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'Iatrogenic' Brain Stem Infarction
Two patients sustained an ischemic brain stem infarction during medical examination and treatment. The first patient lost consciousness and the spontaneous respiration ceased during X-ray examination of the cervical spine when the neck was hyperextended. After some minutes he regained conciousness but was found to be tetraplegic, and the patient deceased 4 months later. The angiogram revealed thrombosis of the
R. Fogelholm; P. Karli
K-134, a Phosphodiesterase 3 Inhibitor, Prevents Brain Damage by Inhibiting Thrombus Formation in a Rat Cerebral Infarction Model
Background K-134 is a more potent antiplatelet drug with a selective inhibitory effect on phosphodiesterase 3 (PDE3) compared with its analogue, cilostazol. Objectives This study was performed to compare the ameliorating effects of K-134 and cilostazol on brain damage in an experimental photothrombotic cerebral infarction model. Methods and Results We investigated the effects of oral preadministration of PDE3 inhibitors in a rat stroke model established by photothrombotic middle cerebral artery (MCA) occlusion. K-134 significantly prolonged MCA occlusion time at doses >10 mg/kg, and reduced cerebral infarct size at 30 mg/kg in the stroke model (n?=?12, 87.5±5.6 vs. 126.8±7.5 mm3, P<0.01), indicating its potent antithrombotic effect. On the other hand, the effects of cilostazol on MCA occlusion time and cerebral infarct size are relatively weak even at the high dosage of 300 mg/kg. Furthermore, K-134 blocked rat platelet aggregation more potently than cilostazol in vitro. Also in an arteriovenous shunt thrombosis model, K-134 showed an antithrombotic effect greater than cilostazol. Conclusions These findings suggest that K-134, which has strong antithrombotic activity, is a promising drug for prevention of cerebral infarction associated with platelet hyperaggregability.
Yoshida, Hideo; Ashikawa, Yuka; Itoh, Shinsuke; Nakagawa, Takashi; Asanuma, Akimune; Tanabe, Sohei; Inoue, Yoshihiro; Hidaka, Hiroyoshi
Cystatin C and Subclinical Brain Infarction
Subclinical brain infarcts (SBI) are common in the elderly and are associated with covert neurologic and cognitive impairment. Although renal impairment is associated with accelerated cerebrovascular disease and an increased risk for clinically apparent brain infarct, few studies have examined the relationship between renal function and SBI, and these may have been limited by the inaccuracy of creatinine as a
Stephen L. Seliger; W. T. Longstreth Jr; Ronit Katz; Teri Manolio; Linda F. Fried; Michael Shlipak; Catherine O. Stehman-Breen; Anne Newman; Mark Sarnak; Daniel L. Gillen; Anthony Bleyer; David S. Siscovick
Neovasculature and blood-brain barrier in ischemic brain infarct
The cellular events occurring in ischemic brain infarcts of 1 day to 8 weeks duration were investigated. The material consisted of 17 human postmortem brains with anemic infarcts caused by occlusive vascular diseases. Using antiserum against human plasma albumin as a marker for the breakdown of blood-brain barrier and ammoniacal silver nitrate stain to demonstrate the vasculature, the onset and
H. Mei Liu
A New Algorithm for Computing Infarct Volume in a Rat Stroke Model
There are several methods for computing the infarct volume from brain images of stroke animal models. However, most methods rely on the discretion of the user to detect the infarct region and do not differentiate the levels of infarction within the infarct region when computing the infarct volume. We have developed a new algorithm for detecting the infarct region in
Jaetak Lee; Sven Le Saint; Ja-Kyeong Lee; Kyungsook Han
Ischemic neurons recruit natural killer cells that accelerate brain infarction
Brain ischemia and reperfusion activate the immune system. The abrupt development of brain ischemic lesions suggests that innate immune cells may shape the outcome of stroke. Natural killer (NK) cells are innate lymphocytes that can be swiftly mobilized during the earliest phases of immune responses, but their role during stroke remains unknown. Herein, we found that NK cells infiltrated the ischemic lesions of the human brain. In a mouse model of cerebral ischemia, ischemic neuron-derived fractalkine recruited NK cells, which subsequently determined the size of brain lesions in a T and B cell-independent manner. NK cell-mediated exacerbation of brain infarction occurred rapidly after ischemia via the disruption of NK cell tolerance, augmenting local inflammation and neuronal hyperactivity. Therefore, NK cells catalyzed neuronal death in the ischemic brain.
Gan, Yan; Liu, Qiang; Wu, Wei; Yin, Jun-Xiang; Bai, Xue-Feng; Shen, Rulong; Wang, Yongjun; Chen, Jieli; La Cava, Antonio; Poursine-Laurent, Jennifer; Yokoyama, Wayne; Shi, Fu-Dong
Induction of reproducible brain infarction by photochemically initiated thrombosis.
We have used a photochemical reaction in vivo to induce reproducible thrombosis leading to cerebral infarction in rats. After the intravenous injection of rose bengal, a potent photosensitizing dye, an ischemic lesion was formed by irradiating the left parietal convexity of the exposed skull for 20 minutes with green light (560 nm) from a filtered xenon arc lamp. Animals were allowed to survive from 30 minutes to 15 days after irradiation. Early microscopic alterations within the irradiated zone included the formation of thrombotic plugs and adjacent red blood cell stasis within pial and parenchymal vessels. Scanning electron microscopy revealed frequent platelet aggregates adhering to the vascular endothelium, often resulting in vascular occlusion. Carbon-black brain perfusion demonstrated that occlusion of vascular channels progressed after irradiation and was complete within 4 hours. Histopathological examination at 1, 5, and 15 days revealed that the associated infarct evolved reproducibly through several characteristic stages, including a phase of massive macrophage infiltration. Although cerebral infarction in this model is initiated by thrombosis of small blood vessels, the fact that the main pathological features of stroke are consistently reproduced should permit its use in assessing treatment regimens. Further, the capability of producing infarction in preselected cortical regions may facilitate the study of behavioral, functional, and structural consequences of acute and chronic stroke. PMID:4004172
Watson, B D; Dietrich, W D; Busto, R; Wachtel, M S; Ginsberg, M D
Metabolic penumbra of acute brain infarction: a correlation with infarct growth.
Volume expansion associated with brain infarction occurs in perfusion-diffusion mismatch of magnetic resonance imaging. We aimed at elucidating the metabolic impairment of this phenomenon with (15)O positron emission tomography and perfusion and diffusion magnetic resonance imaging. Eleven patients with acute unilateral embolic occlusion of the internal carotid or middle cerebral artery were studied within 6 hours of onset. Regional cerebral blood flow and cerebral metabolic rate of oxygen (CMRO(2)) were compared with those in the contralateral cerebral hemisphere. The relative apparent diffusion coefficient of water was estimated as a marker of cytotoxic edema. Relative cerebral blood flow and relative CMRO(2) in an evolving infarct (normal diffusion initially, but abnormal on day 3) were significantly (p < 0.05) less than those in the periinfarct area (normal diffusion initially and on day 3). The relative apparent diffusion coefficient between the evolving infarct and periinfarct showed no significant difference. These findings indicated that the initial 3-day volume expansion of an embolic brain infarction was associated with disturbed CMRD(2) but not with cytotoxic edema as early as 6 hours after onset. The "metabolic penumbra" defined as normal water diffusion with depressed CMRO(2) is a target to reduce the volume expansion of brain infarction. PMID:15786459
Shimosegawa, Eku; Hatazawa, Jun; Ibaraki, Masanobu; Toyoshima, Hideto; Suzuki, Akifumi
Watershed infarcts in the brain caused by microemboli.
Multiple vascular occlusions are frequently found in the leptomeningeal arteries over watershed infarcts in the brain. These occlusions have largely been interpreted as thrombi secondary to slowing of the blood flow. This report suggests that most of the occlusions are microemboli, which may lodge preferentially in these areas, and that they are the cause of the infarcts rather than secondary events. These suggestions are based upon the analysis of three groups of patients. The first group consists of four cases, two of which had atheromatous masses and the other two, tumor emboli in the overlying leptomeningeal arteries. These cases prove beyond doubt that microemboli can lodge preferentially in the watershed areas and cause infarcts in the brain. The second group consists of the cases of watershed infarcts that were precipitated by hypotensive episodes. Only one of these showed occlusion of the overlying arteries, although all of them obviously had slowing of the blood flow during the acute phase. These cases thus discredit the concept that stagnation thrombosis is a frequent event. Finally, three cases with watershed infarcts and vascular occlusions interpreted as platelet microemboli are presented to demonstrate different pathogenetic mechanisms effective in the process of embolization. PMID:7168920
Torvik, A; Skullerud, K
Aortic Graft Infection as a Cause of Multiple Brain Infarcts
Brain embolism of cardiac origin is common in clinical practice. However, embolic brain infarcts due to aortic graft infection are very rare. We present a case of a 53-year-old woman with multiple brain infarcts, following an infection of ascending aortic graft. She was presented with fever and acute onset neurological deficit, and she had a previous history of replacement of ascending aorta with a prosthetic graft, because of aortic aneurysm 2 years before her admission. The patient had positive blood cultures and echocardiographic evidence of vegetation in the graft aortic joint, nearby the aortic valves. Despite the severe clinical condition and the poor prognosis, because of the coexistence of cardioembolism and aortic graft infection, our patient had a good outcome with conservative treatment and she will be considered for surgical graft replacement after her full recovery.
Tsirka, Vassiliki; Maletic, Jelena; Ioannidis, Panagiotis; Karacostas, Dimitrios
Relationship between silent brain infarction and chronic kidney disease
Background. The presence of silent brain infarction (SBI) increases the risk of symptomatic stroke and dementia. The associationbetweenSBIandchronickidneydisease(CKD) has not been clarified. Moreover, little is known about what factors are related to SBI in CKD patients and whether the prevalence of SBI differs in CKD stage or cause of CKD. Methods. This is a cross-sectional study. A total of 375
Mayumi Kobayashi; Nobuhito Hirawa; Keisuke Yatsu; Yusuke Kobayashi; Yuichiro Yamamoto; Sanae Saka; Daisaku Andoh; Yoshiyuki Toya; Gen Yasuda; Satoshi Umemura
The 'silence' of silent brain infarctions may be related to chronic ischemic preconditioning and nonstrategic locations rather than to a small infarction size
OBJECTIVE: Silent brain infarctions are the silent cerebrovascular events that are distinguished from symptomatic lacunar infarctions by their 'silence'; the origin of these infarctions is still unclear. This study analyzed the characteristics of silent and symptomatic lacunar infarctions and sought to explore the mechanism of this 'silence'. METHODS: In total, 156 patients with only silent brain infarctions, 90 with only symptomatic lacunar infarctions, 160 with both silent and symptomatic lacunar infarctions, and 115 without any infarctions were recruited. Vascular risk factors, leukoaraiosis, and vascular assessment results were compared. The National Institutes of Health Stroke Scale scores were compared between patients with only symptomatic lacunar infarctions and patients with two types of infarctions. The locations of all of the infarctions were evaluated. The evolution of the two types of infarctions was retrospectively studied by comparing the infarcts on the magnetic resonance images of 63 patients obtained at different times. RESULTS: The main risk factors for silent brain infarctions were hypertension, age, and advanced leukoaraiosis; the main factors for symptomatic lacunar infarctions were hypertension, atrial fibrillation, and atherosclerosis of relevant arteries. The neurological deficits of patients with only symptomatic lacunar infarctions were more severe than those of patients with both types of infarctions. More silent brain infarctions were located in the corona radiata and basal ganglia; these locations were different from those of the symptomatic lacunar infarctions. The initial sizes of the symptomatic lacunar infarctions were larger than the silent brain infarctions, whereas the final sizes were almost equal between the two groups. CONCLUSIONS: Chronic ischemic preconditioning and nonstrategic locations may be the main reasons for the 'silence' of silent brain infarctions.
Feng, Chao; Bai, Xue; Xu, Yu; Hua, Ting; Liu, Xue-Yuan
Polymorphism of angiotensinogen gene M235T in myocardial infarction and brain infarction: a meta-analysis.
The angiotensinogen (AGT) gene M235T polymorphism has been reported to be associated with myocardial infarction (MI) and brain infarction (BI), but the results remain inconclusive. This meta-analysis was designed to clarify these controversies. Electronic databases were systematically searched before February 2013. A total of 38 studies with 17304 subjects met our inclusion criteria. In East Asian group, significant association was found between AGT M235T polymorphism and risk of MI (for dominant model: OR=1.79; 95% CI=1.04-3.06; for recessive model OR=2.01; 95% CI=1.21-3.36; for additive model OR=1.79; 95% CI=1.14-2.86) as well as BI (for dominant model: OR=1.66; 95% CI=1.22-2.27; for recessive model OR=1.78, 95% CI=1.29-2.46; for additive model: OR=1.64, 95% CI=1.34-2.00), while the M235T polymorphism did not impact the risk of MI in total population and other ethnicity. In the subgroup analyses by gender and age, there was lack of evidence for the association. This meta-analysis suggested an association between the M235T polymorphism and MI as well as BI in East Asian population. Further studies with larger numbers of worldwide participants are needed to understand the genetic basis of MI and BI. PMID:23933419
Liang, Xinyue; Qiu, Jie; Liu, Xiangju; Li, Xiao; Zhao, Shaohua; Wang, Jing; Ma, Yabing; Gao, Haiqing
Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts
Background and Purpose Atrial fibrillation (AF) has been associated with cognitive decline independant of stroke, suggesting additional effects of AF on the brain. We aimed to assess the association between AF and brain function and structure in a general elderly population. Methods This is a cross-sectional analysis on 4251 non-demented participants (mean age 76 ± 5 years) in the population-based AGES-Reykjavik Study. Medical record data were collected on the presence, subtype and time from first diagnosis of AF; 330 participants had AF. Brain volume measurements, adjusted for intracranial volume, and presence of cerebral infarcts were determined with MRI. Memory, speed of processing and executive function composites were calculated from a cognitive test battery. In a multivariable linear regression model, adjustments were made for demographic, cardiovascular risk factors and cerebral infarcts. Results Participants with AF had lower total brain volume compared to those without AF (p<0.001). The association was stronger with persistent/permanent than paroxysmal AF and with increased time from the first diagnosis of the disease. Of the brain tissue volumes, AF was associated with lower volume of gray and white matter (p<0.001 and p=0.008 respectively) but not of white matter hyperintesities (p=0.49). Participants with AF scored lower on tests on memory. Conclusions AF is associated with smaller brain volume and the association is stronger with increasing burden of the arrhythmia. These findings suggest that AF has a cumulative negative effect on the brain independent of cerebral infarcts.
Stefansdottir, Hrafnhildur; Arnar, David O.; Aspelund, Thor; Sigurdsson, Sigurdur; Jonsdottir, Maria K.; Hjaltason, Haukur; Launer, Lenore J.; Gudnason, Vilmundur
Prolonged Exposure to Isoflurane Ameliorates Infarction Severity in the Rat Pup Model of Neonatal Hypoxia-Ischemia
The neonatal hypoxia-ischemia rat model referred to as the Rice–Vannucci model is extensively used to study perinatal hypoxia-ischemia\\u000a and child brain injury. One of the major weaknesses of this model is its inconsistency of brain infarction among animals.\\u000a We hypothesize that the inconsistency of infarction is caused by prolonged operation time and therefore isoflurane exposure.\\u000a Neonatal hypoxia-ischemia was induced in
Hank Chen; Michael Burris; Adrain Fajilan; Fred Spagnoli; John H. Zhang; Jiping Tang
Immunological Profile of Silent Brain Infarction and Lacunar Stroke
Neuroinflammation is believed to be involved in the pathophysiological mechanisms of silent brain infarcts (SBI). However, the immunological profile of SBI has been scarcely investigated. In the context of a national research project named SILENCE, aimed at investigating clinical, biochemical and pathogenic features of SBI, we have measured the plasma profile of some inflammatory-related molecules in SBI patients (n?=?21), patients with recent lacunar infarcts (LI, n?=?28) and healthy controls (n?=?31), consecutively enrolled in four Italian centres. A panel of chemokines (MIG, CTACK, IL16, SDF1a, MCP1), growth factors (SCF, SCGFb, HGF, IL3), immunoglobulin-type adhesion molecules (ICAM1, VCAM1), proinflammatory cytokines (IL18, INFa2, MIF, IL12p40), cell surface receptors on T-cells (IL2Ra), and inductors of apoptosis (TRAIL) was assessed in plasma samples by Luminex xMAP™ technology. Immunological parameters were compared using non-parametric statistics and performance to distinguish SBI and LI was evaluated by receiver operating characteristic (ROC) analysis. Plasma levels of ICAM1 were significantly higher in both SBI and LI patients as compared to controls (SBI?LI>Ctrl). A different trend was observed for IL16 (SBI
Chiasserini, Davide; Eusebi, Paolo; Tantucci, Michela; Di Piero, Vittorio; Altieri, Marta; Marini, Carmine; Russo, Tommasina; Silvestrini, Mauro; Paolino, Isabella; Calabresi, Paolo; Parnetti, Lucilla
Silent brain infarcts and the risk of dementia and cognitive decline
BACKGROUND: Silent brain infarcts are frequently seen on magnetic\\u000a resonance imaging (MRI) in healthy elderly people and may be associated\\u000a with dementia and cognitive decline. METHODS: We studied the association\\u000a between silent brain infarcts and the risk of dementia and cognitive\\u000a decline in 1015 participants of the prospective, population-based\\u000a Rotterdam Scan Study, who were 60 to 90 years of age
Sarah E. Vermeer; Niels D. Prins; Tom den Heijer; P. J. Koudstaal; M. M. B. Breteler; A. Hofman
Epidemiology and characteristics of occipital brain infarcts in young adults in southwestern Finland
Occipital stroke and occipital epilepsy are possible manifestations of mitochondrial diseases. A previous study in northern\\u000a Finland suggested a frequency of 10% for mitochondrial disorder in young patients with stroke. Here we studied the epidemiology\\u000a of occipital brain infarcts in a defined population in southwestern Finland. Patients diagnosed with brain infarct or visual\\u000a field defect with onset at the ages
Mika H. Martikainen; Kari Majamaa
Immunological profile of silent brain infarction and lacunar stroke.
Neuroinflammation is believed to be involved in the pathophysiological mechanisms of silent brain infarcts (SBI). However, the immunological profile of SBI has been scarcely investigated. In the context of a national research project named SILENCE, aimed at investigating clinical, biochemical and pathogenic features of SBI, we have measured the plasma profile of some inflammatory-related molecules in SBI patients (n?=?21), patients with recent lacunar infarcts (LI, n?=?28) and healthy controls (n?=?31), consecutively enrolled in four Italian centres. A panel of chemokines (MIG, CTACK, IL16, SDF1a, MCP1), growth factors (SCF, SCGFb, HGF, IL3), immunoglobulin-type adhesion molecules (ICAM1, VCAM1), proinflammatory cytokines (IL18, INFa2, MIF, IL12p40), cell surface receptors on T-cells (IL2Ra), and inductors of apoptosis (TRAIL) was assessed in plasma samples by Luminex xMAP™ technology. Immunological parameters were compared using non-parametric statistics and performance to distinguish SBI and LI was evaluated by receiver operating characteristic (ROC) analysis. Plasma levels of ICAM1 were significantly higher in both SBI and LI patients as compared to controls (SBI?LI>Ctrl). A different trend was observed for IL16 (SBI
Sarchielli, Paola; Nardi, Katiuscia; Chiasserini, Davide; Eusebi, Paolo; Tantucci, Michela; Di Piero, Vittorio; Altieri, Marta; Marini, Carmine; Russo, Tommasina; Silvestrini, Mauro; Paolino, Isabella; Calabresi, Paolo; Parnetti, Lucilla
Physiological Correlates of Intellectual Function in Children with Sickle Cell Disease: Hypoxaemia, Hyperaemia and Brain Infarction
ERIC Educational Resources Information Center
Lowered intelligence relative to controls is evident by mid-childhood in children with sickle cell disease. There is consensus that brain infarct contributes to this deficit, but the subtle lowering of IQ in children with normal MRI scans might be accounted for by chronic systemic complications leading to insufficient oxygen delivery to the brain.…
Hogan, Alexandra M.; Pit-ten Cate, Ineke M.; Vargha-Khadem, Faraneh; Prengler, Mara; Kirkham, Fenella J.
Surgery-Related Thrombosis Critically Affects the Brain Infarct Volume in Mice Following Transient Middle Cerebral Artery Occlusion
Transient middle cerebral artery occlusion (tMCAO) model is widely used to mimic human focal ischemic stroke in order to study ischemia/reperfusion brain injury in rodents. In tMCAO model, intraluminal suture technique is widely used to achieve ischemia and reperfusion. However, variation of infarct volume in this model often requires large sample size, which hinders the progress of preclinical research. Our previous study demonstrated that infarct volume was related to the success of reperfusion although the reason remained unclear. The aim of present study is to explore the relationship between focal thrombus formation and model reproducibility with respect to infarct volume. We hypothesize that suture-induced thrombosis causes infarct volume variability due to insufficient reperfusion after suture withdrawal. Seventy-two adult male CD-1 mice underwent 90 minutes of tMCAO with or without intraperitoneal administration of heparin. Dynamic synchrotron radiation microangiography (SRA) and laser speckle contrast imaging (LSCI) were performed before and after tMCAO to observe the cerebral vascular morphology and to measure the cerebral blood flow in vivo. Infarct volume and neurological score were examined to evaluate severity of ischemic brain injury. We found that the rate of successful reperfusion was much higher in heparin-treated mice compared to that in heparin-free mice according to the result of SRA and LSCI at 1 and 3 hours after suture withdrawal (p<0.05). Pathological features and SRA revealed that thrombus formed in the internal carotid artery, middle cerebral artery or anterior cerebral artery, which blocked reperfusion following tMCAO. LSCI showed that cortical collateral circulation could be disturbed by thrombi. Our results demonstrated that suture-induced thrombosis was a critical element, which affects the success of reperfusion. Appropriate heparin management provides a useful approach for improving reproducibility of reperfusion model in mice.
Lin, Xiaojie; Miao, Peng; Wang, Jixian; Yuan, Falei; Guan, Yongjing; Tang, Yaohui; He, Xiaosong; Wang, Yongting; Yang, Guo-Yuan
The influence of meteorological and geomagnetic factors on acute myocardial infarction and brain stroke in Moscow, Russia.
Evidence of the impact of air temperature and pressure on cardiovascular morbidity is still quite limited and controversial, and even less is known about the potential influence of geomagnetic activity. The objective of this study was to assess impacts of air temperature, barometric pressure and geomagnetic activity on hospitalizations with myocardial infarctions and brain strokes. We studied 2,833 myocardial infarctions and 1,096 brain strokes registered in two Moscow hospitals between 1992 and 2005. Daily event rates were linked with meteorological and geomagnetic conditions, using generalized linear model with controls for day of the week, seasonal and long-term trends. The number of myocardial infarctions decreased with temperature, displayed a U-shaped relationship with pressure and variations in pressure, and increased with geomagnetic activity. The number of strokes increased with temperature, daily temperature range and geomagnetic activity. Detrimental effects on strokes of low pressure and falling pressure were observed. Relative risks of infarctions and strokes during geomagnetic storms were 1.29 (95 % CI 1.19-1.40) and 1.25 (1.10-1.42), respectively. The number of strokes doubled during cold spells. The influence of barometric pressure on hospitalizations was relatively greater than the influence of geomagnetic activity, and the influence of temperature was greater than the influence of pressure. Brain strokes were more sensitive to inclement weather than myocardial infarctions. This paper provides quantitative estimates of the expected increases in hospital admissions on the worst days and can help to develop preventive health plans for cardiovascular diseases. PMID:23700198
Shaposhnikov, Dmitry; Revich, Boris; Gurfinkel, Yuri; Naumova, Elena
Prolonged exposure to isoflurane ameliorates infarction severity in the rat pup model of neonatal hypoxia-ischemia.
The neonatal hypoxia-ischemia rat model referred to as the Rice-Vannucci model is extensively used to study perinatal hypoxia-ischemia and child brain injury. One of the major weaknesses of this model is its inconsistency of brain infarction among animals. We hypothesize that the inconsistency of infarction is caused by prolonged operation time and therefore isoflurane exposure. Neonatal hypoxia-ischemia was induced in postnatal days 7 and 10 rat pups by unilateral right common carotid ligation followed by 2.5 h of hypoxia (8% oxygen). The incision-to-ligation (ITL) was defined as the amount of time from initial incision (4 min after 2% isoflurane exposure) to completion of carotid ligation (at which point isoflurane exposure was also terminated). In the first part of the study, the ITL of each group was designated to be 5, 13, and 21 min. In the second part of the study, the ITL is designated to 4 min; however, continued isoflurane was used to make 5, 13, and 21 min isoflurane exposure for each group. Percentages of brain infarction were assessed at 48 h following surgery. Motor deficits were accessed by Rotarod test. Marked brain infarction was observed in the 5-min ITL group and a decrease of brain infarction observed in the 13-and 21-min groups (P<0.05). In the second part of the study, marked brain infarction was observed in the 5-min isoflurane exposure group, and a decrease of brain infarction was observed in each of the 13- and 21-min isoflurane exposure groups (P<0.05). Similar tendencies were observed in Rotarod tests than 5-min ITL and 5-min isoflurane groups showed more marked deficits (P<0.05). This study demonstrated that brain infarction inconsistency of the neonatal hypoxia-ischemia rat pup model is related to the operation time. The observed time-dependent decrease of brain infarction is correlated to the isoflurane exposure time. Shorter operation and isoflurane exposure improves this model consistency of brain infarction and motor deficits. PMID:21892364
Chen, Hank; Burris, Michael; Fajilan, Adrain; Spagnoli, Fred; Tang, Jiping; Zhang, John H
The effect of butylphthalide on the brain edema, blood-brain barrier of rats after focal cerebral infarction and the expression of rho a.
The aim of this study was to explore the effect of butylphthalide on the brain edema, blood-brain barrier of rats of rats after focal cerebral infarction and the expression of Rho A. A total of 195 sprague-dawley male rats were randomly divided into control group, model group, and butylphthalide group (40 mg/kg, once a day, by gavage). The model was made by photochemical method. After surgery 3, 12, 24, 72, and 144 h, brain water content was done to see the effect of butylphthalide for the cerebral edema. Evans blue extravasation method was done to see the changes in blood-brain barrier immunohistochemistry, and Western blot was done to see the expression of Rho A around the infarction. Compared with the control group, the brain water content of model group and butylphthalide group rats was increased, the permeability of blood-brain barrier of model group and butylphthalide group rats was increased, and the Rho A protein of model group and butylphthalide group rats was increased. Compared with the model group, the brain water content of butylphthalide group rats was induced (73.67 ± 0.67 vs 74.14 ± 0.46; 74.89 ± 0.57 vs 75.61 ± 0.52; 77.49 ± 0.34 vs 79.33 ± 0.49; 76.31 ± 0.56 vs 78.01 ± 0.48; 72.36 ± 0.44 vs 73.12 ± 0.73; P < 0.05), the permeability of blood-brain barrier of butylphthalide group rats was induced (319.20 ± 8.11 vs 394.60 ± 6.19; 210.40 ± 9.56 vs 266.40 ± 7.99; 188.00 ± 9.22 vs 232.40 ± 7.89; 288.40 ± 7.86 vs 336.00 ± 6.71; 166.60 ± 6.23 vs 213.60 ± 13.79; P < 0.05), and the Rho A protein of butylphthalide group rats was decreased (western blot result: 1.2230 ± 0.0254 vs 1.3970 ± 0.0276; 1.5985 ± 0.0206 vs 2.0368 ± 0.0179; 1.4229 ± 0.0167 vs 1.7930 ± 0.0158;1.3126 ± 0.0236 vs 1.5471 ± 0.0158; P < 0.05). The butylphthalide could reduce the brain edema, protect the blood-brain barrier, and decrease the expression of Rho A around the infarction. PMID:24442989
Hu, Jinyang; Wen, Qingping; Wu, Yue; Li, Baozhu; Gao, Peng
Significant association of metabolic syndrome with silent brain infarction in elderly people
A silent brain infarction (SBI) can predict clinical overt stroke or dementia. Studies focusing on the elderly population,\\u000a where SBI is most common, are sparse. We examined the associations between SBI and metabolic syndrome (MetS) in healthy elderly\\u000a individuals. Neurologically healthy subjects (1,254 persons, 723 males) aged ?65 years who underwent brain MRI were evaluated.\\u000a MetS was diagnosed following the AHA\\/NHLBI-2005
Hyung-Min Kwon; Beom Joon Kim; Jin-Ho Park; Wi-Sun Ryu; Chi-Kyung Kim; Su-Ho Lee; Sang-Bae Ko; Hyunwoo Nam; Seung-Hoon Lee; Yong-Seok Lee; Byung-Woo Yoon
Metabolic Syndrome as an Independent Risk Factor of Silent Brain Infarction in Healthy People
Background and Purpose—Metabolic syndrome (MetS) is associated with an increased risk of the subsequent development of cardiovascular disease or stroke. Moreover, a silent brain infarction (SBI) can predict clinical overt stroke or dementia. We examined the associations between SBI and MetS in apparently healthy individuals. Methods—We evaluated 1588 neurologically healthy subjects (927 males and 661 females) who underwent brain MRI
Hyung-Min Kwon; Beom Joon Kim; Seung-Hoon Lee; Seung Ho Choi; Byung-Hee Oh; Byung-Woo Yoon
Cardiomyocyte Transplantation in a Porcine Myocardial Infarction Model
Transplantation of cardiomyocytes into the heart is a potential treatment for replacing damaged cardiac muscle. To investigate the feasibility and efficiency of this technique, either a cardiac-derived cell line (HL-1 cells), or normal fetal or neonatal pig cardiomyocytes were grafted into a porcine model of myocardial infarction. The myocardial infarction was created by the placement of an embolization coil in
Eiichi Watanabe; Duane M Smith; Joseph B Delcarpio; Jian Sun; Frank W Smart; Clifford H Van Meter; William C Claycomb
A simple brain atrophy measure improves the prediction of malignant middle cerebral artery infarction by acute DWI lesion volume.
In patients with malignant middle cerebral artery infarction (MMI) decompressive surgery within 48 h improves functional outcome. In this respect, early identification of patients at risk of developing MMI is crucial. While the acute diffusion weighted imaging (DWI) lesion volume was found to predict MMI with high predictive values, the potential impact of preexisting brain atrophy on the course of space-occupying middle cerebral artery (MCA) infarction and the development of MMI remains unclear. We tested the hypothesis that the combination of the acute DWI lesion volume with simple measures of brain atrophy improves the early prediction of MMI. Data from a prospective, multicenter, observational study, which included patients with acute middle cerebral artery main stem occlusion studied by MRI within 6 h of symptom onset, was analyzed retrospectively. The development of MMI was defined according to the European randomized controlled trials of decompressive surgery. Acute DWI lesion volume, as well as brain and cerebrospinal fluid volume (CSF) were delineated. The intercaudate distance (ICD) was assessed as a linear brain atrophy marker by measuring the hemi-ICD of the intact hemisphere to account for local brain swelling. Binary logistic regression analysis was used to identify significant predictors of MMI. Cut-off values were determined by Classification and Regression Trees analysis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the resulting models were calculated. Twenty-one (18 %) of 116 patients developed a MMI. Malignant middle cerebral artery infarctions patients had higher National Institutes of Health Stroke Scale scores on admission and presented more often with combined occlusion of the internal carotid artery and MCA. There were no differences in brain and CSF volume between the two groups. Diffusion weighted imaging lesion volume was larger (p < 0.001), while hemi-ICD was smaller (p = 0.029) in MMI patients. Inclusion of hemi-ICD improved the prediction of MMI. Best cut-off values to predict the development of MMI were DWI lesion volume > 87 ml and hemi-ICD ? 9.4 mm. The addition of hemi-ICD to the decision tree strongly increased PPV (0.93 vs. 0.70) resulting in a reduction of false positive findings from 7/23 (30 %) to 1/15 (7 %), while there were only slight changes in specificity, sensitivity and NPV. The absolute number of correct classifications increased by 4 (3.4 %). The integration of hemi-ICD as a linear marker of brain atrophy, that can easily be assessed in an emergency setting, may improve the prediction of MMI by lesion volume based predictive models. PMID:24687898
Beck, Christoph; Kruetzelmann, Anna; Forkert, Nils D; Juettler, Eric; Singer, Oliver C; Köhrmann, Martin; Kersten, Jan F; Sobesky, Jan; Gerloff, Christian; Fiehler, Jens; Schellinger, Peter D; Röther, Joachim; Thomalla, Götz
Accumulated Mannitol and Aggravated Cerebral Edema in a Rat Model of Middle Cerebral Artery Infarction
Objective Repeated administration of mannitol in the setting of large hemispheric infarction is a controversial and poorly defined therapeutic intervention. This study was performed to examine the effects of multiple-dose mannitol on a brain edema after large hemispheric infarction. Methods A middle cerebral artery was occluded with the rat suture model for 6 hours and reperfused in 22 rats. The rats were randomly assigned to either control (n=10) or the mannitol-treated group (n=12) in which intravenous mannitol infusions (0.8 g/kg) were performed six times every four hours. After staining a brain slice with 2,3,5-triphenyltetrazolium chloride, the weight of hemispheres, infarcted (IH) and contralateral (CH), and the IH/CH weight ratio were examined, and then hemispheric accumulation of mannitol was photometrically evaluated based on formation of NADH catalyzed by mannitol dehydrogenase. Results Mannitol administration produced changes in body weight of -7.6±1.1%, increased plasma osmolality to 312±8 mOsm/L. It remarkably increased weight of IH (0.77±0.06 gm versus 0.68±0.03 gm : p<0.01) and the IH/CH weight ratio (1.23±0.07 versus 1.12±0.05 : p<0.01). The photometric absorption at 340 nm of the cerebral tissue in the mannitol-treated group was increased to 0.375±0.071 and 0.239±0.051 in the IH and CH, respectively from 0.167±0.082 and 0.162±0.091 in the IH and CH of the control group (p<0.01). Conclusion Multiple-dose mannitol is likely to aggravate cerebral edema due to parenchymal accumulation of mannitol in the infarcted brain tissue.
Cho, Jaeman; Kim, Yeon-Hee; Han, Hyung Soo
Anticoagulation management of myocardial infarction after deep brain stimulation: a comparison of two cases.
Deep brain stimulation (DBS) is an established treatment of various diseases, particularly used for idiopathic Parkinson's disease. Frequently, DBS patients are multimorbid and managing them may be challenging, since postoperative complications can become more likely with age. In this article, we present two cases of myocardial infarction after DBS with different therapeutic strategies. Case 1 was anticoagulated with a heparin infusion with a target partial thromboplastine time (PTT) between 50 and 60 s after the myocardial infarction and showed 3 days later, after an initial postoperative inconspicuous cranial computer tomography, an intracerebral haematoma, which was evacuated without explanting the DBS lead. Case 2 was only treated with enoxaparine 40 mg s.c. twice a day after the myocardial infarction without any further complications. Both cases benefited from the DBS with respect to the motor fluctuations, but case 1 continued to suffer from psychomotor slowdown, mild hemiparesis of the left side, visual neglect and a gaze paresis. Unfortunately, there are no established guidelines or therapy recommendations for the management of such patients. An individual therapy regime is necessary for this patient population regarding the bleeding risk, the cardial risk and the symptoms of the patient. Retrospectively, the rejection of the intravenous application of heparin in case 2 seems to be the right decision. But regarding the small number of cases, it remains still an individual therapy. Further experience will help us to develop optimal therapy strategies for this patient population. PMID:23563744
Polanski, Witold; Koy, Jan; Juratli, Tareq; Wolz, Martin; Klingelhöfer, Lisa; Fauser, Mareike; Storch, Alexander; Schackert, Gabriele; Sobottka, Stephan B
Myocardial infarction and intramyocardial injection models in swine
Sustainable and reproducible large animal models that closely replicate the clinical sequelae of myocardial infarction (MI) are important for the translation of basic science research into bedside medicine. Swine are well accepted by the scientific community for cardiovascular research, and they represent an established animal model for preclinical trials for US Food and Drug Administration (FDA) approval of novel therapies. Here we present a protocol for using porcine models of MI created with a closed-chest coronary artery occlusion-reperfusion technique. This creates a model of MI encompassing the anteroapical, lateral and septal walls of the left ventricle. This model infarction can be easily adapted to suit individual study design and enables the investigation of a variety of possible interventions. This model is therefore a useful tool for translational research into the pathophysiology of ventricular remodeling and is an ideal testing platform for novel biological approaches targeting regenerative medicine. This model can be created in approximately 8–10 h.
McCall, Frederic C; Telukuntla, Kartik S; Karantalis, Vasileios; Suncion, Viky Y; Heldman, Alan W; Mushtaq, Muzammil; Williams, Adam R; Hare, Joshua M
Infarct Volume After Hyperacute Infusion of Hypertonic Saline in a Rat Model of Acute Embolic Stroke
Introduction Hypertonic saline (HS) can treat cerebral edema arising from a number of pathologic conditions. However, physicians are reluctant to use it during the first 24 h after stroke because of experimental evidence that it increases infarct volume when administered early after reperfusion. Here, we determined the effect of HS on infarct size in an embolic clot model without planned reperfusion. Methods A clot was injected into the internal carotid artery of male Wistar rats to reduce perfusion in the middle cerebral artery territory to less than 40 % of baseline, as monitored by laser-Doppler flowmetry. After 25 min, rats were randomized to receive 10 mL/kg of 7.5 % HS (50:50 chloride:acetate) or normal saline (NS) followed by a 0.5 mL/h infusion of the same solution for 22 h. Results Infarct volume was similar between NS and HS groups (in mm3: cortex 102 ± 65 mm3 vs. 93 ± 49 mm3, p = 0.72; caudoputamenal complex 15 ± 9 mm3 vs. 21 ± 14, p = 0.22; total hemisphere 119 ± 76 mm3 vs. 114 ± 62, p = 0.88, respectively). Percent water content was unchanged in the infarcted hemisphere (NS 81.6 ± 1.5 %; HS 80.7 ± 1.3 %, p = 0.16), whereas the HS-treated contralateral hemisphere was significantly dehydrated (NS 79.4 ± 0.8 %; HS 77.5 ± 0.8 %, p < 0.01). Conclusions HS reduced contralateral hemispheric water content but did not affect ipsilateral brain water content when compared to NS. Infarct volume was unaffected by HS administration at all evaluated locations.
Toung, Thomas J. K.; Gottschalk, Allan; Mirski, Marek A.; Koehler, Raymond C.
Evaluation and simplified measurement of infarct size by myocardial contrast echocardiography in a rat model of myocardial infarction
To test the feasibility and accuracy of myocardial contrast echocardiography (MCE) for predicting infarct size (IS) in a rat\\u000a model of myocardial infarction (MI) and to compare a simplified single plane-based measurement of IS with the conventional\\u000a three plane-based approach. Fifty male SD rats underwent left anterior descending artery ligation and were evaluated by MCE\\u000a 8 h post MI. IS was
Xianghui Chen; Kai Cui; Jiancheng Xiu; Huanbing Lin; Yi Lao; Biying Zhou; Feixue Liang; Daogang Zha; Jianping Bin; Yili Liu
Depressed glucose consumption at reperfusion following brain ischemia does not correlate with mitochondrial dysfunction and development of infarction: an in vivo positron emission tomography study.
Glucose consumption is severely depressed in the ischemic core, whereas it is maintained or even increased in penumbral regions during ischemia. Conversely, glucose utilization is severely reduced early after reperfusion in spite that glucose and oxygen are available. Experimental studies suggest that glucose hypometabolism might be an early predictor of brain infarction. However, the relationship between early glucose hypometabolism with later development of infarction remains to be further studied in the same subjects. Here, glucose consumption was assessed in vivo by positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG) in a rat model of ischemia/reperfusion. Perfusion was evaluated by PET with (13)NH(3) during and after 2-hour (h) middle cerebral artery occlusion, and (18)F-FDG was given after 2h of reperfusion. Brain infarction was evaluated at 24h. Mitochondrial oxygen consumption was examined ex vivo using a biochemical method. Cortical (18)F-FDG uptake was reduced by 45% and 25% in the ischemic core and periphery, respectively. However, substantial alteration of mitochondrial respiration was not apparent until 24h, suggesting that mitochondria retained the ability to consume oxygen early after reperfusion. These results show reduced glucose use at early reperfusion in regions that will later develop infarction and, to a lesser extent, in adjacent regions. Depressed glucose metabolism in the ischemic core might be attributable to reduced metabolic requirement due to irreversible cellular injury. However, reduced glucose metabolism in peripheral regions suggests either an impairment of glycolysis or reduced glucose demand. Thus, our study supports that glycolytic depression early after reperfusion is not always related to subsequent development of infarction. PMID:19442156
Martín, Abraham; Rojas, Santiago; Pareto, Deborah; Santalucia, Tomŕs; Millán, Olga; Abasolo, Ibane; Gómez, Vanessa; Llop, Jordi; Gispert, Joan D; Falcon, Carles; Bargalló, Núria; Planas, Anna M
MAP2 immunostaining in thick sections for early ischemic stroke infarct volume in non-human primate brain
The delineation of early infarction in large gyrencephalic brain cannot be accomplished with triphenyl-tetrazolium chloride (TTC) due to its limitations in the early phase, nor can it be identified with microtubule-associated protein 2 (MAP2) immunohistochemistry, due to the fragility of large thin sections. We hypothesize that MAP2 immunostaining of thick brain sections can accurately identify early ischemia in the entire
Alexander Kharlamov; George C. LaVerde; Edwin M. Nemoto; Charles A. Jungreis; Victor E. Yushmanov; Stephen C. Jones; Fernando E. Boada
Cosmic rays as indicator of space weather influence on frequency of infarct myocardial, brain strokes, car and train accidents
NASA Astrophysics Data System (ADS)
By Dorman et al. (1999) was shown that CR Forbush-decreases can be considered as indicators of space phenomenon influence on the infarct myocardial, brain stroke, and car accident frequency. The obtained results are bigger than statistical errors in 4-7 times. In Dorman et al. (1999) we used daily averaged data on frequency of infarcts myocardial, brain strokes, and car accidents, obtained from ambulance organizations of Moscow for the period January 1979 December 1981 and of Leningrad (now St. Petersburg) for the period January 1987 December 1989. In the present researchwe will use monthly averaged data of infarct myocardial, brain stroke, and car accident frequencies as well as monthly data of train accident frequencies of two types (1-stcaused by the man factor, and the 2-nd ~@~S caused by the technological factorss) on the Siberian railways for the period 1 January 1986 ~@~S 30 November 1993. These daata allow us to estimate the possible connection of space weather changing (controlled by CR intensity and solar activity long-term variations) with frequency of people deceases (as infarcts myocardial and brain strokes), and car accidents as well as with frequency of train accidents caused by the man factor.
Dorman, L. I.; Iucci, N.; Ptitsyna, N. G.; Villoresi, G.
Post-Traumatic Cerebral Infarction : Outcome after Decompressive Hemicraniectomy for the Treatment of Traumatic Brain Injury
Objective Posttraumatic cerebral infarction (PTCI), an infarction in well-defined arterial distributions after head trauma, is a known complication in patients with severe head trauma. The primary aims of this study were to evaluate the clinical and radiographic characteristics of PTCI, and to assess the effect on outcome of decompressive hemicraniectomy (DHC) in patients with PTCI. Methods We present a retrospective analysis of 20 patients with PTCI who were treated between January 2003 and August 2005. Twelve patients among them showed malignant PTCI, which is defined as PTCI including the territory of Middle Cerebral Artery (MCA). Medical records and radiologic imaging studies of patients were reviewed. Results Infarction of posterior cerebral artery distribution was the most common site of PTCI. Fourteen patients underwent DHC an average of 16 hours after trauma. The overall mortality rate was 75%. Glasgow outcome scale (GOS) of survivors showed that one patient was remained in a persistent vegetative state, two patients were severely disabled and only two patients were moderately disabled at the time of discharge. Despite aggressive treatments, all patients with malignant PTCI had died. Malignant PTCI was the indicator of poor clinical outcome. Furthermore, Glasgow coma scale (GCS) at the admission was the most valuable prognostic factor. Significant correlation was observed between a GCS less than 5 on admission and high mortality (p<0.05). Conclusion In patients who developed non-malignant PTCI and GCS higher than 5 after head injury, early DHC and duroplasty should be considered, before occurrence of irreversible ischemic brain damage. High mortality rate was observed in patients with malignant PTCI or PTCI with a GCS of 3-5 at the admission. A large prospective randomized controlled study will be required to justify for aggressive treatments including DHC and medical treatment in these patients.
Ham, Hyung-Yong; Jang, Jae-Won; Seo, Bo-Ra; Kim, Jae-Hyoo; Choi, Jeong-Wook
Early menopause and the risk of silent brain infarction in community-dwelling elderly subjects: the Sefuri brain MRI study.
Our previous study showed that the male predominance of silent brain infarction (SBI) was largely because of higher prevalence of alcohol habit and smoking in men than in women. In the present study, we further conducted an analysis of brain magnetic resonance imaging findings to examine whether early menopause contributes to SBI in community-dwelling subjects. Women were queried as to the age and cause of menopause, the total number of children, and the age at giving birth to her last child. Among 306 female subjects aged 60 years or older, univariate analysis showed that early menopause (total or natural) was significantly associated with SBI but age at natural menopause, number of children, and age at the last parity were not. In the total of 715 subjects (283 men and 432 women with a mean age of 67.2 years), the forward stepwise method of logistic analysis revealed that natural early menopause (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.07-17.11), in addition to age, hypertension, alcohol intake, and smoking, was a significant factor concerning SBI. Also in the subgroup of female subjects aged 60 years or older, natural early menopause was a significant factor concerning SBI (OR 4.35, 95% CI 1.05-18.08) adjusted for covariates. Although the prevalence of natural early menopause was low (3.3% of 306 female subjects), natural menopause before the age of 40 years may be a risk for SBI or small-vessel disease of the brain. PMID:24045081
Fukuda, Kenji; Takashima, Yuki; Hashimoto, Manabu; Uchino, Akira; Yuzuriha, Takefumi; Yao, Hiroshi
Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats
Puerarin, a major isoflavonoid derived from the Chinese medical herb Radix puerariae (kudzu root), has been reported to be useful in the treatment of various cardiovascular diseases. In the present study, we examined the detailed mechanisms underlying the inhibitory effects of puerarin on inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAO) in rats. Treatment of puerarin (25 and 50 mg/kg; intraperitoneally) 10 min before MCAO dose-dependently attenuated focal cerebral ischemia in rats. Administration of puerarin at 50 mg/kg, showed marked reduction in infarct size compared with that of control rats. MCAO-induced focal cerebral ischemia was associated with increases in hypoxia-inducible factor-1? (HIF-1?), inducible nitric oxide synthase (iNOS), and active caspase-3 protein expressions as well as the mRNA expression of tumor necrosis factor-? (TNF-?) in ischemic regions. These expressions were markedly inhibited by the treatment of puerarin (50 mg/kg). In addition, puerarin (10~50 ?M) concentration-dependently inhibited respiratory bursts in human neutrophils stimulated by formyl-Met-Leu-Phe. On the other hand, puerarin (20~500 ?M) did not significantly inhibit the thiobarbituric acid-reactive substance reaction in rat brain homogenates. An electron spin resonance (ESR) method was conducted on the scavenging activity of puerarin on the free radicals formed. Puerarin (200 and 500 ?M) did not reduce the ESR signal intensity of hydroxyl radical formation. In conclusion, we demonstrate that puerarin is a potent neuroprotective agent on MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both HIF-1? and TNF-? activation, followed by the inhibition of inflammatory responses (i.e., iNOS expression), apoptosis formation (active caspase-3), and neutrophil activation, resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, puerarin treatment may represent a novel approach to lowering the risk of or improving function in ischemia-reperfusion brain injury-related disorders.
Chang, Yi; Hsieh, Cheng-Ying; Peng, Zi-Aa; Yen, Ting-Lin; Hsiao, George; Chou, Duen-Suey; Chen, Chien-Ming; Sheu, Joen-Rong
Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats.
Puerarin, a major isoflavonoid derived from the Chinese medical herb Radix puerariae (kudzu root), has been reported to be useful in the treatment of various cardiovascular diseases. In the present study, we examined the detailed mechanisms underlying the inhibitory effects of puerarin on inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAO) in rats. Treatment of puerarin (25 and 50 mg/kg; intraperitoneally) 10 min before MCAO dose-dependently attenuated focal cerebral ischemia in rats. Administration of puerarin at 50 mg/kg, showed marked reduction in infarct size compared with that of control rats. MCAO-induced focal cerebral ischemia was associated with increases in hypoxia-inducible factor-1alpha (HIF-1alpha), inducible nitric oxide synthase (iNOS), and active caspase-3 protein expressions as well as the mRNA expression of tumor necrosis factor-alpha (TNF-alpha) in ischemic regions. These expressions were markedly inhibited by the treatment of puerarin (50 mg/kg). In addition, puerarin (10-50 microM) concentration-dependently inhibited respiratory bursts in human neutrophils stimulated by formyl-Met-Leu-Phe. On the other hand, puerarin (20-500 microM) did not significantly inhibit the thiobarbituric acid-reactive substance reaction in rat brain homogenates. An electron spin resonance (ESR) method was conducted on the scavenging activity of puerarin on the free radicals formed. Puerarin (200 and 500 microM) did not reduce the ESR signal intensity of hydroxyl radical formation. In conclusion, we demonstrate that puerarin is a potent neuroprotective agent on MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both HIF-1alpha and TNF-alpha activation, followed by the inhibition of inflammatory responses (i.e., iNOS expression), apoptosis formation (active caspase-3), and neutrophil activation, resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, puerarin treatment may represent a novel approach to lowering the risk of or improving function in ischemia-reperfusion brain injury-related disorders. PMID:19272172
Chang, Yi; Hsieh, Cheng-Ying; Peng, Zi-Aa; Yen, Ting-Lin; Hsiao, George; Chou, Duen-Suey; Chen, Chien-Ming; Sheu, Joen-Rong
Myocardial infarction with aortic banding. A combined rat model of heart failure.
