valerie; Roy, Sashwati; Sen, Chandan K

2014-01-01

We recently performed proteomic characterization of a modified collagen gel (MCG) dressing and reported promising effects of the gel in healing full-thickness excisional wounds. In this work, we test the translational relevance of our aforesaid findings by testing the dressing in a swine model of chronic ischemic wounds recently reported by our laboratory. Full-thickness excisional wounds were established in the center of bipedicle ischemic skin flaps on the backs of animals. Ischemia was verified by laser Doppler imaging, and MCG was applied to the test group of wounds. Seven days post wounding, macrophage recruitment to the wound was significantly higher in MCG-treated ischemic wounds. In vitro, MCG up-regulated expression of Mrc-1 (a reparative M2 macrophage marker) and induced the expression of anti-inflammatory cytokine interleukin (IL)-10 and of fibroblast growth factor-basic (β-FGF). An increased expression of CCR2, an M2 macrophage marker, was noted in the macrophages from MCG treated wounds. Furthermore, analyses of wound tissues 7 days post wounding showed up-regulation of transforming growth factor-β, vascular endothelial growth factor, von Willebrand's factor, and collagen type I expression in MCG-treated ischemic wounds. At 21 days post wounding, MCG-treated ischemic wounds displayed higher abundance of proliferating endothelial cells that formed mature vascular structures and increased blood flow to the wound. Fibroblast count was markedly higher in MCG-treated ischemic wound-edge tissue. In addition, MCG-treated wound-edge tissues displayed higher abundance of mature collagen with increased collagen type I : III deposition. Taken together, MCG helped mount a more robust inflammatory response that resolved in a timely manner, followed by an enhanced proliferative phase, angiogenic outcome, and postwound tissue remodeling. Findings of the current study warrant clinical testing of MCG in a setting of ischemic chronic wounds. © 2014 by the Wound Healing Society.

Stroke prediction with CHA2DS2-VASc score in patients with mesenteric ischemia without atrial fibrillation-insights from a nationwide cohort.

PubMed

Hu, Wei-Syun; Lin, Cheng-Li

2017-11-01

The current study sought to evaluate the accuracy of CHA 2 DS 2 -VASc score for ischemic stroke prediction in patients with mesenteric ischemia without atrial fibrillation (AF). The study participants included patients aged ≥18years with a new diagnosis of mesenteric ischemia during hospitalization between January 1, 2000 and December 31, 2011. Individuals with atrial fibrillation (AF) or atrial flutter during the study period were excluded. The study participants were followed up until the ischemic stroke appeared or they were censored due to withdrawal from this program, mortality, or the end of the study period, whichever came first. Cox proportional hazards regression models were applied for ischemic stroke risk stratification in the study participants by CHA 2 DS 2 -VASc score. The c-statistic based on the receiver operating characteristic (ROC) analysis was applied to investigate the accuracy of CHA 2 DS 2 -VASc score for ischemic stroke risk discrimination. A total of 24039 study participants were enrolled. Ischemic stroke incidence increased from 1.54% in CHA 2 DS 2 -VASc score of 0 to 9.23% in CHA 2 DS 2 -VASc score of 6 or more. Moreover, the Kaplan-Meier curve with a log rank test demonstrated that patients with a higher CHA 2 DS 2 -VASc score were associated with an increased cumulative incidence rate of ischemic stroke during the follow-up period (p<0.001). The discriminatory performance of the CHA2DS2-VASc score resulted in C-statistics of 0.65(95% CI=0.63-0.66) for predicting ischemic stroke risk among patients with mesenteric ischemia without AF. A higher CHA 2 DS 2 -VASc score is demonstrated to be associated with an increased risk of ischemic stroke among patients with mesenteric ischemia without comorbid AF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lipoprotein (a) as a risk factor for ischemic stroke: a meta-analysis.