The effect of additional abdominal aortic banding on parameters of heart failure was studied in male Wistar rats with myocardial infarction. Contractile function was studied 8-9 weeks after operation, with an isoprenaline dose response protocol, in a retrograde Langendorff perfusion. Also, plasma noradrenaline concentration, infarct size and morphology were determined. Compared with controls, myocardial infarction/aortic banding animals showed a decreased contractile function, both at baseline and after maximal isoprenaline stimulation, and elevated noradrenaline levels (1316 +/- 94) vs 1909 +/- 174 pg/ml, both p < 0.05). In myocardial infarction rats, baseline values, but not those after inotropic stimulation were decreased, when compared with controls, while the calculated Emax was significantly decreased. In aortic banding rats, contractile parameters were not significantly impaired, compared with controls. Both myocardial infarction and the myocardial infarction/aortic banding animals, but not aortic banding rats, had a significantly increased heart weight (1.4 +/- 0.04 g for controls vs 1.7 +/- 0.08 g for myocardial infarction and 2.0 +/- 0.12 g for myocardial infarction/aortic banding), and left ventricular cavity volume (19 +/- 1.4 mm3 for controls vs 49 +/- 5.5 mm3 for myocardial infarction and 48 +/- 4.3 mm3 for myocardial infarction/aortic banding) compared to control animals. Infarct size was 36.0% and 39.4% for the myocardial infarction and myocardial infarction/aortic banding animals, respectively. We conclude that myocardial infarction/aortic banding provides a new experimental model, which may yield important information and pathophysiology which allow evaluation of changes that may mimic clinical myocardial infarction with concomitant hypertension. PMID:9462419
Anthonio, R L; van Veldhuisen, D J; Scholtens, E; van Bekkum, C; de Boer, E; van Gilst, W H
The blood-brain barrier to protein tracers in focal cerebral ischemia and infarction caused by occlusion of the middle cerebral artery
A study was made on the blood-brain barrier (BBB) to protein tracers in focal cerebral ischemia and infarction caused by permanent or temporary occlusion of the middle cerebral artery (MCA) in the rhesus monkey.
Yngve Olsson; Robert M. Crowell; Igor Klatzo
Effects of nitric oxide synthase inhibition on brain infarction in SOD-1-transgenic mice following transient focal cerebral ischemia.
To investigate the role of superoxide in the toxicity of nitric oxide (NO), we examined the effect of nitric oxide synthase (NOS) inhibition on brain infarction in transgenic mice overexpressing CuZn-superoxide dismutase (SOD-1). Male SOD-transgenic mice and non-transgenic littermates (30-35 g) were subjected to 60 min of middle cerebral artery occlusion followed by 24 h of reperfusion. Either NG-nitro-L-arginine methyl ester (L-NAME; 3 mg/kg), a mixed neuronal and endothelial NOS inhibitor, or 7-nitroindazole (7-NI; 25 mg/kg), a selective neuronal NOS inhibitor, was administered intraperitoneally 5 min after the onset of ischemia. At 24 h of reperfusion, the mice were decapitated and the infarct volume was evaluated in each group. In the nontransgenic mice, L-NAME significantly increased the infarct volume as compared with the vehicle, while 7-NI significantly decreased it. In the SOD-transgenic mice, L-NAME-treated animals showed a significantly larger infarct volume than vehicle-treated ones, whereas there were no significant differences between 7-NI- and vehicle-treated mice. Our findings suggest that selective inhibition of neuronal NOS ameliorates ischemic brain injury and that both neuronal and endothelial NOS inhibition may result in the deterioration of ischemic injury due to vasoconstriction of the brain. Since L-NAME increased infarct volume even in SOD-transgenic mice, the protective effect of SOD could result from the vasodilation by increased endothelial NO as well as the reduction of neuronal injury due to less production of peroxynitrite compared to wild-type mice. Moreover, the neurotoxic role of NO might not be dependent on NO itself, but the reaction with superoxide to form peroxynitrite, because of no additive effects of SOD and a neuronal NOS inhibitor. PMID:8898687
Kamii, H; Mikawa, S; Murakami, K; Kinouchi, H; Yoshimoto, T; Reola, L; Carlson, E; Epstein, C J; Chan, P H
Purinergic Receptor Stimulation Reduces Cytotoxic Edema and Brain Infarcts in Mouse Induced by Photothrombosis by Energizing Glial Mitochondria
Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5? diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y1R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP3)-dependent Ca2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries.
Zheng, Wei; Watts, Lora Talley; Holstein, Deborah M.; Prajapati, Suresh I.; Keller, Charles; Grass, Eileen H.; Walter, Christi A.; Lechleiter, James D.
[Experimental model of venous hemorrhagic infarction by cerebral sinus occlusion].
A new experimental model of the hemorrhagic infarction was devised to study the pathophysiology of the hemorrhagic infarction of the venous origin. To make a model of the hemorrhagic infarction by sinus occlusion, mixture of alpha-cyanoacrylate monomer and pantopaque was injected through a catheter introduced into the superior sagittal sinus in 15 dogs, using embolization technique. These dogs were divided into three groups according to the volume of the mixture injected into the sinus. In control groups (3 dogs), no mixture was injected. For partial sinus occlusion (5 dogs), 0.5-1.0 ml of mixture was injected into the sinus and 1.0-1.5 ml of mixture, for complete sinus occlusion (7 dogs). Changes of intracranial pressure (ICP), superior sagittal sinus pressure (SSSP), tissue pressure (TP) rCBF and histological changes were evaluated before and after sinus occlusion. The following results were obtained. (1) In control groups, ICP, SSSP and TP were 9 +/- 2.2 mmHg, 4 +/- 2.5 mmHg and 4-5 mmHg respectively, but in partial and complete sinus occlusion, SSSP and TP were higher than ICP. ICP, SSSP & TP were 32 +/- 5.4 mmHg, 35 +/- 6.5 mmHg and 37-42 mg, in partial sinus occlusion and 62 +/- 5.9 mmHg, 65 +/- 6.0 mmHg, 65-72 mmHg in complete sinus occlusion. (2) R-CBF in partial sinus occlusion showed no change even after sinus occlusion, but in complete sinus occlusion, decreased to 20% of that of the control group due to marked venous congestion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6504262
Fujita, K; Kojima, N; Matsumoto, S
Successful Treatment of Pulmonary Aspiration Due to Brain Stem Infarction by Using Cough Exercise Based on Swallowing Scintigraphy: Preliminary Observations
Although dysphagia in stroke may result in lethal chest infection, it can be prevented by coughing. We report on a patient\\u000a with dysphagia and aspiration who regained oral ingestion by swallowing with voluntary cough. A 54-year-old man with subarachnoidal\\u000a hemorrhage underwent endovascular coiling and developed brain stem infarction. Scintigraphy showed pulmonary aspiration just\\u000a after swallowing, but no radioactivity was detected
Naoko Kanai; Hitoshi Kurabayashi; Natsumi Nakamata; Etsuko Yamamoto; Akiko Hishinuma; Eiji Suzuki; Mitsuru Majima
Ischaemic infarct of the brain stem combined with bisymptomatic Klippel-Tr?naunay-Weber syndrome and cutis laxa.
The combination of Klippel-Trénaunay-Weber syndrome (KTWS) with intracranial vascular malformations is documented by angiography in a 25 year old man with the classical features of KTWS: systematized naevi, hypertrophy of the right side, and varicosis. In addition, the syndrome was associated with "cuts laxa", a coincidence of somar rarity. The patient suffered from an ischaemic infarct of the brain stem with several neurological deficits. Images
Alberti, E
The Seattle Post Myocardial Infarction Model (SPIM): prediction of mortality after acute myocardial infarction with left ventricular dysfunction
Aims: Ischemic heart disease is a leading worldwide cause of death. The Seattle Post Myocardial Infarction Model (SPIM) was developed to predict survival 6 months to 2 years after an acute myocardial infarction with evidence of left ventricular dysfunction. Methods and Results: A total of 6632 subjects from the EPHESUS trial were used to derive the predictive model, while 5477 subjects from the OPTIMAAL trial were used to validate the model. Cox proportional hazards modeling was used to develop a multivariate risk score predictive of all-cause mortality. The SPIM risk score integrated lab and vital parameters, Killip class, reperfusion or revascularization, the number of cardiac evidence-based medicines (aspirin, statin, ? blocker, ACEI/ARB, aldosterone blocker), and the number of cardiac risk factors. The model was predictive of all-cause mortality after myocardial infarction, with an AUC of 0.75 at 6 months and 0.75 at 2 years in the derivation cohort and 0.77 and 0.78 for the same time points in the validation cohort. Model predicted versus Kaplan-Meier observed survival was excellent in the derivation cohort. It remained so in the validation cohort—84.9% versus 85.0% at 2 years. The 10% of subjects with the highest predicted risk had approximately 25 times higher mortality at 2 years than the 10% of subjects with the lowest predicted risk. Conclusion: The SPIM score was a powerful predictor of outcomes after myocardial infarction with left ventricular dysfunction. Its highly accurate predictions should improve patient and physician understanding of survival and may prove a useful tool in post-infarct risk stratification.
Dickstein, Kenneth; Kjekshus, John; Pitt, Bertram; Wong, Meagan F; Linker, David T; Levy, Wayne C
Kinetic Models of Brain Activity
Brain imaging sciences, like neurosciences in general, have predominantly been an empirical endeavour. This paper argues that\\u000a the maturation of "kinetic models" of large-scale neuronal activity will provide a unifying theory to underpin brain imaging\\u000a sciences. In particular, this framework will provide a means of unifying data from different imaging modalities, afford a\\u000a direct link with cognitive theories of brain
Michael Breakspear; Stuart Knock
A minimally invasive method for induction of myocardial infarction in an animal model using tungsten spirals
Most animal models use surgical thoracotomy with ligation of a coronary artery to induce myocardial infarction. Incision of\\u000a the chest wall and myocardium affect remodeling after myocardial infarction. The aim of our study was to evaluate a new minimally\\u000a invasive technique for inducing acute myocardial infarction in pigs. To this end, coronary angiography using a 6-F cardiac\\u000a catheter was performed
Daniel Peukert; Michael Laule; Nicola Kaufels; Jörg Schnorr; Matthias Taupitz; Bernd Hamm; Marc Dewey
Clinical significance of detection of multiple acute brain infarcts on diffusion weighted magnetic resonance imaging
Background: Detection of multiple acute brain infarcts (MABI) by diffusion weighted magnetic resonance imaging (DWI) may provide information about stroke mechanism in (1) acute lacunar stroke, where evidence of MABI suggests a cause other than small artery disease (SAD), such as embolism or vasculitis (type 1 MABI); or (2) acute non-lacunar stroke, where MABI in the territory of at least two of the aortic branches supplying the brain indicates the presence of aortic or cardiac embolism rather than artery to artery embolism (type 2 MABI). Objective: To evaluate the prevalence of MABI and their impact on aetiological classification and prevention of stroke in patients with acute ischaemic stroke examined with DWI. Methods: 182 consecutive patients defined by DWI were evaluated. Stroke aetiology was classified according to the TOAST criteria, though "lacunar stroke" included patients with possible aetiologies other than SAD. Results: Type 1 MABI were detected in 21/72 patients (29%) with lacunar stroke, and type 2 MABI in 8/110 (7%) with non-lacunar stroke. A possible stroke mechanism different from SAD was found in nine type 1 MABI cases (43%): cardiac embolism (4); other determined aetiology (3); aortic embolism (2). Cardiac (2) or aortic (1) sources of embolism were detected in eight type 2 MABI cases. MABI patients with cardiac or aortic sources of embolism were treated with warfarin, the remainder with aspirin. Conclusions: Detection of type 1 MABI in patients with lacunar stroke improved diagnostic confidence and the choice of antithrombotic treatment. Further study is needed on stroke prevention in MABI cases caused by SAD alone.
Caso, V; Budak, K; Georgiadis, D; Schuknecht, B; Baumgartner, R
Relation of hyperglycemia early in ischemic brain infarction to cerebral anatomy, metabolism, and clinical outcome.
We studied the relation of serum glucose level measured in the first 12 hours of symptoms to the clinical findings, results of computed tomography (CT), and patterns of cerebral metabolism in 39 patients who had acute ischemic cerebral infarction. Structural damage was assessed by CT. Metabolic disruption was assessed using 18F-fluorodeoxyglucose and positron emission tomography (PET). Median initial serum glucose concentration was 155 mg/dl (6.7 mM). Clinical recovery was significantly poorer in patients with initial serum glucose levels higher than the median (p less than 0.05, chi square). PET tended to show normal results or minor abnormalities in patients with initial glucose levels less than the median, as opposed to lobar or multilobe abnormalities in patients with levels that were higher than the median (p less than 0.05, Kendall's Tau b). The severity of hypometabolism in the ischemic region, expressed as the percent asymmetry of local cerebral glucose metabolism between homologous brain regions, was greater in patients with initial glycemia concentrations higher than the median (p less than 0.001, t test). Relationships of serum glucose level with metabolic derangement and structural damage, but not outcome, held true in patients without a history of diabetes mellitus. PMID:2221843
Kushner, M; Nencini, P; Reivich, M; Rango, M; Jamieson, D; Fazekas, F; Zimmerman, R; Chawluk, J; Alavi, A; Alves, W
Late-onset Depression in the Absence of Stroke: Associated with Silent Brain Infarctions, Microbleeds and Lesion Locations
Background: Late-onset depression (LOD) is a frequent mood disorder among elderly. Previous studies have proved that LOD is associated with cerebral silent lesions especially white matter lesions (WML) and yielded the "vascular depression" hypothesis to explain the pathogenesis of LOD. However, there were relatively few studies about the association between silent brain infarctions (SBIs), microbleeds (MBs) and the prevalence of LOD. In this study we sought to evaluate the presence, accumulation and locations of SBIs and MBs, and explore the possible association between them and LOD. Methods: 65 patients of LOD diagnosed according to DSM-IV and 270 subjects of control group were enrolled and scanned by MRI to analyze the presence, numbers and locations of SBIs and MBs. Clinical and radiological characteristics were compared between LOD patients and control group. Logistic regression models were constructed to identify the independent risk factors for LOD. Results: LOD patients had higher prevalence and numbers of both SBIs and MBs. SBIs and MBs in the left hemisphere, SBIs in basal ganglia and lobar MBs were all independent risk factors for LOD. Conclusion: The presence of both SBIs and MBs were associated with a higher rate LOD. Lesions in some specific locations might be critical for the presence of LOD.
Wu, Ri-Han; Feng, Chao; Xu, Yu; Hua, Ting; Liu, Xue-Yuan; Fang, Min
Ginkgo biloba leaf extract (EGb761) combined with neuroprotective agents reduces the infarct volumes of gerbil ischemic brain.
Ginkgo biloba exerts many pharmacological actions. It possesses antioxidant properties, the ability of neurotransmitter/receptor modulation and antiplatelet activation factor. This research is designed to investigate the neuroprotective effects of long-term treatment with EGb761 (a standard form of the extract of Ginkgo biloba leaf) in combination with MgSO(4), FK506, or MK-801 on the infarct volume of male gerbils' brain induced by unilateral middle cerebral artery occlusion (MCAO). Thirty-five gerbils fed a standard diet were intragastrically given water or EGb761 (100 mg/kg/day) for one week. Five randomized groups were established: control (n = 7), EGb761 (n = 8), EGb761 + MgSO(4) (n = 7), EGb761 + FK506 (n = 7), and EGb761 + MK-801 (n = 6). The three drug-combination groups were injected with MgSO(4) (90 mg/kg), FK506 (0.5 mg/kg), or MK-801 (1 mg/kg), respectively 30 min before MCAO. Gerbils were anesthetized and craniectomized to expose the right middle cerebral artery (MCA). The right MCA was constricted with an 8-0 suture to produce a permanent ligation for 24 hours. Postmortem infarct volumes were determined by quantitative image analysis of 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections. Results showed that the total infarct volumes of the four treated groups either EGb761 alone or in combination with drugs were lower than the control group by 36.1% (EGb761 alone), 40.3% (EGb761 + MgSO(4)), 35.3% (EGb761 + FK506), and 56.4% (EGb761 + MK-801), respectively (p < 0.01). The main affected areas of the brain in the four treated groups were significantly focused between 4 and 6 mm from the frontal pole, when compared to the control group (p < 0.01). All animals in the five groups had infarctions in both cortex and subcortex. These results indicate that long-term pre-treatment of EGb761 administered either alone or in combination with drugs significantly effective neuroprotection on infarct volume in gerbil ischemic brains. PMID:17080546
Chung, Shu-Ying; Cheng, Fu-Chou; Lee, Ming-Shih; Lin, Jing-Ying; Lin, Ming-Cheng; Wang, Ming-Fu
Therapeutic Potential of Human Umbilical Cord Derived Stem Cells in a Rat Myocardial Infarction Model
Background. Cell transplantation offers the promise in the restoration of cardiac function after myocardial in- farction. We investigate the therapeutic potential of hu- man umbilical cord derived stem (UCDS) cells in a rat myocardial infarction model. Methods. Two weeks after induction of myocardial infarction, the surviving rats with left ventricular ejec- tion fraction less than 60% were randomly divided into
Kai Hong Wu; Bin Zhou; Cun Tao Yu; Bin Cui; Shi Hong Lu; Zhong Chao Han; Ying Long Liu
Risk of recurrent stroke in patients with silent brain infarction in the PRoFESS Imaging Substudy
Background and Purpose Silent brain infarctions are associated with an increased risk of stroke in healthy individuals. Risk of recurrent stroke in patients with both symptomatic and silent brain infarction (SBI) has only been investigated in patients with cardioembolic stroke in the European Atrial Fibrillation Trial. We assessed whether patients with recent non-cardioembolic stroke and SBI detected on MRI are at increased risk for recurrent stroke, other cardiovascular events, and mortality. Methods The prevalence of SBI detected on MRI was assessed in 1014 patients enrolled in the imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. The primary outcome was first recurrence of stroke in patients with both symptomatic stroke and SBI in comparison with age and sex matched stroke patients without SBI. Secondary outcomes were a combined vascular endpoint, other vascular events and mortality. The two groups were compared using conditional logistic regression. Results Silent brain infarction was detected in 207 (20.4%) patients of the 1014 patients. Twenty-seven (13.0%) patients with SBI and 19 (9.2%) without SBI had a recurrent stroke (odds ratio 1.42, 95% confidence interval 0.79 to 2.56; p=0.24) during a mean follow-op of 2.5 years. Similarly, there was no statistically significant difference for all secondary outcome parameters between patients with SBI and matched patients without SBI. Conclusion The presence of SBI in patients with recent mild non-cardioembolic ischemic stroke could not be shown to be an independent risk factor for recurrent stroke, other vascular events, or a higher mortality.
Weber, Ralph; Weimar, Christian; Wanke, Isabel; Moller-Hartmann, Claudia; Gizewski, Elke R.; Blatchford, Jon; Hermansson, Karin; Demchuk, Andrew M.; Forsting, Michael; Sacco, Ralph L.; Saver, Jeffrey L.; Warach, Steven; Diener, Hans Christoph; Diehl, Anke
Neuroprotective effects of focal brain cooling on photochemically-induced cerebral infarction in rats: analysis from a neurophysiological perspective.
Although systemic hypothermia provides favorable outcomes in stroke patients, it has only been adopted in a limited number of patients because of fatal complications. To resolve these issues, focal brain cooling (FBC) has recently drawn attention as a less-invasive treatment for brain injuries. Therefore, we investigated whether FBC has a favorable effect on focal cerebral ischemia (FCI). Male-adult-Wistar rats were used. Under general anesthesia, a small burr hole was made and FCI was induced in the primary sensorimotor area (SI-MI) using photothrombosis. An additional craniotomy was made over the SI-MI and FBC was performed at a temperature of 15°C for 5h. Electrocorticograms (ECoG) were recorded on the border cortex of the ischemic focus. Thereafter, rats were sacrificed and the infarct area was measured. In another experiment, rats were allowed to recover for 5 days after cooling and neurobehavioral function was evaluated. FBC suppressed all ECoG frequency bands during and after cooling (p<0.05), except for the delta frequency band in the precooling versus rewarming periods. The injured areas in the cooling and non-cooling groups were 0.99±0.30 and 1.71±0.54 mm(2), respectively (p<0.03). The grip strength at 2 days after surgery was preserved in the cooling group (p<0.05). We report the novel finding that epileptiform discharges were suppressed in the ischemic border, the infarct area was reduced and neurobehaviour was preserved by FBC. These results indicate that FBC is neuroprotective in the ischemic brain and has demonstrated therapeutic potential for cerebral infarction. PMID:23268352
He, Yeting; Fujii, Masami; Inoue, Takao; Nomura, Sadahiro; Maruta, Yuichi; Oka, Fumiaki; Shirao, Satoshi; Owada, Yuji; Kida, Hiroyuki; Kunitsugu, Ichiro; Yamakawa, Toshitaka; Tokiwa, Tatsuji; Yamakawa, Takeshi; Suzuki, Michiyasu
A phosphodiesterase inhibitor, cilostazol, prevents the onset of silent brain infarction in Japanese subjects with Type II diabetes
.\\u000a Aims\\/hypothesis: This study aimed to evaluate the effect of a phosphodiesterase inhibitor, cilostazol, on the prevention of silent brain infarction\\u000a in diabetic patients without symptoms of vascular events. \\u000a \\u000a \\u000a \\u000a Methods: A total of 89 subjects were allocated at random to the cilostazol group (n = 43) or the control group (n = 46). \\u000a \\u000a \\u000a \\u000a Results: After the study period (3.2 ±
T. Shinoda-Tagawa; Y. Yamasaki; S. Yoshida; Y. Kajimoto; T. Tsujino; N. Hakui; M. Matsumoto; M. Hori
... infarct dementia (MID) is a common cause of memory loss in the elderly. MID is caused by multiple strokes (disruption of blood flow to the brain). Disruption of blood flow leads to damaged brain ...
Influence of an enriched environment and cortical grafting on functional outcome in brain infarcts of adult rats.
The purpose of this work was to study if enriched housing conditions and fetal neocortical transplantation could enhance the functional outcome after focal brain ischemia in adult rats. The right middle cerebral artery (MCA) was ligated in 34 inbred, spontaneously hypertensive male rats, which were then randomly divided into three groups. Groups A and B were transferred to an enriched environment, i.e., a large cage with opportunities for various activities but not forcing the rats to do any particular tasks; group C was kept in standard laboratory cages. Three weeks after the MCA occlusion blocks of fetal neocortical tissue (Embryonic Day 17) were transplanted to the infarct cavity in groups B and C. Rats in group A (n = 11) and group B (n = 11) performed equally well and significantly better than rats in group C (n = 10) when placed on an inclined plane and when traversing a rotating pole 6 and 9 weeks after the MCA occlusion and in a leg placement test at 9, but not 6 and 12 weeks. Skilled forelimb function did not differ between the groups. Infarct size and thalamic atrophy did not differ between the groups and graft size was similar in group B and C. There was no correlation between infarct size and motor function in any of the tests in rats housed in an enriched environment. Since the environment can significantly alter functional outcome without reducing infarct size we suggest that more attention should be given to the role of the laboratory environment and to long term behavioral outcome in experimental stroke. PMID:7601267
Grabowski, M; Sřrensen, J C; Mattsson, B; Zimmer, J; Johansson, B B
'Iatrogenic' brain stem infarction. A complication of x-ray examination of the cervical spine and following posterior tamponation of the nose.
Two patients sustained an ischemic brain stem infarction during medical examination and treatment. The first patient lost consciousness and the spontaneous respiration ceased during X-ray examination of the cervical spine when the neck was hyperextended. After some minutes he regained conciousness but was found to be tetraplegic, and the patient deceased 4 months later. The angiogram revealed thrombosis of the basilar artery. The other patient had profuse nosebleed and was treated with posterior tamponation during which she sat for about 10 min with the neck hyperextended. Some hours after this procedure symptoms and signs of lateral caudal brain stem infarction emerged. PMID:1126348
Fogelholm, R; Karli, P
Hierarchical Models in the Brain
This paper describes a general model that subsumes many parametric models for continuous data. The model comprises hidden layers of state-space or dynamic causal models, arranged so that the output of one provides input to another. The ensuing hierarchy furnishes a model for many types of data, of arbitrary complexity. Special cases range from the general linear model for static data to generalised convolution models, with system noise, for nonlinear time-series analysis. Crucially, all of these models can be inverted using exactly the same scheme, namely, dynamic expectation maximization. This means that a single model and optimisation scheme can be used to invert a wide range of models. We present the model and a brief review of its inversion to disclose the relationships among, apparently, diverse generative models of empirical data. We then show that this inversion can be formulated as a simple neural network and may provide a useful metaphor for inference and learning in the brain.
Friston, Karl
Antiphospholipid Antibodies, Brain Infarcts, and Cognitive and Motor Decline in Aging (ABICMA): Design of a Community-based, Longitudinal, Clinical-pathological Study
The overall goal of the Antiphospholipid antibodies, Brain Infarcts, and Cognitive and Motor decline in Aging study (ABICMA) is to test the hypothesis that antiphospholipid antibodies (aPL) are associated with an increased risk of pathologically-proven brain infarcts and related to cognitive and motor decline in aging. Putative biologic mechanisms underlying the association of aPL with infarcts and the relation of aPL with clinical outcomes of cognitive and motor impairment, including vascular and other processes, will be examined. The design of this longitudinal, clinical-pathologic study involves quantifying four aPL assays, and relating these to brain infarcts, and to cognitive and motor decline. Vascular mechanisms assessed using ante-mortem magnetic resonance neuroimaging and postmortem neuropathology, as well as non-vascular mechanisms of inflammation and blood-brain barrier permeability alterations will be examined as plausible mediators of the relation of aPL to cognitive and motor impairment. We will take advantage of ante-mortem biologic specimens (longitudinally-collected sera and plasma from which aPL, annexins, C-reactive protein, and matrix metalloproteinases will be quantified), and clinical, neuroimaging, and postmortem neuropathologic data from about 800 older, community-dwelling women and men who have agreed to brain autopsy at time of death, participating in one of two ongoing studies of aging: the Religious Orders Study and the Memory and Aging Project.
Arvanitakis, Zoe; Brey, Robin L.; Rand, Jacob H.; Schneider, Julie A.; Leurgans, Sue E.; Yu, Lei; Buchman, Aron S.; Arfanakis, Konstantinos; Fleischman, Debra A.; Boyle, Patricia A.; Bennett, David A.; Levine, Steven R.
Electromechanical Characterization of Chronic Myocardial Infarction in the Canine Coronary Occlusion Model
Background—Defining the presence, extent, and nature of the dysfunctional myocardial tissue remains a cornerstone in diagnostic cardiology. A nonfluoroscopic, catheter-based mapping technique that can spatially associate endocardial mechanical and electrical data was used to quantify electromechanical changes in the canine chronic infarction model. Methods and Results—We mapped the left ventricular (LV) electromechanical regional properties in 11 dogs with chronic infarction
Lior Gepstein; Alexander Goldin; Jonathan Lessick; Gal Hayam; Shlomo Shpun; Yitzhak Schwartz; Guil Hakim; Rona Shofty; Aharon Turgeman; Dina Kirshenbaum; Shlomo A. Ben-Haim
Hyperhomocysteinemia as an Independent Risk Factor for Silent Brain Infarction - Inverse Correlation with Folate in Patients with MTHFR 677TT Genotype
Background : Silent brain infarction (SBI) are common in elderly people and are associated with an increased risk of clinically apparent stroke. Hyperhomocysteinemia is also an independent risk factor for ischemic stroke. This study was undertaken to determine whether hyperhomocysteinemia was associated with SBI, and also to find prevention against SBI through correlation among homocysteine, folate, and vitamin B12. Methods
Byung-Ok Choi; Yong Seong Kim; Ok-Joon Kim; Jung-Ho Seo
Effect of dichloracetate on infarct size in a primate model of focal cerebral ischaemia.
Acidosis is a major contributing factor towards spread of the ischaemic focus in the brain. Drugs that increase pyruvate dehydrogenase activity could decrease the formation of lactic acidosis. The sodium salt of dichloracetic acid (DCA) has been found to be effective in reducing lactate. This study was undertaken to study the efficacy of DCA in reducing infarct size in experimental focal ischaemia in monkeys. Macaca radiata monkeys in the treatment group were given 35 mg per kilogram of dichloracetate intravenously immediately before occluding and interrupting the middle cerebral artery, and the control group was given saline as placebo under similar conditions. Mean infarct size expressed as a percentage of the size of the hemisphere in all the three brain slices was 35.38 in the control group as against l2.06 in the treated group (p=0. 0008). PMID:11025625
Chandy, M J; Ravindra, J
Evolution of changes in the computed tomography scans of the brain of a patient with left middle cerebral artery infarction: a case report
Introduction Stroke is a common and important condition in medicine. Effective early management of acute stroke can reduce morbidity and mortality. Case presentation A 63-year-old man presented to the Accident and Emergency department with a history of collapse and progressive right-sided weakness. Clinically this was a cerebrovascular accident affecting the left hemisphere of the brain causing right hemiplegia. Computed tomography scans, performed 3 days apart, showed the evolution of infarction in the brain caused by the thrombus in the left middle cerebral artery. This is one of the early signs for stroke seen on computed tomography imaging and it is called the hyperdense middle cerebral artery sign. Conclusion Patients admitted with a stroke, undergo CT brain within 24 hours. The scan usually takes place at admission into the hospital and is done to rule out a bleed or a space occupying lesion within the brain. A normal CT brain does not confirm a stroke has not taken place. When scanned early, the changes seen on the CT due to an infarction from a thrombus may not have taken place yet. This paper highlights the early changes that can be seen on the CT brain following a stroke caused by infarction due to a thrombus in the middle cerebral artery.
John, Kurien; Singhal, Parag; Cook, Chris
Tachycardia in post-infarction hearts: insights from 3D image-based ventricular models.
Ventricular tachycardia, a life-threatening regular and repetitive fast heart rhythm, frequently occurs in the setting of myocardial infarction. Recently, the peri-infarct zones surrounding the necrotic scar (termed gray zones) have been shown to correlate with ventricular tachycardia inducibility. However, it remains unknown how the latter is determined by gray zone distribution and size. The goal of this study is to examine how tachycardia circuits are maintained in the infarcted heart and to explore the relationship between the tachycardia organizing centers and the infarct gray zone size and degree of heterogeneity. To achieve the goals of the study, we employ a sophisticated high-resolution electrophysiological model of the infarcted canine ventricles reconstructed from imaging data, representing both scar and gray zone. The baseline canine ventricular model was also used to generate additional ventricular models with different gray zone sizes, as well as models in which the gray zone was represented as different heterogeneous combinations of viable tissue and necrotic scar. The results of the tachycardia induction simulations with a number of high-resolution canine ventricular models (22 altogether) demonstrated that the gray zone was the critical factor resulting in arrhythmia induction and maintenance. In all models with inducible arrhythmia, the scroll-wave filaments were contained entirely within the gray zone, regardless of its size or the level of heterogeneity of its composition. The gray zone was thus found to be the arrhythmogenic substrate that promoted wavebreak and reentry formation. We found that the scroll-wave filament locations were insensitive to the structural composition of the gray zone and were determined predominantly by the gray zone morphology and size. The findings of this study have important implications for the advancement of improved criteria for stratifying arrhythmia risk in post-infarction patients and for the development of new approaches for determining the ablation targets of infarct-related tachycardia. PMID:23844245
Arevalo, Hermenegild; Plank, Gernot; Helm, Patrick; Halperin, Henry; Trayanova, Natalia
Tachycardia in Post-Infarction Hearts: Insights from 3D Image-Based Ventricular Models
Ventricular tachycardia, a life-threatening regular and repetitive fast heart rhythm, frequently occurs in the setting of myocardial infarction. Recently, the peri-infarct zones surrounding the necrotic scar (termed gray zones) have been shown to correlate with ventricular tachycardia inducibility. However, it remains unknown how the latter is determined by gray zone distribution and size. The goal of this study is to examine how tachycardia circuits are maintained in the infarcted heart and to explore the relationship between the tachycardia organizing centers and the infarct gray zone size and degree of heterogeneity. To achieve the goals of the study, we employ a sophisticated high-resolution electrophysiological model of the infarcted canine ventricles reconstructed from imaging data, representing both scar and gray zone. The baseline canine ventricular model was also used to generate additional ventricular models with different gray zone sizes, as well as models in which the gray zone was represented as different heterogeneous combinations of viable tissue and necrotic scar. The results of the tachycardia induction simulations with a number of high-resolution canine ventricular models (22 altogether) demonstrated that the gray zone was the critical factor resulting in arrhythmia induction and maintenance. In all models with inducible arrhythmia, the scroll-wave filaments were contained entirely within the gray zone, regardless of its size or the level of heterogeneity of its composition. The gray zone was thus found to be the arrhythmogenic substrate that promoted wavebreak and reentry formation. We found that the scroll-wave filament locations were insensitive to the structural composition of the gray zone and were determined predominantly by the gray zone morphology and size. The findings of this study have important implications for the advancement of improved criteria for stratifying arrhythmia risk in post-infarction patients and for the development of new approaches for determining the ablation targets of infarct-related tachycardia.
Arevalo, Hermenegild; Plank, Gernot; Helm, Patrick; Halperin, Henry; Trayanova, Natalia
Peri-infarct flow transients predict outcome in rat focal brain ischemia.
Spreading depolarizations are accompanied by transient changes in cerebral blood flow (CBF). In a post hoc analysis of previously studied control rats we analyzed CBF time courses after middle cerebral artery occlusion in the rat in order to test whether intra-ischemic flow, reperfusion, and different parameters of peri-infarct flow transients (PIFTs) (amplitude, number) can predict outcome. Sprague-Dawley rats anesthetized with either halothane (n=23) or isoflurane (n=32) underwent 90-min filament occlusion of the middle cerebral artery followed by 72 h of reperfusion. The infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Relative CBF changes were monitored by laser Doppler flowmetry at 4-5 mm lateral, and 1-2mm posterior to Bregma. An additional filament occlusion study (n=12) was performed to validate that PIFTs were coupled to direct current shifts of spreading depolarization. The PIFT-direct current shift study revealed that every PIFT was associated with a negative direct current shift typical of spreading depolarization. Post-hoc analysis showed that the number of PIFTs, especially with the combination of intra-ischemic level of flow, can predict the development of cortical infarcts. These findings show that PIFTs can serve as an early biomarker in predicting outcome in preclinical animal studies. PMID:22986160
Lückl, J; Dreier, J P; Szabados, T; Wiesenthal, D; Bari, F; Greenberg, J H
Incorporation of a left ventricle finite element model defining infarction into the XCAT imaging phantom.
The 4D extended cardiac-torso (XCAT) phantom was developed to provide a realistic and flexible model of the human anatomy and cardiac and respiratory motions for use in medical imaging research. A prior limitation to the phantom was that it did not accurately simulate altered functions of the heart that result from cardiac pathologies such as coronary artery disease (CAD). We overcame this limitation in a previous study by combining the phantom with a finite-element (FE) mechanical model of the left ventricle (LV) capable of more realistically simulating regional defects caused by ischemia. In the present work, we extend this model giving it the ability to accurately simulate motion abnormalities caused by myocardial infarction (MI), a far more complex situation in terms of altered mechanics compared with the modeling of acute ischemia. The FE model geometry is based on high resolution CT images of a normal male subject. An anterior region was defined as infarcted and the material properties and fiber distribution were altered, according to the bio-physiological properties of two types of infarction, i.e., fibrous and remodeled infarction (30% thinner wall than fibrous case). Compared with the original, surface-based 4D beating heart model of the XCAT, where regional abnormalities are modeled by simply scaling down the motion in those regions, the FE model was found to provide a more accurate representation of the abnormal motion of the LV due to the effects of fibrous infarction as well as depicting the motion of remodeled infarction. In particular, the FE models allow for the accurate depiction of dyskinetic motion. The average circumferential strain results were found to be consistent with measured dyskinetic experimental results. Combined with the 4D XCAT phantom, the FE model can be used to produce realistic multimodality sets of imaging data from a variety of patients in which the normal or abnormal cardiac function is accurately represented. PMID:21041157
Veress, Alexander I; Segars, W Paul; Tsui, Benjamin M W; Gullberg, Grant T
Left Brain, Right Brain, Super Brain: The Holistic Model.
ERIC Educational Resources Information Center
Recent discoveries about the whole brain seem to call for a holistic approach to learning, one in which educators would teach the whole person, including physical and emotional states as well as cognitive abilities. Three holistic techniques are particularly relevant to education: (1) biofeedback; (2) yoga; and (3) the Lozanov method. Biofeedback…
Yellin, David
The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke.
Microglia and brain infiltrating macrophages significantly contribute to the secondary inflammatory damage in the wake of ischemic stroke. Here, we investigated whether inhibition of KCa3.1 (IKCa1/KCNN4), a calcium-activated K(+) channel that is involved in microglia and macrophage activation and expression of which increases on microglia in the infarcted area, has beneficial effects in a rat model of ischemic stroke. Using an HPLC/MS assay, we first confirmed that our small molecule KCa3.1 blocker TRAM-34 effectively penetrates into the brain and achieves micromolar plasma and brain concentrations after intraperitoneal injection. Then, we subjected male Wistar rats to 90 minutes of middle cerebral artery occlusion (MCAO) and administered either vehicle or TRAM-34 (10 or 40 mg/kg intraperitoneally twice daily) for 7 days starting 12 hours after reperfusion. Both compound doses reduced infarct area by ? 50% as determined by hematoxylin & eosin staining on day 7 and the higher dose also significantly improved neurological deficit. We further observed a significant reduction in ED1(+)-activated microglia and TUNEL-positive neurons as well as increases in NeuN(+) neurons in the infarcted hemisphere. Our findings suggest that KCa3.1 blockade constitutes an attractive approach for the treatment of ischemic stroke because it is still effective when initiated 12 hours after the insult. PMID:21750563
Chen, Yi-Je; Raman, Girija; Bodendiek, Silke; O'Donnell, Martha E; Wulff, Heike
Cognitive informatics models of the brain
The human brain is the most complicated organ in the universe and a new frontier yet to be explored by an interdisciplinary approach. This paper attempts to develop logical and cognitive models of the brain by using cognitive informatics and formal methodologies. This paper adopts a memory-based approach to explore the brain and to demonstrate that memory is the foundation
Yingxu Wang; Ying Wang
Comparison of two preclinical myocardial infarct models: coronary coil deployment versus surgical ligation
Background Despite recent advances, myocardial infarction (MI) remains the leading cause of death worldwide. Pre-clinical animal models that closely mimic human MI are pivotal for a quick translation of research and swine have similarities in anatomy and physiology. Here, we compared coronary surgical ligation versus coil embolization MI models in swine. Methods Fifteen animals were randomly distributed to undergo surgical ligation (n?=?7) or coil embolization (n?=?8). We evaluated infarct size, scar fibrosis, inflammation, myocardial vascularization, and cardiac function by magnetic resonance imaging (MRI). Results Thirty-five days after MI, there were no differences between the models in infarct size (P?=?0.53), left ventricular (LV) ejection fraction (P?=?0.19), LV end systolic volume (P?=?0.22), LV end diastolic volume (P?=?0.84), and cardiac output (P?=?0.89). Histologically, cardiac scars did not differ and the collagen content, collagen type I (I), collagen type III (III), and the I/III ratio were similar in both groups. Inflammation was assessed using specific anti-CD3 and anti-CD25 antibodies. There was similar activation of inflammation throughout the heart after coil embolization (P?=?0.78); while, there were more activated lymphocytes in the infarcted myocardium in the surgical occlusion model (P?=?0.02). Less myocardial vascularization in the infarction areas compared with the border and remote zones only in coil embolization animals was observed (P?=?0.004 and P?=?0.014, respectively). Conclusions Our results support that surgical occlusion and coil embolization MI models generate similar infarct size, cardiac function impairment, and myocardial fibrosis; although, inflammation and myocardial vascularization levels were closer to those found in humans when coil embolization was performed.
Long-term effects of sequential cortical infarcts on scar size, brain volume and cognitive function
Focal ischemia induces long-term pathophysiological consequences in widespread brain areas. Here we analyzed long-term effects of sequential cortical lesions on brain volume and cognitive function. Rats received either single photothrombotic lesions in the forelimb sensorimotor cortex (SL) or two lesions in sequence either immediately (DL0), 2 days (DL2), 7 days (DL7), or 10 days (DL10) after the first surgery in
Elena V. Shanina; Christoph Redecker; Sonja Reinecke; Timothy Schallert; Otto W. Witte
Artery of Percheron infarction.
Artery of Percheron (AOP) is small perforating arteries supplying paramedian thalamus and mid-brain. The incidence of infarction is rare. We presented a 62-year-old man found conscious drowsy for 4 days. MRI revealed bilateral thalamic and midbrain infarction due to AOP occlusion. PMID:22879120
Yu, Guo-Sheng; Kuo, Kuei-Hong; Chan, Lung
Engraftment of Human Mesenchymal Stem Cells in a Rat Photothrombotic Cerebral Infarction Model : Comparison of Intra-Arterial and Intravenous Infusion Using MRI and Histological Analysis
Objective This study aimed to evaluate the hypotheses that administration routes [intra-arterial (IA) vs. intravenous (IV)] affect the early stage migration of transplanted human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in acute brain infarction. Methods Male Sprague-Dawley rats (n=40) were subjected to photothrombotic infarction. Three days after photothrombotic infarction, rats were randomly allocated to one of four experimental groups [IA group : n=12, IV group : n=12, superparamagnetic iron oxide (SPIO) group : n=8, control group : n=8]. All groups were subdivided into 1, 6, 24, and 48 hours groups according to time point of sacrifice. Magnetic resonance imaging (MRI) consisting of T2 weighted image (T2WI), T2* weighted image (T2*WI), susceptibility weighted image (SWI), and diffusion weighted image of rat brain were obtained prior to and at 1, 6, 24, and 48 hours post-implantation. After final MRI, rats were sacrificed and grafted cells were analyzed in brain and lung specimen using Prussian blue and immunohistochemical staining. Results Grafted cells appeared as dark signal intensity regions at the peri-lesional zone. In IA group, dark signals in peri-lesional zone were more prominent compared with IV group. SWI showed largest dark signal followed by T2*WI and T2WI in both IA and IV groups. On Prussian blue staining, IA administration showed substantially increased migration and a large number of transplanted hBM-MSCs in the target brain than IV administration. The Prussian blue-positive cells were not detected in SPIO and control groups. Conclusion In a rat photothrombotic model of ischemic stroke, selective IA administration of human mesenchymal stem cells is more effective than IV administration. MRI and histological analyses revealed the time course of cell migration, and the numbers and distribution of hBM-MSCs delivered into the brain.
Byun, Jun Soo; Kim, Jae Kyun; Jung, Jisung; Ha, Bon Chul; Park, Serah
On the influence of space storms on the frequency of infarct-myocardial, brain strokes, and hard car accidents; possible using of CR for their forecasting
NASA Astrophysics Data System (ADS)
We consider the influence of space storms as strong interplanetary shock waves causing great cosmic ray Forbush-decreases and big geomagnetic storms on the people health at the ground level We used data of more than 7 millions ambulance cases in Moscow and St Petersburg included information on daily numbers of the hard traffic accidents infarctions and brain strokes We found that during space storms the average daily numbers of hard traffic accidents with using ambulances as well as infarctions and brain strokes confirmed by medical personal increase by 17 4 pm 3 1 10 5 pm 1 2 and 7 0 pm 1 7 respectively We show that the forecasting of these dangerous apace phenomena can be done partly by using cosmic ray data on pre-increase and pre-decrease effects as well as on the change of 3-D cosmic ray anisotropy
Dorman, L. I.; Iucci, N.; Ptitsyna, N. G.; Villoresi, G.
Plasma N-Terminal Pro-Brain Natriuretic Peptide and Adrenomedullin New Neurohormonal Predictors of Left Ventricular Function and Prognosis After Myocardial Infarction
Background—Newly discovered circulating peptides, N-terminal pro- brain natriuretic peptide (N-BNP) and ad- renomedullin (ADM), were examined for prediction of cardiac function and prognosis and compared with previously reported markers in 121 patients with myocardial infarction. Methods and Results—The association between radionuclide left ventricular ejection fraction (LVEF) and N-BNP at 2 to 4 days (r52.63, P,.0001) and 3 to 5 months
A. Mark Richards; M. Gary Nicholls; Tim G. Yandle; Chris Frampton; Eric A. Espiner; John G. Turner; Rona C. Buttimore; John G. Lainchbury; John M. Elliott; Hamid Ikram; Ian G. Crozier; David W. Smyth
Supervised classification models to detect the presence of old myocardial infarction in Body Surface Potential Maps
In this study we have investigated the classification of old myocardial infarction through the analysis of 192 lead body surface potential maps (BSPM). Following an analysis of the most prominent features based on a signal to noise ratio ranking criterion the top 6 features were selected. These features were subsequently used as inputs to a series of supervised classification models
H. Zheng; H. Wang; C. D. Nugent; D. D. Finlay
A Nonthoracotomy Myocardial Infarction Model in an Ovine Using Autologous Platelets
Objective. There is a paucity of a biological large animal model of myocardial infarction (MI). We hypothesized that, using autologous-aggregated platelets, we could create an ovine model that was reproducible and more closely mimicked the pathophysiology of MI. Methods. Mepacrine stained autologous platelets from male sheep (n = 7) were used to create a myocardial infarction via catheter injection into the mid-left anterior descending (LAD) coronary artery. Serial daily serum troponin measurements were taken and tissue harvested on post-embolization day three. Immunofluorescence microscopy was used to detect the mepacrine-stained platelet-induced thrombus, and histology performed to identify three distinct myocardial (infarct, peri-ischemic "border zone," and remote) zones. Results. Serial serum troponin levels (?g/mL) measured 0.0 ± 0.0 at baseline and peaked at 297.4 ± 58.0 on post-embolization day 1, followed by 153.0 ± 38.8 on day 2 and 76.7 ± 19.8 on day 3. Staining confirmed distinct myocardial regions of inflammation and fibrosis as well as mepacrine-stained platelets as the cause of intravascular thrombosis. Conclusion. We report a reproducible, unique model of a biological myocardial infarction in a large animal model. This technique can be used to study acute, regional myocardial changes following a thrombotic injury.
Spata, Tyler; Bobek, Daniel; Whitson, Bryan A.; Parthasarathy, Sampath; Mohler, Peter J.; Higgins, Robert S. D.; Kilic, Ahmet
The microvascular changes in cases of hereditary multi-infarct disease of the brain
A report on a cerebro-vascular disease with autosomal dominant inheritance, characterised by stroke-like episodes beginning in early adulthood and progressive dementia, afflicting one family living in Sweden was presented in 1977. Another afflicted member showing gait and coordination disturbances and impaired cognitive functions is now introduced. Magnetic resonance imaging revealed multiple brain lesions indicating ischaemic injuries. Previous autopsy studies of
Wei Wei Zhang; Kuo Chun Ma; Oluf Andersen; Patrick Sourander; Per Olof Tollesson; Yngve Olsson
MR study of the effect of infarct size and location on left ventricular functional and microstructural alterations in porcine models
Purpose: To investigate the effect of infarct size and loca- tion on left ventricular (LV) functional and microstructural alterations in well-established porcine models. Materials and Methods: Myocardium infarction was in- duced in mini-pigs at apical septum (Group 1, n 6) or basal lateral wall (Group 2, n 6) by permanent occlusion of the left anterior descending or left circumflex coronary
Yin Wu; Carmen W. Chan; John M. Nicholls; Songyan Liao; Hung-Fat Tse; Ed X. Wu
Effects of Cortical Spreading Depression on Cortical Blood Flow, Impedance, DC Potential, and Infarct Size in a Rat Venous Infarct Model
A cortical venous infarction model has been evaluated as to the degree of regional flow reduction and by studying effects of cortical spreading depression (CSD). Two adjacent cortical veins were occluded photochemically with rose bengal and fiberoptic illumination. Seven rats served to demonstrate effects on regional cortical blood flow using laser Doppler scanning. In 36 rats local CBF, DC potential,
H. Otsuka; K. Ueda; A. Heimann; O. Kempski
Functional integration of cortical grafts placed in brain infarcts of rats.
Five to 6 days after a right middle cerebral artery occlusion, a cell suspension of fetal neocortex was grafted into the infarcted area of adult spontaneously hypertensive rats. Three to 17 months later, functional integration of the grafts into the afferent somatosensory pathway was tested using the 2-[14C]deoxyglucose method for estimation of glucose utilization. Grafted rats (n = 8) and control rats (n = 5) with no arterial occlusion were stimulated in the left vibrissal region resulting in an increased glucose utilization in the left trigeminal sensory nucleus and the right ventroposterior nucleus of the thalamus, whereas the same regions in a group (n = 5) of nonstimulated grafted rats were not activated. Glucose uptake in the right somatosensory cortex of control rats was 96 +/- 5 (mean +/- SEM) mumol/100 gm/min. Neocortical grafts consumed less glucose than cortex in control rats but the vibrissae-stimulated group displayed a 110% higher value than the nonstimulated grafted group (32 +/- 5 vs 15 +/- 2, p < 0.05). We conclude that graft glucose metabolism is increased following stimulation of the host somatosensory pathway, which demonstrates that transplanted neurons can be functionally integrated with neural circuitries of the host after an ischemic insult. PMID:8363353
Grabowski, M; Brundin, P; Johansson, B B
Inter-rater reliability of modified Alberta Stroke program early computerized tomography score in patients with brain infarction
BACKGROUND: The Alberta Stroke Program Early Computerized Tomography Score (ASPECTS) was used to detect significant early ischemic changes on brain CT of acute stroke patients. We designed the modified ASPECTS and compared it to the above system based on the inter-rater reliability. METHODS: A cross-sectional validation study was conducted based on the inter-rater reliability. The CT images were chosen from the stroke data bank of Ghaem hospital, Mashhad in 2010. The inclusion criteria were the presence of middle cerebral artery territory infarction and performance of CT within 6 hours after stroke onset. Axial CT scans were performed on a third-generation CT scanner (Siemens, ARTX, Germany). Section thickness above posterior fossa was 10 mm (130 kV, 150 mAs). Films were made at window level of 35 HU. The brain CTs were scored by four independent radiologists based on the ASPECTS and modified ASPECTS. The readers were blind to clinical information except symptom side. Cochrane Q and Kappa tests served for statistical analysis. RESULTS: 24 CT scans were available and of sufficient quality. Difference in distribution of dichotomized ?7 and >7 ASPECT scores between four raters was significant (Q=13.071, df=3, p=0.04). Distribution of dichotomized <6 and ?6 scores based on modified ASPECT system between 4 raters was not significantly different (Q=6.349, df=3, p=0.096). CONCLUSIONS: Modified ASPECT method is more reliable than ASPECTS in detecting major early ischemic changes in stroke patients candidated to tPA thrombolysis.
Ghandehari, Kavian; Rezvani, Mohammad Reza; Shakeri, Mohammad Taghi; Mohammadifard, Mahdi; Ehsanbakhsh, Alireza; Mohammadifard, Mahyar; Mirgholami, Alireza; Boostani, Reza; Ghandehari, Kosar; Izadi-Mood, Zahra
Sulfonylurea Receptor 1 Expression in Human Cerebral Infarcts
Abstract In animal models of stroke, sulfonylurea receptor 1 (Sur1), a member of the adenosine triphosphate binding cassette transporter gene family, is transcriptionally upregulated in neural and vascular cells in which it plays a leading role in edema formation and necrotic cell death. To date, expression of Sur1 in the brains of humans with cerebral infarcts has not been systematically evaluated. We examined Sur1 expression in postmortem specimens obtained from 13 patients within the first 31 days after focal infarcts, 5 patients with lacunar infarcts, and 6 normal control brains using immunohistochemistry. Elevated immunoreactivity for Sur1 was detected in all cases of focal infarcts, with 3 distinct temporal patterns of expression: 1) neurons and endothelium showed the greatest elevation during the first week, after which levels declined; 2) astrocytes and microglia/macrophages showed progressive increases during the first 31 days; and 3) neutrophils near the infarct showed prominent immunoreactivity that did not change over time. Upregulation of Sur1 was corroborated using in situ hybridization for Abcc8 mRNA. Sulfonylurea receptor 1 immunoreactivity in lacunar infarcts was less prominent and more sporadic than in nonlacunar infarcts. In conjunction with previous studies, these data suggest that Sur1 may be a promising treatment target in patients with acute cerebral infarction.
Mehta, Rupal I.; Ivanova, Svetlana; Tosun, Cigdem; Castellani, Rudy J.; Gerzanich, Volodymyr
Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia-ischaemia in the developing brain.
Phosphorus magnetic resonance spectroscopy (31P MRS) was used to determine whether focal cerebral injury caused by unilateral carotid artery occlusion and graded hypoxia in developing rats led to a delayed impairment of cerebral energy metabolism and whether the impairment was related to the magnitude of cerebral infarction. Forty-two 14-day-old Wistar rats were subjected to right carotid artery ligation, followed by 8% oxygen for 90 min. Using a 7T MRS system. 31P brain spectra were collected during the period from before until 48 h after hypoxia-ischaemia. Twenty-eight control animals were studied similarly. In controls, the ratio of the concentration of phosphocreatine ([PCr]) to inorganic orthophosphate ([Pi]) was 1.75 (SD 0.34) and nucleotide triphosphate (NTP) to total exchangeable phosphate pool (EPP) was 0.20 (SD 0.04): both remained constant. In animals subjected to hypoxia-ischaemia, [PCr] to [Pi] and [NTP] to [EPP] were lower in the 0- to 3-h period immediately following the insult: 0.87 (0.48) and 0.13 (0.04), respectively. Values then returned to baseline level, but subsequently declined again: [PCr] to [Pi] at -0.02 h-1 (P < 0.0001). [PCr] to [Pi] attained a minimum of 1.00 (0.33) and [NTP] to [EPP] a minimum of 0.14 (0.05) at 30-40 h. Both ratios returned towards baseline between 40 and 48 h. The late declines in high-energy phosphates were not associated with a fall in pHi. There was a significant relation between the extent of the delayed impairment of energy metabolism and the magnitude of the cerebral infarction (P < 0.001). Transient focal hypoxia-ischaemia in the 14-day-old rat thus leads to a biphasic disruption of cerebral energy metabolism, with a period of recovery after the insult being followed by a secondary impairment some hours later. PMID:9028781
Blumberg, R M; Cady, E B; Wigglesworth, J S; McKenzie, J E; Edwards, A D
Hyperglycaemia and infarct size in animal models of middle cerebral artery occlusion: systematic review and meta-analysis
Poststroke hyperglycaemia (PSH) is common, has an unclear pathophysiology, and is associated with poor outcomes. Animal studies report conflicting findings. We systematically reviewed the effects of hyperglycaemia on infarct volume in middle cerebral artery occlusion (MCAO) models, generating weighted mean differences between groups using random effects models summarised as effect size (normalised to control group infarct volume as 100%) and 95% confidence interval. Of 72 relevant papers, 23 reported infarct volume. Studies involved 664 animals and 35 distinct comparisons. Hyperglycaemia was induced by either streptozotocin (STZ, 17 comparisons, n=303) or dextrose (18 comparisons, n=356). Hyperglycaemic animals had infarcts that were 94% larger, but STZ was associated with significantly greater increase in infarct volumes than dextrose infusion (140% larger versus 48% larger). In seven studies, insulin did not significantly reduce infarct size and results were heterogeneous. Although hyperglycaemia exacerbates infarct volume in MCAO models, studies are heterogeneous, and do not address the common clinical problem of PSH because they have used either the STZ model of type I diabetes or extremely high glucose loads. Insulin had a nonsignificant and significantly heterogeneous effect. Further studies with relevant models may inform clinical trial design.
MacDougall, Niall J J; Muir, Keith W
Somatostatin analogue mimics acute ischemic preconditioning in a rat model of myocardial infarction.
We tested the hypothesis that octreotide, a somatostatin analogue, can mimic ischemic preconditioning (PC) to provide cardioprotection against myocardial infarction. An ischemia-reperfusion model of adult Wistar rats was used. Infarct size was expressed as a percentage of the area at risk under different treatment protocols. Octreotide PC (35 microg/Kg 20 minutes before ischemia-reperfusion) significantly decreased infarct size (18 +/- 4%) versus control (60 +/- 7%). The somatostatin receptor antagonist cyclo-somatostatin (0.5 mg/Kg) could blunt the above cardioprotection. Administration of either chelerythrine (a protein kinase C inhibitor, 2 mg/Kg) or genistein (a tyrosine kinase inhibitor, 5 mg/Kg) could also block octreotide PC (54 +/- 7% and 58 +/- 6%, respectively). Pretreatment with the mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoic acid (5-HD) and the sarcolemmal ATP-sensitive potassium channel antagonist glibenclamide could abolish the effects of octreotide PC (54 +/- 6% and 52 +/- 6%). Chelerythrine, however, had no effect on octreotide PC. In conclusion, the present study demonstrates that octreotide can mimic ischemic PC to reduce infarct size. Acute effects of octreotide PC involve the activation of protein kinase C, tyrosine kinase C, and mitochondrial ATP-sensitive potassium channels, but not systemic IGF-I activation. PMID:15772521
Wang, Tzong-Luen; Huang, Yu-Hui; Chang, Hang
Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model.
We investigated the long-term effects of human hepatocyte growth factor (HGF) gene therapy in a rat myocardial infarct model. Treatment adenovirus coexpressing the HGF therapeutic gene and the human sodium/iodide symporter (NIS) reporter gene or control adenovirus expressing the NIS gene alone were injected directly into the infarct border zone immediately after permanent coronary ligation in rats (n=6 each). A uniform disease state was confirmed in the acute phase in terms of impaired left ventricular (LV) function by cine magnetic resonance imaging (MRI), large infarct extent by (99m)Tc-tetrofosmin single-photon emission computed tomography (SPECT) and successful gene transfer and expression by (99m)TcO(4)(-) SPECT. After a 10-week follow-up, repeated cine MRI demonstrated no significant difference in the LV ejection fraction between the time points or groups, but a significantly increased end-diastolic volume from the acute to the chronic phase without a significant difference between the groups. Capillary density was significantly higher in the treatment group, whereas arteriole density remained unchanged. Two-photon excitation fluorescence microscopy revealed extremely thin capillaries (2-5??m), and their irregular networks increased in the infarct border zone of the treated myocardium. Our results indicated that single HGF gene therapy alone induced an immature and irregular microvasculature. PMID:21918549
Jin, Y-N; Inubushi, M; Masamoto, K; Odaka, K; Aoki, I; Tsuji, A B; Sagara, M; Koizumi, M; Saga, T
The effect of polypyrrole on arteriogenesis in an acute rat infarct model
The conductive polymer polypyrrole was blended with alginate to investigate its potential in tissue engineering applications. This study showed that increasing the polypyrrole content altered the macroscopic structural morphology of the polymer blend scaffold, but did not alter the overall conductivity of the polymer blend, which was 10?2 S/cm2. Culturing of human umbilical vein endothelial cells on the polymer blend scaffolds showed that addition of polypyrrole mediated cell attachment to the polymer scaffold. However, cell proliferation was dependent on the polypyrrole content, with 0.025% v/v polypyrrole giving the best results. Using an ischemia-reperfusion rat myocardial infarction model, local injection of 0.025% polypyrrole in alginate polymer blend into the infarct zone yielded significantly higher levels of arteriogenesis at 5 weeks post-treatment when compared with the saline control group and the alginate only treatment group. In addition, this alginate-polypyrrole polymer blend significantly enhanced infiltration of myofibroblasts into the infarct area when compared with the control group. The results of this study highlight the potential clinical benefit of using this alginate-polypyrrole polymer blend as an injectable scaffold to repair ischemic myocardium after myocardial infarction.
Mihardja, Shirley; Sievers, Richard; Lee, Randall J.
Effects of edaravone, a free radical scavenger, on photochemically induced cerebral infarction in a rat hemiplegic model.
Edaravone is a free radical scavenger that protects the adjacent cortex during cerebral infarction. We created a hemiparetic model of cerebral thrombosis from a photochemically induced infarction with the photosensitive dye, rose bengal, in rats. We examined the effects of edaravone on recovery in the model. A total of 36 adult Wistar rats were used. The right sensorimotor area was irradiated with green light with a wavelength of 533 nm (10 mm diameter), and the rose bengal was injected intravenously to create an infarction. The edaravone group was injected intraperitoneally with edaravone (3 mg/kg), and the control group was injected with saline. The recovery process of the hemiplegia was evaluated with the 7-step scale of Fenny. The infarcted areas were measured after fixation. The recovery of the paralysis in the edaravone-treated group was significantly earlier than that in the untreated group. Seven days later, both groups were mostly recovered and had scores of 7, and the infarction region was significantly smaller in the edaravone-treated group. Edaravone reduced the infarction area and promoted the functional recovery of hemiparesis from cerebral thrombosis in a rat model. These findings suggest that edaravone treatment would be effective in clinical patients recovering from cerebral infarction. PMID:23853531
Ikeda, Satoshi; Harada, Katsuhiro; Ohwatashi, Akihiko; Kamikawa, Yurie
Effects of Edaravone, a Free Radical Scavenger, on Photochemically Induced Cerebral Infarction in a Rat Hemiplegic Model
Edaravone is a free radical scavenger that protects the adjacent cortex during cerebral infarction. We created a hemiparetic model of cerebral thrombosis from a photochemically induced infarction with the photosensitive dye, rose bengal, in rats. We examined the effects of edaravone on recovery in the model. A total of 36 adult Wistar rats were used. The right sensorimotor area was irradiated with green light with a wavelength of 533?nm (10?mm diameter), and the rose bengal was injected intravenously to create an infarction. The edaravone group was injected intraperitoneally with edaravone (3?mg/kg), and the control group was injected with saline. The recovery process of the hemiplegia was evaluated with the 7-step scale of Fenny. The infarcted areas were measured after fixation. The recovery of the paralysis in the edaravone-treated group was significantly earlier than that in the untreated group. Seven days later, both groups were mostly recovered and had scores of 7, and the infarction region was significantly smaller in the edaravone-treated group. Edaravone reduced the infarction area and promoted the functional recovery of hemiparesis from cerebral thrombosis in a rat model. These findings suggest that edaravone treatment would be effective in clinical patients recovering from cerebral infarction.
Harada, Katsuhiro; Ohwatashi, Akihiko; Kamikawa, Yurie
Acute brain infarction detected by CCT and stroke risk in patients with transient ischemic attack lasting <1 hour.
Background and purpose: This study aimed to determine the frequency and associated factors of acute brain infarction (ABI) detected by noncontrast cranial computed tomography (CCT) in patients with transient ischemic attack (TIA) of symptom duration <1 h and to investigate the association between evidence of ABI and short-term risk of stroke. Methods: During a 54-month period (starting November 2007), consecutive patients with TIA (symptom duration <1 h) admitted and imaged with CCT were prospectively evaluated. Adjusted logistic regression was used to estimate odds ratios (ORs). Results: Of 1021 patients (mean age, 74.5 ± 11 years; 52% female) with TIA (symptom duration <1 h) imaged with CCT at admission, 68 patients (6.7%; 95% CI, 5.3-8.3%) exhibited TIA-related ABI. Adjusted logistic regression showed that ABI was independently correlated with atrial fibrillation (AF) (OR, 3.3; 95% CI, 1.4-7.9; p = 0.006) and time between onset and CT assessment >6 h (OR, 2.5; 95% CI, 1.1-6.1; p = 0.034). During hospitalization (5 ± 3 d), 22 patients (2.2%; 95% CI, 1.4-3.1%) developed a stroke. Patients with ABI had higher stroke rates than those without (10.3% and 1.6%, respectively; p < 0.001). Adjusted logistic regression revealed that stroke risk was independently correlated with ABI (OR, 5.3; 95% CI, 1.8-15.0; p = 0.002) and AF (OR, 2.6; 95% CI, 1.1-6.4; p = 0.026). Conclusions: Detection of ABI by CCT in TIA patients with symptom duration <1 h may depend on timing of CCT assessment and presence of AF. Evidence of ABI indicates an elevated stroke risk during hospitalization. PMID:24098915
Al-Khaled, Mohamed; Rauch, Linus; Roessler, Florian; Eggers, Jürgen
A Soluble Fn14-Fc Decoy Receptor Reduces Infarct Volume in a Murine Model of Cerebral Ischemia
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts on responsive cells via binding to a small cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production, but the role of this cytokine in cardiovascular disease and stroke has not been established. The present study investigated whether TWEAK or Fn14 expression was regulated in a murine model of cerebral ischemia and whether TWEAK played a role in ischemia-mediated cell death. We found that TWEAK and Fn14 were expressed by primary mouse cerebral cortex-derived astrocytes and neurons cultured in vitro. Also, both the TWEAK and Fn14 proteins were present at elevated levels in the ischemic penumbra region after middle cerebral artery occlusion. Finally, we report that intracerebroventricular injection of a soluble Fn14-Fc decoy receptor immediately after middle cerebral artery occlusion significantly reduced infarct volume and the extent of microglial cell activation and apoptotic cell death in the ischemic penumbra. We conclude that the cytokine TWEAK may play an important role in ischemia-induced brain injury and that inhibition of TWEAK expression or function in the brain may represent a novel neuroprotective strategy to treat ischemic stroke.
Yepes, Manuel; Brown, Sharron A.N.; Moore, Elizabeth G.; Smith, Elizabeth P.; Lawrence, Daniel A.; Winkles, Jeffrey A.
Apolipoprotein A1 regulates coenzyme q10 absorption, mitochondrial function, and infarct size in a mouse model of myocardial infarction.
HDL and apolipoprotein A1 (apoA1) concentrations inversely correlate with risk of death from ischemic heart disease; however, the role of apoA1 in the myocardial response to ischemia has not been well defined. To test whether apoA1, the primary HDL apolipoprotein, has an acute anti-inflammatory role in ischemic heart disease, we induced myocardial infarction via direct left anterior descending coronary artery ligation in apoA1 null (apoA1(-/-)) and apoA1 heterozygous (apoA1(+/-)) mice. We observed that apoA1(+/-) and apoA1(-/-) mice had a 52% and 125% increase in infarct size as a percentage of area at risk, respectively, compared with wild-type (WT) C57BL/6 mice. Mitochondrial oxidation contributes to tissue damage in ischemia-reperfusion injury. A substantial defect was present at baseline in the electron transport chain of cardiac myocytes from apoA1(-/-) mice localized to the coenzyme Q (CoQ) pool with impaired electron transfer (67% decrease) from complex II to complex III. Administration of coenzyme Q10 (CoQ10) to apoA1 null mice normalized the cardiac mitochondrial CoQ pool and reduced infarct size to that observed in WT mice. CoQ10 administration did not significantly alter infarct size in WT mice. These data identify CoQ pool content leading to impaired mitochondrial function as major contributors to infarct size in the setting of low HDL/apoA1. These data suggest a previously unappreciated mechanism for myocardial stunning, cardiac dysfunction, and muscle pain associated with low HDL and low apoA1 concentrations that can be corrected by CoQ10 supplementation and suggest populations of patients that may benefit particularly from CoQ10 supplementation. PMID:24759932
Dadabayev, Alisher R; Yin, Guotian; Latchoumycandane, Calivarathan; McIntyre, Thomas M; Lesnefsky, Edward J; Penn, Marc S
Novel drug development opportunity for relaxin in acute myocardial infarction: evidences from a swine model
The hormone relaxin has been shown to cause coronary vasodilation and to prevent ischemia\\/reperfusion-induced cardiac injury in rodents. This study provides evidence that relaxin, used as an adjunctive drug to coronary reperfusion, reduces the functional, biochemical, and histopathological signs of myocardial injury in an in vivo swine model of heart ischemia\\/reperfusion, currently used to test cardiotropic drugs for myocardial infarction.
Avio-Maria Perna; Emanuela Masini; Silvia Nistri; Vittorio Briganti; Laura Chiappini; Pierluigi Stefano; Mario Bigazzi; Cesco Pieroni; Tatiana Bani Sacchi; Daniele Bani
Neural differentiation of transplanted neural stem cells in a rat model of striatal lacunar infarction: light and electron microscopic observations
The increased risk and prevalence of lacunar stroke and Parkinson's disease (PD) makes the search for better experimental models an important requirement for translational research. In this study we assess ischemic damage of the nigrostriatal pathway in a model of lacunar stroke evoked by damaging the perforating arteries in the territory of the substantia nigra (SN) of the rat after stereotaxic administration of endothelin-1 (ET-1), a potent vasoconstrictor peptide. We hypothesized that transplantation of neural stem cells (NSCs) with the capacity of differentiating into diverse cell types such as neurons and glia, but with limited proliferation potential, would constitute an alternative and/or adjuvant therapy for lacunar stroke. These cells showed neuritogenic activity in vitro and a high potential for neural differentiation. Light and electron microscopy immunocytochemistry was used to characterize GFP-positive neurons derived from the transplants. 48 h after ET-1 injection, we characterized an area of selective degeneration of dopaminergic neurons within the nigrostriatal pathway characterized with tissue necrosis and glial scar formation, with subsequent behavioral signs of Parkinsonism. Light microscopy showed that grafted cells within the striatal infarction zone differentiated with a high yield into mature glial cells (GFAP-positive) and neuron types present in the normal striatum. Electron microscopy revealed that NSCs-derived neurons integrated into the host circuitry establishing synaptic contacts, mostly of the asymmetric type. Astrocytes were closely associated with normal small-sized blood vessels in the area of infarct, suggesting a possible role in the regulation of the blood brain barrier and angiogenesis. Our results encourage the use of NSCs as a cell-replacement therapy for the treatment of human vascular Parkinsonism.
Muneton-Gomez, Vilma C.; Doncel-Perez, Ernesto; Fernandez, Ana P.; Serrano, Julia; Pozo-Rodrigalvarez, Andrea; Vellosillo-Huerta, Lara; Taylor, Julian S.; Cardona-Gomez, Gloria P.; Nieto-Sampedro, Manuel; Martinez-Murillo, Ricardo
Modeling neck and brain injuries in infants.
Researchers have studied brain injury in children by assessing linear and angular accelerations, without taking into account vibratory loads. A proposed approach employs a new mathematical head model that includes vibration to analyze how shaken-baby syndrome affects babies. To account for vibrations, it applies the finite-element method to model the stresses, strains, and displacements in the neck vertebrae and brain. This research also modeled the effects of a single blow to the head. In both cases, researchers determined the extent of alterations by comparing brain tissue strength with predictions of increased tension. The vibration results predict alterations in the cervical vertebrae in some oscillation modes and are consistent with studies of cervical cord whiplash injuries. The single-blow results predict brain and spinal cord alterations and are consistent with scanner slices made by other researchers. PMID:24808262
Ponce, E; Ponce, D
Cardiac Motion Analysis Using High-Speed Video Images in a Rat Model for Myocardial Infarction
NASA Astrophysics Data System (ADS)
In this study, we performed a cardiac motion analysis by using 1000-frames per second (fps) stereo images to capture the three-dimensional motion of small color markers in a rat heart. This method of recording cardiac motion could quantify the rate of change in the myocardial area, which indicated localized myocardial activity of rhythmic expansion and contraction. We analyzed the three-dimensional motion distributions in a rat model for myocardial infarction, in which the heart rate was 4 times/s or more. In the analysis, we spatiotemporally quantified the characteristic cardiac motion in ischemic heart diseases and found that infarction due to ischemia in the rat heart was spread around the left ventricle.
Ishii, Idaku; Okuda, Toshikazu; Nie, Yuman; Takaki, Takeshi; Orito, Kensuke; Tanaka, Akane; Matsuda, Hiroshi
A comparison between percutaneous and surgical transplantation of autologous skeletal myoblasts in a swine model of chronic myocardial infarction
Objective: Our aim was to compare the efficacy of surgical versus percutaneous administration of skeletal myoblasts (SkM) in a swine model of chronic myocardial infarction and to determine the mechanism(s) involved in their beneficial effect. Methods: Two months after induction of myocardial infarction (MI), Goettingen miniature pigs underwent autologous SkM transplant either by direct surgical injection (n=6) or percutaneous access
Juan José Gavira; Maitane Perez-Ilzarbe; Gloria Abizanda; Alba García-Rodríguez; Josune Orbe; José Antonio Páramo; Miriam Belzunce; Gregorio Rábago
Electrocardiographic Characterization of Rhesus Monkey Model of Ischemic Myocardial Infarction Induced by Left Anterior Descending Artery Ligation
Myocardial infarction is a leading cause for morbidity and mortality in the modern society. Rhesus monkeys are excellent animal\\u000a models for experimental and translational studies of cardiovascular diseases in humans. However, some detailed characterizations\\u000a of cardiovascular disease, such as myocardial infarction, in Rhesus monkeys have not been available. The present study was\\u000a undertaken to examine the progressive electrocardiographic changes in
Pingliang Yang; Pengfei Han; Jianglong Hou; Lizhi Zhang; Haibo Song; Yuping Xie; Yonglin Chen; Huiqi Xie; Fabao Gao; Y. James Kang
Traumatic brain injury using mouse models.
The use of mouse models in traumatic brain injury (TBI) has several advantages compared to other animal models including low cost of breeding, easy maintenance, and innovative technology to create genetically modified strains. Studies using knockout and transgenic mice demonstrating functional gain or loss of molecules provide insight into basic mechanisms of TBI. Mouse models provide powerful tools to screen for putative therapeutic targets in TBI. This article reviews currently available mouse models that replicate several clinical features of TBI such as closed head injuries (CHI), penetrating head injuries, and a combination of both. CHI may be caused by direct trauma creating cerebral concussion or contusion. Sudden acceleration-deceleration injuries of the head without direct trauma may also cause intracranial injury by the transmission of shock waves to the brain. Recapitulation of temporary cavities that are induced by high-velocity penetrating objects in the mouse brain are difficult to produce, but slow brain penetration injuries in mice are reviewed. Synergistic damaging effects on the brain following systemic complications are also described. Advantages and disadvantages of CHI mouse models induced by weight drop, fluid percussion, and controlled cortical impact injuries are compared. Differences in the anatomy, biomechanics, and behavioral evaluations between mice and humans are discussed. Although the use of mouse models for TBI research is promising, further development of these techniques is warranted. PMID:24493632
Zhang, Yi Ping; Cai, Jun; Shields, Lisa B E; Liu, Naikui; Xu, Xiao-Ming; Shields, Christopher B
Novel drug development opportunity for relaxin in acute myocardial infarction: evidences from a swine model.
The hormone relaxin has been shown to cause coronary vasodilation and to prevent ischemia/reperfusion-induced cardiac injury in rodents. This study provides evidence that relaxin, used as an adjunctive drug to coronary reperfusion, reduces the functional, biochemical, and histopathological signs of myocardial injury in an in vivo swine model of heart ischemia/reperfusion, currently used to test cardiotropic drugs for myocardial infarction. Human recombinant relaxin, given at reperfusion at doses of 1.25, 2.5, and 5 microg/kg b.wt. after a 30-min ischemia, caused a dose-related reduction of key markers of myocardial damage (serum myoglobin, CK-MB, troponin T) and cardiomyocyte apoptosis (caspase 3, TUNEL assay), as well as of cardiomyocyte contractile dysfunction (myofibril hypercontraction). Compared with the controls, relaxin also increased the uptake of the viability tracer 201Thallium and improved ventricular performance (cardiac index). Relaxin likely acts by reducing oxygen free radical-induced myocardial injury (malondialdehyde, tissue calcium overload) and inflammatory leukocyte recruitment (myeloperoxidase). The present findings show that human relaxin, given as a drug to counteract reperfusion-induced cardiac injury, affords a clear-cut protection to the heart of swine with induced myocardial infarction. The findings also provide background to future clinical trials with relaxin as adjunctive therapy to catheter-based coronary angioplasty in patients with acute myocardial infarction. PMID:16009702
Perna, Avio-Maria; Masini, Emanuela; Nistri, Silvia; Briganti, Vittorio; Chiappini, Laura; Stefano, Pierluigi; Bigazzi, Mario; Pieroni, Cesco; Bani Sacchi, Tatiana; Bani, Daniele
Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion.
1. Defibrotide, a single-stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, pro-fibrinolytic and prostacyclin-stimulating properties. 2. The present study was designed to evaluate the effects of defibrotide on infarct size and regional myocardial blood flow in a rabbit model of myocardial ischaemia and reperfusion. 3. Defibrotide (32 mg kg-1 bolus + 32 mg kg-1 h-1, i.v.) either with or without co-administration of indomethacin (5 mg kg-1 x 2, i.v.) was administered 5 min after occlusion of the left anterior-lateral coronary artery and continued during the 60 min occlusion and subsequent 3 h reperfusion periods. 4. Defibrotide significantly attenuated the ischaemia-induced ST-segment elevation and abolished the reperfusion-related changes (R-wave reduction and Q-wave development) in the electrocardiogram. In addition, defibrotide significantly improved myocardial blood flow in normal and in ischaemic, but not in infarcted sections of the heart. The improvement in blood flow in normal perfused myocardium, but not in the ischaemic area was prevented by indomethacin. 5. Although the area at risk was similar in all animal groups studied, defibrotide treatment resulted in a 51% reduction of infarct size. Indomethacin treatment abolished the reduction of infarct size seen with defibrotide alone. 6. The data demonstrate a considerable cardioprotective effect of defibrotide in the reperfused ischaemic rabbit myocardium. This effect may be related, at least in part, to a stimulation of endogenous prostaglandin formation. Other possible mechanisms are discussed.
Thiemermann, C.; Thomas, G. R.; Vane, J. R.
Electrocardiographic characterization of rhesus monkey model of ischemic myocardial infarction induced by left anterior descending artery ligation.
Myocardial infarction is a leading cause for morbidity and mortality in the modern society. Rhesus monkeys are excellent animal models for experimental and translational studies of cardiovascular diseases in humans. However, some detailed characterizations of cardiovascular disease, such as myocardial infarction, in Rhesus monkeys have not been available. The present study was undertaken to examine the progressive electrocardiographic changes in Rhesus monkeys after left anterior descending (LAD) artery ligation. Male Rhesus monkeys, aged 2-3 years and weighed 4.5-6.0 kg, were subjected to LAD ligation along with sham-operated controls. At 1 week, 1 month, and 6 months after the LAD ligation, ECG recording was performed to detect the progressive changes in ECG. In addition, cardiac magnetic resonance imaging (MRI) and echocardiography were applied to detect the myocardial infarction induced by LAD ligation, and histopathological examination was performed at the end of the experiment to measure the morphological changes. The results showed that QRS and ST-T changed significantly within 1 month after LAD ligation, but recovered to normal at the end of the experiment. The most significant change was a progressive QTc prolongation, which occurred corresponding to the development of myocardial infarction. Both cardiac MRI and echocardiography detected the myocardial infarction that was confirmed by the histopathological examination. This detailed characterization of ECG changes along with the development of myocardial infarction induced by LAD ligation thus demonstrated that the Rhesus monkey model of ischemic myocardial infarction would be an excellent surrogate for human myocardial infarction. This model would also provide an excellent tool for drug discovery and development for cardiac disease. PMID:21792668
Yang, Pingliang; Han, Pengfei; Hou, Jianglong; Zhang, Lizhi; Song, Haibo; Xie, Yuping; Chen, Yonglin; Xie, Huiqi; Gao, Fabao; Kang, Y James
MALDI Mass Spectrometric Imaging of Cardiac Tissue Following Myocardial Infarction in a Rat Coronary Artery Ligation Model
Although acute myocardial infarction (MI) is consistently among the top causes of death in the United States, the spatial distribution of lipids and metabolites following MI remains to be elucidated. This work presents the investigation of an in vivo rat model of MI using mass spectrometric imaging (MSI) and multivariate data analysis. MSI was conducted on cardiac tissue following a 24-hour left anterior descending coronary artery ligation in order to analyze multiple compound classes. First, the spatial distribution of a small metabolite, creatine, was used to identify areas of infarcted myocardium. Second, multivariate data analysis and tandem mass spectrometry were used to identify phospholipid (PL) markers of MI. A number of lysophospholipids demonstrated increased ion signal in areas of infarction. In contrast, select intact PLs demonstrated decreased ion signal in the area of infarction. The complementary nature of these two lipid classes suggest increased activity of phospholipase A2, an enzyme that has been implicated in coronary heart disease and inflammation.
Menger, Robert F.; Stutts, Whitney L.; Anbukumar, Dhanam S.; Bowden, John A.; Ford, David A.; Yost, Richard A.
Inadvertent Occlusion of the Anterior Choroidal Artery Explains Infarct Variability in the Middle Cerebral Artery Thread Occlusion Stroke Model
Intraluminal occlusion of the middle cerebral artery (MCAo) in rodents is perhaps the most widely used model of stroke, however variability of infarct volume and the ramifications of this on sample sizes remains a problem, particularly for preclinical testing of potential therapeutics. Our data and that of others, has shown a dichotomous distribution of infarct volumes for which there had previously been no clear explanation. When studying perfusion computed tomography cerebral blood volume (CBV) maps obtained during intraluminal MCAo in rats, we observed inadvertent occlusion of the anterior choroidal artery (AChAo) in a subset of animals. We hypothesized that the combined occlusion of the MCA and AChA may be a predictor of larger infarct volume following stroke. Thus, we aimed to determine the correlation between AChAo and final infarct volume in rats with either temporary or permanent MCA occlusion (1 h, 2 h, or permanent MCAo). Outbred Wistar rats (n?=?28) were imaged prior to and immediately following temporary or permanent middle cerebral artery occlusion. Presence of AChAo on CBV maps was shown to be a strong independent predictor of 24 h infarct volume (??=?0.732, p <0.001). This provides an explanation for the previously observed dichotomous distribution of infarct volumes. Interestingly, cortical infarct volumes were also larger in rats with AChAo, although the artery does not supply cortex. This suggests an important role for perfusion of the MCA territory beyond the proximal occlusion through AChA-MCA anastomotic collateral vessels in animals with a patent AChAo. Identification of combined MCAo and AChAo will allow other investigators to tailor their stroke model to reduce variability in infarct volumes, improve statistical power and reduce sample sizes in preclinical stroke research.
McLeod, Damian D.; Beard, Daniel J.; Parsons, Mark W.; Levi, Christopher R.; Calford, Mike B.; Spratt, Neil J.
A Locus Mapping to Mouse Chromosome 7 Determines Infarct Volume in a Mouse Model of Ischemic Stroke
Background In a mouse model of focal cerebral ischemia, infarct volume is highly variable and strain dependent, but the natural genetic determinants responsible for this difference remain unknown. To identify genetic determinants regulating ischemic neuronal damage and to dissect apart the role of individual genes and physiological mechanisms in infarction in mice, we performed quantitative trait locus analysis of surgically induced cerebral infarct volume. Methods and Results After permanent occlusion of the distal middle cerebral artery, infarct volume was determined for 16 inbred strains of mice, chromosome substitution strains, and for 2 intercross cohorts, F2 (B6×BALB/c) and F2 (B6×SWR/J). Genome-wide linkage analysis was performed for infarct volume as a quantitative trait. Infarct volume varied up to 30-fold between strains, with heritability estimated at 0.88. Overall, 3 quantitative trait locus were identified that modulate infarct volume, with a major locus (Civq1) on chromosome 7 accounting for >50% of the variation, with a combined LOD score of 21.7. Interval-specific single nucleotide polymorphism haplotype analysis for Civq1 results in 12 candidate genes. Conclusions The extent of ischemic tissue damage after distal middle cerebral artery occlusion in inbred strains of mice is modulated by genetic variation mapping to at least 3 different loci. A single locus on chromosome 7 determines the majority of the observed variation in the trait. This locus seems to be identical to LSq1, a locus conferring limb salvage and reperfusion in a mouse model of hindlimb ischemia. The identification of the genes underlying these loci may uncover novel genetic and physiological pathways that modulate cerebral infarction and provide new targets for therapeutic intervention in ischemic stroke, and possibly other ischemic diseases.
Keum, Sehoon; Marchuk, Douglas A.
Magnetic targeting enhances retrograde cell retention in a rat model of myocardial infarction
Introduction Retrograde coronary venous infusion is a promising delivery method for cellular cardiomyoplasty. Poor cell retention is the major obstacle to the establishment of this method as the preferred route for cell delivery. Here, we explored whether magnetic targeting could enhance retrograde cell retention in a rat model of myocardial infarction. Methods Rat mesenchymal stem cells were labeled with superparamagnetic oxide nanoparticles. The magnetic responsiveness of MSCs was observed while cells flowed through a tube that served as a model of blood vessels in a 0.6-Tesla magnetic field. In a Sprague–Dawley rat model of acute myocardial infarction, 1?×?106 magnetic mesenchymal stem cells were transjugularly injected into the left cardiac vein while a 0.6-Tesla magnet was placed above the heart. The cardiac retention of transplanted cells was assessed by using quantitative Y chromosome-specific polymerase chain reaction, cardiac magnetic resonance imaging, and optical imaging. Cardiac function was measured by using echocardiography, and histologic analyses of infarct morphology and angiogenesis were obtained. Results The flowing iron oxide-labeled mesenchymal stem cells were effectively attracted to the area where the magnet was positioned. Twenty-four hours after cellular retrocoronary delivery, magnetic targeting significantly increased the cardiac retention of transplanted cells by 2.73- to 2.87-fold. Histologic analyses showed that more transplanted cells were distributed in the anterior wall of the left ventricle. The enhanced cell engraftment persisted for at least 3 weeks, at which time, left ventricular remodeling was attenuated, and cardiac function benefit was improved. Conclusions These results suggest that magnetic targeting offers new perspectives for retrograde coronary venous delivery to enhance cell retention and subsequent functional benefit in heart diseases.
A model to determine the effect of collagen fiber alignment on heart function post myocardial infarction
Background Adverse remodeling of the left ventricle (LV) following myocardial infarction (MI) leads to heart failure. Recent studies have shown that scar anisotropy is a determinant of cardiac function post-MI, however it remains unclear how changes in extracellular matrix (ECM) organization and structure contribute to changes in LV function. The objective of this study is to develop a model to identify potential mechanisms by which collagen structure and organization affect LV function post-MI. Methods A four-region, multi-scale, cylindrical model of the post-MI LV was developed. The mechanical properties of the infarct region are governed by a constitutive equation based on the uncrimping of collagen fibers. The parameters of this constitutive equation include collagen orientation, angular dispersion, fiber stiffness, crimp angle, and density. Parametric variation of these parameters was used to elucidate the relationship between collagen properties and LV function. Results The mathematical model of the LV revealed several factors that influenced cardiac function post-MI. LV function was maximized when collagen fibers were aligned longitudinally. Increased collagen density was also found to improve stroke volume for longitudinal alignments while increased fiber stiffness decreased stroke volume for circumferential alignments. Conclusions The results suggest that cardiac function post-MI is best preserved through increased circumferential compliance. Further, this study identifies several collagen fiber-level mechanisms that could potentially regulate both infarct level and organ level mechanics. Improved understanding of the multi-scale relationships between the ECM and LV function will be beneficial in the design of new diagnostic and therapeutic technologies.
Studies of isolated global brain ischaemia: I. A new large animal model of global brain ischaemia and its baseline perfusion studies
OBJECTIVES Neurological injury after global brain ischaemia (i.e. sudden death) remains problematic, despite improving cardiac survival. Unfortunately, sudden death models introduce unwanted variables for studying the brain because of multiple organ injury. To circumvent this, a new minimally invasive large animal model of isolated global brain ischaemia, together with baseline perfusion studies is described. METHODS The model employs neck and small (3–4 inches) supra-sternal incisions to block inflow from carotid and vertebral arteries for 30 min of normothermic ischaemia. Neurological changes after 24 h in six pigs was compared with six Sham pigs assessing neurological deficit score (NDS, 0 = normal, 500 = brain death), brain oedema and cerebral infarction by 2,3,5-triphenyltetrazolium chloride (TTC) stain. Six other pigs had baseline perfusion characteristics in this new model evaluated at carotid flows of 750, 550 and 450 cc/min, with cerebral perfusion pressure, cerebral oximeter saturation [IN Vivo Optical Spectroscopy (INVOS)] and transcranial O2 uptake measurements. RESULTS The model never altered cardiac or pulmonary function, and six Sham pigs had normal (NDS = 0) neurological recovery without brain injury. Conversely, 24 h analysis showed that 30 min of global normothermic brain ischaemia caused multiple post-reperfusion seizures (P < 0.001 versus Sham), raised NDS (231 ± 16; P < 0.001 versus Sham) in four of six survivors and caused marked post-brain oedema (P < 0.001 versus Sham) and extensive cerebral infarctions (TTC stain; P < 0.001 versus Sham). Baseline perfusion showed 750 cc/min flow rate produced normal INVOS levels and O2 consumption at mean 90–100 mmHg carotid pressure. Carotid pressure and INVOS fell at mid- and low-flow rates. Although INVOS did not change, 450 cc/min flow lowered global O2 consumption, which further decreased after transient ischaemia (30 s) and 5 min of reperfusion. CONCLUSIONS This new isolated global brain model consistently caused anatomic, biochemical and functional neurological damage in pigs after 30 min of ischaemia. Flows of 750 cc/min maintained normal mean systemic arterial (90–100 mmHg) pressure, INVOS levels and O2 consumption. Cerebral pressure and INVOS fell in mid- and low-flow studies. A disparity existed between INVOS oxygen saturation and global O2 consumption at lower flow rates of 450 cc/min following transient ischaemia, indicating that surface oxygen saturation measurement does not reflect global brain O2 consumption.
Allen, Bradley S.; Ko, Yoshihiro; Buckberg, Gerald D.; Sakhai, Sean; Tan, Zhong
A rat model of photothrombotic capsular infarct with a marked motor deficit: a behavioral, histologic, and microPET study.
We present a new method for inducing a circumscribed subcortical capsular infarct (SCI), which imposes a persistent motor impairment in rats. Photothrombotic destruction of the internal capsule (IC) was conducted in Sprague Dawley rats (male; n=38). The motor performance of all animals was assessed using forelimb placing, forelimb use asymmetry, and the single pellet reaching test. On the basis of the degree of motor recovery, rats were subdivided into either the poor recovery group (PRG) or the moderate recovery group (MRG). Imaging assessment of the impact of SCI on brain metabolism was performed using 2-deoxy-2-[(18)F]-fluoro-D-glucose ([(18)F]-FDG) microPET (positron emission tomography). Photothrombotic lesioning using low light energy selectively disrupted circumscribed capsular fibers. The MRG showed recovery of motor performance after 1 week, but the PRG showed a persistent motor impairment for >3 weeks. Damage to the posterior limb of the IC (PLIC) is more effective for producing a severe motor deficit. Analysis of PET data revealed decreased regional glucose metabolism in the ipsilesional motor and bilateral sensory cortex and increased metabolism in the contralesional motor cortex and bilateral hippocampus during the early recovery period after SCI. Behavioral, histologic, and functional imaging findings support the usefulness of this novel SCI rat model for investigating motor recovery. PMID:24473479
Kim, Hyung-Sun; Kim, Donghyeon; Kim, Ra Gyung; Kim, Jin-Myung; Chung, Euiheon; Neto, Pedro R; Lee, Min-Cheol; Kim, Hyoung-Ihl
Brain drain, remittances, and fertility model
How do high and low skilled migration affect fertility and human capital in migrants' origin countries? This question is analyzed within an overlapping generations model where parents choose the number of high and low skilled children they would like to have. Individuals migrate with a certain probability and remit to their parents. It is shown that a brain drain induces
Luca Marchiori; Patrice Pieretti; Benteng Zou
Cytokine Combination Therapy with Erythropoietin and Granulocyte Colony Stimulating Factor in a Porcine Model of Acute Myocardial Infarction
Purpose Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial\\u000a infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the\\u000a impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI\\u000a in a porcine model.\\u000a \\u000a \\u000a \\u000a \\u000a Methods MI
Franca S. Angeli; Nicolas Amabile; Mia Shapiro; Rachel Mirsky; Lauren Bartlett; Yan Zhang; Renu Virmani; Kanu Chatterjee; Andrew Boyle; William Grossman; Yerem Yeghiazarians
Neurodynamical model of collective brain
NASA Technical Reports Server (NTRS)
A dynamical system which mimics collective purposeful activities of a set of units of intelligence is introduced and discussed. A global control of the unit activities is replaced by the probabilistic correlations between them. These correlations are learned during a long term period of performing collective tasks, and are stored in the synaptic interconnections. The model is represented by a system of ordinary differential equations with terminal attractors and repellers, and does not contain any man-made digital devices.
Zak, Michail
We have described a patient with an acute condition of the abdomen who had infarction of the stomach and the small intestine due to atheromatous thrombus of celiac and superior mesenteric arteries. We believe this unusual simultaneous occurrence of gastric and small intestinal infarction is coincidental. The outcome of gastric infarction is frequently fatal. PMID:2000538
Lin, J I; Park, Y S; Gopalsway, N
Beneficial Effects of Schisandrin B on the Cardiac Function in Mice Model of Myocardial Infarction
The fruit of Schisandra chinensis has been used in the traditional Chinese medicine for thousands of years. Accumulating evidence suggests that Schisandrin B (Sch B) has cardioprotection effect on myocardial ischemia in vitro. However, it is unclear whether Sch B has beneficial effects on continuous myocardial ischemia in vivo. The aim of the present study was to investigate whether Sch B could improve cardiac function and attenuate myocardial remodeling after myocardial infarction (MI) in mice. Mice model of MI was established by permanent ligation of the left anterior descending (LAD) coronary artery. Then the MI mice were randomly treated with Sch B or vehicle alone. After treatment for 3 weeks, Sch B could increase survival rate, improve heart function and decrease infarct size compared with vehicle. Moreover, Sch B could down-regulate some inflammatory cytokines, activate eNOS pathway, inhibit cell apoptosis, and enhance cell proliferation. Further in vitro study on H9c2 cells showed similar effects of Sch B on prevention of hypoxia-induced inflammation and cell apoptosis. Taken together, our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after ischemic injury. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.
Chen, Pengsheng; Pang, Sisi; Yang, Naiquan; Meng, Haoyu; Liu, Jia; Zhou, Ningtian; Zhang, Min; Xu, Zhihui; Gao, Wei; Chen, Bo; Tao, Zhengxian; Wang, Liansheng; Yang, Zhijian
Erythropoietin Enhances the Angiogenic Potency of Autologous Bone Marrow Stromal Cells in a Rat Model of Myocardial Infarction
Background: Transplantation of marrow stromal cells (MSC) has been shown to improve heart perfusion and cardiac function after ischemia. Erythropoietin (EPO) is capable of inducing angiogenesis and inhibiting cell apoptosis. The aim of this study was to investigate the effect of EPO on the therapeutic potency of MSC transplantation in a rat model of myocardial infarction. Methods: MSC viability was
Dingguo Zhang; Fumin Zhang; Yuqing Zhang; Xiang Gao; Chuanfu Li; Wengzhu Ma; Kejiang Cao
The Detection of Surfactant Proteins A, B, C and D in the Human Brain and Their Regulation in Cerebral Infarction, Autoimmune Conditions and Infections of the CNS
Surfactant proteins (SP) have been studied intensively in the respiratory system. Surfactant protein A and surfactant protein D are proteins belonging to the family of collectins each playing a major role in the innate immune system. The ability of surfactant protein A and surfactant protein D to bind various pathogens and facilitate their elimination has been described in a vast number of studies. Surfactant proteins are very important in modulating the host's inflammatory response and participate in the clearance of apoptotic cells. Surfactant protein B and surfactant protein C are proteins responsible for lowering the surface tension in the lungs. The aim of this study was an investigation of expression of surfactant proteins in the central nervous system to assess their specific distribution patterns. The second aim was to quantify surfactant proteins in cerebrospinal fluid of healthy subjects compared to patients suffering from different neuropathologies. The expression of mRNA for the surfactant proteins was analyzed with RT-PCR done with samples from different parts of the human brain. The production of the surfactant proteins in the brain was verified using immunohistochemistry and Western blot. The concentrations of the surfactant proteins in cerebrospinal fluid from healthy subjects and patients suffering from neuropathologic conditions were quantified using ELISA. Our results revealed that surfactant proteins are present in the central nervous system and that the concentrations of one or more surfactant proteins in healthy subjects differed significantly from those of patients affected by central autoimmune processes, CNS infections or cerebral infarction. Based on the localization of the surfactant proteins in the brain, their different levels in normal versus pathologic samples of cerebrospinal fluid and their well-known functions in the lungs, it appears that the surfactant proteins may play roles in host defense of the brain, facilitation of cerebrospinal fluid secretion and maintenance of the latter's rheological properties.
Schob, Stefan; Schicht, Martin; Sel, Saadettin; Stiller, Dankwart; Kekule, Alexander; Paulsen, Friedrich; Maronde, Erik; Brauer, Lars
Zebrafish as an alternative model for hypoxic-ischemic brain damage
Acute cerebral ischemia is one of the leading causes of mortality and chronic disability. Animal models provide an essential tool for understanding the complex cellular and molecular pathophysiology of hypoxic-ischemia and for testing novel neuroprotective drugs in the pre-clinical setting. In this study we tested zebrafish as a novel model for hypoxic-ischemic brain damage. We built an air-proof chamber where water inside had a low oxygen concentration (0.6-0.8 mg/L) proximate to complete hypoxia. Each zebrafish was placed individually in the hypoxia chamber and was subjected to hypoxia treatment until it became motionless, lying on its side on the bottom of the chamber (time to hypoxia = 679.52 ± 90 seconds, mean ± SD, n =23), followed by transferring into a recovery beaker. Overall, 60.87% of subjects did not recover from hypoxia while 39% survived. The size and distribution of brain injury were determined by triphenyltetrazolium chloride (TTC) staining. Bilateral, moderate to complete TTC decoloration or demarcation of the infarct after 10 minutes of hypoxic treatment was clearly visible in the optic tectum of the optic lobe. The size of the infarct expanded to the deep structure of the optic lobe with longer hypoxic treatments. The zebrafish that survived hypoxia experienced initial twitching followed by unbalanced erratic movements until they regained coordinated, balanced swimming ability. These data indicate that zebrafish are susceptible to hypoxic attack and suggest that the model we present in this study can be used as an alternative model to evaluate hypoxia-induced brain damage.
Yu, Xinge; Li, Yang V
New Strategies for Echocardiographic Evaluation of Left Ventricular Function in a Mouse Model of Long-Term Myocardial Infarction
Background The aim of this article is to present an optimized acquisition and analysis protocol for the echocardiographic evaluation of left ventricle (LV) remodeling in a mouse model of myocardial infarction (MI). Methodology 13 female DBA/2J mice underwent permanent occlusion of the left anterior descending (LAD) coronary artery leading to MI. Mice echocardiography was performed using a Vevo 770 (Visualsonics, Canada) before infarction, and 7, 14, 30, 60, 90 and 120 days after LAD ligation. LV systolic function was evaluated using different parameters, including the fractional area change (FAC%) computed in four high-temporal resolution B-mode short axis images taken at different ventricular levels, and in one parasternal long axis. Pulsed wave and tissue Doppler modes were used to evaluate the diastolic function and Tei Index for global cardiac function. The echocardiographic measurements of infarct size were validated histologically using collagen deposition labeled by Sirius red staining. All data was analyzed using Shapiro-Wilk and Student's t-tests. Principal Findings Our results reveal LV dilation resulting in marked remodeling an severe systolic dysfunction, starting seven days after MI (LV internal apical diameter, basal?=?2.82±0.24, 7d?=?3.49±0.42; p<0.001. End-diastolic area, basal?=?18.98±1.81, 7d?=?22.04±2.11; p<0.001). A strong statistically significant negative correlation exists between the infarct size and long-axis FAC% (r?=??0.946; R2?=?0.90; p<0.05). Moreover, the measured Tei Index values confirmed significant post-infarction impairment of the global cardiac function (basal?=?0.46±0.07, 7d?=?0.55±0.08, 14 d?=?0.57±0.06, 30 d?=?0.54±0.06, 60 d?=?0.54±0.07, 90 d?=?0.57±0.08; p<0.01). Conclusions/Significance In summary, we have performed a complete characterization of LV post-infarction remodeling in a DBA/2J mouse model of MI, using parameters adapted to the particular characteristics of the model In the future, this well characterized model will be used in both investigative and pharmacological studies that require accurate quantitative monitoring of cardiac recovery after myocardial infarction.
Benavides-Vallve, Carolina; Corbacho, David; Iglesias-Garcia, Olalla; Pelacho, Beatriz; Albiasu, Edurne; Castano, Sara; Munoz-Barrutia, Arrate; Prosper, Felipe; Ortiz-de-Solorzano, Carlos
On a Quantum Model of Brain Activities
NASA Astrophysics Data System (ADS)
One of the main activities of the brain is the recognition of signals. A first attempt to explain the process of recognition in terms of quantum statistics was given in [6]. Subsequently, details of the mathematical model were presented in a (still incomplete) series of papers (cf. [7, 2, 5, 10]). In the present note we want to give a general view of the principal ideas of this approach. We will introduce the basic spaces and justify the choice of spaces and operations. Further, we bring the model face to face with basic postulates any statistical model of the recognition process should fulfill. These postulates are in accordance with the opinion widely accepted in psychology and neurology.
Fichtner, K.-H.; Fichtner, L.; Freudenberg, W.; Ohya, M.
Animal models of traumatic brain injury.
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies. PMID:23329160
Xiong, Ye; Mahmood, Asim; Chopp, Michael
Effects of nerve growth factor on the action potential duration and repolarizing currents in a rabbit model of myocardial infarction
Objectives To investigate the effect of nerve growth factor (NGF) on the action potential and potassium currents of non-infarcted myocardium in the myocardial infarcted rabbit model. Methods Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (healed myocardial infarction, HMI). During ligation surgery of the left coronary artery, a polyethylene tube was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/d for eight weeks (HMI + NGF group). Cardiomyocytes were isolated from regions of the non-infarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps. Results Compared with HMI and control cardiomyocytes, significant prolongation of APD50 or APD90 (Action potential duration (APD) measured at 50% and 90% of repolarization) in HMI + NGF cardiomyocytes was found. The results showed that the 4-aminopyridine sensitive transient outward potassium current (Ito), the rapidly activated omponent of delayed rectifier potassium current (IKr), the slowly activated component of delayed rectifier potassium current (IKs), and the L-type calcium current (ICaL) were significantly altered in NGF + HMI cardiomyocytes compared with HMI and control cells. Conclusions Our results suggest that NGF treatment significantly prolongs APD in HMI cardiomyocytes and that a decrease in outward potassium currents and an increase of inward Ca2+ current are likely the underlying mechanism of action.