PubMed

Nave, Alexander H; Lange, Kristin S; Leonards, Christopher O; Siegerink, Bob; Doehner, Wolfram; Landmesser, Ulf; Steinhagen-Thiessen, Elisabeth; Endres, Matthias; Ebinger, Martin

2015-10-01

Lipoprotein (a) [Lp(a)] harbors atherogenic potential but its role as a risk factor for ischemic stroke remains controversial. We conducted a meta-analysis to determine the relative strength of the association between Lp(a) and ischemic stroke and identify potential subgroup-specific risk differences. A systematic search using the MeSH terms "lipoproteins" OR "lipoprotein a" AND "stroke" was performed in PubMed and ScienceDirect for case-control studies from June 2006 and prospective cohort studies from April 2009 until December 20th 2014. Data from eligible papers published before these dates were reviewed and extracted from previous meta-analyses. Studies that assessed the relationship between Lp(a) levels and ischemic stroke and reported generic data-i.e. odds ratio [OR], hazard ratio, or risk ratio [RR]-were eligible for inclusion. Studies that not distinguish between ischemic and hemorrhagic stroke and transient ischemic attack were excluded. Random effects meta-analyses with mixed-effects meta-regression were performed by pooling adjusted OR or RR. A total of 20 articles comprising 90,904 subjects and 5029 stroke events were eligible for the meta-analysis. Comparing high with low Lp(a) levels, the pooled estimated OR was 1.41 (95% CI, 1.26-1.57) for case-control studies (n = 11) and the pooled estimated RR was 1.29 (95% CI, 1.06-1.58) for prospective studies (n = 9). Sex-specific differences in RR were inconsistent between case-control and prospective studies. Study populations with a mean age of ≤55 years had an increased RR compared to older study populations. Reported Lp(a) contrast levels and ischemic stroke subtype significantly contributed to the heterogeneity observed in the analyses. Elevated Lp(a) is an independent risk factor for ischemic stroke and may be especially relevant for young stroke patients. Sex-specific risk differences remain conflicting. Further studies in these subgroups may be warranted. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Intake of antioxidants and B vitamins is inversely associated with ischemic stroke and cerebral atherosclerosis

PubMed Central

Choe, Hansaem; Hwang, Ji-Yun; Yun, Jin A; Kim, Ji-Myung; Song, Tae-Jin; Chang, Namsoo; Kim, Yong-Jae

2016-01-01

BACKGROUND/OBJECTIVES This study was conducted to examine relationships between dietary habits and intakes of antioxidants and B vitamins and the risk of ischemic stroke, and to compare dietary factors according to the presence of cerebral artery atherosclerosis and stroke subtypes. SUBJECTS/METHODS A total of 147 patients and 144 control subjects were recruited consecutively in the metropolitan area of Seoul, Korea. Sixty participants each in the case and control groups were included in analyses after 1:1 frequency matching. In addition, 117 acute ischemic stroke patients were classified into subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) guidelines. Dietary intake was measured using a semi-quantitative food frequency questionnaire composed of 111 food items and plasma lipid and homocysteine levels were analyzed. RESULTS When compared with control subjects, stroke patients had unfavorable dietary behaviors and lower intakes of fruits (73.1 ± 83.2 g vs. 230.9 ± 202.1 g, P < 0.001), vegetables (221.1 ± 209.0 g vs. 561.7 ± 306.6 g, P < 0.001), and antioxidants, including vitamins C, E, B6, β-carotene, and folate. The intakes of fruits, vegetables, vitamin C, and folate were inversely associated with the risk of ischemic stroke after adjusting for confounding factors. Intakes of vegetables, vitamins C, B6, B12, and folate per 1,000 kcal were lower in ischemic stroke with cerebral atherosclerosis than in those without. Overall vitamin B12 intake per 1,000 kcal differed according to the TOAST classification (P = 0.004), but no differences among groups existed based on the post-hoc test. CONCLUSIONS When compared with control subjects, ischemic stroke patients, particularly those with cerebral atherosclerosis, had unfavorable dietary intake, which may have contributed to the development of ischemic stroke. These results indicate that proper dietary recommendations are important for the prevention of ischemic stroke. PMID:27698959

Intake of antioxidants and B vitamins is inversely associated with ischemic stroke and cerebral atherosclerosis.