Lan, Yun-Feng; Zhang, Jian-Cheng; Gao, Jin-Lao; Wang, Xue-Ping; Fang, Zhou; Fu, Yi-Cheng; Chen, Mei-Yan; Lin, Min; Xue, Qiao; Li, Yang
Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells.
Recently, preclinical studies have shown that allogeneic adipose-derived stem cells (ASCs), like bone marrow-derived mesenchymal stem cell (BMSCs) have significant clinical benefits in treating cardiovascular diseases, such as ischemic/infarcted heart. In this study, we tested whether ASCs are also immune tolerant, such that they can be used as universal donor cells for myocardial regenerative therapy. The study also focuses on investigating the potential therapeutic effects of human ASCs (hASCs) for myocardial infarction in xenotransplant model, and compares its effects with that of hBMSCs. The in vitro study confirms the superior proliferation potential and viability of hASCs under normoxic and stressed hypoxic conditions compared with hBMSCs. hASCs also show higher potential in adopting cardiomyocyte phenotype. The major findings of the in vivo study are that (1) both hASCs and hBMSCs implanted into immunocompetent rat hearts with acute myocardial infarction survived the extreme environment of xenogeneic mismatch for 6 weeks; (2) both hASCs and hBMSCs showed significant improvement in myocardial pro/anti-inflammatory cytokine levels with no detectable inflammatory reaction, despite the lack of any immunosuppressive therapy; and (3) hASCs contributed to the remarkable improvement in cardiac function and reduced infarction which was significantly better than that of hBMSC and untreated control groups. Thus, our findings suggest the feasibility of using ASCs, instead of BMSCs, as universal donor cells for xenogeneic or allogeneic cell therapy. PMID:22205499
Paul, Arghya; Srivastava, Sapna; Chen, Guangyong; Shum-Tim, Dominique; Prakash, Satya
Quantitative assessment of regional myocardial function in a rat model of myocardial infarction using tagged MRI
We characterized global and regional left ventricular (LV) function during post myocardium infarction (MI) remodeling in rats, which has been incompletely described by previous MRI studies. To assess regional wall motion, four groups of infarcted animals corresponding to 1–2, 3–4, 6–8 and 9–12 weeks post-MI respectively were imaged using a fast gradient echo sequence with a 2D spatial modulation of magnetization (SPAMM) tagging preparation. An additional group was serially imaged (1–2 and 6–7 weeks post-MI) to assess the global function. Regional and global functional parameters of infarcted rats were compared to non-infarcted normal rats. Compared to normal rats, a decrease in ejection fraction (70 ± 7 vs. 40 ± 8%, p < 0.05) was observed in rats with MI. Maximal and minimal principal stretches (?1, ?2) and strains (E1, E2), principal angle (?) and displacement varied regionally in normal rats but deviated significantly from the normal values in rats with MI particularly in the infarcted and adjacent zones. Not only was strain magnitude reduced segmentally post-MI, but strain direction became more circumferentially oriented, particularly in rats with larger infarctions. We report the first regional myocardial strain values in normal and infarcted rats. These results parallel findings in humans, and provide a unique tool to examine regional mechanical influences on the remodeling process.
Thomas, D.; Ferrari, V. A.; Janik, M.; Kim, D. H.; Pickup, S.; Glickson, J. D.; Zhou, R.
Modelling brain emergent behaviours through coevolution of neural agents
Recently, many research efforts focus on modelling partial brain areas with the long-term goal to support cognitive abilities of artificial organisms. Existing models usually suffer from heterogeneity, which constitutes their integration very difficult. The present work introduces a computational framework to address brain modelling tasks, emphasizing on the integrative performance of substructures. Moreover, implemented models are embedded in a robotic
Michail Maniadakis; Panos Trahanias
An Improved Transplantation Strategy for Mouse Mesenchymal Stem Cells in an Acute Myocardial Infarction Model
To develop an effective therapeutic strategy for cardiac regeneration using bone marrow mesenchymal stem cells (BM-MSCs), the primary mouse BM-MSCs (1st BM-MSCs) and 5th passage BM-MSCs from ?-galactosidase transgenic mice were respectively intramyocardially transplanted into the acute myocardial infarction (AMI) model of wild type mice. At the 6th week, animals/tissues from the 1st BM-MSCs group, the 5th passage BM-MSCs group, control group were examined. Our results revealed that, compared to the 5th passage BM-MSCs, the 1st BM-MSCs had better therapeutic effects in the mouse MI model. The 1st BM-MSCs maintained greater differentiation potentials towards cardiomocytes or vascular endothelial cells in vitro. This is indicated by higher expressions of cardiomyocyte and vascular endothelial cell mature markers in vitro. Furthermore, we identified that 24 proteins were down-regulated and 3 proteins were up-regulated in the 5th BM-MSCs in comparison to the 1st BM-MSCs, using mass spectrometry following two-dimensional electrophoresis. Our data suggest that transplantation of the 1st BM-MSCs may be an effective therapeutic strategy for cardiac tissue regeneration following AMI, and altered protein expression profiles between the 1st BM-MSCs and 5th passage BM-MSCs may account for the difference in their maintenance of stemness and their therapeutic effects following AMI.
Jin, Jianliang; Zhao, Yingming; Tan, Xiao; Guo, Chun; Yang, Zhijian; Miao, Dengshun
Ventricular Arrhythmias and Mortality Associated with Isoflurane and Sevoflurane in a Porcine Model of Myocardial Infarction
Ischemia of the myocardium can lead to reversible or irreversible injury depending on the severity and duration of the preceding ischemia. Here we compared sevoflurane and isoflurane with particular reference to their hemodynamic effects and ability to modify the effects of acute severe myocardial ischemia and reperfusion on ventricular arrhythmias and mortality in a porcine model of myocardial infarction. Female Large White pigs were premedicated with ketamine, midazolam, and atropine. Propofol was given intravenously for the anesthetic induction, and anesthesia was maintained with isoflurane or sevoflurane. Endovascular, fluoroscopy-guided, coronary procedures were performed to occlude the midleft anterior descending artery by using a coronary angioplasty balloon. After 75 min, the balloon catheter system was withdrawn and the presence of adequate reperfusion flow was verified. The pigs were followed for 2 mo, and overall mortality rate was calculated. The isoflurane group showed lower arterial pressure throughout the procedure, with the difference reaching statistical significance after induction of myocardial ischemia. The ventricular fibrillation rate was higher in isoflurane group (81.3%) than the sevoflurane group (51.7%; relative risk, 1.57 [1.03 to 2.4]). Overall survival was lower in the isoflurane group (75%) than the sevoflurane group (96.4%). In conclusion, in this porcine model of myocardial ischemia and reperfusion, sevoflurane was associated with higher hemodynamic stability and fewer ventricular arrhythmias and mortality than was isoflurane.
Regueiro-Purrinos, Marta; Fernandez-Vazquez, Felipe; de Prado, Armando Perez; Altonaga, Jose R; Cuellas-Ramon, Carlos; Ajenjo-Silverio, Jose M; Orden, Asuncion; Gonzalo-Orden, Jose M
Selection of a suitable numerical model to represent brain tissue
Mathematical models are often employed to better understand the internal dynamics of the human head under impact loading. Mathematical models require accurate material properties of the brain in order to make accurate predictions. The objective of this study was to determine a specific material model for the brain tissue by examining different material laws and determining respective constants. Five finite
Jagadish K Narayanaswamy
Peri-infarct Blood-Brain Barrier Dysfunction Facilitates Induction of Spreading Depolarization Associated with Epileptiform Discharges
Recent studies showed that spreading depolarizations (SDs) occur abundantly in patients following ischemic stroke and experimental evidence suggests that SDs recruit tissue at risk into necrosis. We hypothesized that BBB opening with consequent alterations of the extracellular electrolyte composition and extravasation of albumin facilitates generation of SDs since albumin mediates an astrocyte transcriptional response with consequent disturbance of potassium and glutamate homeostasis. Here we show extravasation of Evans blue-albumin complex into the hippocampus following cortical photothrombotic stroke in the neighbouring neocortex. Using extracellular field potential recordings and exposure to serum electrolytes we observed spontaneous SDs in 80 % of hippocampal slices obtained from rats 24 h after cortical photothrombosis. Hippocampal exposure to albumin for 24 h through intraventricular application together with serum electrolytes lowered the threshold for the induction of SDs in most slices irrespective of the pathway of stimulation. Exposing acute slices from naive animals to albumin led also to a reduced SD threshold. In albumin-exposed slices the onset of SDs was usually associated with larger stimulus-induced accumulation of extracellular potassium, and preceded by epileptiform activity, which was also observed during the recovery phase of SDs. Application of ifenprodil (3?M), an NMDA-receptor type 2 B antagonist, blocked stimulus dependent epileptiform discharges and generation of SDs in slices from animals treated with albumin in-vivo. We suggest that BBB opening facilitates the induction of peri-infarct SDs through impaired homeostasis of K+.
Lapilover, EG; Lippman, K.; Salar, S.; Maslarova, A.; Dreier, JP; Heinemann, U.; Friedman, A.
Stem Cell Therapy with Overexpressed VEGF and PDGF Genes Improves Cardiac Function in a Rat Infarct Model
BackgroundTherapeutic potential was evaluated in a rat model of myocardial infarction using nanofiber-expanded human cord blood derived hematopoietic stem cells (CD133+\\/CD34+) genetically modified with VEGF plus PDGF genes (VIP).Methods and FindingsMyocardial function was monitored every two weeks up to six weeks after therapy. Echocardiography revealed time dependent improvement of left ventricular function evaluated by M-mode, fractional shortening, anterior wall tissue
Hiranmoy Das; Jon C. George; Matthew Joseph; Manjusri Das; Nasreen Abdulhameed; Anna Blitz; Mahmood Khan; Ramasamy Sakthivel; Hai-Quan Mao; Brian D. Hoit; Periannan Kuppusamy; Vincent J. Pompili
A novel method for the estimation of infarct size in a reperfused rat model for pinhole SPECT
Cardiac SPECT imaging using pinhole collimators can be used to perform in-vivo rat studies in order to evaluate cardiovascular diseases. The estimation of infarct size in a rat model of coronary artery disease, with [99mTc]sestamibi, is typically done using a single threshold for all the studies. However, the presence of high statistical noise in the data can result in inaccuracies
Harshali Bal; Daniel Thomas; Zixiong Cao; Victor Ferrari; Jim Horowitz; Paul D. Acton
Association between common genetic variants of ?2A-, ?2B? and ?2C-adrenoceptors and the risk of silent brain infarction.
Silent brain infarction (SBI) is an asymptomatic cerebrovascular disorder. The aim of the present study was to investigate the association between adrenoceptor??2 (ADRA2) gene polymorphisms and SBI. A total of 361 patients with SBI and 467 healthy control subjects were examined. The polymerase chain reaction was performed to genotype the ADRA2A 1780G>A, ADRA2B 301?303 insertion/deletion (I/D) and ADRA2C 322?325I/D polymorphisms. The frequency of the ADRA2C 322?325I/D polymorphism was significantly different between patients with SBI and control subjects. When interaction analyses were performed for vascular risk factors, the ADRA2C 322?325ID genotype increased the risk for SBI in the presence of hypertension and elevated plasma homocysteine levels. The ADRA2C 322?325ID genotype and plasma homocysteine levels showed a significant synergistic effect for SBI. In addition, the ADRA2A 1780AA genotype was associated with elevated plasma homocysteine levels. Although further analysis of the association between ADRA2 polymorphisms and clinical risk factors of SBI is required, the present study of a limited set of SBI risk factors with ADRA2 polymorphisms provides the first evidence of the involvement of ADRA2 gene family members in the development of SBI. Further studies using larger and more heterogeneous populations are required to validate the association of ADRA2 polymorphisms with SBI. PMID:24676565
Kim, Jung O; Jeon, Young Joo; Kim, Ok Joon; Oh, Seung Hun; Kim, Hyun Sook; Shin, Byoung Soo; Oh, Doyeun; Kim, Eo Jin; Cho, Yun Kyung; Kim, Nam Keun
Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain
Objective To test the co-occurrence and interrelation of ictal activity and cortical spreading depressions (CSDs) - including the related periinfarct depolarisations in acute brain injury caused by trauma, and spontaneous subarachnoid and/or intracerebral haemorrhage. Methods 63 patients underwent craniotomy and electrocorticographic (ECoG) recordings were taken near foci of damaged cortical tissue for up to 10 days. Results 32 of 63 patients exhibited CSDs (5 to 75 episodes), and 11 had ECoGraphic seizure activity (1-81 episodes). Occurrence of seizures was significantly associated with CSD, as 10 of 11 patients with seizures also had CSD (p=0.007, 2-tailed Fishers exact test). Clinically overt seizures were only observed in one patient. Each patient with CSD and seizures displayed one of four different patterns of interaction between CSD and seizures. In four patients CSD was immediately preceded by prolonged seizure activity. In three patients the two phenomena were separated in time: multiple CSDs were replaced by ictal activity. In one patient seizures appeared to trigger repeated CSDs at the adjacent electrode. In two patients ongoing repeated seizures were interrupted each time CSD occurred. Conclusions Seizure activity occurs in association with CSD in the injured human brain. Significance ECoG recordings in brain injury patients provide insight into pathophysiological mechanisms that is not accessible by scalp EEG recordings.
Fabricius, Martin; Fuhr, Susanne; Willumsen, Lisette; Dreier, Jens P; Bhatia, Robin; Boutelle, Martyn G.; Hartings, Jed A; Bullock, Ross; Strong, Anthony J; Lauritzen, Martin
Models of the Aging Brain Structure and Individual Decline
The aging brain's structural development constitutes a spatiotemporal process that is accessible by MR-based computational morphometry. Here we introduce basic concepts and analytical approaches to quantify age-related differences and changes in neuroanatomical images of the human brain. The presented models first address the estimation of age trajectories, then we consider inter-individual variations of structural decline, using a repeated measures design. We concentrate our overview on preprocessed neuroanatomical images of the human brain to facilitate practical applications to diverse voxel- and surface-based structural markers. Together these methods afford analysis of aging brain structure in relation to behavioral, health, or cognitive parameters.
Ziegler, Gabriel; Dahnke, Robert; Gaser, Christian
Non-invasive estimation of myocardial infarction by means of a heart-model-based imaging approach: a simulation study.
In the study, a new myocardial infarction (MI) estimation method was developed for estimating MI in the three-dimensional myocardium by means of a heart-model-based inverse approach. The site and size of MI are estimated from body surface electrocardiograms by minimising multiple objective functions of the measured body surface potential maps (BSPMs) and the heart-model-generated BSPMs. Computer simulations were conducted to evaluate the performance of the developed method, using a single-site MI and dual-site MI protocols. The simulation results show that, for the single-site MI, the averaged spatial distance (SD) between the weighting centres of the 'true' and estimated MIs, and the averaged relative error (RE) between the numbers of the 'true' and estimated infarcted units are 3.0 +/- 0.6/3.6 +/- 0.6 mm and 0.11 +/- 0.02/0.14 +/- 0.02, respectively, when 5 microV/10 microV Gaussian white noise was added to the body surface potentials. For the dual-site MI, the averaged SD between the weighting centres of the 'true' and estimated MIs, and the averaged RE between the numbers of the 'true' and estimated infarcted units are 3.8 +/- 0.7/3.9 +/- 0.7mm and 0.12 +/- 0.02/0.14 +/- 0.03, respectively, when 5 microV/10 microV Gaussian white noise was added to the body surface potentials. The simulation results suggest the feasibility of applying the heart-model-based imaging approach to the estimation of myocardial infarction from body surface potentials. PMID:14977234
Li, G; He, B
Build-a-Brain Project: Students Design and Model the Brain of an Imaginary Animal
NSDL National Science Digital Library
The brain is a truly fascinating structure! Although the brain is a single organ, it is very complex and has several regions, each having a specific function. In this fun-filled, "minds-on" lesson, students learn about the various regions of the brain and then build brains of imaginary animals using modeling dough and other art supplies in an inquiry based format. (See sidebar onpage 30, and Resources for a downloadable student handout on this topic as well as for other sites containing additional information and diagrams).
Jr., Archibald J.; Johnson, John I.; Pecore, John; Rose, Jordan D.; Carruth, Laura L.; Demetrikopoulos, Melissa K.
Comparative study among three different methods of bone marrow mesenchymal stem cell transplantation following cerebral infarction in rats.
The objective of this study was to investigate the effects of transplanted bone marrow mesenchymal stem cells (BMSCs) administered via internal jugular vein injection, carotid artery injection, or intraventricular transplantation for the treatment of cerebral infarction, which was modeled in rats. The neurological scores of the treated rats and the distribution of the transplanted cells (GFP-labeled) in the infarction area were evaluated. The cerebral infarction model was produced by inserting a modified Zea-longa suture, which generated middle cerebral artery occlusion (MCAO). The GFP-labeled BMSCs were transplanted through the jugular vein or the carotid artery or by stereotactic intraventricular delivery to the infarction models 1 week after the cerebral infarction was established. The 'Nerve Function Score' of the model rats was recorded before and after BMSC transplantation. Brain tissue sections were examined under a fluorescence microscope. We determined that the transplanted BMSCs rescued brain function, which was indicated by a decrease in the neurological scores (P<0·05) following BMSC transplantation. The effect of BMSC transplantation was reflected in decreases in the neurological score in the intraventricular transplantation group, the carotid artery transplantation group, and the jugular vein graft group*. The transplanted BMSCs were able to migrate to the brain injury area and the cortex and survived the infarction; thus, BMSCs may promote the recovery of nerve function. PMID:23452580
Ruan, Guang-Ping; Han, Yi-Bing; Wang, Ting-Hua; Xing, Zhi-Guo; Zhu, Xing-Bao; Yao, Xiang; Ruan, Guang-Hong; Wang, Jin-Xiang; Pang, Rong-Qing; Cai, Xue-Min; He, Jie; Zhao, Jing; Pan, Xing-Hua
Brain repair after stroke--a novel neurological model.
Following stroke, patients are commonly left with debilitating motor and speech impairments. This article reviews the state of the art in neurological repair for stroke and proposes a new model for the future. We suggest that stroke treatment--from the time of the ictus itself to living with the consequences--must be fundamentally neurological, from limiting the extent of injury at the outset, to repairing the consequent damage. Our model links brain and behaviour by targeting brain circuits, and we illustrate the model though action observation treatment, which aims to enhance brain network connectivity. The model is based on the assumptions that the mechanisms of neural repair inherently involve cellular and circuit plasticity, that brain plasticity is a synaptic phenomenon that is largely stimulus-dependent, and that brain repair required both physical and behavioural interventions that are tailored to reorganize specific brain circuits. We review current approaches to brain repair after stroke and present our new model, and discuss the biological foundations, rationales, and data to support our novel approach to upper-extremity and language rehabilitation. We believe that by enhancing plasticity at the level of brain network interactions, this neurological model for brain repair could ultimately lead to a cure for stroke. PMID:24217509
Small, Steven L; Buccino, Giovanni; Solodkin, Ana
Finite Element Analysis and Experimental Study on Mechanism of Brain Injury Using Brain Model
The aim of this study is to discuss the occurrence mechanism of the brain injury analytically and experimentally. In this paper, first, an experimental system to do an impact experiment was presented. The pressure changes inside a brain agar phantom were measured. Second, a three-dimensional FEM model of the impact experiment was constructed. From the results of the fundamental analysis,
R. Ishikawa; K. Kato; M. Kubo; T. Uzuka; H. Takahashi
Cardiodynamics and Infarct Size in Regional and Global Ischemic Isolated Heart Model: Comparison of 1 Hour and 2 Hours Reperfusion
Background and Objectives We investigated whether 1 hour reperfusion is enough to assess cardiodynamics and infarct size in both regional ischemia (RI) and global ischemia (GI) in isolated rat heart models. Materials and Methods Hearts were randomly assigned to one of the following groups (each n=14): 1) Sham hearts for 1 hour; 2) Sham hearts for 2 hours; 3) 30 minutes RI followed by 1 hour reperfusion; 4) 30 minutes of RI followed by 2 hours reperfusion; 5) 30 minutes GI followed by 1 hour reperfusion; and 6) 30 minutes GI followed by 2 hours reperfusion. Results There were no significant differences in infarct size between 1 hour and 2 hours reperfusion in both RI and GI. Left ventricular developed pressure was significantly decreased at both 1 hour and 2 hours reperfusion in groups of RI and GI compared to baseline (p<0.01). Rate-pressure product and +dP/dtmax also significantly decreased compared to baseline level at both 1 hour and 2 hours reperfusion in groups of RI and GI (p<0.05). Conclusion There was no significant difference in infarct size between 1 hour and 2 hours reperfusion in groups of RI and GI. Cardiodynamic variables measured at 1 hour and 2 hours reperfusion significantly decreased compared to baseline level. Our data suggests that reperfusion of 1 hour is sufficient to assess cardiodynamics in both regional and global ischemic isolated hearts model.
Kim, June Hong; Kim, Jun; Park, Yong Hyun; Chun, Kook Jin; Kim, Jeong Su; Lee, Mi Young; Xu, Zhelong
Stem cell-loaded nanofibrous patch promotes the regeneration of infarcted myocardium with functional improvement in rat model.
Myocardial infarction (MI) leads to the loss of cardiomyocytes, followed by left ventricular (LV) remodeling and cardiac dysfunction. The authors hypothesize that an elastic, biodegradable nanofibrous cardiac patch loaded with mesenchymal stem cells (MSC) could restrain LV remodeling and improve cardiac function after MI. Poly(?-caprolactone)/gelatin (PG) nanofibers were fabricated by electrospinning, and the nanofibers displayed a porous and uniform nanofibrous structure with a diameter of 244±51nm. An MI model was established by ligation of the left anterior descending coronary artery of female Sprague-Dawley rats. The PG nanofibrous patch seeded with MSC, isolated from rat bone marrow, was implanted on the epicardium of the infarcted region of the LV wall of the heart. After transplantation, the PG-cell patch restricted the expansion of the LV wall effectively and reduced the scar size, and the density of the microvessels increased. Cells within the patch were able to migrate towards the scar tissue, and promoted new blood vessel formation at the infarct site. Angiogenesis and the cardiac functions improved significantly after 4weeks of implantation. The MSC-seeded PG nanofibrous patches are demonstrated to provide sufficient mechanical support, to induce angiogenesis and to accelerate cardiac repair in a rat model of MI. The study highlights the positive impact of implantation of an MSC-seeded PG nanofibrous patch as a novel constituent for MI repair. PMID:24576580
Kai, Dan; Wang, Qiang-Li; Wang, Hai-Jie; Prabhakaran, Molamma P; Zhang, Yanzhong; Tan, Yu-Zhen; Ramakrishna, Seeram
Assessment of distribution and evolution of Mechanical dyssynchrony in a porcine model of myocardial infarction by cardiovascular magnetic resonance
Background We sought to investigate the relationship between infarct and dyssynchrony post- myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality. Methods Cine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 ± 2 days (early post-MI), and 33 ± 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro-anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice. Results Mean infarct size was 21 ± 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 ± 1.6% vs. -18 ± 2.5% (early) and -17 ± 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early (440 ± 40 ms vs. 329 ± 40 ms and 332 ± 36 ms, respectively; p = 0.0002) and late post-MI (442 ± 63 ms vs. 321 ± 40 ms and 355 ± 61 ms, respectively; p = 0.012). The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 ± 7 ms to 50 ± 10 ms (early, p = 0.012) to 54 ± 19 ms (late, p = 0.004), with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 ± 2.4 cm/s), when compared to peri-infarct (18.7 ± 10.3 cm/s) and remote myocardium (39 ± 20.5 cm/s). Conclusions Mechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct.
Mathematical modeling of human brain physiological data
NASA Astrophysics Data System (ADS)
Recently, a mathematical model of the basic physiological processes regulating the cerebral perfusion and oxygen supply was introduced [Jung , J. Math. Biol.JMBLAJ0303-681210.1007/s00285-005-0343-5 51, 491 (2005)]. Although this model correctly describes the interdependence of arterial blood pressure (ABP) and intracranial pressure (ICP), it fails badly when it comes to explaining certain abnormal correlations seen in about 80% of the recordings of ABP together with ICP and the partial oxygen pressure (TiPO2) of the neuronal tissue, taken at an intensive care unit during neuromonitoring of patients with a severe brain trauma. Such recordings occasionally show segments, where the mean arterial blood pressure is correlated with the partial oxygen pressure in tissue but anticorrelated with the intracranial pressure. The origin of such abnormal correlations has not been fully understood yet. Here, two extensions to the previous approach are proposed which can reproduce such abnormal correlations in simulations quantitatively. Furthermore, as the simulations are based on a mathematical model, additional insight into the physiological mechanisms from which such abnormal correlations originate can be gained.
Böhm, Matthias; Faltermeier, Rupert; Brawanski, Alexander; Lang, Elmar W.
Physical model simulations of brain injury in the primate.
Diffuse brain injuries resulting from non-impact rotational acceleration are investigated with the aid of physical models of the skull-brain structure. These models provide a unique insight into the relationship between the kinematics of head motion and the associated deformation of the surrogate brain material. Human and baboon skulls filled with optically transparent surrogate brain tissue are subjected to lateral rotations like those shown to produce diffuse injury to the deep white matter in the brain of the baboon. High-speed cinematography captures the deformations of the grids embedded within the surrogate brain tissue during the applied load. The overall deformation pattern is compared to the pathological portrait of diffuse brain injury as determined from animal studies and autopsy reports. Shear strain and pathology spatial distributions mirror each other. Load levels and resulting surrogate brain tissue deformations are related from one species to the other. Increased primate brain mass magnified the strain amplified without significantly altering the spatial distribution. An empirically-derived value for a critical shear strain associated with the onset of severe diffuse axonal injury in primates is determined, assuming constitutive similarity between baboon and human brain tissue. The primate skull physical model data and the critical shear strain associated with the threshold for severe diffuse axonal injury were used to scale data obtained from previous studies to man, and thus derive a diffuse axonal injury tolerance for rotational acceleration for humans. PMID:2384494
Margulies, S S; Thibault, L E; Gennarelli, T A
Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct.
Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein-transgenic rats and were labeled with quantum dots. The BMSCs (1?×?10(5) or 1?×?10(6) ) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post-ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post-transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post-ischemia, but such therapeutic effects were observed only when the high-dose BMSCs were transplanted at 4 weeks post-ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri-infarct area when the high-dose BMSCs were transplanted at 1 or 4 weeks post-ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects. PMID:22725254
Kawabori, Masahito; Kuroda, Satoshi; Ito, Masaki; Shichinohe, Hideo; Houkin, Kiyohiro; Kuge, Yuji; Tamaki, Nagara
S-values calculated from a tomographic head/brain model for brain imaging
NASA Astrophysics Data System (ADS)
A tomographic head/brain model was developed from the Visible Human images and used to calculate S-values for brain imaging procedures. This model contains 15 segmented sub-regions including caudate nucleus, cerebellum, cerebral cortex, cerebral white matter, corpus callosum, eyes, lateral ventricles, lenses, lentiform nucleus, optic chiasma, optic nerve, pons and middle cerebellar peduncle, skull CSF, thalamus and thyroid. S-values for C-11, O-15, F-18, Tc-99m and I-123 have been calculated using this model and a Monte Carlo code, EGS4. Comparison of the calculated S-values with those calculated from the MIRD (1999) stylized head/brain model shows significant differences. In many cases, the stylized head/brain model resulted in smaller S-values (as much as 88%), suggesting that the doses to a specific patient similar to the Visible Man could have been underestimated using the existing clinical dosimetry.
Chao, Tsi-chian; Xu, X. George
Effect of Pacing Site and Infarct Location on Regional Mechanics and Global Hemodynamics in a Model Based Study of Heart Failure
Clinical trials evaluating cardiac resynchronization therapy (CRT) have demonstrated that 30% of patients with heart failure\\u000a and wide QRS do not respond to CRT (especially patients with myocardial infarcts). We have developed 3D numerical models of\\u000a failing hearts, with and without chronic infarcts in different regions of the left ventricle. The hearts were coupled to a\\u000a closed circulation, and the
Roy C. P. Kerckhoffs; Andrew D. Mcculloch; Jeffrey H. Omens; Lawrence J. Mulligan
Prediction of 6 months left ventricular dilatation after myocardial infarction in relation to cardiac morbidity and mortality. Application of a new dilatation model to GISSI-3 data
Aims To predict the long-term left ventricular volume index early after myocardial infarction and to investigate the relationship between long-term left ventricular dilatation risk and clinical outcome. Methods and Results By applying a previously developed dilatation model, we predicted the 6-month left ventricular volume index early after myocardial infarction (median 9 days) in 13 679 GISSI-3 patients, to identify patients
P. J. de Kam; G. L. Nicolosi; A. A. Voors; M. P. van den Berg; J. Brouwer; D. J. van Veldhuisen; S. Barlera; A. P. Maggioni; P. Giannuzzi; P. L. Temporelli; R. Latini; W. H. van Gilst
ACHTUNG-Rule: a new and improved model for prognostic assessment in myocardial infarction
Background: Thrombolysis In Myocardial Infarction (TIMI), Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (PURSUIT) and Global Registry of Acute Coronary Events (GRACE) scores have been developed for risk stratification in myocardial infarction (MI). The latter is the most validated score, yet active research is ongoing for improving prognostication in MI. Aim: Derivation and validation of a new model for intrahospital, post-discharge and combined/total all-cause mortality prediction – ACHTUNG-Rule – and comparison with the GRACE algorithm. Methods: 1091 patients admitted for MI (age 68.4 ± 13.5, 63.2% males, 41.8% acute MI with ST-segment elevation (STEMI)) and followed for 19.7 ± 6.4 months were assigned to a derivation sample. 400 patients admitted at a later date at our institution (age 68.3 ± 13.4, 62.7% males, 38.8% STEMI) and followed for a period of 7.2 ± 4.0 months were assigned to a validation sample. Three versions of the ACHTUNG-Rule were developed for the prediction of intrahospital, post-discharge and combined (intrahospital plus post-discharge) all-cause mortality prediction. All models were evaluated for their predictive performance using the area under the receiver operating characteristic (ROC) curve, calibration through the Hosmer–Lemeshow test and predictive utility within each individual patient through the Brier score. Comparison through ROC curve analysis and measures of risk reclassification – net reclassification improvement index (NRI) or Integrated Discrimination Improvement (IDI) – was performed between the ACHTUNG versions for intrahospital, post-discharge and combined mortality prediction and the equivalent GRACE score versions for intrahospital (GRACE-IH), post-discharge (GRACE-6PD) and post-admission 6-month mortality (GRACE-6). Results: Assessment of calibration and overall performance of the ACHTUNG-Rule demonstrated a good fit (p value for the Hosmer–Lemeshow goodness-of-fit test of 0.258, 0.101 and 0.550 for ACHTUNG-IH, ACHTUNG-T and ACHTUNG-R, respectively) and high discriminatory power in the validation cohort for all the primary endpoints (intrahospital mortality: AUC ACHTUNG-IH 0.886 ± 0.035 vs. AUC GRACE-IH 0.906 ± 0.026; post-discharge mortality: AUC ACHTUNG-R 0.827 ± 0.036 vs. AUC GRACE-6PD 0.811 ± 0.034; combined/total mortality: AUC ACHTUNG-T 0.831 ± 0.028 vs. AUC GRACE-6 0.815 ± 0.033). Furthermore, all versions of the ACHTUNG-Rule accurately reclassified a significant number of patients in different, more appropriate, risk categories (NRI ACHTUNG-IH 17.1%, p (2-sided) = 0.0021; NRI ACHTUNG-R 22.0%, p = 0.0002; NRI ACHTUNG-T 18.6%, p = 0.0012). The prognostic performance of the ACHTUNG-Rule was similar in both derivation and validation samples. Conclusions: All versions of the ACHTUNG-Rule have shown excellent discriminative power and good calibration for predicting intrahospital, post-discharge and combined in-hospital plus post-discharge mortality. The ACHTUNG version for intrahospital mortality prediction was not inferior to its equivalent GRACE model, and ACHTUNG versions for post-discharge and combined/total mortality demonstrated apparent superiority. External validation in wider, independent, preferably multicentre, registries is warranted before its potential clinical implementation.
Providencia, Rui; Paiva, Luis; Caetano, Francisca; Almeida, Ines; Gomes, Pedro; Marques, Antonio Leitao
On a Mathematical Model of Brain Activities
NASA Astrophysics Data System (ADS)
The procedure of recognition can be described as follows: There is a set of complex signals stored in the memory. Choosing one of these signals may be interpreted as generating a hypothesis concerning an ``expexted view of the world''. Then the brain compares a signal arising from our senses with the signal chosen from the memory leading to a change of the state of both signals. Furthermore, measurements of that procedure like EEG or MEG are based on the fact that recognition of signals causes a certain loss of excited neurons, i.e. the neurons change their state from ``excited'' to ``nonexcited''. For that reason a statistical model of the recognition process should reflect both-the change of the signals and the loss of excited neurons. A first attempt to explain the process of recognition in terms of quantum statistics was given in [1]. In the present note it is not possible to present this approach in detail. In lieu we will sketch roughly a few of the basic ideas and structures of the proposed model of the recognition process (Section). Further, we introduce the basic spaces and justify the choice of spaces used in this approach. A more elaborate presentation including all proofs will be given in a series of some forthcoming papers [2, 3]. In this series also the procedures of creation of signals from the memory, amplification, accumulation and transformation of input signals, and measurements like EEG and MEG will be treated in detail.
Fichtner, K.-H.; Fichtner, L.; Freudenberg, W.; Ohya, M.
On a Mathematical Model of Brain Activities
The procedure of recognition can be described as follows: There is a set of complex signals stored in the memory. Choosing one of these signals may be interpreted as generating a hypothesis concerning an 'expexted view of the world'. Then the brain compares a signal arising from our senses with the signal chosen from the memory leading to a change of the state of both signals. Furthermore, measurements of that procedure like EEG or MEG are based on the fact that recognition of signals causes a certain loss of excited neurons, i.e. the neurons change their state from 'excited' to 'nonexcited'. For that reason a statistical model of the recognition process should reflect both--the change of the signals and the loss of excited neurons. A first attempt to explain the process of recognition in terms of quantum statistics was given. In the present note it is not possible to present this approach in detail. In lieu we will sketch roughly a few of the basic ideas and structures of the proposed model of the recognition process (Section). Further, we introduce the basic spaces and justify the choice of spaces used in this approach. A more elaborate presentation including all proofs will be given in a series of some forthcoming papers. In this series also the procedures of creation of signals from the memory, amplification, accumulation and transformation of input signals, and measurements like EEG and MEG will be treated in detail.
Fichtner, K.-H. [Friedrich Schiller Unversity Jena, Institute of Applied Mathematics, E.-Abbe-Platz 2, 07743 Jena (Germany); Fichtner, L. [Friedrich Schiller Unversity Jena, Institute of Psychology, Am Steiger 3, 07743 Jena (Germany); Freudenberg, W. [Brandenb. Techn. University Cottbus, Dep. of Mathematics, PO box 10 13 44, 03013 Cottbus (Germany); Ohya, M. [Tokyo University of Science, Department of Information Science, Noda City, Chiba 278-8510 (Japan)
Therapeutic application of adipose derived stem cells in acute myocardial infarction: lessons from animal models.
The majority of patients survive an acute myocardial infarction (AMI). Their outcome is negatively influenced by post-AMI events, such as loss of viable cardiomyocytes due to a post-AMI inflammatory response, eventually resulting in heart failure and/or death. Recent pre-clinical animal studies indicate that mesenchymal stem cells derived from adipose tissue (ASC) are new promising candidates that may facilitate cardiovascular regeneration in the infarcted myocardium. In this review we have compared all animal studies in which ASC were used as a therapy post-AMI and have focused on aspects that might be important for future successful clinical application of ASC. PMID:24577790
Naaijkens, B A; van Dijk, A; Kamp, O; Krijnen, P A J; Niessen, H W M; Juffermans, L J M
The cardiomyocyte lineage is critical for optimization of stem cell therapy in a mouse model of myocardial infarction
We recently described a murine embryonic stem cell (ESC) line engineered to express the activated Notch 4 receptor in a tetracycline (doxcycline; Dox) regulated fashion (tet-notch4 ESCs). Notch 4 induction in Flk1+ hematopoietic and vascular progenitors from this line respecified them to a cardiovascular fate. We reasoned that these cells would be ideal for evaluating the contribution of the cardiomyocyte and vascular lineages to the functional improvement noted following stem cell transplantation in infarcted hearts. Flk-1+ Tet-notch4 cells from d 3 embryoid bodies exposed to doxycycline (Dox+) were compared to uninduced (Dox?) Flk-1+ cells. Mice underwent transplantation of 5 × 105 Dox+ cells, Dox?cells, or an equal volume of serum-free medium after surgically induced myocardial infarction. The mean ejection fraction was 59 ± 15, 46 ± 17, and 39 ± 13% in the Dox+, Dox?, and serum-free medium groups, respectively (P<0.05 for the differences among all 3 groups). Immunohistochemistry of hearts injected with Dox+ grafts expressed myocardial and vascular markers, whereas grafts of Dox? cells expressed primarily vascular markers. We conclude that cardiovascular progenitors are more effective than vascular progenitors in improving function after myocardial infarction. The transplantation of appropriate cell types is critical for maximizing the benefit of cardiovascular cell therapy.—Adler, E. D., Chen, V. C., Bystrup, A., Kaplan, A. D., Giovannone, S., Briley-Saebo, K., Young, W., Kattman, S., Mani, V., Laflamme, M., Zhu, W.-Z., Fayad, Z., Keller, G. The cardiomyocyte lineage is critical for optimization of stem cell therapy in a mouse model of myocardial infarction.
Adler, Eric D.; Chen, Vincent C.; Bystrup, Anne; Kaplan, Aaron D.; Giovannone, Steven; Briley-Saebo, Karen; Young, Wilson; Kattman, Steve; Mani, Venkatesh; Laflamme, Michael; Zhu, Wei-Zhong; Fayad, Zahi; Keller, Gordon
Cerebral infarction does not occur typically at night.
In a hospital-based series of 66 consecutive patients with non-progressive cerebral infarction, the time of onset and the type of infarction on computed tomography were studied retrospectively. Forty-six (78%) patients suffered cerebral infarction between 6 am and 6 pm. Only five patients (8%) had their infarct between midnight and 6 am. Only three patients had a watershed-infarct, and these occurred during the daytime. Our results do not support the belief that atherothrombotic brain infarction is largely determined by haemodynamic factors.
van der Windt, C; van Gijn, J
Hypericin as a marker for determination of myocardial viability in a rat model of myocardial infarction.
The aim of this study was to investigate the necrosis-avid agent hypericin as a potential indicator for determination of myocardial infarction (MI). Male Sprague-Dawley rats (n = 30) weighing 350 ± 20 g were subjected to acute reperfused MI. Animals were divided into four groups (n = 6), in which hypericin was intravenously injected at 0, 1, 2 and 5 mg kg(-1) respectively. One day after injection, rats were euthanized with their hearts excised for qualitative and quantitative studies by means of microscopic fluorescence examination to decide the dosage of hypericin. Another group was injected with hypericin at the decided dose and evaluated by fluorescence macroscopy in colocalization with triphenyltetrazoliumchloride (TTC) and histomorphology. Infarct-to-normal contrast ratio and relative infarct size were quantified. Hypericin-induced red fluorescence was significantly brighter in necrotic than in viable myocardium as proven by a six times higher mean fluorescence density. Mean MI area was 35.66 ± 22.88% by hypericin fluorescence and 32.73 ± 21.98% by TTC staining (R(2) = 0.9803). Global MI-volume was 34.56 ± 21.07% by hypericin and 35.11 ± 20.47% by TTC staining (R(2) = 0.9933). The results confirm that hypericin specifically labeled necrosis, and enhanced the imaging contrast between the infarcted and normal myocardium, suggesting its potential applications for the assessment of myocardial viability. PMID:24460608
Jiang, Cuihua; Li, Yue; Jiang, Xiao; Yao, Nan; Gao, Meng; Zhang, Xueli; Wang, Junying; Wang, Xiaoning; Sun, Ziping; Zhang, Jian; Ni, Yicheng
Corticonic models of brain mechanisms underlying cognition and intelligence
The concern of this review is brain theory or more specifically, in its first part, a model of the cerebral cortex and the way it: (a) interacts with subcortical regions like the thalamus and the hippocampus to provide higher-level-brain functions that underlie cognition and intelligence, (b) handles and represents dynamical sensory patterns imposed by a constantly changing environment, (c) copes
Nabil H. Farhat
Bayesian approach for network modeling of brain structural features
NASA Astrophysics Data System (ADS)
Brain connectivity patterns are useful in understanding brain function and organization. Anatomical brain connectivity is largely determined using the physical synaptic connections between neurons. In contrast statistical brain connectivity in a given brain population refers to the interaction and interdependencies of statistics of multitudes of brain features including cortical area, volume, thickness etc. Traditionally, this dependence has been studied by statistical correlations of cortical features. In this paper, we propose the use of Bayesian network modeling for inferring statistical brain connectivity patterns that relate to causal (directed) as well as non-causal (undirected) relationships between cortical surface areas. We argue that for multivariate cortical data, the Bayesian model provides for a more accurate representation by removing the effect of confounding correlations that get introduced due to canonical dependence between the data. Results are presented for a population of 466 brains, where a SEM (structural equation modeling) approach is used to generate a Bayesian network model, as well as a dependency graph for the joint distribution of cortical areas.
Joshi, Anand A.; Joshi, Shantanu H.; Leahy, Richard M.; Shattuck, David W.; Dinov, Ivo; Toga, Arthur W.
Distributed brain modelling by means of hierarchical collaborative coevolution
The current work addresses the development of cognitive abilities in artificial organisms. In the pro- posed approach, neural network-based agent structures are employed to represent distinct brain areas. We in- troduce a Hierarchical Collaborative CoEvolutionary (HCCE) approach to design autonomous, yet cooper- ating agents. Thus, partial brain models consisting of many substructures can be designed. Replication of le- sion studies
Michail Maniadakis; Panos E. Trahanias
Temperature distributions in the human brain model during ultrasound hyperthermia
One of the important applications of ultrasound hyperthermia is temperature elevation at specified locations in the human brain. The ultrasound applicator used is a circular phased array surrounding the human head. The human head model is assumed to be two concentric spheres of skin and bone containing a hemisphere of brain. The single and multiple foci patterns of the ultrasound
N. H. Ismail; A. T. Ibrahim
The Virtual Brain Integrates Computational Modeling and Multimodal Neuroimaging
Abstract Brain function is thought to emerge from the interactions among neuronal populations. Apart from traditional efforts to reproduce brain dynamics from the micro- to macroscopic scales, complementary approaches develop phenomenological models of lower complexity. Such macroscopic models typically generate only a few selected—ideally functionally relevant—aspects of the brain dynamics. Importantly, they often allow an understanding of the underlying mechanisms beyond computational reproduction. Adding detail to these models will widen their ability to reproduce a broader range of dynamic features of the brain. For instance, such models allow for the exploration of consequences of focal and distributed pathological changes in the system, enabling us to identify and develop approaches to counteract those unfavorable processes. Toward this end, The Virtual Brain (TVB) (www.thevirtualbrain.org), a neuroinformatics platform with a brain simulator that incorporates a range of neuronal models and dynamics at its core, has been developed. This integrated framework allows the model-based simulation, analysis, and inference of neurophysiological mechanisms over several brain scales that underlie the generation of macroscopic neuroimaging signals. In this article, we describe how TVB works, and we present the first proof of concept.
Schirner, Michael; McIntosh, Anthony R.; Jirsa, Viktor K.
Multidetector-row computed tomographic evaluation of myocardial perfusion in reperfused chronic myocardial infarction: value of color-coded perfusion map in a porcine model.
We aimed to develop color-coded CT perfusion maps (CPM) of infarcted myocardium and assess the utility of CPM in evaluating ischemic heart disease on a cardiac multi-detector CT (MDCT) in a porcine reperfused-myocardial-infarction model. Myocardial infarctions were induced by 30 min occlusions of the proximal left anterior descending coronary artery (LAD) in 17 healthy adult female pigs. First-pass and 5 min-delayed cardiac MDCTs were performed after 4 weeks of LAD occlusion. Myocardial CPMs were obtained by using the CPM program. Triphenyltetrazolium chloride (TTC)-staining was performed on the cardiac specimens. We analyzed the intermodality agreement on the size and location of the myocardial infarctions. TTC staining revealed myocardial infarction in 16 of 17 pigs, and 15 of these (94%) showed matched infarcts on the CPM and first-pass images. The areas of perfusion deficit noted in early arterial phase images and CPM coincided exactly with the areas of poor TTC staining in 12 of 15 pigs (80%). In the three remaining pigs, the areas of poor TTC staining were larger than those of a perfusion deficit demonstrated by either early arterial phase images or CPM. The agreement between these tests is calculated to be moderate to good (k = 0.736, P < 0.05). Ten myocardial segments in 4 of the 15 pigs (27%) with hypoattenuated myocardium showed a delayed enhancement on the 5 min-delayed images. Contrast-enhanced MDCT was useful and accurate in detecting chronic myocardial infarction; CPM was helpful in visualizing the infarcted myocardium. PMID:19153820
Yim, Nam Yeol; Kim, Yun-Hyeon; Choi, Song; Seon, Hyun Ju; Kim, Yeong Cheol; Jeong, Gwang Woo; Min, Byeong In; Lee, Sang Rok; Jeong, Myeong Ho; Kim, Jae Kyu; Park, Jin Gyoon; Kang, Heoung Keun
Controlling ferrofluid permeability across the blood–brain barrier model.
In the present study, an in vitro blood–brain barrier model was developed using murine brain endothelioma cells (b.End3 cells). Confirmation of the blood–brain barrier model was completed by examining the permeability of FITCDextran at increasing exposure times up to 96 h in serum-free medium and comparing such values with values from the literature. After such confirmation, the permeability of five novel ferrofluid (FF) nanoparticle samples, GGB (ferrofluids synthesized using glycine, glutamic acid and BSA), GGC (glycine, glutamic acid and collagen), GGP (glycine, glutamic acid and PVA), BPC (BSA, PEG and collagen) and CPB (collagen, PVA and BSA), was determined using this blood–brain barrier model. All of the five FF samples were characterized by zeta potential to determine their charge as well as TEM and dynamic light scattering for determining their hydrodynamic diameter. Results showed that FF coated with collagen passed more easily through the blood–brain barrier than FF coated with glycine and glutamic acid based on an increase of 4.5% in permeability. Through such experiments, diverse magnetic nanomaterials (such as FF) were identified for: (1) MRI use since they were less permeable to penetrate the blood–brain barrier to avoid neural tissue toxicity (e.g. GGB) or (2) brain drug delivery since they were more permeable to the blood–brain barrier (e.g. CPB). PMID:24457539
Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J
Brain microabscesses in a porcine model of Staphylococcus aureus sepsis
Background Sepsis caused by Staphylococcus aureus often leads to brain microabscesses in humans. Animal models of haematogenous brain abscesses would be useful to study this condition in detail. Recently, we developed a model of S. aureus sepsis in pigs and here we report that brain microabscesses develop in pigs with such induced S. aureus sepsis. Twelve pigs were divided into three groups. Nine pigs received an intravenous inoculation of S. aureus once at time 0 h (group 1) or twice at time 0 h and 12 h (groups 2 and 3). In each group the fourth pig served as control. The pigs were euthanized at time 12 h (Group 1), 24 h (Group 2) and 48 h (Group 3) after the first inoculation. The brains were collected and examined histopathologically. Results All inoculated pigs developed sepsis and seven out of nine pigs developed brain microabscesses. The microabscesses contained S. aureus and were located in the prosencephalon and mesencephalon. Chorioditis and meningitis occurred from 12 h after inoculation. Conclusions Pigs with experimental S. aureus sepsis often develop brain microabscesses. The porcine brain pathology mirrors the findings in human sepsis patients. We therefore suggest the pig as a useful animal model of the development of brain microabscesses caused by S. aureus sepsis.
Myocardial motion and deformation patterns in an experimental swine model of acute LBBB/CRT and chronic infarct.
In cardiac resynchronization therapy (CRT), specific changes in motion/deformation happen with left-bundle-branch-block (LBBB) and following treatment. However, they remain sub-optimally studied. We propose a two-fold improvement of their characterization. This includes controlling them through an experimental model and using more suitable quantification techniques. We used a swine model of acute LBBB and CRT with/without chronic infarct (pure-LBBB: N = 11; LBBB + left-anterior-descending infarct: N = 11). Myocardial displacement, velocity and strain were extracted from short-axis echocardiographic sequences using 2D speckle-tracking. The data was transformed to a single spatiotemporal system of coordinates to perform subject comparisons and quantify pattern changes at similar locations and instants. Pure-LBBB animals showed a specific intra-ventricular dyssynchrony pattern with LBBB (11/11 animals), and the recovery towards a normal pattern with CRT (10/11 animals). Pattern variability was low within the pure-LBBB population, as quantified by our method. This was not correctly assessed by more conventional measurements. Infarct presence affected the pattern distribution and CRT efficiency (improvements in 6/11 animals). Pattern changes correlated with global cardiac function (global circumferential strain) changes in all the animals (corrected: pLBBBvsBaseline < 0.001, pCRTvsBaseline = NS; non-corrected: pLBBBvsBaseline = NS, pCRTvsBaseline = 0.028). Our LBBB/CRT experimental model allowed controlling specific factors responsible for changes in mechanical dyssynchrony and therapy. We illustrated the importance of our quantification method to study these changes and their variability. Our findings confirm the importance of myocardial viability and of specific LBBB-related mechanical dyssynchrony patterns. PMID:24651923
Duchateau, Nicolas; Sitges, Marta; Doltra, Adelina; Fernández-Armenta, Juan; Solanes, Nuria; Rigol, Montserrat; Gabrielli, Luigi; Silva, Etelvino; Barceló, Aina; Berruezo, Antonio; Mont, Lluís; Brugada, Josep; Bijnens, Bart
The site of embolization related to infarct size, oedema and clinical outcome in a rat stroke model - further translational stroke research
Background and purpose Reliable models are essential for translational stroke research to study the pathophysiology of ischaemic stroke in an effort to find therapies that may ultimately reduce oedema, infarction and mortality in the clinic. The purpose of this study was to investigate the relation between the site of arterial embolization and the subsequent oedema, infarction and clinical outcome in a rat embolic stroke model. Methods Thirty-six male Sprague-Dawley rats were thromboembolized into the internal carotid artery. The site of occlusion was demonstrated by arteriography. Following histological preparation and evaluation, the size of the hemispheres and the infarcts were measured by quantitative histology and planimetry. Another parallel stroke model study was subsequently examined to investigate if the conclusions from the first study could be applied to the second study. Results The median size of the infarct was 40% of the ipsilateral hemisphere in both the 19 animals with occlusion localised to the intracranial part of the internal carotid artery and in the 11 animals where the main trunk of the middle cerebral artery was occluded. In 5 animals, occlusion of the extracranial part of the internal carotid artery resulted in significantly smaller infarcts compared to other groups (p < 0.01). Another independent study re-confirmed these results. Furthermore, significant correlations (R > 0.76, p < 0.0001) were found between 1) cortical, subcortical, and total infarct volumes, 2) oedema in percent of the left hemisphere, 3) clinical score before termination and 4) postoperative weight loss. Conclusions Distal occlusions of the intracranial part of the internal carotid or middle cerebral arteries resulted in comparable large sized infarctions and oedema. This indicates that investigators do not need a similar number of such occlusions in each experimental group. Contrary to observations in the clinic, distal internal carotid artery occlusions did not result in worse outcome than middle cerebral stem occlusions, but this finding may be explained by the controlled emboli size in this experimental stroke model.