PubMed

Choe, Hansaem; Hwang, Ji-Yun; Yun, Jin A; Kim, Ji-Myung; Song, Tae-Jin; Chang, Namsoo; Kim, Yong-Jae; Kim, Yuri

2016-10-01

This study was conducted to examine relationships between dietary habits and intakes of antioxidants and B vitamins and the risk of ischemic stroke, and to compare dietary factors according to the presence of cerebral artery atherosclerosis and stroke subtypes. A total of 147 patients and 144 control subjects were recruited consecutively in the metropolitan area of Seoul, Korea. Sixty participants each in the case and control groups were included in analyses after 1:1 frequency matching. In addition, 117 acute ischemic stroke patients were classified into subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) guidelines. Dietary intake was measured using a semi-quantitative food frequency questionnaire composed of 111 food items and plasma lipid and homocysteine levels were analyzed. When compared with control subjects, stroke patients had unfavorable dietary behaviors and lower intakes of fruits (73.1 ± 83.2 g vs. 230.9 ± 202.1 g, P < 0.001), vegetables (221.1 ± 209.0 g vs. 561.7 ± 306.6 g, P < 0.001), and antioxidants, including vitamins C, E, B 6 , β-carotene, and folate. The intakes of fruits, vegetables, vitamin C, and folate were inversely associated with the risk of ischemic stroke after adjusting for confounding factors. Intakes of vegetables, vitamins C, B 6 , B 12 , and folate per 1,000 kcal were lower in ischemic stroke with cerebral atherosclerosis than in those without. Overall vitamin B 12 intake per 1,000 kcal differed according to the TOAST classification ( P = 0.004), but no differences among groups existed based on the post-hoc test. When compared with control subjects, ischemic stroke patients, particularly those with cerebral atherosclerosis, had unfavorable dietary intake, which may have contributed to the development of ischemic stroke. These results indicate that proper dietary recommendations are important for the prevention of ischemic stroke.

Lamina cribrosa position and Bruch's membrane opening differences between anterior ischemic optic neuropathy and open-angle glaucoma.

PubMed

Rebolleda, Gema; Pérez-Sarriegui, Ane; Díez-Álvarez, Laura; De Juan, Victoria; Muñoz-Negrete, Francisco J

2018-06-01

To compare the optic nerve head morphology among primary open-angle glaucoma, non-arteritic anterior ischemic optic neuropathy eyes, their fellow healthy eyes and control eyes, using spectral-domain optical coherence tomography with enhanced depth imaging. Observational cross-sectional study including 88 eyes of 68 patients. In this study, 23 non-arteritic anterior ischemic optic neuropathy eyes, 17 fellow unaffected eyes, 25 primary open-angle glaucoma eyes, and 23 age-matched control eyes were included. Peripapillary retinal nerve fiber layer thickness and optic disk area were evaluated. Bruch's membrane opening diameter, optic cup depth, anterior lamina cribrosa depth, and prelaminar tissue thickness were assessed. Non-arteritic anterior ischemic optic neuropathy and primary open-angle glaucoma eyes had similar visual field mean deviation and peripapillary retinal nerve fiber layer thickness (P = 0.6 and P = 0.56, respectively). Bruch's membrane opening diameter was significantly larger in primary open-angle glaucoma eyes than in control eyes (P = 0.02). Lamina cribrosa and disk cup were deeper in eyes with primary open-angle glaucoma than both control and non-arteritic anterior ischemic optic neuropathy eyes (P < 0.001). Prelaminar tissue thickness was significantly thinner in primary open-angle glaucoma eyes than in non-arteritic anterior ischemic optic neuropathy eyes (P < 0.001). Lamina cribrosa was shallower in both non-arteritic anterior ischemic optic neuropathy and unaffected fellow eyes compared to healthy eyes (P < 0.001 and P = 0.04, respectively). No differences were found in the optic disk area. A forward lamina cribrosa placement and not a smaller disk could be involved in the pathogenesis of non-arteritic anterior ischemic optic neuropathy. A significantly larger Bruch's membrane opening diameter was found in primary open-angle glaucoma eyes compared with control eyes. This issue has clinical implications because Bruch's membrane opening has been considered a stable reference for disk-related measures.

Heart rate is a prognostic risk factor for myocardial infarction: a post hoc analysis in the PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack) study population.

PubMed

Fox, Kim; Bousser, Marie-Germaine; Amarenco, Pierre; Chamorro, Angel; Fisher, Marc; Ford, Ian; Hennerici, Michael G; Mattle, Heinrich P; Rothwell, Peter M

2013-10-09

Elevated resting heart rate is known to be detrimental to morbidity and mortality in cardiovascular disease, though its effect in patients with ischemic stroke is unclear. We analyzed the effect of baseline resting heart rate on myocardial infarction (MI) in patients with a recent noncardioembolic cerebral ischemic event participating in PERFORM. We compared fatal or nonfatal MI using adjusted Cox proportional hazards models for PERFORM patients with baseline heart rate <70 bpm (n=8178) or ≥70 bpm (n=10,802). In addition, heart rate was analyzed as a continuous variable. Other cerebrovascular and cardiovascular outcomes were also explored. Heart rate ≥70 bpm was associated with increased relative risk for fatal or nonfatal MI (HR 1.32, 95% CI 1.03-1.69, P=0.029). For every 5-bpm increase in heart rate, there was an increase in relative risk for fatal and nonfatal MI (11.3%, P=0.0002). Heart rate ≥70 bpm was also associated with increased relative risk for a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (excluding hemorrhagic death) (P<0001); vascular death (P<0001); all-cause mortality (P<0001); and fatal or nonfatal stroke (P=0.04). For every 5-bpm increase in heart rate, there were increases in relative risk for fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (4.7%, P<0.0001), vascular death (11.0%, P<0.0001), all-cause mortality (8.0%, P<0.0001), and fatal and nonfatal stroke (2.4%, P=0.057). Elevated heart rate ≥70 bpm places patients with a noncardioembolic cerebral ischemic event at increased risk for MI. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Total donor ischemic time: relationship to early hemodynamics and intensive care morbidity in pediatric cardiac transplant recipients.

PubMed

Rodrigues, Warren; Carr, Michelle; Ridout, Deborah; Carter, Katherine; Hulme, Sara Louise; Simmonds, Jacob; Elliott, Martin; Hoskote, Aparna; Burch, Michael; Brown, Kate L

2011-11-01

Single-center studies have failed to link modest increases in total donor ischemic time to mortality after pediatric orthotopic heart transplant. We aimed to investigate whether prolonged total donor ischemic time is linked to pediatric intensive care morbidity after orthotopic heart transplant. Retrospective cohort review. Tertiary pediatric transplant center in the United Kingdom. Ninety-three pediatric orthotopic heart transplants between 2002 and 2006. Total donor ischemic time was investigated for association with early post-orthotopic heart transplant hemodynamics and intensive care unit morbidities. Of 43 males and 50 females with median age 7.2 (interquartile range 2.2, 13.0) yrs, 62 (68%) had dilated cardiomyopathy, 20 (22%) had congenital heart disease, and nine (10%) had restrictive cardiomyopathy. The mean total donor ischemic time was 225.9 (sd 65.6) mins. In the first 24 hrs after orthotopic heart transplant, age-adjusted mean arterial blood pressure increased (p < .001), mean pulmonary arterial pressure fell (p = .012), but central venous pressure (p = .58) and left atrial pressure (p = .20) were unchanged. After adjustment for age, primary diagnosis, pre-orthotopic heart transplant mechanical support, and marginal donor factors, longer total donor ischemic time was significantly associated with lower mean arterial blood pressure (p < .001) in the first 24 hrs after orthotopic heart transplant, longer post-orthotopic heart transplant mechanical ventilation (p = .03), longer post-orthotopic heart transplant stay in the intensive care unit (p = .004), and longer post-orthotopic heart transplant stay in hospital (p = .02). Total donor ischemic time was not related to levels of mean pulmonary arterial pressure (p = .62), left atrial pressure (p = .38), or central venous pressure (p = .76) early after orthotopic heart transplant. Prolonged total donor ischemic time has an adverse effect on the donor organ, contributing to lower mean arterial blood pressure, as well as more prolonged ventilation and intensive care unit and hospital stays post-orthotopic heart transplant, reflecting increased morbidity.