Retinal Infarcts in a Patient with an Acute Confusional Syndrome
A 46-year-old man presented with acute confusional syndrome, ataxia, dysarthria, and right hemiparesthesia. Brain MRI showed small bilateral infarcts and fluorescein angiography revealed multiple peripheral retinal infarcts bilaterally. No visual loss was present, and no other organs were involved. The diagnosis of Susac syndrome (microangiopathy of the brain, retina and cochlea) was made and immunosuppressive therapy begun.
Elena Bitrian; Bernardo Sanchez-Dalmau; Molly E. Gilbert; Alfredo Adan; John O. Susac
Effects of progesterone administration on infarct volume and functional deficits following permanent focal cerebral ischemia in rats
Recent experimental evidence indicates that progesterone (PROG) protects against various models of brain injury, including ischemic stroke. Most human studies of pharmacologic treatments for acute cerebral stroke have failed despite initial success in animal models. To simulate better the typical human stroke without reperfusion, the present study was conducted to examine the efficacy of PROG on infarct volume and functional
Tauheed Ishrat; Iqbal Sayeed; Fahim Atif; Donald G. Stein
Blast Model of Traumatic Brain Injury in Swine.
National Technical Information Service (NTIS)
Although blast-induced traumatic brain injury (BI-TBI) is a significant cause of morbidity and behavioral dysfunction in warfighters returning from Iraq, laboratory models are not currently available to study the mechanisms underlying this critical injury...
S. S. Panter
Erythropoietin as a neuroprotectant for neonatal brain injury: animal models.
Prematurity and perinatal hypoxia-ischemia are common problems that result in significant neurodevelopmental morbidity and high mortality worldwide. The Vannucci model of unilateral brain injury was developed to model perinatal brain injury due to hypoxia-ischemia. Because the rodent brain is altricial, i.e., it develops postnatally, investigators can model either preterm or term brain injury by varying the age at which injury is induced. This model has allowed investigators to better understand developmental changes that occur in susceptibility of the brain to injury, evolution of brain injury over time, and response to potential neuroprotective treatments. The Vannucci model combines unilateral common carotid artery ligation with a hypoxic insult. This produces injury of the cerebral cortex, basal ganglia, hippocampus, and periventricular white matter ipsilateral to the ligated artery. Varying degrees of injury can be obtained by varying the depth and duration of the hypoxic insult. This chapter details one approach to the Vannucci model and also reviews the neuroprotective effects of erythropoietin (Epo), a neuroprotective treatment that has been extensively investigated using this model and others. PMID:23456865
Traudt, Christopher M; Juul, Sandra E
Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study.
Focal cerebral ischemia elicits strong inflammatory responses involving activation of resident microglia and recruitment of monocytes/macrophages. These cells express peripheral benzodiazepine receptors (PBRs) and can be visualized by positron emission tomography (PET) using [(11)C]PK11195 that selectively binds to PBRs. Earlier research suggests that transient ischemia in rats induces increased [(11)C]PK11195 binding within the infarct core. In this study, we investigated the expression of PBRs during permanent ischemia in rats. Permanent cerebral ischemia was induced by injection of macrospheres into the middle cerebral artery. Multimodal imaging 7 days after ischemia comprised (1) magnetic resonance imaging that assessed the extent of infarcts; (2) [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG)-PET characterizing cerebral glucose transport and metabolism; and (3) [(11)C]PK11195-PET detecting neuroinflammation. Immunohistochemistry verified ischemic damage and neuroinflammatory processes. Contrasting with earlier data for transient ischemia, no [(11)C]PK11195 binding was found in the infarct core. Rather, permanent ischemia caused increased [(11)C]PK11195 binding in the normoperfused peri-infarct zone (mean standard uptake value (SUV): 1.93+/-0.49), colocalizing with a 60% increase in the [(18)F]FDG metabolic rate constant with accumulated activated microglia and macrophages. These results suggest that after permanent focal ischemia, neuroinflammation occurring in the normoperfused peri-infarct zone goes along with increased energy demand, therefore extending the tissue at risk to areas adjacent to the infarct. PMID:19352400
Schroeter, Michael; Dennin, Maria A; Walberer, Maureen; Backes, Heiko; Neumaier, Bernd; Fink, Gereon R; Graf, Rudolf
Fluid-percussion–induced traumatic brain injury model in rats
Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Various attempts have been made to replicate clinical TBI using animal models. The fluid-percussion model (FP) is one of the oldest and most commonly used models of experimentally induced TBI. Both central (CFP) and lateral (LFP) variations of the model have been used. Developed initially for use in
Shruti V Kabadi; Genell D Hilton; Bogdan A Stoica; David N Zapple; Alan I Faden
Modelling convection-enhanced delivery in normal and oedematous brain.
Convection-enhanced delivery (CED) could have clinical applications in the delivery of neuroprotective agents in brain injury states, such as ischaemic stroke. For CED to be safe and effective, a physician must have accurate knowledge of how concentration distributions will be affected by catheter location, flow rate and other similar parameters. In most clinical applications of CED, brain microstructures will be altered by pathological injury processes. Ischaemic stroke and other acute brain injury states are complicated by formation of cytotoxic oedema, in which cellular swelling decreases the fractional volume of the extracellular space (ECS). Such changes would be expected to significantly alter the distribution of neuroprotective agents delivered by CED. Quantitative characterization of these changes will help confirm this prediction and assist in efforts to model the distribution of therapeutic agents. Three-dimensional computational models based on a Nodal Point Integration (NPI) scheme were developed to model infusions in normal brain and brain with cytotoxic oedema. These models were compared to experimental data in which CED was studied in normal brain and in a middle cerebral artery (MCA) occlusion model of cytotoxic oedema. The computational models predicted concentration distributions with reasonable accuracy. PMID:24446800
Haar, P J; Chen, Z-J; Fatouros, P P; Gillies, G T; Corwin, F D; Broaddus, W C
Intramyocardial Transplantation and Tracking of Human Mesenchymal Stem Cells in a Novel Intra-Uterine Pre-Immune Fetal Sheep Myocardial Infarction Model: A Proof of Concept Study
Although stem-cell therapies have been suggested for cardiac-regeneration after myocardial-infarction (MI), key-questions regarding the in-vivo cell-fate remain unknown. While most available animal-models require immunosuppressive-therapy when applying human cells, the fetal-sheep being pre-immune until day 75 of gestation has been proposed for the in-vivo tracking of human cells after intra-peritoneal transplantation. We introduce a novel intra-uterine myocardial-infarction model to track human mesenchymal stem cells after direct intra-myocardial transplantation into the pre-immune fetal-sheep. Thirteen fetal-sheep (gestation age: 70–75 days) were included. Ten animals either received an intra-uterine induction of MI only (n?=?4) or MI+intra-myocardial injection (IMI;n?=?6) using micron-sized, iron-oxide (MPIO) labeled human mesenchymal stem cells either derived from the adipose-tissue (ATMSCs;n?=?3) or the bone-marrow (BMMSCs;n?=?3). Three animals received an intra-peritoneal injection (IPI;n?=?3; ATMSCs;n?=?2/BMMSCs;n?=?1). All procedures were performed successfully and follow-up was 7–9 days. To assess human cell-fate, multimodal cell-tracking was performed via MRI and/or Micro-CT, Flow-Cytometry, PCR and immunohistochemistry. After IMI, MRI displayed an estimated amount of 1×105–5×105 human cells within ventricular-wall corresponding to the injection-sites which was further confirmed on Micro-CT. PCR and IHC verified intra-myocardial presence via detection of human-specific ?-2-microglobulin, MHC-1, ALU-Sequence and anti-FITC targeting the fluorochrome-labeled part of the MPIOs. The cells appeared viable, integrated and were found in clusters or in the interstitial-spaces. Flow-Cytometry confirmed intra-myocardial presence, and showed further distribution within the spleen, lungs, kidneys and brain. Following IPI, MRI indicated the cells within the intra-peritoneal-cavity involving the liver and kidneys. Flow-Cytometry detected the cells within spleen, lungs, kidneys, thymus, bone-marrow and intra-peritoneal lavage, but not within the heart. For the first time we demonstrate the feasibility of intra-uterine, intra-myocardial stem-cell transplantation into the pre-immune fetal-sheep after MI. Utilizing cell-tracking strategies comprising advanced imaging-technologies and in-vitro tracking-tools, this novel model may serve as a unique platform to assess human cell-fate after intra-myocardial transplantation without the necessity of immunosuppressive-therapy.
Wolint, Petra; Frauenfelder, Thomas; Zeisberger, Steffen M.; Behr, Luc; Sammut, Sebastien; Scherman, Jacques; Brokopp, Chad E.; Schwartlander, Ruth; Vogel, Viola; Vogt, Peter; Grunenfelder, Jurg; Alkadhi, Hatem; Falk, Volkmar; Boss, Andreas; Hoerstrup, Simon P.
Infarct density distribution by MRI in the porcine model of acute and chronic myocardial infarction as a potential method transferable to the clinic.
To study the feasibility of a myocardial infarct (MI) quantification method [signal intensity-based percent infarct mapping (SI-PIM)] that is able to evaluate not only the size, but also the density distribution of the MI. In 14 male swine, MI was generated by 90 min of closed-chest balloon occlusion followed by reperfusion. Seven (n = 7) or 56 (n = 7) days after reperfusion, Gd-DTPA-bolus and continuous-infusion enhanced late gadolinium enhancement (LGE) MRI, and R1-mapping were carried out and post mortem triphenyl-tetrazolium-chloride (TTC) staining was performed. MI was quantified using binary [2 or 5 standard deviation (SD)], SI-PIM and R1-PIM methods. Infarct fraction (IF), and infarct-involved voxel fraction (IIVF) were determined by each MRI method. Bias of each method was compared to the TTC technique. The accuracy of MI quantification did not depend on the method of contrast administration or the age of the MI. IFs obtained by either of the two PIM methods were statistically not different from the IFs derived from the TTC measurements at either MI age. IFs obtained from the binary 2SD method overestimated IF obtained from TTC. IIVF among the three different PIM methods did not vary, but with the binary methods the IIVF gradually decreased with increasing the threshold limit. The advantage of SI-PIM over the conventional binary method is the ability to represent not only IF but also the density distribution of the MI. Since the SI-PIM methods are based on a single LGE acquisition, the bolus-data-based SI-PIM method can effortlessly be incorporated into the clinical image post-processing procedure. PMID:24718787
Varga-Szemes, Akos; Simor, Tamas; Lenkey, Zsofia; van der Geest, Rob J; Kirschner, Robert; Toth, Levente; Brott, Brigitta C; Elgavish, Ada; Elgavish, Gabriel A
Cerebral organoids model human brain development and microcephaly
The complexity of the human brain has made it difficult to study many brain disorders in model organisms, and highlights the need for an in vitro model of human brain development. We have developed a human pluripotent stem cell-derived 3D organoid culture system, termed cerebral organoid, which develops various discrete though interdependent brain regions. These include cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNAi and patient-specific iPS cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could explain the disease phenotype. Our data demonstrate that 3D organoids can recapitulate development and disease of even this most complex human tissue.
Lancaster, Madeline A.; Renner, Magdalena; Martin, Carol-Anne; Wenzel, Daniel; Bicknell, Louise S.; Hurles, Matthew E.; Homfray, Tessa; Penninger, Josef M.; Jackson, Andrew P.; Knoblich, Juergen A.
Treatment of reperfused ischemia with adipose-derived stem cells in a preclinical Swine model of myocardial infarction.
The aim of the study was to determine the long-term effect of transplantation of adipose-derived stromal cells (ADSCs) in a preclinical model of ischemia/reperfusion (I/R). I/R was induced in 28 Goettingen minipigs by 120 min of coronary artery occlusion followed by reperfusion. Nine days later, surviving animals were allocated to receive transendocardial injection of a mean of 213.6 ± 41.78 million green fluorescent protein (GFP)-expressing ADSCs (n = 7) or culture medium as control (n = 9). Heart function, cell engraftment, and histological analysis were performed 3 months after transplantation. Transplantation of ADSCs induced a statistically significant long-lasting (3 months) improvement in cardiac function and geometry in comparison with control animals. Functional improvement was associated with an increase in angiogenesis and vasculogenesis and a positive effect on heart remodeling with a decrease in fibrosis and cardiac hypertrophy in animals treated with ADSCs. Despite the lack of cell engraftment after 3 months, ADSC transplantation induced changes in the ratio between MMP/TIMP. Our results indicate that transplantation of ADSCs, despite the lack of long-term significant cell engraftment, increases vessel density and prevents adverse remodeling in a clinically relevant model of myocardial infarction, strongly suggesting a paracrine-mediated effect. ADSCs thus constitute an attractive candidate for the treatment of myocardial infarction. PMID:22524986
Mazo, Manuel; Hernández, Salomón; Gavira, Juan José; Abizanda, Gloria; Arańa, Miriam; López-Martínez, Tania; Moreno, Cristina; Merino, Juana; Martino-Rodríguez, Alba; Uixeira, Alicia; García de Jalón, José A; Pastrana, Juan; Martínez-Caro, Diego; Prósper, Felipe
Investigation into the optimal surgical conditions for coronary artery ligation for establishing a myocardial infarction model in mice
In the present study, the left anterior descending coronary arteries of mice under anesthesia were ligated, and the optimal surgical conditions for coronary artery ligation (CAL) in the establishment of a myocardial infarction (MI) mouse model were investigated. All mice that survived were sacrificed seven days subsequent to the successful surgery. Body weight, blood serum and heart tissues were obtained for further analysis or biochemical and histopathological examinations. The survival rate of the mice following the CAL procedure was 70%. The aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) concentrations in the serum of the experimental mice were significantly increased compared with those of the control mice, which reflected the enzyme release from the infarcted myocardial cells. Histopathological examination showed different degrees of MI in the heart tissues of the experimental mice. The results indicate that an MI model in mice may be successfully established using CAL under the surgical conditions utilized in the present study. These conditions were cost effective and the results may be replicated by laboratories that are less well-equipped.
Systematic review of prognostic models in traumatic brain injury
BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability world-wide. The ability to accurately predict patient outcome after TBI has an important role in clinical practice and research. Prognostic models are statistical models that combine two or more items of patient data to predict clinical outcome. They may improve predictions in TBI patients. Multiple prognostic models
Pablo Perel; Phil Edwards; Reinhard Wentz; Ian Roberts
Development of a Model for Whole Brain Learning of Physiology
ERIC Educational Resources Information Center
In this report, a model was developed for whole brain learning based on Curry's onion model. Curry described the effect of personality traits as the inner layer of learning, information-processing styles as the middle layer of learning, and environmental and instructional preferences as the outer layer of learning. The model that was developed…
Eagleton, Saramarie; Muller, Anton
Biothermal Model of Patient and Automatic Control System of Brain Temperature for Brain Hypothermia Treatment
NASA Astrophysics Data System (ADS)
Various surface-cooling apparatus such as the cooling cap, muffler and blankets have been commonly used for the cooling of the brain to provide hypothermic neuro-protection for patients of hypoxic-ischemic encephalopathy. The present paper is aimed at the brain temperature regulation from the viewpoint of automatic system control, in order to help clinicians decide an optimal temperature of the cooling fluid provided for these three types of apparatus. At first, a biothermal model characterized by dynamic ambient temperatures is constructed for adult patient, especially on account of the clinical practice of hypothermia and anesthesia in the brain hypothermia treatment. Secondly, the model is represented by the state equation as a lumped parameter linear dynamic system. The biothermal model is justified from their various responses corresponding to clinical phenomena and treatment. Finally, the optimal regulator is tentatively designed to give clinicians some suggestions on the optimal temperature regulation of the patient's brain. It suggests the patient's brain temperature could be optimally controlled to follow-up the temperature process prescribed by the clinicians. This study benefits us a great clinical possibility for the automatic hypothermia treatment.
Wakamatsu, Hidetoshi; Gaohua, Lu
Image guided constitutive modeling of the silicone brain phantom
NASA Astrophysics Data System (ADS)
The goal of this work is to develop reliable constitutive models of the mechanical behavior of the in-vivo human brain tissue for applications in neurosurgery. We propose to define the mechanical properties of the brain tissue in-vivo, by taking the global MR or CT images of a brain response to ventriculostomy - the relief of the elevated intracranial pressure. 3D image analysis translates these images into displacement fields, which by using inverse analysis allow for the constitutive models of the brain tissue to be developed. We term this approach Image Guided Constitutive Modeling (IGCM). The presented paper demonstrates performance of the IGCM in the controlled environment: on the silicone brain phantoms closely simulating the in-vivo brain geometry, mechanical properties and boundary conditions. The phantom of the left hemisphere of human brain was cast using silicon gel. An inflatable rubber membrane was placed inside the phantom to model the lateral ventricle. The experiments were carried out in a specially designed setup in a CT scanner with submillimeter isotropic voxels. The non-communicative hydrocephalus and ventriculostomy were simulated by consequently inflating and deflating the internal rubber membrane. The obtained images were analyzed to derive displacement fields, meshed, and incorporated into ABAQUS. The subsequent Inverse Finite Element Analysis (based on Levenberg-Marquardt algorithm) allowed for optimization of the parameters of the Mooney-Rivlin non-linear elastic model for the phantom material. The calculated mechanical properties were consistent with those obtained from the element tests, providing justification for the future application of the IGCM to in-vivo brain tissue.
Puzrin, Alexander; Skrinjar, Oskar; Ozan, Cem; Kim, Sihyun; Mukundan, Srinivasan
Epidural cooling for selective brain hypothermia in porcine model
Summary Background. Hypothermia has been shown to be neuroprotective in many animal models and several human trials of brain ischemic and trauma.\\u000a However systemic hypothermia may result in fatal complications. This study was undertaken to test epidural cooling as a new\\u000a method of inducing selective brain hypothermia.\\u000a \\u000a Method. Six adult swine (mean mass, 33.8 3.6?kg) were studied. Anesthesia was maintained with
H. Cheng; J. Shi; L. Zhang; Q. Zhang; H. Yin; L. Wang
Apyrase treatment of myocardial infarction according to a clinically applicable protocol fails to reduce myocardial injury in a porcine model
Background Ectonucleotidase dependent adenosine generation has been implicated in preconditioning related cardioprotection against ischemia-reperfusion injury, and treatment with a soluble ectonucleotidase has been shown to reduce myocardial infarct size (IS) when applied prior to induction of ischemia. However, ectonucleotidase treatment according to a clinically applicable protocol, with administration only after induction of ischemia, has not previously been evaluated. We therefore investigated if treatment with the ectonucleotidase apyrase, according to a clinically applicable protocol, would reduce IS and microvascular obstruction (MO) in a large animal model. Methods A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min, in 16 anesthetized pigs (40-50 kg). The pigs were randomized to 40 min of 1 ml/min intracoronary infusion of apyrase (10 U/ml, n = 8) or saline (0.9 mg/ml, n = 8), twenty minutes after balloon inflation. Area at risk (AAR) was evaluated by ex vivo SPECT. IS and MO were evaluated by ex vivo MRI. Results No differences were observed between the apyrase group and saline group with respect to IS/AAR (75.7 ± 4.2% vs 69.4 ± 5.0%, p = NS) or MO (10.7 ± 4.8% vs 11.4 ± 4.8%, p = NS), but apyrase prolonged the post-ischemic reactive hyperemia. Conclusion Apyrase treatment according to a clinically applicable protocol, with administration of apyrase after induction of ischemia, does not reduce myocardial infarct size or microvascular obstruction.
Cell tracking and therapy evaluation of bone marrow monocytes and stromal cells using SPECT and CMR in a canine model of myocardial infarction
Background The clinical application of stem cell therapy for myocardial infarction will require the development of methods to monitor treatment and pre-clinical assessment in a large animal model, to determine its effectiveness and the optimum cell population, route of delivery, timing, and flow milieu. Objectives To establish a model for a) in vivo tracking to monitor cell engraftment after autologous transplantation and b) concurrent measurement of infarct evolution and remodeling. Methods We evaluated 22 dogs (8 sham controls, 7 treated with autologous bone marrow monocytes, and 7 with stromal cells) using both imaging of 111Indium-tropolone labeled cells and late gadolinium enhancement CMR for up to12 weeks after a 3 hour coronary occlusion. Hearts were also examined using immunohistochemistry for capillary density and presence of PKH26 labeled cells. Results In vivo Indium imaging demonstrated an effective biological clearance half-life from the injection site of ~5 days. CMR demonstrated a pattern of progressive infarct shrinkage over 12 weeks, ranging from 67–88% of baseline values with monocytes producing a significant treatment effect. Relative infarct shrinkage was similar through to 6 weeks in all groups, following which the treatment effect was manifest. There was a trend towards an increase in capillary density with cell treatment. Conclusion This multi-modality approach will allow determination of the success and persistence of engraftment, and a correlation of this with infarct size shrinkage, regional function, and left ventricular remodeling. There were overall no major treatment effects with this particular model of transplantation immediately post-infarct.
Wisenberg, Gerald; Lekx, Katie; Zabel, Pam; Kong, Huafu; Mann, Rupinder; Zeman, Peter R; Datta, Sudip; Culshaw, Caroline N; Merrifield, Peter; Bureau, Yves; Wells, Glenn; Sykes, Jane; Prato, Frank S
Bone marrow mesenchymal stem cells improve myocardial function in a swine model of acute myocardial infarction.
The aim of the current study was to confirm the effect and elucidate the mechanism of bone marrow mesenchymal stem cells (BMSCs) in acute myocardial infarction (AMI). AMI was induced in mini?swine by ligating the left anterior descending coronary artery, and BMSCs (1x107) were injected via a sterile microinjection into the ischemic area. Six months postoperatively, electrocardiograph?gated single photon emission computed tomography revealed that the myocardial filling defect was reduced and the left ventricular ejection fraction was improved in the BMSC group compared with the control group (P<0.05). Histopathological examination indicated that, in the BMSC treatment group, the percentage of survived myocardial tissue and the vessel density were increased, and the percentage of apoptosis was decreased compared with controls (P<0.05). Reverse transcription?polymerase chain reaction results indicated that the expression levels of multiple inflammatory factors were significantly upregulated in the BMSC group compared with levels in the control group (P<0.05). In conclusion, the present study demonstrated that BMSC injection significantly improved cardiac function and reduced infarct size in six months, indicating that this method may be valuable for future study in clinical trials. PMID:25060678
Zhao, Jing-Jie; Liu, Xiao-Cheng; Kong, Feng; Qi, Tong-Gang; Cheng, Guang-Hui; Wang, Jue; Sun, Chao; Luan, Yun
Corticonic models of brain mechanisms underlying cognition and intelligence
NASA Astrophysics Data System (ADS)
The concern of this review is brain theory or more specifically, in its first part, a model of the cerebral cortex and the way it: (a) interacts with subcortical regions like the thalamus and the hippocampus to provide higher-level-brain functions that underlie cognition and intelligence, (b) handles and represents dynamical sensory patterns imposed by a constantly changing environment, (c) copes with the enormous number of such patterns encountered in a lifetime by means of dynamic memory that offers an immense number of stimulus-specific attractors for input patterns (stimuli) to select from, (d) selects an attractor through a process of "conjugation" of the input pattern with the dynamics of the thalamo-cortical loop, (e) distinguishes between redundant (structured) and non-redundant (random) inputs that are void of information, (f) can do categorical perception when there is access to vast associative memory laid out in the association cortex with the help of the hippocampus, and (g) makes use of "computation" at the edge of chaos and information driven annealing to achieve all this. Other features and implications of the concepts presented for the design of computational algorithms and machines with brain-like intelligence are also discussed. The material and results presented suggest, that a Parametrically Coupled Logistic Map network (PCLMN) is a minimal model of the thalamo-cortical complex and that marrying such a network to a suitable associative memory with re-entry or feedback forms a useful, albeit, abstract model of a cortical module of the brain that could facilitate building a simple artificial brain. In the second part of the review, the results of numerical simulations and drawn conclusions in the first part are linked to the most directly relevant works and views of other workers. What emerges is a picture of brain dynamics on the mesoscopic and macroscopic scales that gives a glimpse of the nature of the long sought after brain code underlying intelligence and other higher level brain functions.
Farhat, Nabil H.
Realistic modeling of neurons and networks: towards brain simulation
Summary Realistic modeling is a new advanced methodology for investigating brain functions. Realistic modeling is based on a detailed biophysical description of neurons and synapses, which can be integrated into microcircuits. The latter can, in turn, be further integrated to form large-scale brain networks and eventually to reconstruct complex brain systems. Here we provide a review of the realistic simulation strategy and use the cerebellar network as an example. This network has been carefully investigated at molecular and cellular level and has been the object of intense theoretical investigation. The cerebellum is thought to lie at the core of the forward controller operations of the brain and to implement timing and sensory prediction functions. The cerebellum is well described and provides a challenging field in which one of the most advanced realistic microcircuit models has been generated. We illustrate how these models can be elaborated and embedded into robotic control systems to gain insight into how the cellular properties of cerebellar neurons emerge in integrated behaviors. Realistic network modeling opens up new perspectives for the investigation of brain pathologies and for the neurorobotic field.
D'Angelo, Egidio; Solinas, Sergio; Garrido, Jesus; Casellato, Claudia; Pedrocchi, Alessandra; Mapelli, Jonathan; Gandolfi, Daniela; Prestori, Francesca
Realistic modeling of neurons and networks: towards brain simulation.
Realistic modeling is a new advanced methodology for investigating brain functions. Realistic modeling is based on a detailed biophysical description of neurons and synapses, which can be integrated into microcircuits. The latter can, in turn, be further integrated to form large-scale brain networks and eventually to reconstruct complex brain systems. Here we provide a review of the realistic simulation strategy and use the cerebellar network as an example. This network has been carefully investigated at molecular and cellular level and has been the object of intense theoretical investigation. The cerebellum is thought to lie at the core of the forward controller operations of the brain and to implement timing and sensory prediction functions. The cerebellum is well described and provides a challenging field in which one of the most advanced realistic microcircuit models has been generated. We illustrate how these models can be elaborated and embedded into robotic control systems to gain insight into how the cellular properties of cerebellar neurons emerge in integrated behaviors. Realistic network modeling opens up new perspectives for the investigation of brain pathologies and for the neurorobotic field. PMID:24139652
D'Angelo, Egidio; Solinas, Sergio; Garrido, Jesus; Casellato, Claudia; Pedrocchi, Alessandra; Mapelli, Jonathan; Gandolfi, Daniela; Prestori, Francesca
Classical Wave Model of Quantum-Like Processing in Brain
NASA Astrophysics Data System (ADS)
We discuss the conjecture on quantum-like (QL) processing of information in the brain. It is not based on the physical quantum brain (e.g., Penrose) - quantum physical carriers of information. In our approach the brain created the QL representation (QLR) of information in Hilbert space. It uses quantum information rules in decision making. The existence of such QLR was (at least preliminary) confirmed by experimental data from cognitive psychology. The violation of the law of total probability in these experiments is an important sign of nonclassicality of data. In so called "constructive wave function approach" such data can be represented by complex amplitudes. We presented 1,2 the QL model of decision making. In this paper we speculate on a possible physical realization of QLR in the brain: a classical wave model producing QLR . It is based on variety of time scales in the brain. Each pair of scales (fine - the background fluctuations of electromagnetic field and rough - the cognitive image scale) induces the QL representation. The background field plays the crucial role in creation of "superstrong QL correlations" in the brain.
Khrennikov, A.
Metabolism of orthotopic mouse brain tumor models.
We used magnetic resonance spectroscopy to determine whether orthotopic mouse brain tumors grown as xenografts in immunocompromised mice either from human brain tumor cells implanted immediately after surgery or from cultured human tumor lines show metabolic profiles comparable to those of the original tumors. Using a 7 T scanner, spectra were acquired from mice with a human atypical teratoid/rhabdoid tumor (AT/RT) either implanted directly from the surgical specimen or first grown in culture, directly implanted choroid plexus carcinoma (CPC), and two medulloblastoma cell lines. The results were compared with spectra from these same tumors or tumor types in patients and with controls. Metabolic variability of tumors from a single cell line was also evaluated using the medulloblastoma lines. The main metabolic features of human tumors were qualitatively replicated in xenografts. AT/RTs in mice exhibited choline, creatine, and myo-inositol levels comparable to those observed in the patient. As in patients, choline was prominent in experimental CPC. Tumors from a single cell line were comparable. Significant correlations were found with key metabolites in humans and mice; however, differences including lower lipids in the implanted AT/RTs than in patient spectra and taurine observed in all animal spectra were also noted. The causes of these dissimilarities warrant further investigation. PMID:19728974
Rosol, Michael; Harutyunyan, Ira; Xu, Jingying; Melendez, Elizabeth; Smbatyan, Goar; Finlay, Jonathan L; Krieger, Mark D; Gonzalez-Gomez, Ignacio; Reynolds, C Patrick; Nelson, Marvin D; Erdreich-Epstein, Anat; Blüml, Stefan
Finite element analysis and experimental study on mechanism of brain injury using brain model.
The aim of this study is to discuss the occurrence mechanism of the brain injury analytically and experimentally. In this paper, first, an experimental system to do an impact experiment was presented. The pressure changes inside a brain agar phantom were measured. Second, a three-dimensional FEM model of the impact experiment was constructed. From the results of the fundamental analysis, the transmitted pressure inside the brain agar phantom could be presented. The comparison of the computer simulation and experimental results showed that the negative pressure values, same as the positive pressure occurred in the coup side region of the agar, also appeared in the contrecoup side region of the agar. PMID:17945634
Ishikawa, R; Kato, K; Kubo, M; Uzuka, T; Takahashi, H
Distributed local MRF models for tissue and structure brain segmentation.
Accurate tissue and structure segmentation of magnetic resonance (MR) brain scans is critical in several applications. In most approaches this task is handled through two sequential steps. We propose to carry out cooperatively both tissue and subcortical structure segmentation by distributing a set of local and cooperative Markov random field (MRF) models Tissue segmentation is performed by partitioning the volume into subvolumes where local MRFs are estimated in cooperation with their neighbors to ensure consistency. Local estimation fits precisely to the local intensity distribution and thus handles nonuniformity of intensity without any bias field modelization. Similarly, subcortical structure segmentation is performed via local MRF models that integrate localization constraints provided by a priori fuzzy description of brain anatomy. Subcortical structure segmentation is not reduced to a subsequent processing step but joined with tissue segmentation: the two procedures cooperate to gradually and conjointly improve model accuracy. We propose a framework to implement this distributed modeling integrating cooperation, coordination, and local model checking in an efficient way. Its evaluation was performed using both phantoms and real 3 T brain scans, showing good results and in particular robustness to nonuniformity and noise with a low computational cost. This original combination of local MRF models, including anatomical knowledge, appears as a powerful and promising approach for MR brain scan segmentation. PMID:19228553
Scherrer, Benoit; Forbes, Florence; Garbay, Catherine; Dojat, Michel
Intramyocardial sustained delivery of placental growth factor using nanoparticles as a vehicle for delivery in the rat infarct model
Background Acute myocardial ischemia results in scar formation with ventricular dilatation and eventually heart failure. Placental growth factor (PlGF) is reported to stimulate angiogenesis and improve cardiac function. In this study, it was hypothesized that intramyocardial injection of PlGF contained in nanoparticles can be released at the site of action for an extended time period as a sustained slow-release protective mechanism that accelerates myocardial recovery in a rat model of ischemic cardiomyopathy. Methods PlGF-loaded chitosan-alginate nanoparticles were injected into an acute myocardial infarction model in rats (n = 10 per group). Transthoracic echocardiography was performed at different time intervals. Enzyme-linked immunosorbent assay was used to measure the serum cytokines levels at 8 weeks. Hearts were stained with Masson's trichrome for scar area analysis. Immunofluorostaining was performed to evaluate the extent of myocardial angiogenesis at the infarction border. PlGF enzyme-linked immunosorbent assay was used to measure the in vitro release kinetics of PlGF-loaded nanoparticles. Results At 8 weeks after coronary ligation, hearts that were treated with PlGF-loaded chitosan-alginate nanoparticles had significant increases in left-ventricular function (P < 0.01), vascular density (P < 0.01), and in the serum level of the anti-inflammatory cytokine interleukin-10 (P < 0.05). There was significant decrease in scar area formation (P < 0.05) and in serum levels of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 (P < 0.01). In vitro PlGF-release kinetic studies showed a sustained release of PlGF from the particles over a 120-hour period. Conclusion The use of nanoparticles as a vehicle for PlGF delivery, as opposed to the direct injection of the growth factor after acute myocardial infarction, can provide sustained slow-release PlGF therapy, enhancing the positive effects of the growth factor in the setting of acute myocardial ischemia.
Binsalamah, Ziyad Mohammed; Paul, Arghya; Khan, Afshan Afsar; Prakash, Satya; Shum-Tim, Dominique
Modeling Brain Resonance Phenomena Using a Neural Mass Model
Stimulation with rhythmic light flicker (photic driving) plays an important role in the diagnosis of schizophrenia, mood disorder, migraine, and epilepsy. In particular, the adjustment of spontaneous brain rhythms to the stimulus frequency (entrainment) is used to assess the functional flexibility of the brain. We aim to gain deeper understanding of the mechanisms underlying this technique and to predict the
Andreas Spiegler; Thomas R. Knösche; Karin Schwab; Jens Haueisen; Fatihcan M. Atay
Esophageal infarction or acute necrotizing esophagitis is a rare condition that has a dramatic endoscopic appearance of a "black esophagus." The esophageal involvement can vary from the distal third to the total esophagus. Excluding corrosive injury and other well-known rare causes of black esophagus, the etiology of this condition is unknown. Ischemia due to hypoperfusion state is thought to play a central role in the pathogenesis. The treatment is supportive with acid suppression and gastrointestinal rest. Mortality is high due to comorbid conditions. PMID:17298765
Hawari, Rami; Pasricha, Pankaj J
Modeling the impact of COPD on the brain
Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p ? 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities.
Borson, Soo; Scanlan, James; Friedman, Seth; Zuhr, Elizabeth; Fields, Julie; Aylward, Elizabeth; Mahurin, Rodney; Richards, Todd; Anzai, Yoshimi; Yukawa, Michi; Yeh, Shingshing
The thrombomodulin analog Solulin promotes reperfusion and reduces infarct volume in a thrombotic stroke model
See also Andreou AP, Crawley JTB. Thrombomodulin analogues for the treatment of ischemic stroke. This issue, pp 1171–3. Summary Background: Currently there is no approved anticoagulant for treating acute stroke. This is largely because of concern for hemorrhagic complications, and suggests a critical need for safer anticoagulants. Solulin is a soluble analog of the endothelial cell receptor thrombomodulin, able to bind free thrombin and convert it to an activator of the anticoagulant, protein C. Objective: Solulin was tested for its ability to inhibit middle cerebral artery occlusion (MCAO) induced by photothrombosis, and to restore MCA patency after establishment of stable occlusion. Methods: Cerebral blood flow (CBF) was monitored by laser Doppler for 1.5 h after occlusion and again 72 h later. Results: Solulin treatment 30 min before thrombosis resulted in an approximately 50% increase in time to form a stable occlusion. When administered 30 or 60 min after MCAO, Solulin significantly improved CBF within 90 min of treatment. In contrast, none of the vehicle-treated mice showed restoration of CBF in the first 90 min and only 17% did so by 72 h. Solulin treatment was associated with a significant reduction in infarct volume, and was well tolerated with no overt hemorrhage observed in any treatment group. Mechanistic studies in mice homozygous for the factor (F)V Leiden mutation, suggest that Solulin's efficacy derives primarily from the anticoagulant activity of the thrombin–Solulin complex and not from direct anti-inflammatory or neuroprotective effects of Solulin or activated protein C. Conclusions: Our data indicate that Solulin is a safe and effective anticoagulant that is able to antagonize active thrombosis in acute ischemic stroke, and to reduce infarct volume.
Constitutive model for brain tissue under finite compression.
While advances in computational models of mechanical phenomena have made it possible to simulate dynamically complex problems in biomechanics, accurate material models for soft tissues, particularly brain tissue, have proven to be very challenging. Most studies in the literature on material properties of brain tissue are performed in shear loading and very few tackle the behavior of brain in compression. In this study, a viscoelastic constitutive model of bovine brain tissue under finite step-and-hold uniaxial compression with 10 s(-1) ramp rate and 20 s hold time has been developed. The assumption of quasi-linear viscoelasticity (QLV) was validated for strain levels of up to 35%. A generalized Rivlin model was used for the isochoric part of the deformation and it was shown that at least three terms (C(10), C(01) and C(11)) are needed to accurately capture the material behavior. Furthermore, for the volumetric deformation, a two parameter Ogden model was used and the extent of material incompressibility was studied. The hyperelastic material parameters were determined through extracting and fitting to two isochronous curves (0.06 s and 14 s) approximating the instantaneous and steady-state elastic responses. Viscoelastic relaxation was characterized at five decay rates (100, 10, 1, 0.1, 0 s(-1)) and the results in compression and their extrapolation to tension were compared against previous models. PMID:22281404
Laksari, Kaveh; Shafieian, Mehdi; Darvish, Kurosh
The influence of myocardial substrate on ventricular fibrillation waveform: A swine model of acute and postmyocardial infarction
Objective In cardiac arrest resulting from ventricular fibrillation, the ventricular fibrillation waveform may be a clue to its duration and predict the likelihood of shock success. However, ventricular fibrillation occurs in different myocardial substrates such as ischemia, heart failure, and structurally normal hearts. We hypothesized that ventricular fibrillation is altered by myocardial infarction and varies from the acute to postmyocardial infarction periods. Design An animal intervention study was conducted with comparison to a control group. Setting This study took place in a university animal laboratory. Subjects Study subjects included 37 swine. Interventions Myocardial infarction was induced by occlusion of the midleft anterior descending artery. Ventricular fibrillation was induced in control swine, acute myocardial infarction swine, and in postmyocardial infarction swine after a 2-wk recovery period. Measurements and Main Results Ventricular fibrillation was recorded in 11 swine with acute myocardial infarction, ten post-myocardial infarction, and 16 controls. Frequency (mean, median, dominant, and bandwidth) and amplitude-related content (slope, slope-amp [slope divided by amplitude], and amplitude–spectrum area) were analyzed. Frequencies at 5 mins of ventricular fibrillation were altered in both acute myocardial infarction (p < .001 for all frequency characteristics) and postmyocardial infarction swine (p = .015 for mean, .002 for median, .002 for dominant frequency, and <.001 for bandwidth). At 5 mins, median frequency was highest in controls, 10.9 ± .4 Hz; lowest in acute myocardial infarction, 8.4 ± .5 Hz; and intermediate in postmyocardial infarction, 9.7 ± .5 Hz (p < .001 for acute myocardial infarction and p = .002 for postmyocardial infarction compared with control). Slope and amplitude–spectrum area were similar among the three groups with a shallow decline after minute 2, whereas slope-amp remained significantly altered for acute myocardial infarction swine at 5 mins (p = .003). Conclusions Ventricular fibrillation frequencies depend on myocardial substrate and evolve from the acute through healing phases of myocardial infarction. Amplitude related measures, however, are similar among these groups. It is unknown how defibrillation may be affected by relying on the ventricular fibrillation waveform without considering myocardial substrate.
Indik, Julia H.; Donnerstein, Richard L.; Hilwig, Ronald W.; Zuercher, Mathias; Feigelman, Justin; Kern, Karl B.; Berg, Marc D.; Berg, Robert A.
Vulnerability for apoptosis in the limbic system after myocardial infarction in rats: a possible model for human postinfarct major depression
Objective Major depressive disorder occurs in 15%–30% of patients who have had a myocardial infarction (MI), but the neurobiological mechanisms involved are not well understood. Previously, we found early intracellular signalling changes in the limbic system after acute MI in rats. The aim of the present study was to test the presence of behavioural deficits compatible with animal models of depression after acute MI in rats and to verify whether this is associated with apoptosis vulnerability markers. Methods Occlusion of the left-anterior descending artery was induced for 40 minutes under anesthesia in adult male Sprague–Dawley rats. Control sham rats underwent the same surgical procedure without occlusion. After surgery, subgroups of MI and sham rats were treated with desipramine, 10 mg/kg, intraperitoneally for 14 days. All rats were tested on measures of behavioural depression 14 days after surgery with a sucrose preference test, a forced swimming test, and a memory test (Morris water maze [MWM]). The rats were sacrificed, and the MI size was determined; apoptosis was estimated in the prefrontal cortex, hypothalamus, amygdala and hippocampus by measuring Bax:Bcl-2 ratio and caspase-3 activity. Results Untreated MI rats drank significantly less sucrose and swam significantly less than sham rats. No difference was found on the MWM. Behavioural depression was prevented by desipramine. Bax:Bcl-2 ratio was significantly increased in the prefrontal cortex and hypothalamus of MI rats, compared with sham rats; caspase-3 activity showed no difference between the 2 groups. Bax:Bcl-2 ratio in the prefrontal cortex was correlated with swim time in the forced swim test. Conclusion Behavioural impairment and limbic apoptotic events observed after a myocardial infarct are consistent with a model of human post-MI depression.
Wann, Boubacar Pasto; Bah, Thierno Madjou; Boucher, Matthieu; Courtemanche, Jerome; Marec, Nathalie Le; Rousseau, Guy; Godbout, Roger
Endothelial progenitor cell transplantation decreases lymphangiogenesis and adverse myocardial remodeling in a mouse model of acute myocardial infarction.
Cardiac lymphatic system in the remodeling after acute myocardial infarction (AMI) has been overlooked. We wanted to investigate the role of bone marrow-derived endothelial progenitor cells (EPCs) and their contribution to lymphatic distribution in myocardial remodeling after AMI. Mouse (C57bl/6J) MI models were created by ligation of the left anterior descending coronary artery and were treated with phosphate buffered saline (PBS) or EPCs. Real-time RT-PCR with 2- to 4-week myocardial tissue samples revealed that lymphangiogenetic factors such as vascular endothelial growth factor (VEGF)-C (8.5 fold, P < 0.05), VEGF-D (6.1 fold, P < 0.05), Lyve-1 (15 fold, P < 0.05), and Prox-1 (11 fold, P < 0.05) were expressed at significantly higher levels in the PBS group than the EPC group. The PBS group also showed a significantly higher density of lymphatic vessels in the peri-infarction area. Echocardiography showed that from 2 weeks after the treatment, left ventricle (LV) dimensions at both systole and diastole were significantly smaller in the EPC group than in the PBS group (P < 0.01) and LV fractional shortening was higher in the EPC group accordingly (P < 0.01). Lymphangiogenic markers increased in a mouse MI model. EPC transplantation decreased lymphangiogenesis and adverse ventricular remodeling after AMI. These novel findings suggest that new lymphatic vessels may be formed in severely damaged myocardium, and may be involved in adverse myocardial remodeling after AMI. PMID:21694495
Park, Jae-Hyeong; Yoon, Jung Yeon; Ko, Seon Mi; Jin, Seon Ah; Kim, Jun Hyung; Cho, Chung-Hyun; Kim, Jin-Man; Lee, Jae-Hwan; Choi, Si Wan; Seong, In-Whan; Jeong, Jin Ok
Animal models of brain maldevelopment induced by cycad plant genotoxins.
Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., cycasin, macrozamin) and neurotoxic amino acids (notably ?-N-methylamino-l-alanine l-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction. PMID:24339036
Kisby, Glen E; Moore, Holly; Spencer, Peter S
The NIM model as a brain for a humanoid robot
In the context of the PACO+ project (http:\\/\\/www.paco-plus.org\\/), we propose to implement the recently developed Natural Input Memory (NIM) model (2) as a brain for a humanoid robot that operates directly on real-world visual input. The NIM model is a memory model that encompasses a perceptual front-end that takes local samples (i.e., eye fixations) from natural d igitized images and
Joyca Lacroix; Bernhard Hommel; Pascal Haazebroek
Computational modeling of an endovascular approach to deep brain stimulation
NASA Astrophysics Data System (ADS)
Objective. Deep brain stimulation (DBS) therapy currently relies on a transcranial neurosurgical technique to implant one or more electrode leads into the brain parenchyma. In this study, we used computational modeling to investigate the feasibility of using an endovascular approach to target DBS therapy. Approach. Image-based anatomical reconstructions of the human brain and vasculature were used to identify 17 established and hypothesized anatomical targets of DBS, of which five were found adjacent to a vein or artery with intraluminal diameter ?1 mm. Two of these targets, the fornix and subgenual cingulate white matter (SgCwm) tracts, were further investigated using a computational modeling framework that combined segmented volumes of the vascularized brain, finite element models of the tissue voltage during DBS, and multi-compartment axon models to predict the direct electrophysiological effects of endovascular DBS. Main results. The models showed that: (1) a ring-electrode conforming to the vessel wall was more efficient at neural activation than a guidewire design, (2) increasing the length of a ring-electrode had minimal effect on neural activation thresholds, (3) large variability in neural activation occurred with suboptimal placement of a ring-electrode along the targeted vessel, and (4) activation thresholds for the fornix and SgCwm tracts were comparable for endovascular and stereotactic DBS, though endovascular DBS was able to produce significantly larger contralateral activation for a unilateral implantation. Significance. Together, these results suggest that endovascular DBS can serve as a complementary approach to stereotactic DBS in select cases.
Teplitzky, Benjamin A.; Connolly, Allison T.; Bajwa, Jawad A.; Johnson, Matthew D.
A neurovascular blood-brain barrier in vitro model.
The cerebral microvasculature possesses certain cellular features that constitute the blood-brain barrier (BBB) (Abbott et al., Neurobiol Dis 37:13-25, 2010). This dynamic barrier separates the brain parenchyma from peripheral blood flow and is of tremendous clinical importance: for example, BBB breakdown as in stroke is associated with the development of brain edema (Rosenberg and Yang, Neurosurg Focus 22:E4, 2007), inflammation (Kuhlmann et al., Neurosci Lett 449:168-172, 2009; Coisne and Engelhardt, Antioxid Redox Signal 15:1285-1303, 2011), and increased mortality. In vivo, the BBB consists of brain endothelial cells (BEC) that are embedded within a precisely regulated environment containing astrocytes, pericytes, smooth muscle cells, and glial cells. These cells experience modulation by various pathways of intercellular communication and by pathophysiological processes, e.g., through neurovascular coupling (Attwell et al., Nature 468:232-243, 2010), cortical spreading depression (Gursoy-Ozdemir et al., J Clin Invest 113:1447-1455, 2004), or formation of oxidative stress (Yemisci et al., Nat Med 15:1031-1037, 2009). Hence, this interdependent assembly of cells is referred to as the neurovascular unit (NVU) (Zlokovic, Nat Med 16:1370-1371, 2010; Zlokovic, Neuron 57:178-201, 2008). Experimental approaches to investigate the BBB in vitro are highly desirable to study the cerebral endothelium in health and disease. However, due to the complex interactions taking place within the NVU in vivo, it is difficult to mimic this interplay in vitro.Here, we describe a murine blood-brain barrier coculture model consisting of cortical organotypic slice cultures and brain endothelial cells that includes most of the cellular components of the NVU including neurons, astrocytes, and brain endothelial cells. This model allows the experimental analysis of several crucial BBB parameters such as transendothelial electrical resistance or tight junction protein localization by immunohistochemistry and live cell imaging of reactive oxygen species. PMID:24510882
Zehendner, Christoph M; White, Robin; Hedrich, Jana; Luhmann, Heiko J
Modeling the blood-brain barrier using stem cell sources
The blood–brain barrier (BBB) is a selective endothelial interface that controls trafficking between the bloodstream and brain interstitial space. During development, the BBB arises as a result of complex multicellular interactions between immature endothelial cells and neural progenitors, neurons, radial glia, and pericytes. As the brain develops, astrocytes and pericytes further contribute to BBB induction and maintenance of the BBB phenotype. Because BBB development, maintenance, and disease states are difficult and time-consuming to study in vivo, researchers often utilize in vitro models for simplified analyses and higher throughput. The in vitro format also provides a platform for screening brain-penetrating therapeutics. However, BBB models derived from adult tissue, especially human sources, have been hampered by limited cell availability and model fidelity. Furthermore, BBB endothelium is very difficult if not impossible to isolate from embryonic animal or human brain, restricting capabilities to model BBB development in vitro. In an effort to address some of these shortcomings, advances in stem cell research have recently been leveraged for improving our understanding of BBB development and function. Stem cells, which are defined by their capacity to expand by self-renewal, can be coaxed to form various somatic cell types and could in principle be very attractive for BBB modeling applications. In this review, we will describe how neural progenitor cells (NPCs), the in vitro precursors to neurons, astrocytes, and oligodendrocytes, can be used to study BBB induction. Next, we will detail how these same NPCs can be differentiated to more mature populations of neurons and astrocytes and profile their use in co-culture modeling of the adult BBB. Finally, we will describe our recent efforts in differentiating human pluripotent stem cells (hPSCs) to endothelial cells with robust BBB characteristics and detail how these cells could ultimately be used to study BBB development and maintenance, to model neurological disease, and to screen neuropharmaceuticals.
Transplantation of iPSc ameliorates neural remodeling and reduces ventricular arrhythmias in a post-infarcted swine model.