Association of kidney disease measures with ischemic versus hemorrhagic strokes: Pooled analyses of 4 prospective community-based cohorts

PubMed Central

Mahmoodi, Bakhtawar K.; Yatsuya, Hiroshi; Matsushita, Kunihiro; Sang, Yinying; Gottesman, Rebecca F.; Astor, Brad C.; Woodward, Mark; Longstreth, WT; Psaty, Bruce M.; Shlipak, Michael G.; Folsom, Aaron R.; Gansevoort, Ron T.; Coresh, Josef

2015-01-01

Background and purpose Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke. Methods We pooled individual participant data from four community-based cohorts: three from the United States and one from The Netherlands. GFR was estimated by using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of eGFR and ACR were compared for each stroke type (ischemic vs. intraparenchymal hemorrhagic) using study-stratified Cox-regression. Results Amongst 29,595 participants (mean age 61 [SD 12.5] years, 46% males, 17% black), 1,261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low eGFR was significantly associated with increased risk of ischemic, but not hemorrhagic, stroke risk, while high ACR was associated with both stroke types. Adjusted HRs for ischemic and hemorrhagic stroke at eGFR of 45 (vs. 95) ml/min/1.73m2 were 1.30 (95% CI, 1.01–1.68) and 0.92 (0.47–1.81), respectively. In contrast, the corresponding HR for ACR 300 (vs. 5) mg/g were 1.62 (1.27–2.07) for ischemic and 2.57 (1.37–4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P =0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure. Conclusions Whereas albuminuria showed significant association with both stroke types, the association of decreased eGFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations. PMID:24876078

Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

PubMed

Paliwal, Pankaj; Dash, Debabrata; Krishnamurthy, Sairam

2018-04-01

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

Physical activity and risk of ischemic stroke in the Northern Manhattan Study

PubMed Central

Willey, J Z.; Moon, Y P.; Paik, M C.; Boden-Albala, B; Sacco, R L.; Elkind, M S.V.

2009-01-01

Background: It is controversial whether physical activity is protective against first stroke among older persons. We sought to examine whether physical activity, as measured by intensity of exercise and energy expended, is protective against ischemic stroke. Methods: The Northern Manhattan Study is a prospective cohort study in older, urban-dwelling, multiethnic, stroke-free individuals. Baseline measures of leisure-time physical activity were collected via in-person questionnaires. Cox proportional hazards models were constructed to examine whether energy expended and intensity of physical activity were associated with the risk of incident ischemic stroke. Results: Physical inactivity was present in 40.5% of the cohort. Over a median follow-up of 9.1 years, there were 238 incident ischemic strokes. Moderate- to heavy-intensity physical activity was associated with a lower risk of ischemic stroke (adjusted hazard ratio [HR] 0.65, 95% confidence interval [0.44–0.98]). Engaging in any physical activity vs none (adjusted HR 1.16, 95% CI 0.88–1.51) and energy expended in kcal/wk (adjusted HR per 500-unit increase 1.01, 95% CI 0.99–1.03) were not associated with ischemic stroke risk. There was an interaction of sex with intensity of physical activity (p = 0.04), such that moderate to heavy activity was protective against ischemic stroke in men (adjusted HR 0.37, 95% CI 0.18–0.78), but not in women (adjusted HR 0.92, 95% CI 0.57–1.50). Conclusions: Moderate- to heavy-intensity physical activity, but not energy expended, is protective against risk of ischemic stroke independent of other stroke risk factors in men in our cohort. Engaging in moderate to heavy physical activities may be an important component of primary prevention strategies aimed at reducing stroke risk. GLOSSARY CI = confidence interval; HR = hazard ratio; MET = metabolic equivalents. PMID:19933979

Influence of the Cyclooxygenase-2 Gene -765G/C and -1195G/A Polymorphisms on Development of Ischemic Stroke.

PubMed

Wu, Guangliang; Cai, Haiyan; Cai, Haobin; Chen, Zhao; Tan, Lei; Qin, Xiurong; Cai, Yefeng

2016-09-01

Many studies have investigated the association between the cyclooxygenase-2 (COX-2) gene polymorphism and ischemic stroke. However, results of these studies still remain controversial. To better explain the association between COX-2 polymorphisms (-765G/C and -1195G/A) and ischemic stroke risk, a meta-analysis was performed. Relevant studies were identified from 4 Chinese databases (Chinese Biological Medical Literature database, Chinese National Knowledge Infrastructure database, Chongqing VIP database, and Chinese WANFANG database), PUBMED and EMBASE prior to December 2015. The strength of association between COX-2 polymorphism and ischemic stroke was evaluated by the odds ratio (OR) with 95% confidence interval (CI). Inconsistency index (I(2)) and the Cochran's Q statistic were used to check heterogeneity. Publication bias was evaluated by funnel plots and Egger's regression test. A total of 4086 ischemic stroke cases and 4747 controls were identified. Significant association between COX-2 -765G/C polymorphism and the risk of ischemic stroke was found in Brazilians and the African-Americans. The OR of (CC+GC versus GG) for the Brazilians and African-Americans were (6.328, 95% CI = 2.295-17.448) and (1.644, 95% CI = 1.060-2.551). In addition, the recessive model of the Brazilians gave an OR of 3.621 (95% CI: 1.519-8.630). Furthermore, the (GC versus GG) and the allele model of the African-Americans were (OR: 1.615, 95% CI = 1.015-2.572) and (OR: 1.422, 95% CI = 1.033-1.957). Significant association was also observed for COX-2 -1195G/A polymorphism in the subtypes of small vessel disease (SVD) of ischemic stroke. Our study suggests that COX-2 -765G/C and -1195G/A polymorphisms may contribute to susceptibility of ischemic stroke, specifically in Brazilians and the African-Americans, and those of SVD. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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.

Ischemic Strokes Due to Large-Vessel Occlusions Contribute Disproportionately to Stroke-Related Dependence and Death: A Review.

PubMed

Malhotra, Konark; Gornbein, Jeffrey; Saver, Jeffrey L

2017-01-01

Since large-vessel occlusion (LVO)-related acute ischemic strokes (AIS) are associated with more severe deficits, we hypothesize that the endovascular thrombectomy (ET) may disproportionately benefit stroke-related dependence and death. To delineate LVO-AIS impact, systematic search identified studies measuring dependence or death [modified Rankin Scale (mRS) 3-6] or mortality following ischemic stroke among consecutive patients presenting with both LVO and non-LVO events within 24 h of symptom onset. Among 197 articles reviewed, 2 met inclusion criteria, collectively enrolling 1,467 patients. Rates of dependence or death (mRS 3-6) within 3-6 months were higher after LVO than non-LVO ischemic stroke, 64 vs. 24%, odds ratio (OR) 4.46 (CI: 3.53-5.63, p  < 0.0001). Mortality within 3-6 months was higher after LVO than non-LVO ischemic stroke, 26.2 vs. 1.3%, OR 4.09 (CI: 2.5-6.68), p  < 0.0001. Consequently, while LVO ischemic events accounted for 38.7% (CI: 21.8-55.7%) of all acutely presenting ischemic strokes, they accounted for 61.6% (CI: 41.8-81.3%) of poststroke dependence or death and 95.6% (CI: 89.0-98.8%) of poststroke mortality. Using literature-based projections of LVO cerebral ischemia patients treatable within 8 h of onset, ET can be used in 21.4% of acutely presenting patients with ischemic stroke, and these events account for 34% of poststroke dependence and death and 52.8% of poststroke mortality. LVOs cause a little more than one-third of acutely presenting AIS, but are responsible for three-fifths of dependency and more than nine-tenths of mortality after AIS. At the population level, ET has a disproportionate benefit in reducing severe stroke outcomes.