Neural remodeling after myocardial infarction (MI) may cause malignant ventricular arrhythmia, which is the main cause of sudden cardiac death following MI. Herein, we aimed to examine whether induced pluripotent stem cells (iPSc) transplantation can ameliorate neural remodeling and reduce ventricular arrhythmias (VA) in a post-infarcted swine model. Left anterior descending coronary arteries were balloon-occluded to generate MI. Animals were then divided into Sham, PBS control, and iPS groups. Dynamic electrocardiography programmed electric stimulation were performed to evaluate VA. The spatial distribution of vascularization, Cx43 and autonomic nerve regeneration were evaluated by immunofluorescence staining. Associated protein expression was detected by Western blotting. Likewise, we measured the enzymatic activities of superoxide dismutase and content of malondialdehyde. Six weeks later, the number of blood vessels increased significantly in the iPSc group. The expression of vascular endothelial growth factor and connexin 43 in the iPS group was significantly higher than the PBS group; however, the levels of nerve growth factor and tyrosine hydroxylase were lower. The oxidative stress was ameliorated by iPSc transplantation. Moreover, the number of sympathetic nerves in the iPSc group was reduced, while the parasympathetic nerve fibers had no obvious change. The transplantation of iPSc also significantly decreased the low-/high-frequency ratio and arrhythmia score of programmed electric stimulation-induced VA. In conclusion, iPSc intramyocardial transplantation reduces vulnerability to VAs, and the mechanism was related to the remodeling amelioration of autonomic nerves and gap junctions. Moreover, possible mechanisms of iPSc transplantation in improving neural remodeling may be related to attenuated oxidative stress and inflammatory response. PMID:24122925
Zhang, Fengxiang; Song, Guixian; Li, Xiaorong; Gu, Weijuan; Shen, Yahui; Chen, Minglong; Yang, Bing; Qian, Lingmei; Cao, Kejiang
Blood brain barrier breakdown as the starting point of cerebral small vessel disease? - New insights from a rat model
Cerebral small vessel disease (CSVD, cerebral microangiopathy) leads to dementia and stroke-like symptoms. Lacunes, white matter lesions (WML) and microbleeds are the main pathological correlates depicted in in-vivo imaging diagnostics. Early studies described segmental arterial wall disorganizations of small penetrating cerebral arteries as the most pronounced underlying histopathology of lacunes. Luminal narrowing caused by arteriolosclerosis was supposed to result in hypoperfusion with WML and infarcts. We have used the model of spontaneously hypertensive stroke-prone rats (SHRSP) for a longitudinal study to elucidate early histological changes in small cerebral vessels. We suggest that endothelial injuries lead to multiple sites with blood brain barrier (BBB) leakage which cause an ongoing damage of the vessel wall and finally resulting in vessel ruptures and microbleeds. These microbleeds together with reactive small vessel occlusions induce overt cystic infarcts of the surrounding parenchyma. Thus, multiple endothelial leakage sites seem to be the starting point of cerebral microangiopathy. The vascular system reacts with an activated coagulatory state to these early endothelial injuries and by this induces the formation of stases, accumulations of erythrocytes, which represent the earliest detectable histological peculiarity of small vessel disease in SHRSP. In this review we focus on the meaning of the BBB breakdown in CSVD and finally discuss possible consequences for clinicians.
Blood brain barrier breakdown as the starting point of cerebral small vessel disease? - New insights from a rat model.
Cerebral small vessel disease (CSVD, cerebral microangiopathy) leads to dementia and stroke-like symptoms. Lacunes, white matter lesions (WML) and microbleeds are the main pathological correlates depicted in in-vivo imaging diagnostics. Early studies described segmental arterial wall disorganizations of small penetrating cerebral arteries as the most pronounced underlying histopathology of lacunes. Luminal narrowing caused by arteriolosclerosis was supposed to result in hypoperfusion with WML and infarcts.We have used the model of spontaneously hypertensive stroke-prone rats (SHRSP) for a longitudinal study to elucidate early histological changes in small cerebral vessels. We suggest that endothelial injuries lead to multiple sites with blood brain barrier (BBB) leakage which cause an ongoing damage of the vessel wall and finally resulting in vessel ruptures and microbleeds. These microbleeds together with reactive small vessel occlusions induce overt cystic infarcts of the surrounding parenchyma. Thus, multiple endothelial leakage sites seem to be the starting point of cerebral microangiopathy. The vascular system reacts with an activated coagulatory state to these early endothelial injuries and by this induces the formation of stases, accumulations of erythrocytes, which represent the earliest detectable histological peculiarity of small vessel disease in SHRSP.In this review we focus on the meaning of the BBB breakdown in CSVD and finally discuss possible consequences for clinicians. PMID:23497521
Schreiber, Stefanie; Bueche, Celine Zoe; Garz, Cornelia; Braun, Holger
Housekeeping while brain's storming Validation of normalizing factors for gene expression studies in a murine model of traumatic brain injury
BACKGROUND: Traumatic brain injury models are widely studied, especially through gene expression, either to further understand implied biological mechanisms or to assess the efficiency of potential therapies. A large number of biological pathways are affected in brain trauma models, whose elucidation might greatly benefit from transcriptomic studies. However the suitability of reference genes needed for quantitative RT-PCR experiments is missing
Hervé Rhinn; Catherine Marchand-Leroux; Nicole Croci; Michel Plotkine; Daniel Scherman; Virginie Escriou
A model for intratumoural chemotherapy in the rat brain
Summary To achieve the best reproducibility in rat brain tumour models several injection techniques have been used. Although stereotactic cell injections have proved to be effective and reliable, they are expensive and time consuming. A new permanently implanted device is presented here. It allows precise cell delivery for best tumour reproducibility, and it can be left in place for future
M. Saini; F. Roser; M. Samii; M. Bellinzona
Magnetic Resonance Imaging in Experimental Models of Brain Disorders
This review gives an overview of the application of magnetic resonance imaging (MRI) in experimental models of brain disorders. MRI is a noninvasive and versatile imaging modality that allows longitudinal and three-dimensional assessment of tissue morphology, metabolism, physiology, and function. MRI can be sensitized to proton density, T1, T2, susceptibility contrast, magnetization transfer, diffusion, perfusion, and flow. The combination of
Rick M. Dijkhuizen; Klaas Nicolay
Stochastic model of Tsc1 lesions in mouse brain.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to mutations in either TSC1 or TSC2 that affects many organs with hamartomas and tumors. TSC-associated brain lesions include subependymal nodules, subependymal giant cell astrocytomas and tubers. Neurologic manifestations in TSC comprise a high frequency of mental retardation and developmental disorders including autism, as well as epilepsy. Here, we describe a new mouse model of TSC brain lesions in which complete loss of Tsc1 is achieved in multiple brain cell types in a stochastic pattern. Injection of an adeno-associated virus vector encoding Cre recombinase into the cerebral ventricles of mice homozygous for a Tsc1 conditional allele on the day of birth led to reduced survival, and pathologic findings of enlarged neurons, cortical heterotopias, subependymal nodules, and hydrocephalus. The severity of clinical and pathologic findings as well as survival was shown to be dependent upon the dose and serotype of Cre virus injected. Although several other models of TSC brain disease exist, this model is unique in that the pathology reflects a variety of TSC-associated lesions involving different numbers and types of cells. This model provides a valuable and unique addition for therapeutic assessment. PMID:23696872
Prabhakar, Shilpa; Goto, June; Zuang, Xuan; Sena-Esteves, Miguel; Bronson, Roderick; Brockmann, Jillian; Gianni, Davide; Wojtkiewicz, Gregory R; Chen, John W; Stemmer-Rachamimov, Anat; Kwiatkowski, David J; Breakefield, Xandra O
The musician's brain as a model of neuroplasticity
Studies of experience-driven neuroplasticity at the behavioural, ensemble, cellular and molecular levels have shown that the structure and significance of the eliciting stimulus can determine the neural changes that result. Studying such effects in humans is difficult, but professional musicians represent an ideal model in which to investigate plastic changes in the human brain. There are two advantages to studying
Eckart Altenmüller; Lutz Jäncke; Thomas F. Münte
Stochastic Model of Tsc1 Lesions in Mouse Brain
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to mutations in either TSC1 or TSC2 that affects many organs with hamartomas and tumors. TSC-associated brain lesions include subependymal nodules, subependymal giant cell astrocytomas and tubers. Neurologic manifestations in TSC comprise a high frequency of mental retardation and developmental disorders including autism, as well as epilepsy. Here, we describe a new mouse model of TSC brain lesions in which complete loss of Tsc1 is achieved in multiple brain cell types in a stochastic pattern. Injection of an adeno-associated virus vector encoding Cre recombinase into the cerebral ventricles of mice homozygous for a Tsc1 conditional allele on the day of birth led to reduced survival, and pathologic findings of enlarged neurons, cortical heterotopias, subependymal nodules, and hydrocephalus. The severity of clinical and pathologic findings as well as survival was shown to be dependent upon the dose and serotype of Cre virus injected. Although several other models of TSC brain disease exist, this model is unique in that the pathology reflects a variety of TSC-associated lesions involving different numbers and types of cells. This model provides a valuable and unique addition for therapeutic assessment.
Zuang, Xuan; Sena-Esteves, Miguel; Bronson, Roderick; Brockmann, Jillian; Gianni, Davide; Wojtkiewicz, Gregory R.; Chen, John W.; Stemmer-Rachamimov, Anat; Kwiatkowski, David J.; Breakefield, Xandra O.
Experimental model for civilian ballistic brain injury biomechanics quantification.
Biomechanical quantification of projectile penetration using experimental head models can enhance the understanding of civilian ballistic brain injury and advance treatment. Two of the most commonly used handgun projectiles (25-cal, 275 m/s and 9 mm, 395 m/s) were discharged to spherical head models with gelatin and Sylgard simulants. Four ballistic pressure transducers recorded temporal pressure distributions at 308kHz, and temporal cavity dynamics were captured at 20,000 frames/second (fps) using high-speed digital video images. Pressures ranged from 644.6 to -92.8 kPa. Entry pressures in gelatin models were higher than exit pressures, whereas in Sylgard models entry pressures were lower or equivalent to exit pressures. Gelatin responded with brittle-type failure, while Sylgard demonstrated a ductile pattern through formation of micro-bubbles along projectile path. Temporary cavities in Sylgard models were 1.5-2x larger than gelatin models. Pressures in Sylgard models were more sensitive to projectile velocity and diameter increase, indicating Sylgard was more rate sensitive than gelatin. Based on failure patterns and brain tissue rate-sensitive characteristics, Sylgard was found to be an appropriate simulant. Compared with spherical projectile data, full-metal jacket (FMJ) projectiles produced different temporary cavity and pressures, demonstrating shape effects. Models using Sylgard gel and FMJ projectiles are appropriate to enhance understanding and mechanisms of ballistic brain injury. PMID:17166502
Zhang, Jiangyue; Yoganandan, Narayan; Pintar, Frank A; Guan, Yabo; Gennarelli, Thomas A
Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study
Focal cerebral ischemia elicits strong inflammatory responses involving activation of resident microglia and recruitment of monocytes\\/macrophages. These cells express peripheral benzodiazepine receptors (PBRs) and can be visualized by positron emission tomography (PET) using [11C]PK11195 that selectively binds to PBRs. Earlier research suggests that transient ischemia in rats induces increased [11C]PK11195 binding within the infarct core. In this study, we investigated
Michael Schroeter; Maria A Dennin; Maureen Walberer; Heiko Backes; Bernd Neumaier; Gereon R Fink; Rudolf Graf
MCARD-Mediated Gene Transfer of GRK2 Inhibitor in Ovine Model of Acute Myocardial Infarction
?-adrenergic receptor (?AR) dysfunction in acute myocardial infarction (MI) is associated with elevated levels of the G protein-coupled receptor kinase-2 (GRK2), which plays a key role in heart failure progression. Inhibition of GRK2 via expression of a peptide ?ARKct transferred by molecular cardiac surgery with recirculating delivery (MCARD) may be a promising intervention. Five sheep underwent scAAV6-mediated MCARD delivery of ?ARKct and five received no treatment (control). After a 3 week period, the branch of the circumflex artery (OM1) was ligated. Quantitative PCR data showed intense ?ARKct expression in the left ventricle (LV). Circumferential fractional shortening was 23.4±7.1% (baseline) vs. ?2.9±5.2% (p<0.05) in the control at 10 weeks. In the MCARD-?ARKct group this parameter was close to baseline. The same trend was observed with LV wall thickening. Cardiac index fully recovered in the MCARD-?ARKct group. LV end-diastolic volume and LV end-diastolic pressure did not differ in both groups. MCARD-mediated ?ARKct gene expression results in preservation of regional and global systolic function after acute MI without arresting progressive ventricular remodeling.
Swain, JaBaris D.; Fargnoli, Anthony S.; Katz, Michael G.; Tomasulo, Catherine E.; Sumaroka, Marina; Richardville, Kyle C.; Koch, Walter J.; Rabinowitz, Joseph E.; Bridges, Charles R.
Echocardiographic assessment of coronary artery flow in normal canines and model dogs with myocardial infarction
This study was conducted to evaluate the usefulness of coronary arterial profiles from normal dogs (11 animals) and canines (six dogs) with experimental myocardial infarction (MI) induced by ligation of the left coronary artery (LCA). Blood velocity of the LCA and right coronary artery (RCA) were evaluated following transthoracic pulsed-wave Doppler echocardiography. The LCA was observed as an infundibular shape, located adjacent to the sinus of Valsalva. The RCA appeared as a tubular structure located 12 o'clock relative to the aorta. In normal dogs, the LCA and RCA mean peak diastolic velocities were 20.84 ± 3.24 and 19.47 ± 2.67 cm/sec, respectively. The LCA and RCA mean diastolic deceleration times were 0.91 ± 0.14 sec and 1.13 ± 0.20 sec, respectively. In dogs with MI, the LCA had significantly (p < 0.01) lower peak velocities (14.82 ± 1.61 cm/sec) than the RCA (31.61 ± 2.34 cm/sec). The RCA had a significantly (p < 0.01) rapid diastolic deceleration time (0.71 ± 0.06 sec) than that found in the LCA (1.02 ± 0.22 sec) of MI dogs. In conclusion, these profiles may serve as a differential factor for evaluating cardiomyopathy in dogs.
Park, Nohwon; Kim, Jaehwan; Lee, Miyoung; Lee, Soyun; Song, Sunhye; Lee, Seungjun; Kim, Soyoung; Park, Yangwoo
A computational model of direct brain stimulation by electroconvulsive therapy.
Electroconvulsive therapy (ECT) is the most effective treatment for severe depressive disorder, and yet the mechanisms of its therapeutic effects remain largely unknown. A novel computational model is presented in this study to simulate and investigate direct cortical excitation caused by bitemporal electroconvulsive therapy (BT ECT), using a finite element model (FEM) of the human head. The skull was modeled with anisotropic conductivity, with an excitable ionic neural model incorporated into the brain based on the classic Hodgkin-Huxley formulation. Results suggested that this model is able to reproduce direct stimulation of the cortex during the application of ECT. PMID:21095945
Bai, Siwei; Loo, Colleen; Dokos, Socrates
Modeling brain adaptation to focal damage.
Determining how feature maps in the cerebral cortex adapt to sudden, focal damage is important for gaining a deeper understanding of neurological illnesses such as stroke. In this paper we describe a neural model of the region of primary sensory cortex related to upper extremity proprioception, and show how the feature map there reorganizes following a simulated lesion. A perilesion zone with decreased activity appears and then gradually expands with time. These results differ from those seen with previous models of cortical lesions, and offer an alternative mechanism to the "ischemic penumbra" seen in certain types of stroke.
Goodall, S.; Reggia, J. A.; Cho, S.
Beneficial effects of muscone on cardiac remodeling in a mouse model of myocardial infarction
Musk has been traditionally used in East Asia to alleviate the symptoms of angina pectoris. However, it remains unclear as to whether muscone, the main active ingredient of musk, has any beneficial effects on persistent myocardial ischemia in vivo. The aim of the present study was to investigate whether muscone can improve cardiac function and attenuate myocardial remodeling following myocardial infarction (MI) in mice. Mice were subjected to permanent ligation of the left anterior descending coronary artery to induce MI, and then randomly treated with muscone (2 mg/kg/day) or the vehicle (normal saline) for 3 weeks. Sham-operated mice were used as controls and were also administered the vehicle (normal saline). Treatment with muscone significantly improved cardiac function and exercise tolerance, as evidenced by the decrease in the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, as well as an increase in the left ventricular ejection fraction, left ventricular fractional shortening and time to exhaustion during swimming. Pathological and morphological assessments indicated that treatment with muscone alleviated myocardial fibrosis, collagen deposition and improved the heart weight/body weight ratio. Muscone inhibited the inflammatory response by reducing the expression of transforming growth factor (TGF)-?1, tumor necrosis factor (TNF)-?, interleukin (IL)-1? and nuclear factor (NF)-?B. Treatment with muscone also reduced myocardial apoptosis by enhancing Bcl-2 and suppressing Bax expression. Muscone also induced the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS). Our results demonstrate that muscone ameliorates cardiac remodeling and dysfunction induced by MI by exerting anti-fibrotic, anti-inflammatory and anti-apoptotic effects in the ischemic myocardium.
Beneficial effects of muscone on cardiac remodeling in a mouse model of myocardial infarction.
Musk has been traditionally used in East Asia to alleviate the symptoms of angina pectoris. However, it remains unclear as to whether muscone, the main active ingredient of musk, has any beneficial effects on persistent myocardial ischemia in vivo. The aim of the present study was to investigate whether muscone can improve cardiac function and attenuate myocardial remodeling following myocardial infarction (MI) in mice. Mice were subjected to permanent ligation of the left anterior descending coronary artery to induce MI, and then randomly treated with muscone (2 mg/kg/day) or the vehicle (normal saline) for 3 weeks. Sham-operated mice were used as controls and were also administered the vehicle (normal saline). Treatment with muscone significantly improved cardiac function and exercise tolerance, as evidenced by the decrease in the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, as well as an increase in the left ventricular ejection fraction, left ventricular fractional shortening and time to exhaustion during swimming. Pathological and morphological assessments indicated that treatment with muscone alleviated myocardial fibrosis, collagen deposition and improved the heart weight/body weight ratio. Muscone inhibited the inflammatory response by reducing the expression of transforming growth factor (TGF)??1, tumor necrosis factor (TNF)-?, interleukin (IL)-1? and nuclear factor (NF)-?B. Treatment with muscone also reduced myocardial apoptosis by enhancing Bcl-2 and suppressing Bax expression. Muscone also induced the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS). Our results demonstrate that muscone ameliorates cardiac remodeling and dysfunction induced by MI by exerting anti-fibrotic, anti-inflammatory and anti-apoptotic effects in the ischemic myocardium. PMID:24807380
Wang, Xiaoyan; Meng, Haoyu; Chen, Pengsheng; Yang, Naiquan; Lu, Xin; Wang, Ze-Mu; Gao, Wei; Zhou, Ningtian; Zhang, Min; Xu, Zhihui; Chen, Bo; Tao, Zhengxian; Wang, Liangsheng; Yang, Zhijian; Zhu, Tiebin
Self-Organized Criticality Model for Brain Plasticity
NASA Astrophysics Data System (ADS)
Networks of living neurons exhibit an avalanche mode of activity, experimentally found in organotypic cultures. Here we present a model that is based on self-organized criticality and takes into account brain plasticity, which is able to reproduce the spectrum of electroencephalograms (EEG). The model consists of an electrical network with threshold firing and activity-dependent synapse strengths. The system exhibits an avalanche activity in a power-law distribution. The analysis of the power spectra of the electrical signal reproduces very robustly the power-law behavior with the exponent 0.8, experimentally measured in EEG spectra. The same value of the exponent is found on small-world lattices and for leaky neurons, indicating that universality holds for a wide class of brain models.
de Arcangelis, Lucilla; Perrone-Capano, Carla; Herrmann, Hans J.
Modelling blood flow and metabolism in the piglet brain during hypoxia-ischaemia: simulating brain energetics.
We have developed a computational model to simulate hypoxia-ischaemia (HI) in the neonatal piglet brain. It has been extended from a previous model by adding the simulation of carotid artery occlusion and including pH changes in the cytoplasm. Here, simulations from the model are compared with near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (MRS) measurements from two piglets during HI and short-term recovery. One of these piglets showed incomplete recovery after HI, and this is modelled by considering some of the cells to be dead. This is consistent with the results from MRS and the redox state of cytochrome-c-oxidase as measured by NIRS. However, the simulations do not match the NIRS haemoglobin measurements. The model therefore predicts that further physiological changes must also be taking place if the hypothesis of dead cells is correct. PMID:23852513
Moroz, Tracy; Hapuarachchi, Tharindi; Bainbridge, Alan; Price, David; Cady, Ernest; Baer, Ether; Tachtsidis, Ilias; Broad, Kevin; Ezzati, Mojgan; Robertson, Nicola J; Thomas, David; Golay, Xavier; Cooper, Chris E
Acute splenic irradiation reduces brain injury in the rat focal ischemic stroke model.
Removing the spleen prior to ischemic stroke abrogates immunologic response to brain injury and reduces cerebral infarction. However, the effectiveness of splenectomy for neuroprotection after stroke has not been established. Moreover, the risks of the surgical splenectomy in stroke patients create a major obstacle to removing the spleen's inflammatory response. We hypothesized that acute splenic irradiation will ablate splenic cells and thereby will diminish stroke progression. Male adult Sprague Dawley rats were subjected to 2-hour middle cerebral artery occlusion (MCAO), then CT scanned for spleen localization and irradiated to the lateral splenic region with 8Gy of Cobalt 60 at 3, 4, 6 or 8 hrs after start of cerebral ischemia. Untreated controls underwent the same procedures except that sham irradiation was applied. At 2 or 7 days after ischemia the rats were euthanized, and brains recovered for the assessment of brain injury and the extent of neuroinflammation. Irradiation at 3 hrs reduced spleen weight and lymphocyte blood levels after stroke. Splenic irradiation at 3 and 4 hrs after start of ischemia significantly reduced cerebral infarction volumes measured at 48 hrs and 7 days, respectively. The histological analysis on day 7 revealed reduced counts of microglia, infiltrating T cells, and apoptotic neurons in the rats irradiated at 4 hrs. The noninvasive single-dose procedure of splenic irradiation performed within a time interval of up to 4 hours offers neuroprotection against ischemic stroke possibly by abrogating deployment of splenic cells to the brain. PMID:23956805
Ostrowski, Robert P; Schulte, Reinhard W; Nie, Ying; Ling, Ted; Lee, Timothy; Manaenko, Anatol; Gridley, Daila S; Zhang, John H
Acute Splenic Irradiation Reduces Brain Injury in the Rat Focal Ischemic Stroke Model
Removing the spleen prior to ischemic stroke abrogates immunologic response to brain injury and reduces cerebral infarction. However, the effectiveness of splenectomy for neuroprotection after stroke has not been established. Moreover, the risks of the surgical splenectomy in stroke patients create a major obstacle to removing the spleen's inflammatory response. We hypothesized that acute splenic irradiation will ablate splenic cells and thereby will diminish stroke progression. Male adult Sprague Dawley rats were subjected to 2-hour middle cerebral artery occlusion (MCAO), then CT scanned for spleen localization and irradiated to the lateral splenic region with 8Gy of Cobalt 60 at 3, 4, 6 or 8 hrs after start of cerebral ischemia. Untreated controls underwent the same procedures except that sham irradiation was applied. At 2 or 7 days after ischemia the rats were euthanized, and brains recovered for the assessment of brain injury and the extent of neuroinflammation. Irradiation at 3 hrs reduced spleen weight and lymphocyte blood levels after stroke. Splenic irradiation at 3 and 4 hrs after start of ischemia significantly reduced cerebral infarction volumes measured at 48 hrs and 7 days, respectively. The histological analysis on day 7 revealed reduced counts of microglia, infiltrating T cells, and apoptotic neurons in the rats irradiated at 4 hrs. The noninvasive single-dose procedure of splenic irradiation performed within a time interval of up to 4 hours offers neuroprotection against ischemic stroke possibly by abrogating deployment of splenic cells to the brain.
Ostrowski, Robert P.; Schulte, Reinhard W.; Nie, Ying; Ling, Ted; Lee, Timothy; Manaenko, Anatol; Gridley, Daila S.; Zhang, John H.
Using Region-of-Interest Based Finite Element Modeling for Brain-Surgery Simulation
Brain surgery simulation requires a mathematical model of the geometric and elastic properties of the entire brain. To allow\\u000a for realtime manipulation of the model it is necessary to differentiate the level of accuracy between different subparts of\\u000a the brain model. A Finite Element Model (FEM) of the brain is presented capable of differentiating the spatial and temporal\\u000a accuracy in
Kim Vang Hansen; Ole Vilhelm Larsen
Dynamic representations and generative models of brain function.
The main point made in this article is that the representational capacity and inherent function of any neuron, neuronal population or cortical area is dynamic and context-sensitive. This adaptive and contextual specialisation is mediated by functional integration or interactions among brain systems with a special emphasis on backwards or top-down connections. The critical notion is that neuronal responses, in any given cortical area, can represent different things at different times. Our argument is developed under the perspective of generative models of functional brain architectures, where higher-level systems provide a prediction of the inputs to lower-level regions. Conflict between the two is resolved by changes in the higher-level representations, driven by the resulting error in lower regions, until the mismatch is 'cancelled'. In this model the specialisation of any region is determined both by bottom-up driving inputs and by top-down predictions. Specialisation is therefore not an intrinsic property of any region but depends on both forward and backward connections with other areas. Because these other areas have access to the context in which the inputs are generated they are in a position to modulate the selectivity or specialisation of lower areas. The implications for 'classical' models (e.g., classical receptive fields in electrophysiology, classical specialisation in neuroimaging and connectionism in cognitive models) are severe and suggest these models provide incomplete accounts of real brain architectures. Generative models represent a far more plausible framework for understanding selective neurophysiological responses and how representations are constructed in the brain. PMID:11287132
Friston, K J; Price, C J
Lateral Fluid Percussion: Model of Traumatic Brain Injury in Mice
Traumatic brain injury (TBI) research has attained renewed momentum due to the increasing awareness of head injuries, which result in morbidity and mortality. Based on the nature of primary injury following TBI, complex and heterogeneous secondary consequences result, which are followed by regenerative processes 1,2. Primary injury can be induced by a direct contusion to the brain from skull fracture or from shearing and stretching of tissue causing displacement of brain due to movement 3,4. The resulting hematomas and lacerations cause a vascular response 3,5, and the morphological and functional damage of the white matter leads to diffuse axonal injury 6-8. Additional secondary changes commonly seen in the brain are edema and increased intracranial pressure 9. Following TBI there are microscopic alterations in biochemical and physiological pathways involving the release of excitotoxic neurotransmitters, immune mediators and oxygen radicals 10-12, which ultimately result in long-term neurological disabilities 13,14. Thus choosing appropriate animal models of TBI that present similar cellular and molecular events in human and rodent TBI is critical for studying the mechanisms underlying injury and repair. Various experimental models of TBI have been developed to reproduce aspects of TBI observed in humans, among them three specific models are widely adapted for rodents: fluid percussion, cortical impact and weight drop/impact acceleration 1. The fluid percussion device produces an injury through a craniectomy by applying a brief fluid pressure pulse on to the intact dura. The pulse is created by a pendulum striking the piston of a reservoir of fluid. The percussion produces brief displacement and deformation of neural tissue 1,15. Conversely, cortical impact injury delivers mechanical energy to the intact dura via a rigid impactor under pneumatic pressure 16,17. The weight drop/impact model is characterized by the fall of a rod with a specific mass on the closed skull 18. Among the TBI models, LFP is the most established and commonly used model to evaluate mixed focal and diffuse brain injury 19. It is reproducible and is standardized to allow for the manipulation of injury parameters. LFP recapitulates injuries observed in humans, thus rendering it clinically relevant, and allows for exploration of novel therapeutics for clinical translation 20. We describe the detailed protocol to perform LFP procedure in mice. The injury inflicted is mild to moderate, with brain regions such as cortex, hippocampus and corpus callosum being most vulnerable. Hippocampal and motor learning tasks are explored following LFP.
Alder, Janet; Fujioka, Wendy; Lifshitz, Jonathan; Crockett, David P.; Thakker-Varia, Smita
Electrocardiograms Corresponding to the Development of Myocardial Infarction in Anesthetized WHHLMI Rabbits (Oryctolagus cuniculus), an Animal Model for Familial Hypercholesterolemia
The aim of this study was to determine whether features indicative of myocardial ischemia occur in the electrocardiograms (ECG) in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, an animal model for human familial hypercholesterolemia. ECG were recorded in 110 anesthetized WHHLMI rabbits (age, 10 to 39 mo) by using unipolar and bipolar limb leads with or without chest leads. We noted the following electrocardiographic changes: T wave inversion (37.4%), ST segment depression (31.8%), deep Q wave (16.3%), reduced R wave amplitude (7.3%), ST segment elevation (2.7%), and high T wave (1.8%). These ECG changes resembled those in human patients with coronary heart disease. Histopathologic examination revealed that the left ventricular wall showed acute myocardial lesions, including loss of cross-striations, vacuolar degeneration, coagulation necrosis of cardiac myocytes, and edema between myofibrils, in addition to chronic myocardial lesions such as myocardial fibrosis. The coronary arteries that caused these ECG changes were severely stenosed due to atherosclerotic lesions. Ischemic ECG changes corresponded to the locations of the myocardial lesions. Normal ECG waveforms were similar between WHHLMI rabbits and humans, in contrast to the large differences between rabbits and mice or rats. In conclusion, ischemic ECG changes in WHHLMI rabbits reflect the location of myocardial lesions, making this model useful for studying coronary heart disease.
Kobayashi, Tsutomu; Ito, Takashi; Yamada, Satoshi; Kuniyoshi, Nobue; Shiomi, Masashi
Region-of-interest based finite element modelling of the brain-an approach to brain surgery simulation
One of the major problems in brain surgery simulation is to achieve both real-time performance and physical realism without compromising the necessary freedom to perform topological changes like cutting. In an attempt to solve the problem we present a new method for differentiating the spatial and temporal accuracy for the brain tissue models. Finite element methods are used for the
K. V. Hansen; M. S. Eskildsen; O. V. Larsen
In vivo models of primary brain tumors: pitfalls and perspectives
Animal modeling for primary brain tumors has undergone constant development over the last 60 years, and significant improvements have been made recently with the establishment of highly invasive glioblastoma models. In this review we discuss the advantages and pitfalls of model development, focusing on chemically induced models, various xenogeneic grafts of human cell lines, including stem cell–like cell lines and biopsy spheroids. We then discuss the development of numerous genetically engineered models available to study mechanisms of tumor initiation and progression. At present it is clear that none of the current animal models fully reflects human gliomas. Yet, the various model systems have provided important insight into specific mechanisms of tumor development. In particular, it is anticipated that a combined comprehensive knowledge of the various models currently available will provide important new knowledge on target identification and the validation and development of new therapeutic strategies.
Huszthy, Peter C.; Daphu, Inderjit; Niclou, Simone P.; Stieber, Daniel; Nigro, Janice M.; Sakariassen, Per ?.; Miletic, Hrvoje; Thorsen, Frits; Bjerkvig, Rolf
Genetic mouse models of brain ageing and Alzheimer's disease.
Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. PMID:24362083
Bilkei-Gorzo, Andras
Normal brain ageing: models and mechanisms
Normal ageing is associated with a degree of decline in a number of cognitive functions. Apart from the issues raised by the current attempts to expand the lifespan, understanding the mechanisms and the detailed metabolic interactions involved in the process of normal neuronal ageing continues to be a challenge. One model, supported by a significant amount of experimental evidence, views the cellular ageing as a metabolic state characterized by an altered function of the metabolic triad: mitochondria–reactive oxygen species (ROS)–intracellular Ca2+. The perturbation in the relationship between the members of this metabolic triad generate a state of decreased homeostatic reserve, in which the aged neurons could maintain adequate function during normal activity, as demonstrated by the fact that normal ageing is not associated with widespread neuronal loss, but become increasingly vulnerable to the effects of excessive metabolic loads, usually associated with trauma, ischaemia or neurodegenerative processes. This review will concentrate on some of the evidence showing altered mitochondrial function with ageing and also discuss some of the functional consequences that would result from such events, such as alterations in mitochondrial Ca2+ homeostasis, ATP production and generation of ROS.
Toescu, Emil C
Self-organization in a simple brain model
Simulations on a simple model of the brain are presented. The model consists of a set of randomly connected neurons. Inputs and outputs are also connected randomly to a subset of neurons. For each input there is a set of output neurons which must fire in order to achieve success. A signal giving information as to whether or not the action was successful is fed back to the brain from the environment. The connections between firing neurons are strengthened or weakened according to whether or not the action was successful. The system learns, through a self-organization process, to react intelligently to input signals, i.e. it learns to quickly select the correct output for each input. If part of the network is damaged, the system relearns the correct response after a training period.
Stassinopoulos, D.; Bak, P. [Brookhaven National Lab., Upton, NY (United States). Dept. of Physics; Alstroem, P. [Niels Bohr Inst., Copenhagen (Denmark). Dept. of Physics
Brain arteriovenous malformation modeling, pathogenesis, and novel therapeutic targets.
Patients harboring brain arteriovenous malformation (bAVM) are at life-threatening risk of rupture and intracranial hemorrhage (ICH). The pathogenesis of bAVM has not been completely understood. Current treatment options are invasive, and ? 20 % of patients are not offered interventional therapy because of excessive treatment risk. There are no specific medical therapies to treat bAVMs. The lack of validated animal models has been an obstacle for testing hypotheses of bAVM pathogenesis and testing new therapies. In this review, we summarize bAVM model development and bAVM pathogenesis and potential therapeutic targets that have been identified during model development. PMID:24723256
Chen, Wanqiu; Choi, Eun-Jung; McDougall, Cameron M; Su, Hua
Comparison of two sulfonylureas with high and low myocardial K ATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes
Aims\\/hypothesis Sulfonylureas (SUs) may impair outcome in patients with acute coronary syndrome. Most experimental studies of the myocardial\\u000a effects of SU treatment are performed in non-diabetic models. We compared the effect of two widely used SUs, glibenclamide\\u000a (gb) and gliclazide (gc), with high and low myocardial KATP channel affinity, respectively, at therapeutic concentrations on infarct size, left ventricular (LV) function and
S. B. Kristiansen; B. Lřfgren; J. M. Nielsen; N. B. Střttrup; E. S. Buhl; J. E. Nielsen-Kudsk; T. T. Nielsen; J. Rungby; A. Flyvbjerg; H. E. Břtker
Towards dynamical system models of language-related brain potentials
Event-related brain potentials (ERP) are important neural correlates of cognitive processes. In the domain of language processing, the N400 and P600 reflect lexical-semantic integration and syntactic processing problems, respectively. We suggest an interpretation of these markers in terms of dynamical system theory and present two nonlinear dynamical models for syntactic computations where different processing strategies correspond to functionally different regions in the system's phase space.
Gerth, Sabrina; Vasishth, Shravan
Towards dynamical system models of language-related brain potentials
Event-related brain potentials (ERP) are important neural correlates of cognitive processes. In the domain of language processing,\\u000a the N400 and P600 reflect lexical-semantic integration and syntactic processing problems, respectively. We suggest an interpretation\\u000a of these markers in terms of dynamical system theory and present two nonlinear dynamical models for syntactic computations\\u000a where different processing strategies correspond to functionally different regions
Peter beim Graben; Sabrina Gerth; Shravan Vasishth
Signal transmission competing with noise in model excitable brains
NASA Astrophysics Data System (ADS)
This is a short review of recent studies in our group on how weak signals may efficiently propagate in a system with noise-induced excitation-inhibition competition which adapts to the activity at short-time scales and thus induces excitable conditions. Our numerical results on simple mathematical models should hold for many complex networks in nature, including some brain cortical areas. In particular, they serve us here to interpret available psycho-technical data.
Marro, J.; Mejias, J. F.; Pinamonti, G.; Torres, J. J.
Mechanical Properties of Brain Tissue: Characterisation and Constitutive Modelling
The head is often considered as the most critical region of the human body for life-threatening injuries sustained in accidents.\\u000a In order to develop effective protective measures, a better understanding of the process of injury development in the brain\\u000a is required. Finite Element (FE) models are being developed, in order to predict the mechanical response of the contents of\\u000a the
J. A. W. van Dommelen; M. Hrapko; G. W. M. Peters
Enhancement of subsurface brain shift model accuracy: a preliminary study
Biomechanical models that describe soft-tissue deformations provide a relatively inexpensive way to correct registration errors in image guided neurosurgical systems caused by non-rigid brain shifts. Quantifying the factors that cause this deformation to sufficient precision is a challenging task. To circumvent this difficulty, atlas-based method have been developed recently which allow for uncertainty yet still capture the first order effects
Ishita Garg; Siyi Ding; Aaron M. Coffey; Prashanth Dumpuri; Reid C. Thompson; Benoit M. Dawant; Michael I. Miga
In Vivo Diagnostic Imaging Using Micro-CT: Sequential and Comparative Evaluation of Rodent Models for Hepatic/Brain Ischemia and Stroke
Background There is an increasing need for animal disease models for pathophysiological research and efficient drug screening. However, one of the technical barriers to the effective use of the models is the difficulty of non-invasive and sequential monitoring of the same animals. Micro-CT is a powerful tool for serial diagnostic imaging of animal models. However, soft tissue contrast resolution, particularly in the brain, is insufficient for detailed analysis, unlike the current applications of CT in the clinical arena. We address the soft tissue contrast resolution issue in this report. Methodology We performed contrast-enhanced CT (CECT) on mouse models of experimental cerebral infarction and hepatic ischemia. Pathological changes in each lesion were quantified for two weeks by measuring the lesion volume or the ratio of high attenuation area (%HAA), indicative of increased vascular permeability. We also compared brain images of stroke rats and ischemic mice acquired with micro-CT to those acquired with 11.7-T micro-MRI. Histopathological analysis was performed to confirm the diagnosis by CECT. Principal Findings In the models of cerebral infarction, vascular permeability was increased from three days through one week after surgical initiation, which was also confirmed by Evans blue dye leakage. Measurement of volume and %HAA of the liver lesions demonstrated differences in the recovery process between mice with distinct genetic backgrounds. Comparison of CT and MR images acquired from the same stroke rats or ischemic mice indicated that accuracy of volumetric measurement, as well as spatial and contrast resolutions of CT images, was comparable to that obtained with MRI. The imaging results were also consistent with the histological data. Conclusions This study demonstrates that the CECT scanning method is useful in rodents for both quantitative and qualitative evaluations of pathologic lesions in tissues/organs including the brain, and is also suitable for longitudinal observation of the same animals.
Hayasaka, Naoto; Nagai, Nobuo; Kawao, Naoyuki; Niwa, Atsuko; Yoshioka, Yoshichika; Mori, Yuki; Shigeta, Hiroshi; Kashiwagi, Nobuo; Miyazawa, Masaaki; Satou, Takao; Higashino, Hideaki; Matsuo, Osamu; Murakami, Takamichi
Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study
Background In acute stage of cerebral infarction, MRI indices (rDWI & rADC) deteriorate during the first 3-7 days after the ictus and then gradually normalize in approximately 10 days (pseudonormalization time), although the tissue is already infarcted. Since effective treatments improve these indices significantly and in less than the natural pseudonormalization time, a combined analysis of these changes provides an opportunity for objective evaluation on the effectiveness of various treatments for cerebral infarction. Hydroxyl radicals are highly destructive to the tissue and aggravate cerebral infarction. We treated brainstem infarction patients in acute stage with hydroxyl radical scavengers (Edaravone and hydrogen) by intravenous administration and evaluated the effects of the treatment by a serial observation and analysis of these MRI indices. The effects of the treatment were evaluated and compared in two groups, an Edaravone alone group and a combined group with Edaravone and hydrogen, in order to assess beneficial effects of addition of hydrogen. Methods The patients were divided in Edaravone only group (E group. 26 patients) and combined treatment group with Edaravone and hydrogen enriched saline (EH group. 8 patients). The extent of the initial hump of rDWI, the initial dip of rADC and pseudo-normalization time were determined in each patient serially and averages of these data were compared in these two groups and also with the natural course in the literatures. Results The initial hump of rDWI reached 2.0 in the E group which was better than 2.5 of the natural course but was not as good as 1.5 of the EH group. The initial dip of rADC was 0.6 in the E group which was close to the natural course but worse than 0.8 of the EH group. Pseudonormalization time of rDWI and rADC was 9 days only in EH group but longer in other groups. Addition of hydrogen caused no side effects. Conclusions Administration of hydroxyl radical scavengers in acute stage of brainstem infarction improved MRI indices against the natural course. The effects were more obvious and significant in the EH group. These findings may imply the need for more frequent daily administration of hydroxyl scavenger, or possible additional hydrogen effects on scavenger mechanisms.
Differential Effects of HIF-1 Inhibition by YC-1 on the Overall Outcome and Blood-Brain Barrier Damage in a Rat Model of Ischemic Stroke
Hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular adaptation to hypoxia and has been suggested as a potent therapeutic target in cerebral ischemia. Here we show in an ischemic stroke model of rats that inhibiting HIF-1 and its downstream genes by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) significantly increases mortality and enlarges infarct volume evaluated by MRI and histological staining. Interestingly, the HIF-1 inhibition remarkably ameliorates ischemia-induced blood-brain barrier (BBB) disruption determined by Evans blue leakage although it does not affect brain edema. The result demonstrates that HIF-1 inhibition has differential effects on ischemic outcomes and BBB permeability. It indicates that HIF-1 may have different functions in different brain cells. Further analyses show that ischemia upregulates HIF-1 and its downstream genes erythropoietin (EPO), vascular endothelial growth factor (VEGF), and glucose transporter (Glut) in neurons and brain endothelial cells and that YC-1 inhibits their expression. We postulate that HIF-1-induced VEGF increases BBB permeability while certain other proteins coded by HIF-1's downstream genes such as epo and glut provide neuroprotection in an ischemic brain. The results indicate that YC-1 lacks the potential as a cerebral ischemic treatment although it confers certain protection to the cerebral vascular system.
Taheri, Saeid; Shi, Honglian
Intramyocardial Injection of Pig Pluripotent Stem Cells Improves Left Ventricular Function and Perfusion: A Study in a Porcine Model of Acute Myocardial Infarction
Induced pluripotent stem (iPS) cells have the potential to differentiate to various types of cardiovascular cells to repair an injured heart. The potential therapeutic benefits of iPS cell based treatment have been established in small-animal models of myocardial infarction (MI). We?hypothesize that porcine iPS (piPS) cell transplantation may be an effective treatment for MI. After a 90-minute occlusion of the left anterior descending artery in a porcine model, undifferentiated piPS cells or PBS were injected into the ischemic myocardium. Cardiac function, myocardial perfusion and cell differentiation were investigated. One week after piPS cell delivery, global left ventricular ejection fraction (LVEF) significantly decreased in both the iPS group and the PBS group compared to the Sham group (p<0.05, respectively). Six weeks after piPS cell delivery, LVEF of the iPS group significantly improved compared to the PBS group (56.68% vs. 50.93%, p?=?0.04) but was still lower than the Sham group. Likewise, the piPS cell transplantation improved the regional perfusion compared to the PBS injection (19.67% vs. 13.67%, p?=?0.02). The infarct area was significantly smaller in the iPS group than the PBS group (12.04% vs. 15.98% p?=?0.01). PiPS cells engrafted into the myocardium can differentiate into vessel cells, which result in increased formation of new vessels in the infarcted heart. Direct intramyocardial injection of piPS cells can decrease infarct size and improve left ventricular function and perfusion for an immunosuppressed porcine AMI model.
Song, Guixian; Gu, Weijuan; Chen, Minglong; Yang, Bing; Li, Dianfu; Wang, Daowu; Cao, Kejiang
Acute Myocardial Infarction in Rats
With heart failure leading the cause of death in the USA (Hunt), biomedical research is fundamental to advance medical treatments for cardiovascular diseases. Animal models that mimic human cardiac disease, such as myocardial infarction (MI) and ischemia-reperfusion (IR) that induces heart failure as well as pressure-overload (transverse aortic constriction) that induces cardiac hypertrophy and heart failure (Goldman and Tarnavski), are useful models to study cardiovascular disease. In particular, myocardial ischemia (MI) is a leading cause for cardiovascular morbidity and mortality despite controlling certain risk factors such as arteriosclerosis and treatments via surgical intervention (Thygesen). Furthermore, an acute loss of the myocardium following myocardial ischemia (MI) results in increased loading conditions that induces ventricular remodeling of the infarcted border zone and the remote non-infarcted myocardium. Myocyte apoptosis, necrosis and the resultant increased hemodynamic load activate multiple biochemical intracellular signaling that initiates LV dilatation, hypertrophy, ventricular shape distortion, and collagen scar formation. This pathological remodeling and failure to normalize the increased wall stresses results in progressive dilatation, recruitment of the border zone myocardium into the scar, and eventually deterioration in myocardial contractile function (i.e. heart failure). The progression of LV dysfunction and heart failure in rats is similar to that observed in patients who sustain a large myocardial infarction, survive and subsequently develops heart failure (Goldman). The acute myocardial infarction (AMI) model in rats has been used to mimic human cardiovascular disease; specifically used to study cardiac signaling mechanisms associated with heart failure as well as to assess the contribution of therapeutic strategies for the treatment of heart failure. The method described in this report is the rat model of acute myocardial infarction (AMI). This model is also referred to as an acute ischemic cardiomyopathy or ischemia followed by reperfusion (IR); which is induced by an acute 30-minute period of ischemia by ligation of the left anterior descending artery (LAD) followed by reperfusion of the tissue by releasing the LAD ligation (Vasilyev and McConnell). This protocol will focus on assessment of the infarct size and the area-at-risk (AAR) by Evan's blue dye and triphenyl tetrazolium chloride (TTC) following 4-hours of reperfusion; additional comments toward the evaluation of cardiac function and remodeling by modifying the duration of reperfusion, is also presented. Overall, this AMI rat animal model is useful for studying the consequence of a myocardial infarction on cardiac pathophysiological and physiological function.
Wu, Yewen; Yin, Xing; Wijaya, Cori; Huang, Ming-He; McConnell, Bradley K.
Myocardial Infarction Research Unit.
National Technical Information Service (NTIS)
Clinical and laboratory investigations are conducted to provide a better understanding and more effective treatment of myocardial infarction. Patients with acute myocardial infarction are carefully characterized by clinical, hemodynamic, electrophysiologi...
C. E. Rackley
Regulatory effect of Dimethyl Sulfoxide (DMSO) on astrocytic reactivity in a murine model of cerebral infarction by arterial embolization
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 ?-bovine thrombin (40 NIH/Unit.). The treated group received 90 mg (100 ?L) 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.
Rengifo Valbuena, Carlos Augusto; Avila Rodriguez, Marco Fidel; Cespedes Rubio, Angel
Brain damage and hypoxia in an ovine fetal chronic cocaine model
Objective: To assess the development of brain damage in an ovine fetal chronic cocaine model. To evaluate the effect of isolated hypoxic tests on this model and to correlate hemodynamic findings (brain-sparing effect) following fetal hypoxia and the occurrence of brain damage. Study design: Fifteen ewes were divided into a control group (n=7) and a cocaine treated group (n=8). From
R. N. Laurini; B. Arbeille; C. Gemberg; S. Akoka; A. Locatelli; J. Lansac; Ph. Arbeille
Modelling of the human brain with detailed anatomy for numerical simulation of surgical interventions
During the design and simulation process of MEMS medical devices used in neurosurgery, there is a need to build a brain model with detailed anatomy and physical properties incorporated as a platform to conduct numerical analysis. This paper presents a study on constructing a brain model for simulation of medical device interventions during neurosurgery. A brain atlas was utilized to
Chunping Gao; Francis Eng Hock Tay; Wieslaw L Nowinski
Modeling the dynamical effects of anesthesia on brain circuits.
General anesthesia is a neurophysiological state that consists of unconsciousness, amnesia, analgesia, and immobility along with maintenance of physiological stability. General anesthesia has been used in the United States for more than 167 years. Now, using systems neuroscience paradigms how anesthetics act in the brain and central nervous system to create the states of general anesthesia is being understood. Propofol is one of the most widely used and the most widely studied anesthetics. When administered for general anesthesia or sedation, the electroencephalogram (EEG) under propofol shows highly structured, rhythmic activity that is strongly associated with changes in the patient's level of arousal. These highly structured oscillations lend themselves readily to mathematical descriptions using dynamical systems models. We review recent model descriptions of the commonly observed EEG patterns associated with propofol: paradoxical excitation, strong frontal alpha oscillations, anteriorization and burst suppression. Our analysis suggests that propofol's actions at GABAergic networks in the cortex, thalamus and brainstem induce profound brain dynamics that are one of the likely mechanisms through which this anesthetic induces altered arousal states from sedation to unconsciousness. Because these dynamical effects are readily observed in the EEG, the mathematical descriptions of how propofol's EEG signatures relate to its mechanisms of action in neural circuits provide anesthesiologists with a neurophysiologically based approach to monitoring the brain states of patients receiving anesthesia care. PMID:24457211
Ching, Shinung; Brown, Emery N
A family experiential model of recovery after brain injury.
The Family Experiential Model (FEM) described in this article is a therapeutic "navigation tool" for families traversing the recovery process with their loved one after brain injury. Its conception furnishes a personal voice and the pragmatic "stoplight model" depicts how the family's myriad of powerful emotions affects the chosen path in the rehabilitation and recovery process. As an example of mentalizing, the FEM is a healing tool that instills mutual insight and empathy among the family, psychotherapist, and patient. The application of the FEM to individual and group treatment in a holistic treatment milieu is also described. PMID:18637748
Klonoff, Pamela S; Koberstein, Edward; Talley, Melanie C; Dawson, Lauren K
Science Sampler: Modeling the effects of drugs on the brain
NSDL National Science Digital Library
The following activity teaches students about the neurobiological consequences of drug use on their brains and behavior. Students make clay models that allow them to visualize how drugs affect neural communication. If you're concerned that this activity may be too advanced, studies have shown that even third-grade students with some knowledge of the circulatory and nervous systems are able to comprehend the effects of drugs on the body and behavior (Sigelman et al., 2003). This activity aligns with the AAAS science benchmarks on human organisms, cells, model making, and personal health.
Brier, Georgia; Dahlberg, Linda
Canine Spontaneous Brain Tumors: A Large Animal Model for BNCT.
National Technical Information Service (NTIS)
Brain tumors occur spontaneously on dogs with an incidence similar to that in humans. Brain tumors of dogs have histologic, radiologic, and other diagnostic similarities to human brain tumors. Tumor kinetics and biologic behavior of these tumors in dogs a...
P. R. Gavin S. L. Kraft L. R. Wendling D. L. Miller
Xenon contrast CT-CBF scanning of the brain differentiates normal age-related changes from multi-infarct dementia and senile dementia of Alzheimer type
Local cerebral blood flow (LCBF) and partition coefficients (L lambda) were measured during inhalation of stable xenon gas with serial CT scanning among normal volunteers (N . 15), individuals with multi-infarct dementia (MID, N . 10), and persons with senile dementia of Alzheimer type (SDAT, N . 8). Mean gray matter flow values were reduced in both MID and SDAT. Age-related declines in LCBF values in normals were marked in frontal cortex and basal ganglia. LCBF values were decreased beyond normals in frontal and temporal cortices and thalamus in MID and SDAT, in basal ganglia only in MID. Unlike SDAT and age-matched normals, L lambda values were reduced in fronto-temporal cortex and thalamus in MID. Multifocal nature of lesions in MID was apparent. Coefficients of variation for LCBFs were greater in MID compared with SDAT and/or age-matched normals.
Tachibana, H.; Meyer, J.S.; Okayasu, H.; Shaw, T.G.; Kandula, P.; Rogers, R.L.