3H-1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway.

PubMed

Kuo, Ping-Chang; Yu, I-Chen; Scofield, Barbara A; Brown, Dennis A; Curfman, Eric T; Paraiso, Hallel C; Chang, Fen-Lei; Yen, Jui-Hung

2017-05-01

Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in brain tissue induce oxidative stress and inflammatory responses. D3T, the simplest compound of the cyclic, sulfur-containing dithiolethiones, is found in cruciferous vegetables and has been reported to induce antioxidant genes and glutathione biosynthesis through activation of Nrf2. In addition to antioxidant activity, D3T was also reported to possess anti-inflammatory effects. In this study, we evaluated the therapeutic potential of D3T for the treatment of ischemic stroke and investigated the mechanisms underlying the protective effects of D3T in ischemic stroke. Mice subjected to transient middle cerebral artery occlusion/reperfusion (tMCAO/R) were administered with vehicle or D3T to evaluate the effect of D3T in cerebral brain injury. We observed D3T reduced infarct size, decreased brain edema, lessened blood-brain barrier disruption, and ameliorated neurological deficits. Further investigation revealed D3T suppressed microglia (MG) activation and inhibited peripheral inflammatory immune cell infiltration of CNS in the ischemic brain. The protective effect of D3T in ischemic stroke is mediated through Nrf2 induction as D3T-attenuated brain injury was abolished in Nrf2 deficient mice subjected to tMCAO/R. In addition, in vitro results indicate the induction of Nrf2 by D3T is required for its suppressive effect on MG activation and cytokine production. In summary, we demonstrate for the first time that D3T confers protection against ischemic stroke, which is mediated through suppression of MG activation and inhibition of CNS peripheral cell infiltration, and that the protective effect of D3T in ischemic stroke is dependent on the activation of Nrf2. Copyright © 2017 Elsevier Inc. All rights reserved.

A comparison of three approaches for simulating fine-scale surface winds in support of wildland fire management. Part II. An exploratory study of the effect of simulated winds on fire growth simulations

Treesearch

Jason M. Forthofer; Bret W. Butler; Charles W. McHugh; Mark A. Finney; Larry S. Bradshaw; Richard D. Stratton; Kyle S. Shannon; Natalie S. Wagenbrenner

2014-01-01

The effect of fine-resolution wind simulations on fire growth simulations is explored. The wind models are (1) a wind field consisting of constant speed and direction applied everywhere over the area of interest; (2) a tool based on the solution of the conservation of mass only (termed mass-conserving model) and (3) a tool based on a solution of conservation of mass...

Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.

PubMed

Auer, Paul L; Nalls, Mike; Meschia, James F; Worrall, Bradford B; Longstreth, W T; Seshadri, Sudha; Kooperberg, Charles; Burger, Kathleen M; Carlson, Christopher S; Carty, Cara L; Chen, Wei-Min; Cupples, L Adrienne; DeStefano, Anita L; Fornage, Myriam; Hardy, John; Hsu, Li; Jackson, Rebecca D; Jarvik, Gail P; Kim, Daniel S; Lakshminarayan, Kamakshi; Lange, Leslie A; Manichaikul, Ani; Quinlan, Aaron R; Singleton, Andrew B; Thornton, Timothy A; Nickerson, Deborah A; Peters, Ulrike; Rich, Stephen S

2015-07-01

Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

Simulating contaminant attenuation, double-porosity exchange, and water age in aquifers using MOC3D

USGS Publications Warehouse

Goode, Daniel J.

1999-01-01

MOC3D is a general-purpose computer model developed by the U.S. Geological Survey (USGS) for simulation of three-dimensional solute transport in ground water (Konikow and others, 1996). The model is an update to the widely used USGS two-dimensional solute-transport model (MOC) and is implemented as an optional “package” for the ground-water flow model MODFLOW (Harbaugh and McDonald, 1996). Directly coupling the time-tested MOC transport algorithms with the widely used MODFLOW program makes MOC3D a powerful tool for simulation of solute transport in ground water in many hydrogeologic settings. The model simulates transport processes that include:Advection - Transport of dissolved solutes at the same rate as the average ground-water flow velocity.Diffusion - Spreading of solute from areas of high concentration to areas of low concentration, caused by “random” molecular motionDispersion - Diffusion-like spreading of solute that is caused primarily by spatial variability in aquifer properties, which results in spatial variability in transport velocity.Retardation - Reduction in the apparent solute velocity, compared to the ground-water velocity, caused by linear equilibrium sorption on aquifer materials.Decay - Disappearance of solute caused by reactions such as radioactive decay or biodegradation that are proportional to concentration.Growth - Creation (or disappearance) of solute mass caused by reactions that proceed independent of the solute concentration, such as some cases of biodegradationDouble-porosity exchange - rate-limited exchange of solute mass between mobile and immobile zones; for example, between fractures and the rock matrix.

Modeling mass transfer and reaction of dilute solutes in a ternary phase system by the lattice Boltzmann method

NASA Astrophysics Data System (ADS)

Fu, Yu-Hang; Bai, Lin; Luo, Kai-Hong; Jin, Yong; Cheng, Yi

2017-04-01

In this work, we propose a general approach for modeling mass transfer and reaction of dilute solute(s) in incompressible three-phase flows by introducing a collision operator in lattice Boltzmann (LB) method. An LB equation was used to simulate the solute dynamics among three different fluids, in which the newly expanded collision operator was used to depict the interface behavior of dilute solute(s). The multiscale analysis showed that the presented model can recover the macroscopic transport equations derived from the Maxwell-Stefan equation for dilute solutes in three-phase systems. Compared with the analytical equation of state of solute and dynamic behavior, these results are proven to constitute a generalized framework to simulate solute distributions in three-phase flows, including compound soluble in one phase, compound adsorbed on single-interface, compound in two phases, and solute soluble in three phases. Moreover, numerical simulations of benchmark cases, such as phase decomposition, multilayered planar interfaces, and liquid lens, were performed to test the stability and efficiency of the model. Finally, the multiphase mass transfer and reaction in Janus droplet transport in a straight microchannel were well reproduced.

Simulation-based validation and arrival-time correction for Patlak analyses of Perfusion-CT scans

NASA Astrophysics Data System (ADS)

Bredno, Jörg; Hom, Jason; Schneider, Thomas; Wintermark, Max

2009-02-01

Blood-brain-barrier (BBB) breakdown is a hypothesized mechanism for hemorrhagic transformation in acute stroke. The Patlak analysis of a Perfusion Computed Tomography (PCT) scan measures the BBB permeability, but the method yields higher estimates when applied to the first pass of the contrast bolus compared to a delayed phase. We present a numerical phantom that simulates vascular and parenchymal time-attenuation curves to determine the validity of permeability measurements obtained with different acquisition protocols. A network of tubes represents the major cerebral arteries ipsi- and contralateral to an ischemic event. These tubes branch off into smaller segments that represent capillary beds. Blood flow in the phantom is freely defined and simulated as non-Newtonian tubular flow. Diffusion of contrast in the vessels and permeation through vessel walls is part of the simulation. The phantom allows us to compare the results of a permeability measurement to the simulated vessel wall status. A Patlak analysis reliably detects areas with BBB breakdown for acquisitions of 240s duration, whereas results obtained from the first pass are biased in areas of reduced blood flow. Compensating for differences in contrast arrival times reduces this bias and gives good estimates of BBB permeability for PCT acquisitions of 90-150s duration.