Cardioprotective effects of thyroid hormones in a rat model of myocardial infarction are associated with oxidative stress reduction.
Reactive oxygen species (ROS) are involved with progression from infarction to heart failure. Studies show that thyroid hormones (TH) present cardioprotective effects. This study aims to evaluate whether TH effects after infarction are associated to redox balance modulation. Male Wistar rats were divided into four groups: Sham-operated (SHAM), infarcted (AMI), sham-operated+TH (SHAMT), and infarcted+TH (AMIT). During 26days, animals received T3 (2?g/100g/day) and T4 (8?g/100g/day) by gavage. Echocardiographic parameters were assessed and heart tissue was collected to biochemical analysis. AMIT rats presented absence of lung congestion, less cardiac dilatation, and normalization in myocardial performance index, compared with AMI. AMI rats presented an increase in hydrogen peroxide levels and in lipid peroxidation and a decrease in GSH/GSSG. TH prevented these alterations in AMIT. In conclusion, TH seem to reduce the levels of ROS, preventing oxidative stress, and improving cardiac function in infarcted rats. PMID:24784706
de Castro, Alexandre Luz; Tavares, Angela Vicente; Campos, Cristina; Fernandes, Rafael Oliveira; Siqueira, Rafaela; Conzatti, Adriana; Bicca, Amanda M; Fernandes, Tânia Regina G; Sartório, Carmem L; Schenkel, Paulo Cavalheiro; Belló-Klein, Adriane; da Rosa Araujo, Alex Sander
Biothermal Model of Patient for Brain Hypothermia Treatment
NASA Astrophysics Data System (ADS)
A biothermal model of patient is proposed and verified for the brain hypothermia treatment, since the conventionally applied biothermal models are inappropriate for their unprecedented application. The model is constructed on the basis of the clinical practice of the pertinent therapy and characterized by the mathematical relation with variable ambient temperatures, in consideration of the clinical treatments such as the vital cardiopulmonary regulation. It has geometrically clear representation of multi-segmental core-shell structure, database of physiological and physical parameters with a systemic state equation setting the initial temperature of each compartment. Its step response gives the time constant about 3 hours in agreement with clinical knowledge. As for the essential property of the model, the dynamic temperature of its face-core compartment is realized, which corresponds to the tympanic membrane temperature measured under the practical anesthesia. From the various simulations consistent with the phenomena of clinical practice, it is concluded that the proposed model is appropriate for the theoretical analysis and clinical application to the brain hypothermia treatment.
Wakamatsu, Hidetoshi; Gaohua, Lu
Small synthetic hyaluronan disaccharides afford neuroprotection in brain ischemia-related models.
High molecular weight (HMW) glycosaminoglycanes of the extracellular matrix have been implicated in tissue repair. The aim of this study was to evaluate if small synthetic hyaluronan disaccharides with different degrees of sulfation (methyl 2-acetamido-2-deoxy-3-O-(?-d-glucopyranosyluronic acid)-O-sulfo-?-d-glucopyranoside, sodium salt (di0S), methyl 2-acetamido-2-deoxy-3-O-(?-d-glucopyranosyluronic acid)-6-di-O-sulfo-?-d-glucopyranoside, disodium salt (di6S) and methyl 2-acetamido-2-deoxy-3-O-(?-d-glucopyranosyluronic acid)-4,6-di-O-sulfo-?-d-glucopyranoside, trisodium salt (di4,6S)) could improve cell survival in in vitro and in vivo brain ischemia-related models. Rat hippocampal slices subjected to oxygen and glucose deprivation and a photothrombotic stroke model in mice were used. The three hyaluran disaccharides, incubated during the oxygen and glucose deprivation (15min) and re-oxygenation periods (120min), reduced cell death of hippocampal slices measured as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, being the most potent di4,6S; in contrast, high molecular hyaluronan was ineffective. The protective actions of di4,6S against oxygen and glucose deprivation were related to activation of the PI3K/Akt survival pathway, reduction of p65 translocation to the nucleus, inhibition of inducible nitric oxide oxidase induction and reactive oxygen species production, and to an increase in glutathione levels. Administered 1h post-stroke, di4,6S reduced cerebral infarct size and improved motor activity in the beam walk test. In conclusion, di4,6S affords neuroprotection in in vitro and in vivo models of ischemic neuronal damage. Our results suggest that its neuroprotective effect could be exerted through its capability to reduce oxidative stress during ischemia. Its small molecular size makes it a more potential druggable drug to target the brain as compared with its HMW parent compound hyaluronan. PMID:24486437
Egea, J; Parada, E; Gómez-Rangel, V; Buendia, I; Negredo, P; Montell, E; Ruhí, R; Vergés, J; Roda, J M; García, A G; López, M G
High-strain-rate brain injury model using submerged acute rat brain tissue slices.
Blast-induced traumatic brain injury (bTBI) has received increasing attention in recent years due to ongoing military operations in Iraq and Afghanistan. Sudden impacts or explosive blasts generate stress and pressure waves that propagate at high velocities and affect sensitive neurological tissues. The immediate soft tissue response to these stress waves is difficult to assess using current in vivo imaging technologies. However, these stress waves and resultant stretching and shearing of tissue within the nano- to microsecond time scale of blast and impact are likely to cause initial injury. To visualize the effects of stress wave loading, we have developed a new ex vivo model in which living tissue slices from rat brain, attached to a ballistic gelatin substrate, were subjected to high-strain-rate loads using a polymer split Hopkinson pressure bar (PSHPB) with real-time high-speed imaging. In this study, average peak fluid pressure within the test chamber reached a value of 1584±63.3?psi. Cavitation due to a trailing underpressure wave was also observed. Time-resolved images of tissue deformation were collected and large maximum eigenstrains (0.03-0.42), minimum eigenstrains (-0.33 to -0.03), maximum shear strains (0.09-0.45), and strain rates (8.4×10ł/sec) were estimated using digital image correlation (DIC). Injury at 4 and 6?h was quantified using Fluoro-Jade C. Neuronal injury due to PSHPB testing was found to be significantly greater than injury associated with the tissue slice paradigm alone. While large pressures and strains were encountered for these tests, this system provides a controllable test environment to study injury to submerged brain slices over a range of strain rate, pressure, and strain loads. PMID:21970544
Sarntinoranont, Malisa; Lee, Sung J; Hong, Yu; King, Michael A; Subhash, Ghatu; Kwon, Jiwoon; Moore, David F
Comparison of human adipose-derived stem cells and bone marrow-derived stem cells in a myocardial infarction model.
Treatment of myocardial infarction (MI) with bone marrow-derived mesenchymal stem cells and recently also adipose-derived stem cells has shown promising results. In contrast to clinical trials and their use of autologous bone marrow-derived cells from the ischemic patient, the animal MI models are often using young donors and young, often immune-compromised, recipient animals. Our objective was to compare bone marrow-derived mesenchymal stem cells with adipose-derived stem cells from an elderly ischemic patient in the treatment of MI using a fully grown non-immune-compromised rat model. Mesenchymal stem cells were isolated from adipose tissue and bone marrow and compared with respect to surface markers and proliferative capability. To compare the regenerative potential of the two stem cell populations, male Sprague-Dawley rats were randomized to receive intramyocardial injections of adipose-derived stem cells, bone marrow-derived mesenchymal stem cells, or phosphate-buffered saline 1 week following induction of MI. After 4 weeks, left ventricular ejection fraction (LVEF) was improved in the adipose-derived stem cell group, and scar wall thickness was greater compared with the saline group. Adipose-derived as well as bone marrow-derived mesenchymal stem cells prevented left ventricular end diastolic dilation. Neither of the cell groups displayed increased angiogenesis in the myocardium compared with the saline group. Adipose-derived stem cells from a human ischemic patient preserved cardiac function following MI, whereas this could not be demonstrated for bone marrow-derived mesenchymal stem cells, with only adipose-derived stem cells leading to an improvement in LVEF. Neither of the stem cell types induced myocardial angiogenesis, raising the question whether donor age and health have an effect on the efficacy of stem cells used in the treatment of MI. PMID:23211469
Rasmussen, Jeppe Grřndahl; Frřbert, Ole; Holst-Hansen, Claus; Kastrup, Jens; Baandrup, Ulrik; Zachar, Vladimir; Fink, Trine; Simonsen, Ulf
Electrocardiographic changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction.
Epidemiological studies have reported a positive association of short-term increases in ambient particulate matter (PM) with daily mortality and hospital admissions for cardiovascular disease. Although patients with cardiopulmonary disease appear to be most at risk, particulate-related cardiac effects following myocardial infarction (MI) have not been examined. To improve understanding of mechanisms, we developed and tested a model for investigating the effects of inhaled PM on arrhythmias and heart rate variability (HRV), a measure of autonomic nervous system activity, in rats with acute MI. Left-ventricular MI was induced in 31 Sprague-Dawley rats by thermocoagulation of the left coronary artery; 32 additional rats served as sham-operated controls. Diazepam-sedated rats were exposed (1 h) to residual oil fly ash (ROFA), carbon black, or room air at 12-18 h after surgery. Each exposure was immediately preceded and followed by a 1-h exposure to room air (baseline and recovery periods, respectively). Lead-II electrocardiograms were recorded. In the MI group, 41% of rats exhibited one or more premature ventricular complexes (PVCs) during the baseline period. Exposure to ROFA, but not to carbon black or room air, increased arrhythmia frequency in animals with preexisting PVCs. Furthermore, MI rats exposed to ROFA, but not to carbon black or room air, decreased HRV. There was no difference in arrhythmia frequency or HRV among sham-operated animals. These results underscore the usefulness of this model for elucidating the physiologic mechanisms of pollution-induced cardiovascular arrhythmias and contribute to defining the specific constituents of ambient particles responsible for arrhythmias. PMID:11896300
Wellenius, Gregory A; Saldiva, Paulo H N; Batalha, Joao R F; Krishna Murthy, G G; Coull, Brent A; Verrier, Richard L; Godleski, John J
Action of acetylstrophanthidin on experimental myocardial infarction.
NASA Technical Reports Server (NTRS)
An experimental animal model with acute myocardial infarction of a size insufficient to produce profound heart failure or shock was used to study the effects of acute infarction on digitalis tolerance and the hemodynamic changes produced by moderate and large doses of acetylstrophanthidin. With acute myocardial infarction, digitalis toxic arrhythmias could be precipitated with significantly lower doses of digitalis than in animals without myocardial infarction. There was no precise correlation between the size of infarction and the toxic dose of glycoside. Coronary artery ligation produced a stable but relatively depressed circulatory state, as evidenced by lowered cardiac output and stroke volume and elevated systemic vascular resistance and left atrial mean pressure. When digitalis was infused, the following significant changes were observed at nontoxic doses: (1) elevation of aortic and left ventricular pressures; (2) further decline in cardiac output; and (3) decreased left atrial mean pressure.
Nola, G. T.; Pope, S. E.; Harrison, D. C.
A variational Bayes spatiotemporal model for electromagnetic brain mapping.
In this article, we present a new variational Bayes approach for solving the neuroelectromagnetic inverse problem arising in studies involving electroencephalography (EEG) and magnetoencephalography (MEG). This high-dimensional spatiotemporal estimation problem involves the recovery of time-varying neural activity at a large number of locations within the brain, from electromagnetic signals recorded at a relatively small number of external locations on or near the scalp. Framing this problem within the context of spatial variable selection for an underdetermined functional linear model, we propose a spatial mixture formulation where the profile of electrical activity within the brain is represented through location-specific spike-and-slab priors based on a spatial logistic specification. The prior specification accommodates spatial clustering in brain activation, while also allowing for the inclusion of auxiliary information derived from alternative imaging modalities, such as functional magnetic resonance imaging (fMRI). We develop a variational Bayes approach for computing estimates of neural source activity, and incorporate a nonparametric bootstrap for interval estimation. The proposed methodology is compared with several alternative approaches through simulation studies, and is applied to the analysis of a multimodal neuroimaging study examining the neural response to face perception using EEG, MEG, and fMRI. PMID:24354514
Nathoo, F S; Babul, A; Moiseev, A; Virji-Babul, N; Beg, M F
Experimental modeling of explosive blast-related traumatic brain injuries.
This study aims to characterize the interaction of explosive blast waves through simulated anatomical systems. We have developed physical models and a systematic approach for testing traumatic brain injury (TBI) mechanisms and occurrences. A simplified series of models consisting of spherical poly(methyl methacrylate) (PMMA) shells housing synthetic gelatins as brain simulants have been utilized. A series of experiments was conducted to compare the sensitivity of the system response to mechanical properties of the simulants under high strain-rate explosive blasts. Small explosive charges were directed at the models to produce a realistic blast wave in a scaled laboratory setting. Blast profiles were measured and analyzed to compare system response severity. High-speed shadowgraph imaging captured blast wave interaction with the head model while particle tracking captured internal response for displacement and strain correlation. The results suggest amplification of shock waves inside the head near material interfaces due to impedance mismatches. In addition, significant relative displacement was observed between the interacting materials suggesting large strain values of nearly 5%. Further quantitative results were obtained through shadowgraph imaging of the blasts confirming a separation of time scales between blast interaction and bulk movement. These results lead to a conclusion that primary blast effects may potentially contribute significantly to the occurrence of military associated TBI. PMID:20580931
Alley, Matthew D; Schimizze, Benjamin R; Son, Steven F
Toward modeling of regional myocardial ischemia and infarction: generation of realistic coronary arterial tree for the heart model of the XCAT phantom
NASA Astrophysics Data System (ADS)
A realistic 3D coronary arterial tree (CAT) has been developed for the heart model of the computer generated 3D XCAT phantom. The CAT allows generation of a realistic model of the location, size and shape of the associated regional ischemia or infarction for a given coronary arterial stenosis or occlusion. This in turn can be used in medical imaging applications. An iterative rule-based generation method that systematically utilized anatomic, morphometric and physiologic knowledge was used to construct a detailed realistic 3D model of the CAT in the XCAT phantom. The anatomic details of the myocardial surfaces and large coronary arterial vessel segments were first extracted from cardiac CT images of a normal patient with right coronary dominance. Morphometric information derived from porcine data from the literature, after being adjusted by scaling laws, provided statistically nominal diameters, lengths, and connectivity probabilities of the generated coronary arterial segments in modeling the CAT of an average human. The largest six orders of the CAT were generated based on the physiologic constraints defined in the coronary generation algorithms. When combined with the heart model of the XCAT phantom, the realistic CAT provides a unique simulation tool for the generation of realistic regional myocardial ischemia and infraction. Together with the existing heart model, the new CAT provides an important improvement over the current 3D XCAT phantom in providing a more realistic model of the normal heart and the potential to simulate myocardial diseases in evaluation of medical imaging instrumentation, image reconstruction, and data processing methods.
Fung, George S. K.; Segars, W. Paul; Veress, Alexander I.; Gullberg, Grant T.; Tsui, Benjamin M. W.
The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion.
1. The effects were investigated of the ETA receptor antagonist, FR 139317, on endothelin-1 (ET-1)-induced coronary vasoconstriction in the isolated perfused heart of the rabbit. In addition, this study examined whether FR 139317 reduced infarct size in a rabbit model of coronary artery occlusion and reperfusion. 2. In the rabbit isolated perfused heart, ET-1 (1-100 pmol) elicited a dose-dependent increase in coronary perfusion pressure (CPP). For example, 30 pmol ET-1 caused CPP to rise by 22 +/- 8 mmHg and 100 pmol ET-1 by 47 +/- 10 mmHg (n = 8). Infusion of FR 139317 (1 microM) significantly attenuated the increase in CPP caused by ET-1 (30 pmol: 3 +/- 1 mmHg, 100 pmol: 8 +/- 2 mmHg; n = 8). 3. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 45 or 60 min of coronary artery occlusion followed by 2 h of reperfusion was 47 +/- 6% (n = 6) and 55 +/- 7% (n = 5), respectively. A continuous infusion of FR 139317 (0.2 mg kg-1 min-1 preceded by a loading dose of 1.0 mg kg-1, i.v.; n = 5-6) had no effect on the extent of the myocardial infarct size (45 min: 47 +/- 6%; 60 min: 49 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS)
McMurdo, L.; Thiemermann, C.; Vane, J. R.
Long-Term Left Ventricular Remodelling in Rat Model of Nonreperfused Myocardial Infarction: Sequential MR Imaging Using a 3T Clinical Scanner
Purpose. To evaluate whether 3T clinical MRI with a small-animal coil and gradient-echo (GE) sequence could be used to characterize long-term left ventricular remodelling (LVR) following nonreperfused myocardial infarction (MI) using semi-automatic segmentation software (SASS) in a rat model. Materials and Methods. 5 healthy rats were used to validate left ventricular mass (LVM) measured by MRI with postmortem values. 5 sham and 7 infarcted rats were scanned at 2 and 4 weeks after surgery to allow for functional and structural analysis of the heart. Measurements included ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), and LVM. Changes in different regions of the heart were quantified using wall thickness analyses. Results. LVM validation in healthy rats demonstrated high correlation between MR and postmortem values. Functional assessment at 4 weeks after MI revealed considerable reduction in EF, increases in ESV, EDV, and LVM, and contractile dysfunction in infarcted and noninfarcted regions. Conclusion. Clinical 3T MRI with a small animal coil and GE sequence generated images in a rat heart with adequate signal-to-noise ratio (SNR) for successful semiautomatic segmentation to accurately and rapidly evaluate long-term LVR after MI.
Saleh, Muhammad G.; Sharp, Sarah-Kate; Alhamud, Alkathafi; Spottiswoode, Bruce S.; van der Kouwe, Andre J. W.; Davies, Neil H.; Franz, Thomas; Meintjes, Ernesta M.
Cognitive aging as an extension of brain development: A model linking learning, brain plasticity, and neurodegeneration
Differences in cognitive aging rates among mammals suggest that the pace of brain aging is genetically determined. In this work, we investigate the possibility that brain aging is an extension of brain development. It is possible that a subset of developmental mechanisms are extreme cases of antagonistic pleiotropy in that they are necessary for reaching adulthood and yet later cause
Joăo Pedro de Magalhăes; Anders Sandberg
Induction of angiogenesis via topical delivery of basic-fibroblast growth factor from polyvinyl alcohol-dextran blend hydrogel in an ovine model of acute myocardial infarction.
Hydrogels are currently used as interesting constructs for the delivery of proteins. In this study, a novel polyvinyl alcohol-dextran (PVA-Dex) blend hydrogel was used for controlled delivery of basic-fibroblast growth factor (bFGF). These biocompatible constructs were sutured to the epicardium as patches on the heart surface to provide slow release of bFGF to the infarcted site in an ovine model of myocardial infarction (MI). Eighteen sheep were randomly divided into three groups (n = 6 each), including group I (control without any patch and bFGF), group II (patch without bFGF) and group III (patch incorporating 100 µg bFGF). They were subjected to coronary artery ligation after lateral thoracotomy, and then in groups II and III the patches were implanted 20-30 min after MI. Cardiac function was assessed by both echocardiography and magnetic resonance imaging (MRI) 2 months after implantation. Then the animals were sacrificed and the hearts subjected to histopathological examination, immunohistochemistry and electron microscopy. Heart lysates were subject to protein expression analysis through western blotting. The results showed that sustained release of bFGF using PVA-Dex blend hydrogel strongly stimulated angiogenesis and increased wall thickness index in the infarcted myocardium. The patch also significantly attenuated the increase in left ventricular end-systolic diameter, but it did not improve cardiac function within 2 months of myocardial infarction. In conclusion, PVA-Dex gel incorporating bFGF can be used as a sustained release construct for therapeutic angiogenesis in ischaemic heart disease. PMID:22674791
Fathi, Ezzatollah; Nassiri, Seyed Mahdi; Atyabi, Nahid; Ahmadi, Seyed Hossein; Imani, Mohammad; Farahzadi, Raheleh; Rabbani, Shahram; Akhlaghpour, Shahram; Sahebjam, Mohammad; Taheri, Mohammad
Cardioprotective activity of placental growth factor in a rat model of acute myocardial infarction: nanoparticle-based delivery versus direct myocardial injection
Background To comparatively evaluate the cardioprotective activity of placental growth factor (PGF) delivered through direct injection and a nanoparticle-based system respectively and to study the underlying mechanisms in a rat model of acute myocardial infarction (AMI). Methods Poly lactic-co-glycolic acid (PLGA)-based PGF-carrying nanoparticles (PGF-PLGANPs) were created. The mean size and morphology of particles were analyzed with particle size analyzer and transmission electronic microscopy (TEM). Encapsulation efficiency and sustained-release dose curve were analyzed by ELISA. Sprague-Dawley rats were randomized into four groups (n?=?10). While animals in the first group were left untreated as controls, those in the other 3 groups underwent surgical induction of AMI, followed by treatment with physiological saline, PGF, and PGF-PLGANPs, respectively. Cardiac function was evaluated by transthoracic echocardiography at 4 weeks after treatment. At 6 weeks, rats were sacrificed, infarction size was analyzed with Masson trichrome staining, and protein contents of TIMP-2, MT1-MMP and MMP-2 at the infarction border were determined by immunohistochemistry and western blotting analysis. Results PGF was released for at least 15 days, showing successful preparation of PGF-PLGANPs. Coronary artery ligation successfully induced AMI. Compared to physiological saline control, PGF, injected to the myocardium either as a nude molecule or in a form of nanoparticles, significantly reduced infarction size, improved cardiac function, and elevated myocardial expression of TIMP-2, MT1-MMP, and MMP-2 (P?0.05). The effect of PGF-PLGANPs was more pronounced than that of non-encapsulated PGF (P?0.05). Conclusion Target PGF delivery to myocardium may improve cardiac function after AMI in rats. PLGA-based nanoparticles appear to be a better approach to delivery PGF. PGF exerts its cardioprotective effect at least partially through regulating metalloproteinase-mediated myocardial tissue remodeling.
X-Ray Fused With Magnetic Resonance Imaging (XFM) to Target Endomyocardial Injections: Validation in a Swine Model of Myocardial Infarction
Background Magnetic resonance imaging (MRI) permits 3-dimensional (3D) cardiac imaging with high soft tissue contrast. X-ray fluoroscopy provides high-resolution, 2-dimensional (2D) projection imaging. We have developed real-time x-ray fused with MRI (XFM) to guide invasive procedures that combines the best features of both imaging modalities. We tested the accuracy of XFM using external fiducial markers to guide endomyocardial cell injections in infarcted swine hearts. Methods and Results Endomyocardial injections of iron-labeled mesenchymal stromal cells admixed with tissue dye were performed in previously infarcted hearts of 12 Yucatan miniswine (weight, 33 to 67 kg). Features from cardiac MRI were displayed combined with x-ray in real time to guide injections. During 130 injections, operators were provided with 3D surfaces of endocardium, epicardium, myocardial wall thickness (range, 2.6 to 17.7 mm), and infarct registered with live x-ray images to facilitate device navigation and choice of injection location. XFM-guided injections were compared with postinjection MRI and with necropsy specimens obtained 24 hours later. Visual inspection of the pattern of dye staining on 2,3,5-triphenyltetrazolium chloride–stained heart slices agreed (?=0.69) with XFM-derived injection locations mapped onto delayed hyperenhancement MRI and the susceptibility artifacts seen on the postinjection T2*-weighted gradient echo MRI. The distance between the predicted and actual injection locations in vivo was 3.2±2.6 mm (n=64), and 75% of injections were within 4.1 mm of the predicted location. Conclusions Three-dimensional to two-dimensional registration of x-ray and MR images with the use of external fiducial markers accurately targets endomyocardial injection in a swine model of myocardial infarction.
de Silva, Ranil; Gutierrez, Luis F.; Raval, Amish N.; McVeigh, Elliot R.; Ozturk, Cengizhan; Lederman, Robert J.
The Effect of Tobacco Control Measures during a Period of Rising Cardiovascular Disease Risk in India: A Mathematical Model of Myocardial Infarction and Stroke
Background We simulated tobacco control and pharmacological strategies for preventing cardiovascular deaths in India, the country that is expected to experience more cardiovascular deaths than any other over the next decade. Methods and Findings A microsimulation model was developed to quantify the differential effects of various tobacco control measures and pharmacological therapies on myocardial infarction and stroke deaths stratified by age, gender, and urban/rural status for 2013 to 2022. The model incorporated population-representative data from India on multiple risk factors that affect myocardial infarction and stroke mortality, including hypertension, hyperlipidemia, diabetes, coronary heart disease, and cerebrovascular disease. We also included data from India on cigarette smoking, bidi smoking, chewing tobacco, and secondhand smoke. According to the model's results, smoke-free legislation and tobacco taxation would likely be the most effective strategy among a menu of tobacco control strategies (including, as well, brief cessation advice by health care providers, mass media campaigns, and an advertising ban) for reducing myocardial infarction and stroke deaths over the next decade, while cessation advice would be expected to be the least effective strategy at the population level. In combination, these tobacco control interventions could avert 25% of myocardial infarctions and strokes (95% CI: 17%–34%) if the effects of the interventions are additive. These effects are substantially larger than would be achieved through aspirin, antihypertensive, and statin therapy under most scenarios, because of limited treatment access and adherence; nevertheless, the impacts of tobacco control policies and pharmacological interventions appear to be markedly synergistic, averting up to one-third of deaths from myocardial infarction and stroke among 20- to 79-y-olds over the next 10 y. Pharmacological therapies could also be considerably more potent with further health system improvements. Conclusions Smoke-free laws and substantially increased tobacco taxation appear to be markedly potent population measures to avert future cardiovascular deaths in India. Despite the rise in co-morbid cardiovascular disease risk factors like hyperlipidemia and hypertension in low- and middle-income countries, tobacco control is likely to remain a highly effective strategy to reduce cardiovascular deaths. Please see later in the article for the Editors' Summary
Basu, Sanjay; Glantz, Stanton; Bitton, Asaf; Millett, Christopher
In vitro models of the blood-brain barrier for the study of drug delivery to the brain.
The most important obstacle to the drug delivery into the brain is the presence of the blood-brain barrier, which limits the traffic of substances between the blood and the nervous tissue. Therefore, adequate in vitro models need to be developed in order to characterize the penetration properties of drug candidates into the central nervous system. This review article summarizes the presently used and the most promising in vitro BBB models based on the culture of brain endothelial cells. Robust models can be obtained using primary porcine brain endothelial cells and rodent coculture models, which have low paracellular permeability and express functional efflux transporters, showing good correlation of drug penetration data with in vivo results. Models mimicking the in vivo anatomophysiological complexity of the BBB are also available, including triple coculture (culture of brain endothelial cells in the presence of pericytes and astrocytes), dynamic, and microfluidic models; however, these are not suitable for rapid, high throughput studies. Potent human cell lines would be needed for easily available and reproducible models which avoid interspecies differences. PMID:24641309
Wilhelm, Imola; Krizbai, István A
Dissipation and Memory Capacity in the Quantum Brain Model
NASA Astrophysics Data System (ADS)
The quantum model of the brain proposed by Ricciardi and Umezawa is extended to dissipative dynamics in order to study the problem of memory capacity. It is shown that infinitely many vacua are accessible to memory printing in a way that in sequential information recording the storage of a new information does not destroy the previously stored ones, thus allowing a huge memory capacity. The mechanism of information printing is shown to induce breakdown of time-reversal symmetry. Thermal properties of the memory states, as well as their relation with squeezed coherent states, are finally discussed.
Vitiello, Giuseppe
Multiscale modeling for image analysis of brain tumor studies.
Image-based modeling of tumor growth combines methods from cancer simulation and medical imaging. In this context, we present a novel approach to adapt a healthy brain atlas to MR images of tumor patients. In order to establish correspondence between a healthy atlas and a pathologic patient image, tumor growth modeling in combination with registration algorithms is employed. In a first step, the tumor is grown in the atlas based on a new multiscale, multiphysics model including growth simulation from the cellular level up to the biomechanical level, accounting for cell proliferation and tissue deformations. Large-scale deformations are handled with an Eulerian approach for finite element computations, which can operate directly on the image voxel mesh. Subsequently, dense correspondence between the modified atlas and patient image is established using nonrigid registration. The method offers opportunities in atlas-based segmentation of tumor-bearing brain images as well as for improved patient-specific simulation and prognosis of tumor progression. PMID:21813362
Bauer, Stefan; May, Christian; Dionysiou, Dimitra; Stamatakos, Georgios; Büchler, Philippe; Reyes, Mauricio
Neurohumoral and hemodynamic effects of ibopamine in a rat model of chronic myocardial infarction and heart failure
There is increasing evidence that both neurohumoral and hemodynamic factors play a role in disease progression in chronic heart failure (CHF). To examine the influence of the oral dopamine agonist ibopamine on these factors, we studied 20 rats with chronic myocardial infarction and CHF, and compared them with 20 normal rats. After 6 weeks, rats were randomly divided between control
Dirk J. van Veldhuisen; Wiek H. van Gilst; Bart J. G. L. Smet; Pieter A. Graeff; Egbert Scholtens; Hendrik Buikema; Armand R. J. Girbes; Harry Wesseling; K. I. Lie
The striatocapsular infarction and its aftermaths.
Ischaemic stroke syndromes in the vascular territory of middle cerebral artery may have atypical presentation and radiographic findings because of the variable anatomy of that artery. Therefore, misdiagnosis of these syndromes as neoplastic or infectious processes is not uncommon. This case describes a 69-year-old comatose woman who was referred to us as having 'a brain tumour with massive surrounding oedema.' Further work-up revealed that she had a large left-sided lenticular nuclear infarction with some extension into the surrounding areas-the striatocapsular infarction. PMID:22778185
Amin, Osama S M; Zangana, Hero M; Ameen, Nawa A
RNase therapy assessed by magnetic resonance imaging reduces cerebral edema and infarction size in acute stroke.
Ischemic stroke causes cell necrosis with the exposure of extracellular ribonucleic acid (RNA) and other intracellular material. As shown recently, extracellular RNA impaired the blood-brain-barrier and contributed to vasogenic edema-formation. Application of ribonuclease 1 (RNase 1) diminished edema-formation and also reduced lesion volume in experimental stroke. Here we investigate whether reduction of lesion volume is due to the reduction of edema or of other neuroprotective means. Neuroprotective and edema protective effects of RNase 1 pretreatment were assessed using a temporary middle cerebral artery occlusion (MCAO) model in rats. Lesion volume was assessed on magnetic resonance imaging (MRI). T2-relaxation-time and midline-shift as well as brain water content (wet-dry-method) were measured to quantify edema formation. The impact of edema formation on infarct volume was evaluated in craniectomized animals. Exogenous RNase 1 was well tolerated and reduced edema-formation and infarct size (26.7% +/- 10.7% vs. 41.0% +/- 10.3%; p<0.01) at an optimal dose of 42 microg/kg as compared to placebo. Craniectomized animals displayed a comparable edema reduction but no reduction in infarct size. The present study introduces a hitherto unrecognized mechanism of ischemic brain damage and a novel neuroprotective approach towards acute stroke treatment. PMID:19355922
Walberer, Maureen; Tschernatsch, Marlene; Fischer, Silvia; Ritschel, Nouha; Volk, Kai; Friedrich, Carolin; Bachmann, Georg; Mueller, Clemens; Kaps, Manfred; Nedelmann, Max; Blaes, Franz; Preissner, Klaus T; Gerriets, Tibo
Cerebral Atherosclerosis is Associated with Cystic Infarcts and Microinfarcts, but not Alzheimer Pathologic Changes
Background and Purpose Some studies have reported associations between intracranial atherosclerosis and Alzheimer disease (AD) pathology. We aimed to correlate severity of cerebral atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy (CAA) with neurofibrillary tangles, neuritic plaques, and cerebral infarcts. Methods This autopsy study (n = 163) was drawn from a longitudinal study of subcortical ischemic vascular disease, AD, and normal aging. Multivariable logistic regression models were used to test associations among the 3 forms of cerebrovascular disease and the presence of ischemic and neurodegenerative brain lesions. Apolipoprotein E genotype was included as a covariate in these multivariable models. Results Cerebral atherosclerosis was positively associated with microinfarcts (odds ratio (OR) = 2.3; 95% confidence interval (CI) = 1.2–4.4) and cystic infarcts (OR = 2.0, 95%CI = 1.0–4.2), but not AD pathology. Arteriolosclerosis showed a positive correlation with lacunar infarcts (OR = 2.0, 95%CI = 1.0–4.2), but not AD pathology. CAA was inversely associated with lacunar infarcts (OR = 0.6, 95%CI = 0.41–1.1), but positively associated with Braak & Braak stage (OR = 1.5, 95%CI = 1.1–2.1) and CERAD plaque score (OR = 1.5, 95%CI = 1.1–2.2). Conclusions Microinfarcts, which have been correlated with severity of cognitive impairment, were most strongly associated with atherosclerosis. Possible pathogenetic mechanisms include artery-to-artery emboli, especially micro-emboli that may include atheroemboli or platelet-fibrin emboli. Arteriolosclerosis was positively, while CAA was negatively correlated with lacunar infarcts, which might prove helpful in clinical differentiation of arteriolosclerotic from CAA-related vascular brain injury.
Zheng, Ling; Vinters, Harry V.; Mack, Wendy J.; Zarow, Chris; Ellis, William G.; Chui, Helena C.
Development of luciferase tagged brain tumour models in mice for chemotherapy intervention studies
The blood–brain barrier (BBB) is considered one of the major causes for the low efficacy of cytotoxic compounds against primary brain tumours. The aim of this study was to develop intracranial tumour models in mice featuring intact or locally disrupted BBB properties, which can be used in testing chemotherapy against brain tumours. These tumours were established by intracranial injection of
E. M. Kemper; W. P. J. Leenders; B. Küsters; S. Lyons; T. Buckle; A. Heerschap; W. Boogerd; J. H. Beijnen; O. van Tellingen
[A clinical case of young, oral combined contraceptive using women, heterozygous carrier of the Factor V (Leiden) which revealed thrombosis of the left internal jugular vein and brain ischemia with cerebral infarction and ischemic stroke].
Thrombophilia is associated with increased risks of venous thrombosis in women taking oral contraceptive preparations. Universal thrombophilia screening in women prior to prescribing oral contraceptive preparations is not supported by current evidence. The case is presented of a 23 year-old women with a personal history of interruption and on the same day started with oral contraceptive (0.03 microg ethynil estradiol - 0.075 microg gestodene), which due on a 18 pill/day to acute headache, increasing vomiting and speaking defects. Physical/neurologic/gynecologic examinations observed a normal status. The MRI and CT revealed thrombosis of the left internal jugular vein and brain ischemia with cerebral infarction and ischemic stroke. The acute therapy of thrombotic findings was accompanied with many tests. The thrombophilia PCR-Real time - test finds heterozygous carrier of the Factor V (Leiden). This case shows the need of large prospective studies that should be undertaken to refine the risks and establish the associations of thrombophilias with venous thrombosis among contraceptive users. The key to a prompt diagnosis is to know the risk factors. The relative value of a thrombophilia screening programme before contraceptive using needs to be established. PMID:24501870
Kovachev, S; Ramshev, K; Ramsheva, Z; Ivanov, A; Ganovska, A
Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion.
Postconditioning (PoC) with brief intermittent ischemia after myocardial reperfusion has been shown to lessen some elements of postischemic injury including arrhythmias and, in some studies, the size of myocardial infarction. We hypothesized that PoC could improve reflow to the risk zone after reperfusion. Anesthetized, open-chest rabbits were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. In protocol 1, rabbits were randomly assigned to the control group (n = 10, no further intervention after reperfusion) or to the PoC group, which consisted of four cycles of 30-s reocclusions with 30 s of reperfusion in between starting at 30 s after the initial reperfusion (4 x 30/30, n = 10). In protocol 2, rabbits were assigned to the control group (n = 7) or the PoC group, which received PoC consisting of four cycles of 60-s intervals of ischemia and reperfusion starting at 30 s after the initial reperfusion (4 x 60/60, n = 7). No reflow was determined by injecting thioflavine S (a fluorescent marker of capillary perfusion), risk zone by blue dye, and infarct size by triphenyltetrazolium chloride. In protocol 1, there were no statistical differences in hemodynamics, ischemic risk zone, or infarct size (35 +/- 6% of the risk zone in the PoC group vs. 29 +/- 4% in the control group, P = 0.38) between the groups. Similarly, in protocol 2, PoC failed to reduce infarct size compared with the control group (45 +/- 4% of the risk zone in the PoC group vs. 42 +/- 6% in the control group, P = 0.75). There was a strong correlation in both protocols between the size of the necrotic zone and the portion of the necrotic zone that contained an area of no reflow. However, PoC did not affect this relationship. PoC did not reduce infarct size in this model, nor did it reduce the extent of the anatomic zone of no reflow, suggesting that this intervention may not impact postreperfusion microvascular damage due to ischemia. PMID:17993599
Hale, Sharon L; Mehra, Ankur; Leeka, Justin; Kloner, Robert A
Effects of single-dose atorvastatin on interleukin-6, interferon gamma, and myocardial no-reflow in a rabbit model of acute myocardial infarction and reperfusion
The mechanisms of statins relieving the no-reflow phenomenon and the effects of single-dose statins on it are not well known. This study sought to investigate the effects of inflammation on the no-reflow phenomenon in a rabbit model of acute myocardial infarction and reperfusion (AMI/R) and to evaluate the effects of single-dose atorvastatin on inflammation and myocardial no-reflow. Twenty-four New Zealand white male rabbits (5-6 months old) were randomized to three groups of eight: a sham-operated group, an AMI/R group, and an atorvastatin-treated group (10 mg/kg). Animals in the latter two groups were subjected to 4 h of coronary occlusion followed by 2 h of reperfusion. Serum levels of interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. The expression of interferon gamma (IFN-?) in normal and infarcted (reflow and no-reflow) myocardial tissue was determined by immunohistochemical methods. The area of no-reflow and necrosis was evaluated pathologically. Levels of serum IL-6 were significantly lower in the atorvastatin group than in the AMI/R group (P<0.01). Expression of IFN-? in infarcted reflow and no-reflow myocardial tissue was also significantly lower in the atorvastatin group than in the AMI/R group. The mean area of no-reflow [47.01% of ligation area (LA)] was significantly smaller in the atorvastatin group than in the AMI/R group (85.67% of LA; P<0.01). The necrosis area was also significantly smaller in the atorvastatin group (85.94% of LA) than in the AMI/R group (96.56% of LA; P<0.01). In a secondary analysis, rabbits in the atorvastatin and AMI/R groups were divided into two groups based on necrosis area (90% of LA): a small group (<90% of LA) and a large group (>90% of LA). There was no significant difference in the area of no-reflow between the small (61.40% of LA) and large groups (69.87% of LA; P>0.05). Single-dose atorvastatin protected against inflammation and myocardial no-reflow and reduced infarct size during AMI/R in rabbits. No-reflow was not dependent on the reduction of infarct size.
Zhao, X.J.; Liu, X.L.; He, G.X.; Xu, H.P.
Focal brain trauma in the cryogenic lesion model in mice
The method to induce unilateral cryogenic lesions was first described in 1958 by Klatzo. We describe here an adaptation of this model that allows reliable measurement of lesion volume and vasogenic edema by 2, 3, 5-triphenyltetrazolium chloride-staining and Evans blue extravasation in mice. A copper or aluminium cylinder with a tip diameter of 2.5 mm is cooled with liquid nitrogen and placed on the exposed skull bone over the parietal cortex (coordinates from bregma: 1.5 mm posterior, 1.5 mm lateral). The tip diameter and the contact time between the tip and the parietal skull determine the extent of cryolesion. Due to an early damage of the blood brain barrier, the cryogenic cortical injury is characterized by vasogenic edema, marked brain swelling, and inflammation. The lesion grows during the first 24 hours, a process involving complex interactions between endothelial cells, immune cells, cerebral blood flow, and the intracranial pressure. These contribute substantially to the damage from the initial injury. The major advantage of the cryogenic lesion model is the circumscribed and highly reproducible lesion size and location.
Experimental models of brain ischemia: a review of techniques, magnetic resonance imaging, and investigational cell-based therapies.
Stroke continues to be a significant cause of death and disability worldwide. Although major advances have been made in the past decades in prevention, treatment, and rehabilitation, enormous challenges remain in the way of translating new therapeutic approaches from bench to bedside. Thrombolysis, while routinely used for ischemic stroke, is only a viable option within a narrow time window. Recently, progress in stem cell biology has opened up avenues to therapeutic strategies aimed at supporting and replacing neural cells in infarcted areas. Realistic experimental animal models are crucial to understand the mechanisms of neuronal survival following ischemic brain injury and to develop therapeutic interventions. Current studies on experimental stroke therapies evaluate the efficiency of neuroprotective agents and cell-based approaches using primarily rodent models of permanent or transient focal cerebral ischemia. In parallel, advancements in imaging techniques permit better mapping of the spatial-temporal evolution of the lesioned cortex and its functional responses. This review provides a condensed conceptual review of the state of the art of this field, from models and magnetic resonance imaging techniques through to stem cell therapies. PMID:24600434
Canazza, Alessandra; Minati, Ludovico; Boffano, Carlo; Parati, Eugenio; Binks, Sophie
Experimental Models of Brain Ischemia: A Review of Techniques, Magnetic Resonance Imaging, and Investigational Cell-Based Therapies
Stroke continues to be a significant cause of death and disability worldwide. Although major advances have been made in the past decades in prevention, treatment, and rehabilitation, enormous challenges remain in the way of translating new therapeutic approaches from bench to bedside. Thrombolysis, while routinely used for ischemic stroke, is only a viable option within a narrow time window. Recently, progress in stem cell biology has opened up avenues to therapeutic strategies aimed at supporting and replacing neural cells in infarcted areas. Realistic experimental animal models are crucial to understand the mechanisms of neuronal survival following ischemic brain injury and to develop therapeutic interventions. Current studies on experimental stroke therapies evaluate the efficiency of neuroprotective agents and cell-based approaches using primarily rodent models of permanent or transient focal cerebral ischemia. In parallel, advancements in imaging techniques permit better mapping of the spatial-temporal evolution of the lesioned cortex and its functional responses. This review provides a condensed conceptual review of the state of the art of this field, from models and magnetic resonance imaging techniques through to stem cell therapies.
Canazza, Alessandra; Minati, Ludovico; Boffano, Carlo; Parati, Eugenio; Binks, Sophie
In vitro models of the blood-brain barrier.
The blood-brain barrier (BBB) proper is composed of endothelial cells (ECs) of the cerebral microvasculature, which are interconnected by tight junctions (TJs) that in turn form a physical barrier restricting paracellular flux. Tight control of vascular permeability is essential for the homeostasis and functionality of the central nervous system (CNS). In vitro BBB models have been in use for decades and have been of great benefit in the process of investigating and understanding the cellular and molecular mechanisms underlying BBB establishment. BBB integrity changes can be addressed in vitro by determining cell monolayer permeability (Pe) to different solutes and measuring trans-endothelial electrical resistance (TEER).This chapter describes procedures that can be utilized for both freshly isolated mouse brain microvascular ECs (MBMECs) and murine or human brain EC lines (bEnd5 or hCMEC/D3), cultivated either as a single monolayer or in cocultivation with primary mouse astrocytes (ACs). It starts with detailed information on how to perform transwell cell culture, including coating of inserts and seeding of the ECs and ACs. Moreover, it encompasses instructions for electrical assessment of the in vitro BBB using the more recent cellZscope(®) device, which was traditionally performed with chopstick electrodes of voltohmmeter type (EVOM). From continuous impedance measurements, the cellZscope(®) device provides TEER (paracellular resistance) and cell membrane capacitance (Ccl-transcellular resistance), two independent measures of monolayer integrity. Additionally, this chapter provides guidance through subsequent experiments such as permeability analysis (Pe, flux), expression analysis (qRT-PCR and Western blotting), and localization analysis of BBB junction proteins (immunocytochemistry) using the same inserts subjected earlier to impedance analysis.As numerous diseases are associated with BBB breakdown, researchers aim to continuously improve and refine in vitro BBB models to mimic in vivo conditions as closely as possible. This chapter summarizes protocols with the intention to provide a collection of BBB in vitro assays that generate reproducible results not only with primary brain ECs but also with EC lines to open up the field for a broader spectrum of researchers who intend to investigate the BBB in vitro particularly aiming at therapeutic aspects. PMID:24510883
Czupalla, Cathrin J; Liebner, Stefan; Devraj, Kavi
Modeling Brain Responses in an Arithmetic Working Memory Task
NASA Astrophysics Data System (ADS)
Functional magnetic resonance imaging (fMRI) was used to investigate brain responses due to arithmetic working memory. Nine healthy young male subjects were given simple addition and subtraction instructions in noise and in quiet. The general linear model (GLM) and random field theory (RFT) were implemented in modelling the activation. The results showed that addition and subtraction evoked bilateral activation in Heschl's gyrus (HG), superior temporal gyrus (STG), inferior frontal gyrus (IFG), supramarginal gyrus (SG) and precentral gyrus (PCG). The HG, STG, SG and PCG activate higher number of voxels in noise as compared to in quiet for addition and subtraction except for IFG that showed otherwise. The percentage of signal change (PSC) in all areas is higher in quiet as compared to in noise. Surprisingly addition (not subtraction) exhibits stronger activation.
Hamid, Aini Ismafairus Abd; Yusoff, Ahmad Nazlim; Mukari, Siti Zamratol-Mai Sarah; Mohamad, Mazlyfarina; Manan, Hanani Abdul; Hamid, Khairiah Abdul
Fast, Sequence Adaptive Parcellation of Brain MR Using Parametric Models
In this paper we propose a method for whole brain parcellation using the type of generative parametric models typically used in tissue classification. Compared to the non-parametric, multi-atlas segmentation techniques that have become popular in recent years, our method obtains state-of-the-art segmentation performance in both cortical and subcortical structures, while retaining all the benefits of generative parametric models, including high computational speed, automatic adaptiveness to changes in image contrast when different scanner platforms and pulse sequences are used, and the ability to handle multi-contrast (vector-valued intensities) MR data. We have validated our method by comparing its segmentations to manual delineations both within and across scanner platforms and pulse sequences, and show preliminary results on multi-contrast test-retest scans, demonstrating the feasibility of the approach.
Puonti, Oula; Iglesias, Juan Eugenio; Van Leemput, Koen
Multiresolution hierarchical shape models in 3D subcortical brain structures.
Point distribution models (PDM) are one of the most extended methods to characterize the underlying population of set of samples, whose usefulness has been demonstrated in a wide variety of applications, including medical imaging. However, one important issue remains unsolved: the large number of training samples required. This problem becomes critical as the complexity of the problem increases, and the modeling of 3D multiobjects/organs represents one of the most challenging cases. Based on the 3D wavelet transform, this paper introduces a multiresolution hierarchical variant of PDM (MRH-PDM) able to efficiently characterize the different inter-object relationships, as well as the particular locality of each element separately. The significant advantage of this new method over two previous approaches in terms of accuracy has been successfully verified for the particular case of 3D subcortical brain structures. PMID:24579195
Cerrolaza, Juan J; Herrezuelo, Noemí Carranza; Villanueva, Arantxa; Cabeza, Rafael; González Ballester, Miguel Angel; Linguraru, Marius George
Alexithymia-like Disorder in Right Anterior Cingulate Infarction
The frontal midline structures have been demonstrated by functional neuroimaging to be involved in the affective control of human behavior. However, due to the rareness of diseases affecting this part of the brain little is known about behavioral abnormalities following damage to these brain areas. We present a patient with a right anterior cingulate infarct who presented with an alexithymia-like
Ralf Schäfer; Kerstin Popp; Silke Jörgens; Robert Lindenberg; Matthias Franz; Rüdiger J. Seitz
Brain enzyme changes as markers of brain damage in rat cardiac arrest model. Effects of corticosteroid therapy.
Apneic asphyxia to cardiac arrest (CA) in rats of 10 min was reversed by cardiopulmonary resuscitation (CPR), and after controlled ventilation and controlled normotension for 20 min, was followed by decapitation and brain freezing, and determination of brain concentrations of cytosolic and lysosomal enzymes. Normal values came from a control group of 10 rats without CA. In 20 rats with CA brain cytosolic enzymes CK, LD, and ASAT decreased post-arrest, while lysosomal enzyme changes were variable (Table I). Brain lactate increased 8-10-fold post-CA. To test the model, effect of methylprednisolone (MP) was studied. The 20 rats with CA were divided into 4 groups: Group I, received placebo pre-CA; Group II, MP 30 mg/kg i.v. pre-CA; Group III, placebo post-CA; and Group IV, MP post-CA. The post-CA MP Group IV was the only one without norepinephrine requirement and with return of EEG activity at 20 min. Brain CK, LD, and ASAT losses post-CA were not different between groups; and showed no differences between MP groups II and IV vs. placebo Groups I and III. When comparing both pre-CA Groups (I and II) with both post-CA Groups (III and IV), post-CA CK and ASAT levels were the same, but LD was higher in the post-CA treatment group. The lysosomal enzymes acid phosphatase, mannosidase, beta-glucuronidase and hexosaminidase showed variable concentration changes post-CA in the four groups, with a trend toward a lesser increase of some after MP or after post-treatment. Brain enzyme changes in our asphyxial CA rat model can serve as markers of brain damage. MP post-CA might enhance cardiovascular and EEG recovery, but does not seem to influence brain enzyme levels at 20 min post-CA. PMID:2538900
Katz, L; Vaagenes, P; Safar, P; Diven, W
Language Model Applications to Spelling with Brain-Computer Interfaces
Within the Ambient Assisted Living (AAL) community, Brain-Computer Interfaces (BCIs) have raised great hopes as they provide alternative communication means for persons with disabilities bypassing the need for speech and other motor activities. Although significant advancements have been realized in the last decade, applications of language models (e.g., word prediction, completion) have only recently started to appear in BCI systems. The main goal of this article is to review the language model applications that supplement non-invasive BCI-based communication systems by discussing their potential and limitations, and to discern future trends. First, a brief overview of the most prominent BCI spelling systems is given, followed by an in-depth discussion of the language models applied to them. These language models are classified according to their functionality in the context of BCI-based spelling: the static/dynamic nature of the user interface, the use of error correction and predictive spelling, and the potential to improve their classification performance by using language models. To conclude, the review offers an overview of the advantages and challenges when implementing language models in BCI-based communication systems when implemented in conjunction with other AAL technologies.
Mora-Cortes, Anderson; Manyakov, Nikolay V.; Chumerin, Nikolay; Van Hulle, Marc M.
Language model applications to spelling with Brain-Computer Interfaces.
Within the Ambient Assisted Living (AAL) community, Brain-Computer Interfaces (BCIs) have raised great hopes as they provide alternative communication means for persons with disabilities bypassing the need for speech and other motor activities. Although significant advancements have been realized in the last decade, applications of language models (e.g., word prediction, completion) have only recently started to appear in BCI systems. The main goal of this article is to review the language model applications that supplement non-invasive BCI-based communication systems by discussing their potential and limitations, and to discern future trends. First, a brief overview of the most prominent BCI spelling systems is given, followed by an in-depth discussion of the language models applied to them. These language models are classified according to their functionality in the context of BCI-based spelling: the static/dynamic nature of the user interface, the use of error correction and predictive spelling, and the potential to improve their classification performance by using language models. To conclude, the review offers an overview of the advantages and challenges when implementing language models in BCI-based communication systems when implemented in conjunction with other AAL technologies. PMID:24675760
Mora-Cortes, Anderson; Manyakov, Nikolay V; Chumerin, Nikolay; Van Hulle, Marc M
Magnetic Resonance Imaging of Acute Reperfused Myocardial Infarction: Intraindividual Comparison of ECIII-60 and Gd-DTPA in a Swine Model
Purpose To compare a necrosis-avid contrast agent (NACA) bis-Gd-DTPA-pamoic acid derivative (ECIII-60) after intracoronary delivery\\u000a with an extracellular agent Gd-DTPA after intravenous injection on magnetic resonance imaging (MRI) in a swine model of acute\\u000a reperfused myocardial infarction (MI).\\u000a \\u000a \\u000a \\u000a Methods Eight pigs underwent 90 min of transcatheter coronary balloon occlusion and 60 min of reperfusion. After intravenous injection\\u000a of Gd-DTPA at a dose
Jiyang Jin; Gaojun Teng; Yi Feng; Yanping Wu; Qindi Jin; Yu Wang; Zhen Wang; Qin Lu; Yibo Jiang; Shengqi Wang; Feng Chen; Guy Marchal; Yicheng Ni
Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat
Introduction A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg?1 of fluvoxamine. Analysis With increasing dose a disproportional increase in brain concentrations was observed. The kinetics of brain distribution was estimated by simultaneous analysis of plasma, free brain ECF and total brain tissue concentrations. The PK model consists of three compartments for fluvoxamine concentrations in plasma in combination with a catenary two compartment model for distribution into the brain. In this catenary model, the mass exchange between a shallow perfusion-limited and a deep brain compartment is described by a passive diffusion term and a saturable active efflux term. Results The model resulted in precise estimates of the parameters describing passive influx into (kin) of 0.16 min?1 and efflux from the shallow brain compartment (kout) of 0.019 min?1 and the fluvoxamine concentration at which 50% of the maximum active efflux (C50) is reached of 710 ng.ml?1. The proposed brain distribution model constitutes a basis for precise characterization of the PK–PD correlation of fluvoxamine by taking into account the non-linearity in brain distribution.
Geldof, Marian; Freijer, Jan; van Beijsterveldt, Ludy
Homing of neural stem cells from the venous compartment into a brain infarct does not involve conventional interactions with vascular endothelium.
Human neural stem cells (hNSCs) hold great potential for treatment of a wide variety of neurodegenerative and neurotraumatic conditions. Heretofore, administration has been through intracranial injection or implantation of cells. Because neural stem cells are capable of migrating to the injured brain from the intravascular space, it seemed feasible to administer them intravenously if their ability to circumvent the blood-brain barrier was enhanced. In the present studies, we found that interactions of hNSCs in vitro on the luminal surface of human umbilical vein endothelial cells was enhanced following enforced expression of cutaneous lymphocyte antigen on cell surface moieties by incubation of hNSCs with fucosyltransferase VI and GDP-fucose (fhNSCs). Interestingly, ex vivo fucosylation of hNSCs not only did not improve the cells homing into the brain injured by stroke following intravenous administration but also increased mortality of rats compared with the nonfucosylated hNSC group. Efforts to explain these unexpected findings using a three-dimensional flow chamber device revealed that transmigration of fhNSCs (under conditions of physiological shear stress) mediated by stromal cell-derived factor 1? was significantly decreased compared with controls. Further analysis revealed that hNSCs poorly withstand physiological shear stress, and their ability is further decreased following fucosylation. In addition, fhNSCs demonstrated a higher frequency of cellular aggregate formation as well as a tendency for removal of fucose from the cell surface. In summary, our findings suggest that the behavior of hNSCs in circulation is different from that observed with other cell types and that, at least for stroke, intravenous administration is a suboptimal route, even when the in vitro rolling ability of hNSCs is optimized by enforced fucosylation. PMID:24396034
Goncharova, Valentina; Das, Shreyasi; Niles, Walter; Schraufstatter, Ingrid; Wong, Aaron K; Povaly, Tatiana; Wakeman, Dustin; Miller, Leonard; Snyder, Evan Y; Khaldoyanidi, Sophia K
A Model for Diffusion in White Matter in the Brain
Diffusion of molecules in brain and other tissues is important in a wide range of biological processes and measurements ranging from the delivery of drugs to diffusion-weighted magnetic resonance imaging. Diffusion tensor imaging is a powerful noninvasive method to characterize neuronal tissue in the human brain in vivo. As a first step toward understanding the relationship between the measured macroscopic apparent diffusion tensor and underlying microscopic compartmental geometry and physical properties, we treat a white matter fascicle as an array of identical thick-walled cylindrical tubes arranged periodically in a regular lattice and immersed in an outer medium. Both square and hexagonal arrays are considered. The diffusing molecules may have different diffusion coefficients and concentrations (or densities) in different domains, namely within the tubes' inner core, membrane, myelin sheath, and within the outer medium. Analytical results are used to explore the effects of a large range of microstructural and compositional parameters on the apparent diffusion tensor and the degree of diffusion anisotropy, allowing the characterization of diffusion in normal physiological conditions as well as changes occurring in development, disease, and aging. Implications for diffusion tensor imaging and for the possible in situ estimation of microstructural parameters from diffusion-weighted MR data are discussed in the context of this modeling framework.
Sen, Pabitra N.; Basser, Peter J.
Quantitative myocardial perfusion measurement using CT Perfusion: a validation study in a porcine model of reperfused acute myocardial infarction
We validated a CT Perfusion technique with beam hardening (BH) correction for quantitative measurement of myocardial blood\\u000a flow (MBF). Acute myocardial infarction (AMI) was created in four pigs by occluding the distal LAD for 1 h followed by reperfusion.\\u000a MBF was measured from dynamic contrast enhanced CT (DCE-CT) scanning of the heart, with correction of cardiac motion and BH,\\u000a before ischemic
Aaron SoJiang; Jiang Hsieh; Jian-Ying Li; Jennifer Hadway; Hua-Fu Kong; Ting-Yim Lee
Informing Pedagogy Through the Brain-Targeted Teaching Model
Improving teaching to foster creative thinking and problem-solving for students of all ages will require two essential changes in current educational practice. First, to allow more time for deeper engagement with material, it is critical to reduce the vast number of topics often required in many courses. Second, and perhaps more challenging, is the alignment of pedagogy with recent research on cognition and learning. With a growing focus on the use of research to inform teaching practices, educators need a pedagogical framework that helps them interpret and apply research findings. This article describes the Brain-Targeted Teaching Model, a scheme that relates six distinct aspects of instruction to research from the neuro- and cognitive sciences.
Hardiman, Mariale
Mapping Metabolic Brain Activity in Three Models of Hepatic Encephalopathy
Cirrhosis is a common disease in Western countries. Liver failure, hyperammonemia, and portal hypertension are the main factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups.
Mendez, Marta; Fidalgo, Camino; Aller, Maria Angeles; Arias, Jaime; Arias, Jorge L.
Acute infarct selective MRI contrast agent
To determine the infarct affinity of a low molecular weight contrast agent, Gd(ABE-DTTA), during the subacute phase of myocardial\\u000a infarct (MI). Dogs (n = 7) were examined, using a closed-chest, reperfused MI model. MI was generated by occluding for 180 min the Left Anterior\\u000a Descending (LAD) coronary artery with an angioplasty balloon. DE-MRI images with Gd(ABE-DTTA) were obtained on days 4, 14,\\u000a and
Robert KirschnerAkos; Akos Varga-Szemes; Tamas Simor; Pal Suranyi; Pal Kiss; Balazs Ruzsics; Brigitta C. Brott; Ada Elgavish; Gabriel A. Elgavish
Iron Deposition following Chronic Myocardial Infarction as a Substrate for Cardiac Electrical Anomalies: Initial Findings in a Canine Model
Purpose Iron deposition has been shown to occur following myocardial infarction (MI). We investigated whether such focal iron deposition within chronic MI lead to electrical anomalies. Methods Two groups of dogs (ex-vivo (n?=?12) and in-vivo (n?=?10)) were studied at 16 weeks post MI. Hearts of animals from ex-vivo group were explanted and sectioned into infarcted and non-infarcted segments. Impedance spectroscopy was used to derive electrical permittivity () and conductivity (). Mass spectrometry was used to classify and characterize tissue sections with (IRON+) and without (IRON-) iron. Animals from in-vivo group underwent cardiac magnetic resonance imaging (CMR) for estimation of scar volume (late-gadolinium enhancement, LGE) and iron deposition (T2*) relative to left-ventricular volume. 24-hour electrocardiogram recordings were obtained and used to examine Heart Rate (HR), QT interval (QT), QT corrected for HR (QTc) and QTc dispersion (QTcd). In a fraction of these animals (n?=?5), ultra-high resolution electroanatomical mapping (EAM) was performed, co-registered with LGE and T2* CMR and were used to characterize the spatial locations of isolated late potentials (ILPs). Results Compared to IRON- sections, IRON+ sections had higher, but no difference in. A linear relationship was found between iron content and (p<0.001), but not (p?=?0.34). Among two groups of animals (Iron (<1.5%) and Iron (>1.5%)) with similar scar volumes (7.28%±1.02% (Iron (<1.5%)) vs 8.35%±2.98% (Iron (>1.5%)), p?=?0.51) but markedly different iron volumes (1.12%±0.64% (Iron (<1.5%)) vs 2.47%±0.64% (Iron (>1.5%)), p?=?0.02), QT and QTc were elevated and QTcd was decreased in the group with the higher iron volume during the day, night and 24-hour period (p<0.05). EAMs co-registered with CMR images showed a greater tendency for ILPs to emerge from scar regions with iron versus without iron. Conclusion The electrical behavior of infarcted hearts with iron appears to be different from those without iron. Iron within infarcted zones may evolve as an arrhythmogenic substrate in the post MI period.
Wang, Xunzhang; Yang, Hsin-Jung; Tang, Richard L. Q.; Thajudeen, Anees; Shehata, Michael; Amorn, Allen M.; Liu, Enzhao; Stewart, Brian; Bennett, Nathan; Harlev, Doron; Tsaftaris, Sotirios A.; Jackman, Warren M.; Chugh, Sumeet S.; Dharmakumar, Rohan
The Angiogenic Factor Secretoneurin Induces Coronary Angiogenesis in a Model of Myocardial Infarction by Stimulation of VEGF Signaling in Endothelial Cells
Background Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is up-regulated by hypoxia and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells. Methods and Results In-vivo secretoneurin improved left ventricular function, inhibited remodeling and reduced scar formation. In the infarct border zone secretoneurin induced coronary angiogenesis as shown by increased density of capillaries and arteries. In-vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis and activated Akt and ERK in coronary endothelial cells. Effects were abrogated by a VEGF-antibody and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells and binding was blocked by heparinase indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its co-receptor neuropilin 1. In endothelial cells secretoneurin also stimulated FGF receptor-3 and IGF-1 receptor and in coronary vascular smooth muscle cells we observed stimulation of VEGF receptor-1 and FGF receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin m-RNA and protein. Conclusions Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low affinity binding sites and neuropilin 1 and stimulates further growth factor receptors like FGF receptor-3. Our in-vivo findings indicate that secretoneurin might be a promising therapeutic tool in ischemic heart disease.
Albrecht-Schgoer, Karin; Schgoer, Wilfried; Holfeld, Johannes; Theurl, Markus; Wiedemann, Dominik; Steger, Christina; Gupta, Rajesh; Semsroth, Severin; Fischer-Colbrie, Reiner; Beer, Arno G.E.; Stanzl, Ursula; Huber, Eva; Misener, Sol; Dejaco, Daniel; Kishore, Raj; Pachinger, Otmar; Grimm, Michael; Bonaros, Nikolaos; Kirchmair, Rudolf
Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration.
Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies. PMID:24200746
Formiga, Fabio R; Pelacho, Beatriz; Garbayo, Elisa; Imbuluzqueta, Izaskun; Díaz-Herráez, Paula; Abizanda, Gloria; Gavira, Juan J; Simón-Yarza, Teresa; Albiasu, Edurne; Tamayo, Esther; Prósper, Felipe; Blanco-Prieto, Maria J
Multicolor fluorescence imaging of traumatic brain injury in a cryolesion mouse model.
Traumatic brain injury is characterized by initial tissue damage, which then can lead to secondary processes such as cell death and blood-brain-barrier disruption. Clinical and preclinical studies of traumatic brain injury typically employ anatomical imaging techniques and there is a need for new molecular imaging methods that provide complementary biochemical information. Here, we assess the ability of a targeted, near-infrared fluorescent probe, named PSS-794, to detect cell death in a brain cryolesion mouse model that replicates certain features of traumatic brain injury. In short, the model involves brief contact of a cold rod to the head of a living, anesthetized mouse. Using noninvasive whole-body fluorescence imaging, PSS-794 permitted visualization of the cryolesion in the living animal. Ex vivo imaging and histological analysis confirmed PSS-794 localization to site of brain cell death. The nontargeted, deep-red Tracer-653 was validated as a tracer dye for monitoring blood-brain-barrier disruption, and a binary mixture of PSS-794 and Tracer-653 was employed for multicolor imaging of cell death and blood-brain-barrier permeability in a single animal. The imaging data indicates that at 3 days after brain cryoinjury the amount of cell death had decreased significantly, but the integrity of the blood-brain-barrier was still impaired; at 7 days, the blood-brain-barrier was still three times more permeable than before cryoinjury. PMID:22860222
Smith, Bryan A; Xie, Bang-Wen; van Beek, Ermond R; Que, Ivo; Blankevoort, Vicky; Xiao, Shuzhang; Cole, Erin L; Hoehn, Mathias; Kaijzel, Eric L; Löwik, Clemens W G M; Smith, Bradley D
Stretch in Brain Microvascular Endothelial Cells (cEND) as an In Vitro Traumatic Brain Injury Model of the Blood Brain Barrier
Due to the high mortality incident brought about by traumatic brain injury (TBI), methods that would enable one to better understand the underlying mechanisms involved in it are useful for treatment. There are both in vivo and in vitro methods available for this purpose. In vivo models can mimic actual head injury as it occurs during TBI. However, in vivo techniques may not be exploited for studies at the cell physiology level. Hence, in vitro methods are more advantageous for this purpose since they provide easier access to the cells and the extracellular environment for manipulation. Our protocol presents an in vitro model of TBI using stretch injury in brain microvascular endothelial cells. It utilizes pressure applied to the cells cultured in flexible-bottomed wells. The pressure applied may easily be controlled and can produce injury that ranges from low to severe. The murine brain microvascular endothelial cells (cEND) generated in our laboratory is a well-suited model for the blood brain barrier (BBB) thus providing an advantage to other systems that employ a similar technique. In addition, due to the simplicity of the method, experimental set-ups are easily duplicated. Thus, this model can be used in studying the cellular and molecular mechanisms involved in TBI at the BBB.
Salvador, Ellaine; Neuhaus, Winfried; Foerster, Carola
Predictive value of NT-pro BNP after acute myocardial infarction: Relation with acute and chronic infarct size and myocardial function
Aim of the studyWe sought to assess the relation of N-terminal brain natriuretic peptide (NT-pro BNP) determined on day 3 after onset of acute myocardial infarction (AMI) symptoms with acute and chronic infarct size and functional parameters assessed by cardiac magnetic resonance (CMR) imaging. Furthermore, we wanted to investigate its predictive value for recovery of myocardial function.
Agnes Mayr; Johannes Mair; Michael Schocke; Gert Klug; Kathrin Pedarnig; Bernhard Johannes Haubner; Martha Nowosielski; Thomas Grubinger; Otmar Pachinger; Bernhard Metzler
Antidepressant fluvoxamine reduces cerebral infarct volume and ameliorates sensorimotor dysfunction in experimental stroke.
The sigma-1 receptor has been reported to be associated with diverse biological activities including cellular differentiation, neuroplasticity, neuroprotection, and cognitive functioning of the brain. Fluvoxamine, one of the currently known antidepressants, is a sigma-1 receptor agonist; its effectiveness in treating acute cerebral ischemia has not been reported. We studied the in-vivo effects of this compound using an animal model of focal cerebral ischemia. Forty male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion and assigned to five treatment groups (n=8 each). Postischemic neurological deficits and infarct volume were determined 24 h after stroke-inducing surgery. Significant reductions in infarct volume (total and cortical) were found in group 2 (fluvoxamine 20 mg/kg given 6 h before and immediately after ischemic onset) and group 3 (fluvoxamine given immediately after ischemic onset and 2 h later) compared with controls. Fluvoxamine induced significant amelioration of sensorimotor dysfunction, as indicated by the scores of forelimb and hindlimb placing tests. Moreover, NE-100, a selective sigma-1 receptor antagonist, completely blocked the neuroprotective effect of fluvoxamine. The present findings suggest that the sigma-1 receptor agonist fluvoxamine reduces infarct volume and ameliorates neurological impairment even on postischemic treatment. From the clinical viewpoint, fluvoxamine may be a promising new therapeutic approach for cerebral infarction. PMID:24709917
Sato, Shinsuke; Kawamata, Takakazu; Kobayashi, Tomonori; Okada, Yoshikazu
Perinatal Hypoxic-Ischemic Brain Damage: Evolution of an Animal Model
Early research in the Vannucci laboratory prior to 1981 focused largely on brain energy metabolism in the developing rat. At that time, there was no experimental model to study the effects of perinatal hypoxia-ischemia in the rodent, despite the tremendous need to investigate the pathophysiology of perinatal asphyxial brain damage in infants. Accordingly, we developed such a model in the
Robert C. Vannucci; Susan J. Vannucci
A Probabilistic Model of Functional Brain Connectivity Network for Discovering Novel Biomarkers
Graph theoretical analyses of functional brain connectivity networks have been limited to a static view of brain activities over the entire timeseries. In this paper, we propose a new probabilistic model of the functional brain connectivity network, the strong-edge model, which incorporates the temporal fluctuation of neurodynamics. We also introduce a systematic approach to identifying biomarkers based on network characteristics that quantitatively describe the organization of the brain network. The evaluation results of the proposed strong-edge network model is quite promising. The biomarkers derived from the strong-edge model have achieved much higher prediction accuracy of 89% (ROCAUC: 0.96) in distinguishing depression subjects from healthy controls in comparison with the conventional network model (accuracy: 76%, ROC-AUC: 0.87). These novel biomarkers have the high potential of being applied clinically in diagnosing neurological and psychiatric brain diseases with noninvasive neuroimaging technologies.
Bian, Jiang; Xie, Mengjun; Topaloglu, Umit; Cisler, Josh M.
A probabilistic model of functional brain connectivity network for discovering novel biomarkers.
Graph theoretical analyses of functional brain connectivity networks have been limited to a static view of brain activities over the entire timeseries. In this paper, we propose a new probabilistic model of the functional brain connectivity network, the strong-edge model, which incorporates the temporal fluctuation of neurodynamics. We also introduce a systematic approach to identifying biomarkers based on network characteristics that quantitatively describe the organization of the brain network. The evaluation results of the proposed strong-edge network model is quite promising. The biomarkers derived from the strong-edge model have achieved much higher prediction accuracy of 89% (ROCAUC: 0.96) in distinguishing depression subjects from healthy controls in comparison with the conventional network model (accuracy: 76%, ROC-AUC: 0.87). These novel biomarkers have the high potential of being applied clinically in diagnosing neurological and psychiatric brain diseases with noninvasive neuroimaging technologies. PMID:24303289
Bian, Jiang; Xie, Mengjun; Topaloglu, Umit; Cisler, Josh M
Magnetic resonance imaging evaluation of remodeling by cardiac elastomeric tissue scaffold biomaterials in a rat model of myocardial infarction.
Grafting of elastomeric biomaterial scaffolds may offer a radical strategy for the prevention of heart failure after myocardial infarction by increasing efficacy of stem cell delivery as well as acting as mechanical restraint devices to constrain scar expansion. Biomaterials can be partially optimized in vitro, but their in vivo performance is most critical and should ideally be monitored serially and noninvasively. We used magnetic resonance imaging (MRI) to assess three scaffold materials with a range of structural moduli equal to or greater than myocardial tissue: poly(glycerol sebacate) (PGS), poly(ethyleneterephathalate)/dimer fatty acid (PED), and TiO(2)-reinforced PED (PED-TiO(2)). Patches, 1 ?cm in diameter, were grafted onto the hearts of infarcted rats, with biomaterial-free infarcted rat hearts used as controls. MRI was able to determine scaffold size and location on the heart and identified unexpectedly rapid in vivo degradation of the PGS compared with previous in vitro testing. PED patches did not withstand in vivo attachment, but the more rigid PED-TiO(2) material was detrimental to heart function, increasing chamber and scar sizes and reducing ejection fractions compared with controls. In contrast, the mechanically compatible PGS scaffold successfully reduced hypertrophy, giving it potential for limiting excessive postinfarct remodeling. PGS was unable to support systolic function, but it would be suitable for strategies to deliver cardiac stem/progenitor cells, to limit remodeling during the period of functional cellular integration, and to degrade after cell assimilation by the heart. This work has also shown for the first time the value of using MRI as a noninvasive tool for evaluating and optimizing therapeutic biomaterials in vivo. PMID:20528670
Stuckey, Daniel J; Ishii, Hikaru; Chen, Qi-Zhi; Boccaccini, Aldo R; Hansen, Ulrich; Carr, Carolyn A; Roether, Judith A; Jawad, Hedeer; Tyler, Damian J; Ali, Nadire N; Clarke, Kieran; Harding, Sian E
Imaging Long-Term Fate of Intramyocardially Implanted Mesenchymal Stem Cells in a Porcine Myocardial Infarction Model
The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET\\/CT imaging with [18F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [18F]FEAU PET\\/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation
Emerson C. Perin; Mei Tian; Frank C. Marini; Guilherme V. Silva; Yi Zheng; Fred Baimbridge; Xin Quan; Marlos R. Fernandes; Amir Gahremanpour; Daniel Young; Vincenzo Paolillo; Uday Mukhopadhyay; Agatha T. Borne; Rajesh Uthamanthil; David Brammer; James Jackson; William K. Decker; Amer M. Najjar; Michael W. Thomas; Andrei Volgin; Brian Rabinovich; Suren Soghomonyan; Hwan-Jeong Jeong; Jesse M. Rios; David Steiner; Simon Robinson; Osama Mawlawi; Tinsu Pan; Jason Stafford; Vikas Kundra; Chun Li; Mian M. Alauddin; James T. Willerson; Elizabeth Shpall; Juri G. Gelovani
Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction.
Edaravone was originally developed as a potent free radical scavenger and has been widely used to treat cerebral infarction in Japan since 2001. Several free radical scavengers have been developed and some of them have progressed to clinical trials for the treatment of cerebral infarction. One such scavenger, edaravone, has been approved by the regulatory authority in Japan for the treatment of patients with cerebral infarction. Of particular interest is the ability of edaravone to diffuse into the central nervous system in various neurologic diseases. Aside from its hydroxyl radical scavenging effect, edaravone has been found to have beneficial effects on inflammation, matrix metalloproteinases, nitric oxide production and apoptotic cell death. Concordantly, edaravone has been found to have neuroprotective effects in a number of animal models of disease, including stroke, spinal cord injury, traumatic brain injury, neurodegenerative diseases and brain tumors. The proven safety of edaravone following 9 years of use as a free radical scavenger suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans. PMID:22977573
Kikuchi, Kiyoshi; Kawahara, Ko-Ichi; Uchikado, Hisaaki; Miyagi, Naohisa; Kuramoto, Terukazu; Miyagi, Tomoya; Morimoto, Yoko; Ito, Takashi; Tancharoen, Salunya; Miura, Naoki; Takenouchi, Kazunori; Oyama, Yoko; Shrestha, Binita; Matsuda, Fumiyo; Yoshida, Yoshihiro; Arimura, Shinihiro; Mera, Kentaro; Tada, Ko-Ichi; Yoshinaga, Narimasa; Maenosono, Ryuichi; Ohno, Yoshiko; Hashiguchi, Teruto; Maruyama, Ikuro; Shigemori, Minoru
Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction
Edaravone was originally developed as a potent free radical scavenger and has been widely used to treat cerebral infarction in Japan since 2001. Several free radical scavengers have been developed and some of them have progressed to clinical trials for the treatment of cerebral infarction. One such scavenger, edaravone, has been approved by the regulatory authority in Japan for the treatment of patients with cerebral infarction. Of particular interest is the ability of edaravone to diffuse into the central nervous system in various neurologic diseases. Aside from its hydroxyl radical scavenging effect, edaravone has been found to have beneficial effects on inflammation, matrix metalloproteinases, nitric oxide production and apoptotic cell death. Concordantly, edaravone has been found to have neuroprotective effects in a number of animal models of disease, including stroke, spinal cord injury, traumatic brain injury, neurodegenerative diseases and brain tumors. The proven safety of edaravone following 9 years of use as a free radical scavenger suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.
A Drosophila model of closed head traumatic brain injury
Traumatic brain injury (TBI) is a substantial health issue worldwide, yet the mechanisms responsible for its complex spectrum of pathologies remains largely unknown. To investigate the mechanisms underlying TBI pathologies, we developed a model of TBI in Drosophila melanogaster. The model allows us to take advantage of the wealth of experimental tools available in flies. Closed head TBI was inflicted with a mechanical device that subjects flies to rapid acceleration and deceleration. Similar to humans with TBI, flies with TBI exhibited temporary incapacitation, ataxia, activation of the innate immune response, neurodegeneration, and death. Our data indicate that TBI results in death shortly after a primary injury only if the injury exceeds a certain threshold and that age and genetic background, but not sex, substantially affect this threshold. Furthermore, this threshold also appears to be dependent on the same cellular and molecular mechanisms that control normal longevity. This study demonstrates the potential of flies for providing key insights into human TBI that may ultimately provide unique opportunities for therapeutic intervention.
Katzenberger, Rebeccah J.; Loewen, Carin A.; Wassarman, Douglas R.; Petersen, Andrew J.; Ganetzky, Barry; Wassarman, David A.
Local Model of Arteriovenous Malformation of the Human Brain
NASA Astrophysics Data System (ADS)
Vascular diseases of the human brain are one of the reasons of deaths and people's incapacitation not only in Russia, but also in the world. The danger of an arteriovenous malformation (AVM) is in premature rupture of pathological vessels of an AVM which may cause haemorrhage. Long-term prognosis without surgical treatment is unfavorable. The reduced impact method of AVM treatment is embolization of a malformation which often results in complete obliteration of an AVM. Pre-surgical mathematical modeling of an arteriovenous malformation can help surgeons with an optimal sequence of the operation. During investigations, the simple mathematical model of arteriovenous malformation is developed and calculated, and stationary and non-stationary processes of its embolization are considered. Various sequences of embolization of a malformation are also considered. Calculations were done with approximate steady flow on the basis of balanced equations derived from conservation laws. Depending on pressure difference, a fistula-type AVM should be embolized at first, and then small racemose AVMs are embolized. Obtained results are in good correspondence with neurosurgical AVM practice.
Nadezhda Telegina, Ms; Aleksandr Chupakhin, Mr; Aleksandr Cherevko, Mr
A Drosophila model of closed head traumatic brain injury.
Traumatic brain injury (TBI) is a substantial health issue worldwide, yet the mechanisms responsible for its complex spectrum of pathologies remains largely unknown. To investigate the mechanisms underlying TBI pathologies, we developed a model of TBI in Drosophila melanogaster. The model allows us to take advantage of the wealth of experimental tools available in flies. Closed head TBI was inflicted with a mechanical device that subjects flies to rapid acceleration and deceleration. Similar to humans with TBI, flies with TBI exhibited temporary incapacitation, ataxia, activation of the innate immune response, neurodegeneration, and death. Our data indicate that TBI results in death shortly after a primary injury only if the injury exceeds a certain threshold and that age and genetic background, but not sex, substantially affect this threshold. Furthermore, this threshold also appears to be dependent on the same cellular and molecular mechanisms that control normal longevity. This study demonstrates the potential of flies for providing key insights into human TBI that may ultimately provide unique opportunities for therapeutic intervention. PMID:24127584
Katzenberger, Rebeccah J; Loewen, Carin A; Wassarman, Douglas R; Petersen, Andrew J; Ganetzky, Barry; Wassarman, David A
Using computational models to relate structural and functional brain connectivity
Modern imaging methods allow a non-invasive assessment of both structural and functional brain connectivity. This has lead to the identification of disease-related alterations affecting functional connectivity. The mechanism of how such alterations in functional connectivity arise in a structured network of interacting neural populations is as yet poorly understood. Here we use a modeling approach to explore the way in which this can arise and to highlight the important role that local population dynamics can have in shaping emergent spatial functional connectivity patterns. The local dynamics for a neural population is taken to be of the Wilson–Cowan type, whilst the structural connectivity patterns used, describing long-range anatomical connections, cover both realistic scenarios (from the CoComac database) and idealized ones that allow for more detailed theoretical study. We have calculated graph–theoretic measures of functional network topology from numerical simulations of model networks. The effect of the form of local dynamics on the observed network state is quantified by examining the correlation between structural and functional connectivity. We document a profound and systematic dependence of the simulated functional connectivity patterns on the parameters controlling the dynamics. Importantly, we show that a weakly coupled oscillator theory explaining these correlations and their variation across parameter space can be developed. This theoretical development provides a novel way to characterize the mechanisms for the breakdown of functional connectivity in diseases through changes in local dynamics.
Hlinka, Jaroslav; Coombes, Stephen
Characterization and Application of a Large Animal Model of Penetrating Ballistic Brain Injury (PBBI).
National Technical Information Service (NTIS)
The Purpose of the proposal titled Characterization and Application of a Large Animal Model of Penetrating Ballistic Brain Injury (PBBI) is to develop a large animal model with military relevance. Of military casualties with moderate to severe traumatic b...
C. E. Wade
Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke
Background and purpose The role of autophagy in response to ischemic stroke has been confusing with reports that both enhancement and inhibition of autophagy decrease infarct size and improve post-stroke outcomes. We sought to clarify this by comparing pharmacologic modulation of autophagy in two clinically relevant murine models of stroke. Methods We used rapamycin to induce autophagy, and chloroquine to block completion of autophagy, by treating mice immediately after stroke and at 24 hours post-stroke in two different models; permanent Middle Cerebral Artery Ligation (MCAL), which does not allow for reperfusion of distal trunk of middle cerebral artery, and Embolic Clot Middle Cerebral Artery Occlusion (eMCAO) which allows for a slow reperfusion similar to that seen in most human stroke patients. Outcome measures at 48 hours post-stroke included infarct size analysis, behavioral assessment using Bederson neurological scoring, and survival. Results Chloroquine treatment reduced the lesion size by approximately 30% and was significant only in the eMCAO model, where it also improved the neurological score, but did not increase survival. Rapamycin reduced lesion size by 44% and 50% in the MCAL and eMCAO models, respectively. Rapamycin also improved the neurological score to a greater degree than chloroquine and improved survival. Conclusions While both inhibition and enhancement of autophagy by pharmacological intervention decreased lesion size and improved neurological scores, the enhancement with rapamycin showed a greater degree of improvement in outcomes as well as in survival. The protective action seen with chloroquine may be in part due to off-target effects on apoptosis separate from blocking lysosomal activity in autophagy. We conclude pharmacologic induction of autophagy is more advantageous than its blockade in physiologically-relevant permanent and slow reperfusion stroke models.
Approaches to Modelling the Dynamical Activity of Brain Function Based on the Electroencephalogram
NASA Astrophysics Data System (ADS)
The brain is arguably the quintessential complex system as indicated by the patterns of behaviour it produces. Despite many decades of concentrated research efforts, we remain largely ignorant regarding the essential processes that regulate and define its function. While advances in functional neuroimaging have provided welcome windows into the coarse organisation of the neuronal networks that underlie a range of cognitive functions, they have largely ignored the fact that behaviour, and by inference brain function, unfolds dynamically. Modelling the brain's dynamics is therefore a critical step towards understanding the underlying mechanisms of its functioning. To date, models have concentrated on describing the sequential organisation of either abstract mental states (functionalism, hard AI) or the objectively measurable manifestations of the brain's ongoing activity (rCBF, EEG, MEG). While the former types of modelling approach may seem to better characterise brain function, they do so at the expense of not making a definite connection with the actual physical brain. Of the latter, only models of the EEG (or MEG) offer a temporal resolution well matched to the anticipated temporal scales of brain (mental processes) function. This chapter will outline the most pertinent of these modelling approaches, and illustrate, using the electrocortical model of Liley et al, how the detailed application of the methods of nonlinear dynamics and bifurcation theory is central to exploring and characterising their various dynamical features. The rich repertoire of dynamics revealed by such dynamical systems approaches arguably represents a critical step towards an understanding of the complexity of brain function.
Liley, David T. J.; Frascoli, Federico
Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study
Background The detection of early neuropsychological abnormalities as precursors of cognitive decline of vascular origin in patients with lacunar stroke is a subject of increasing interest. The objective of this study was to assess whether there were differences in the performance of a battery of neuropsychological tests in first-ever lacunar stroke patients with and without associated silent multiple lacunar infarctions found incidentally on the brain magnetic resonance imaging (MRI) scan. Methods A total of 72 consecutive patients with first-ever lacunar infarction were studied 1 month after stroke. All patients underwent a comprehensive neuropsychological evaluation, which included the California Verbal Learning Test (CVLT), Phonetic Verbal Fluency Test (PMR), Semantic Verbal Fluency Test (category "animals"), Digit Span Forward and Backward from the Wechsler Adult Intelligence Scale (WAIS-III), and Mini-Mental State Examination (MMSE). Results A total of 38 patients (52.7%) had silent multiple lacunar infarcts, with corona radiata as the most frequent topography (P?0.023). White matter hyperintensities (leukoaraiosis) were observed in 81.1% of patients with silent multiple lacunar infarcts and in 50% with a single lacunar infarction (P?0.007). Patients in both groups showed similar scores in the MMSE, but those with associated silent lacunar infarctions showed a poorer performance in the semantic fluency test (P?0.008) and in short delayed verbal memory (P?0.001). In both cases, however, leukoaraiosis was not statistically significant in multivariate linear regression models adjusted by confounding covariates. In these models, multiple silent lacunar infarctions and education were independent predictors of poor performance in the semantic fluency test and in short delayed verbal memory. Conclusions The presence of silent multiple lacunar infarctions documented on brain MRI scans in patients with first-ever lacunar stroke was associated with mild neuropsychological abnormalities, particularly in the performance of executive functions (semantic fluency) and short delayed verbal memory. According to these findings, in the initial stages of small vessel disease, mild neuropsychological abnormalities appear to be related to lacunes rather than to leukoaraiosis or perivascular hyperintensities of vascular cause.
Heuristic modeling of drug delivery to malignant brain tumors
It is apparent that chemotherapy against malignant brain tumors is generally ineffective. While some agents are more effective than others, none appreciably alters the clinical course of and the poor prognosis for patients with brain tumors. Even though new and more effective agents are being or will be developed, chemotherapy depends as much on the delivery of drug as it
Victor A. Levin; Clifford S. Patlak; Herbert D. Landahl
Quantitative genetic modeling of variation in human brain morphology
The degree to which individual variation in brain structure in humans is genetically or environmentally determined is as yet not well understood. We studied the brains of 54 monozygotic (33 male, 21 female) and 58 dizygotic (17 male, 20 female, 21 opposite sex) pairs of twins and 34 of their full siblings (19 male, 15 female) by means of high
W. F. C. Baare; H. E. Hulshoff-Poll; Dorret I. Boomsma; Daniëlle Posthuma; Geus de E. J. C; H. G. Snack; Haren van N. E. M; Oel van C. J; René S. Kahn
Brain Injury Prediction for Vulnerable Road Users in Vehicle Accidents Using Mathematical Models
\\u000a The objective was to analyze the brain tissue responses and predict head-brain injuries. Accident reconstructions were carried\\u000a out by using MBS and FE models based on real-life accident investigation. Thirty cases of VRUs accidents were selected from\\u000a IVAC and GIDAS databases for simulation study. The brain injury parameters were calculated in terms of coup\\/countercoup pressure,\\u000a von Mises and maximum shear
Y. Chen; Y. Peng; F. Li; J. K. Yang; D. Otte
Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats.
One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration-time profiles of brain ECF, CSF(LV), and CSF(CM) indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC(0-240) ratios of 121%, 28%, and 35% for brain ECF, CSF(LV), and CSF(CM), respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations. PMID:22588644
Westerhout, Joost; Ploeger, Bart; Smeets, Jean; Danhof, Meindert; de Lange, Elizabeth C M
Can pulsed ultrasound increase tissue damage during ischemia? A study of the effects of ultrasound on infarcted and non-infarcted myocardium in anesthetized pigs
BACKGROUND: The same mechanisms by which ultrasound enhances thrombolysis are described in connection with non-beneficial effects of ultrasound. The present safety study was therefore designed to explore effects of beneficial ultrasound characteristics on the infarcted and non-infarcted myocardium. METHODS: In an open chest porcine model (n = 17), myocardial infarction was induced by ligating a coronary diagonal branch. Pulsed ultrasound
Göran K Olivecrona; Bjarne Madsen Härdig; Anders Roijer; Mattias Block; Edgars Grins; Hans W Persson; Leif Johansson; Bertil Olsson
Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase
BACKGROUND AND PURPOSES Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2. EXPERIMENTAL APPROACH Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia). KEY RESULTS In male rats with tMCAO, HYDAMTIQ (0.1–10 mg·kg?1) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO. CONCLUSION AND IMPLICATIONS Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits.
Moroni, F; Cozzi, A; Chiarugi, A; Formentini, L; Camaioni, E; Pellegrini-Giampietro, DE; Chen, Y; Liang, S; Zaleska, MM; Gonzales, C; Wood, A; Pellicciari, R
Apelin-13 protects the brain against ischemic reperfusion injury and cerebral edema in a transient model of focal cerebral ischemia.
The adipocytokine apelin is a peptide that was isolated from a bovine stomach for the first time. This peptide and its receptor are abundantly expressed in the nervous and cardiovascular systems. According to previous studies, apelin-13 protects cardiomyocytes from ischemic injury as well as apoptosis. In addition, this peptide has a neuroprotective effect on hippocampal and cultured mouse cortical neurons against NMDA receptor-mediated excitotoxicity. The present study was conducted to determine whether apelin-13 provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and apelin-13 at doses of 25, 50, and 100 ?g were injected intracerebroventriculary (ICV) at the beginning of ischemia. Infarct volume ,brain edema, motor dysfunction, and apoptosis were assessed 24 h after MCAO. Treatment with apelin-13 at doses of 50 and 100 ?g ICV markedly reduced total infarct volumes by 45 and 55 %, respectively (P?0.001), but injection of apelin at lower dose (25 ?g) did not change infarct volume significantly (P?>?0.05). In addition, apelin-13 at doses of 50 and 100 ?g reduced brain edema (P?0.001) and inhibited apoptosis by decreasing caspase-3 activation (P?0.001). Apelin-13 did not significantly change neurological dysfunction (P?>?0.05). PMID:22638858
Khaksari, Mehdi; Aboutaleb, Nahid; Nasirinezhad, Farinaz; Vakili, Abedin; Madjd, Zahra
Endocannabinoids and traumatic brain injury
Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the 'on-demand' synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7
Shohami, Esther; Cohen-Yeshurun, Ayelet; Magid, Lital; Algali, Merav; Mechoulam, Raphael
Usefulness of MRI to Differentiate Between Temporary and Long-Term Coronary Artery Occlusion in a Minimally Invasive Model of Experimental Myocardial Infarction
The surgical technique employed to determine an experimental ischemic damage is a major factor in the subsequent process of myocardial scar development. We set out to establish a minimally invasive porcine model of myocardial infarction using cardiac contrast-enhanced magnetic resonance imaging (ce-MRI) as the basic diagnostic tool. Twenty-seven domestic pigs were randomized to either temporary or permanent occlusion of the left anterior descending artery (LAD). Temporary occlusion was achieved by inflation of a percutaneous balloon in the left anterior descending artery directly beyond the second diagonal branch. Occlusion was maintained for 30 or 45 min, followed by reperfusion. Permanent occlusion was achieved via thrombin injection. Thirteen animals died peri- or postinterventionally due to arrhythmias. Fourteen animals survived the 30-min ischemia (four animals; group 1), the 45-min ischemia (six animals; group 2), or the permanent occlusion (4 animals; group 3). Coronary angiography and ce-MRI were performed 8 weeks after coronary occlusion to document the coronary flow grade and the size of myocardial scar tissue. The LAD was patent in all animals in groups 1 and 2, with normal TIMI flow; in group 3 animals, the LAD was totally occluded. Fibrosis of the left ventricle in group 1 (4.9 {+-} 4.4%; p = 0.008) and group 2 (9.4 {+-} 2.9%; p = 0.05) was significantly lower than in group 3 (14.5 {+-} 3.9%). Wall thickness of the ischemic area was significantly lower in group 3 versus group 1 and group 2 (2.9 {+-} 0.3, 5.9 {+-} 0.7, and 6.1 {+-} 0.7 mm; p = 0.005). The extent of late enhancement of the left ventricle was also significantly higher in group 3 (16.9 {+-} 2.1%) compared to group 1 (5.3 {+-} 5.4%; p = 0.003) and group 2 (9.7 {+-} 3.4%, p = 0.013). In conclusion, the present model of minimally invasive infarction coupled with ce-MRI may represent a useful alternative to the open chest model for studies of myocardial infarction and scar development.
Abegunewardene, Nico, E-mail: email@example.com; Vosseler, Markus; Gori, Tommaso [Johannes Gutenberg-University Mainz, Second Medical Clinic (Germany); Hoffmann, Nico [Johannes Gutenberg-University Mainz, Section of Medical Physics (Germany); Schmidt, Kai-Helge; Becker, Dietmar [Johannes Gutenberg-University Mainz, Second Medical Clinic (Germany); Kreitner, Karl-Friedrich [Johannes Gutenberg-University Mainz, Clinic for Radiology (Germany); Petersen, Steffen E. [John Radcliffe Hospital, University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR) (United Kingdom); Schreiber, Laura M. [Johannes Gutenberg-University Mainz, Section of Medical Physics (Germany); Horstick, Georg; Muenzel, Thomas [Johannes Gutenberg-University Mainz, Second Medical Clinic (Germany)
The Brain's Router: A Cortical Network Model of Serial Processing in the Primate Brain
The human brain efficiently solves certain operations such as object recognition and categorization through a massively parallel network of dedicated processors. However, human cognition also relies on the ability to perform an arbitrarily large set of tasks by flexibly recombining different processors into a novel chain. This flexibility comes at the cost of a severe slowing down and a seriality
Ariel Zylberberg; Diego Fernández Slezak; Pieter R. Roelfsema; Stanislas Dehaene; Mariano Sigman
Immediate, but Not Delayed, Microsurgical Skull Reconstruction Exacerbates Brain Damage in Experimental Traumatic Brain Injury Model
Moderate to severe traumatic brain injury (TBI) often results in malformations to the skull. Aesthetic surgical maneuvers may offer normalized skull structure, but inconsistent surgical closure of the skull area accompanies TBI. We examined whether wound closure by replacement of skull flap and bone wax would allow aesthetic reconstruction of the TBI-induced skull damage without causing any detrimental effects to
Loren E. Glover; Naoki Tajiri; Tsz Lau; Yuji Kaneko; Harry van Loveren; Cesario V. Borlongan
Allostasis and the Human Brain: Integrating Models of Stress From the Social and Life Sciences
We draw on the theory of allostasis to develop an integrative model of the current stress process that highlights the brain as a dynamically adapting interface between the changing environment and the biological self. We review evidence that the core emotional regions of the brain constitute the primary mediator of the well-established association between stress and health, as well as
Barbara L. Ganzel; Pamela A. Morris; Elaine Wethington
The effect of transcranial magnetic stimulation of rat brain on behavioral models of depression
Magnetic stimulation of the brain in unanesthetized humans and animals can painlessly induce motor movements and has recently been reported to have antidepressant properties. In behavioral models of depression and electroconvulsive therapy including enhancement of apormorphine-induced stereotypy, reduction of immobility in the Porsolt swim test increases in seizure threshold for subsequent stimulation, magnetic stimulation of rat brain had effects similar
Amos Fleischmann; Katrina Prolov; Jacob Abarbanel; R. H. Belmaker
PLATO: Data-oriented approach to collaborative large-scale brain system modeling
The brain is a complex information processing system, which can be divided into sub-systems, such as the sensory organs, functional areas in the cortex, and motor control systems. In this sense, most of the mathematical models developed in the field of neuroscience have mainly targeted a specific sub-system. In order to understand the details of the brain as a whole,
Takayuki Kannon; Keiichiro Inagaki; Nilton L. Kamiji; Kouji Makimura; Shiro Usui
Mesenchymal Stem Cell Transplantation Enhancement in Myocardial Infarction Rat Model under Ultrasound Combined with Nitric Oxide Microbubbles
Objective This study evaluated the effects of ultrasound combined with the homemade nitric oxide (NO) micro-bubble destruction on the in vitro proliferation, apoptosis, and migration of mesenchymal stem cells (MSCs). Furthermore, we studied whether or not irradiation of the NO micro-bubble combined with bone-marrow derived MSC infusion had a better effect on treating myocardial infarction. The possible mechanism of MSC delivery into the infarcted myocardium was also investigated. Methods The murine bone marrow-derived MSCs were isolated, cultured, irradiated, and combined with different concentrations of NO microbubbles. MTT proliferation assay, annexin V-FITC apoptosis detection, migration assay, and RT-PCR were performed 24 h after the irradiation. The NO micro-bubbles was a intravenously injected, followed by the infusion of MSCs, which were labeled by CM-Dil. Myocardium was harvested 48 h later and the distribution of MSCs was observed by laser scanning confocal microscope after frozen sectioning. Echocardiography, histological examination, RT-PCR, and western blotting were performed four weeks after the cell transplantation. Results Ultrasound combined with 1:70 NO micro-bubbles had no significant impact on the proliferation or apoptosis of MSCs. Transwell chamber findings demonstrated that MSCs migrated more efficiently in group that underwent ultrasound combined with 1:70 NO micro-bubbles. The Real-time PCR results indicated that the expression of CXCR4 was much higher in the group undergoing ultrasound combined with 1:70 NO micro-bubbles. The normalized fluorescence intensity greatly increased in the group of US+NO micro-bubbles and the cardiac function was also markedly improved. Immunohistochemical staining showed that the capillary density was much greater in the group of US+NO micro-bubbles as compared to that of the other groups. RT-PCR and western blotting also revealed a higher SDF-1 and VEGF expression in the group of US+NO micro-bubbles. Conclusions NO micro-bubbles could be used in the cell transplantation, which efficiently promoted the MSC homing into the infarcted myocardium.
Tong, Jiayi; Ding, Jiandong; Shen, Xiangbo; Chen, Long; Bian, Yeping; Ma, Genshan; Yao, Yuyu; Yang, Fang
NeuroGPS: automated localization of neurons for brain circuits using L1 minimization model
Drawing the map of neuronal circuits at microscopic resolution is important to explain how brain works. Recent progresses in fluorescence labeling and imaging techniques have enabled measuring the whole brain of a rodent like a mouse at submicron-resolution. Considering the huge volume of such datasets, automatic tracing and reconstruct the neuronal connections from the image stacks is essential to form the large scale circuits. However, the first step among which, automated location the soma across different brain areas remains a challenge. Here, we addressed this problem by introducing L1 minimization model. We developed a fully automated system, NeuronGlobalPositionSystem (NeuroGPS) that is robust to the broad diversity of shape, size and density of the neurons in a mouse brain. This method allows locating the neurons across different brain areas without human intervention. We believe this method would facilitate the analysis of the neuronal circuits for brain function and disease studies.
Quan, Tingwei; Zheng, Ting; Yang, Zhongqing; Ding, Wenxiang; Li, Shiwei; Li, Jing; Zhou, Hang; Luo, Qingming; Gong, Hui; Zeng, Shaoqun
NeuroGPS: automated localization of neurons for brain circuits using L1 minimization model
NASA Astrophysics Data System (ADS)
Drawing the map of neuronal circuits at microscopic resolution is important to explain how brain works. Recent progresses in fluorescence labeling and imaging techniques have enabled measuring the whole brain of a rodent like a mouse at submicron-resolution. Considering the huge volume of such datasets, automatic tracing and reconstruct the neuronal connections from the image stacks is essential to form the large scale circuits. However, the first step among which, automated location the soma across different brain areas remains a challenge. Here, we addressed this problem by introducing L1 minimization model. We developed a fully automated system, NeuronGlobalPositionSystem (NeuroGPS) that is robust to the broad diversity of shape, size and density of the neurons in a mouse brain. This method allows locating the neurons across different brain areas without human intervention. We believe this method would facilitate the analysis of the neuronal circuits for brain function and disease studies.
Quan, Tingwei; Zheng, Ting; Yang, Zhongqing; Ding, Wenxiang; Li, Shiwei; Li, Jing; Zhou, Hang; Luo, Qingming; Gong, Hui; Zeng, Shaoqun
NeuroGPS: automated localization of neurons for brain circuits using L1 minimization model.
Drawing the map of neuronal circuits at microscopic resolution is important to explain how brain works. Recent progresses in fluorescence labeling and imaging techniques have enabled measuring the whole brain of a rodent like a mouse at submicron-resolution. Considering the huge volume of such datasets, automatic tracing and reconstruct the neuronal connections from the image stacks is essential to form the large scale circuits. However, the first step among which, automated location the soma across different brain areas remains a challenge. Here, we addressed this problem by introducing L1 minimization model. We developed a fully automated system, NeuronGlobalPositionSystem (NeuroGPS) that is robust to the broad diversity of shape, size and density of the neurons in a mouse brain. This method allows locating the neurons across different brain areas without human intervention. We believe this method would facilitate the analysis of the neuronal circuits for brain function and disease studies. PMID:23546385
Quan, Tingwei; Zheng, Ting; Yang, Zhongqing; Ding, Wenxiang; Li, Shiwei; Li, Jing; Zhou, Hang; Luo, Qingming; Gong, Hui; Zeng, Shaoqun
How well can in vitro brain microcapillary endothelial cell models predict rodent in vivo blood-brain barrier permeability?
The object of the study was to improve the blood-brain barrier (BBB) permeability in vitro-invivo correlations (IVIVC) between in vitro brain microcapillary endothelial cell (BMEC) models and the well-tested rodent in situ brain perfusion technique. Porcine, bovine, rat, mouse, and human in vitro BMEC apparent permeability values, P(e), (14 studies from several laboratories: 229 P(e), 60 compounds) were analyzed by a novel biophysical model encoded in a weighted nonlinear regression procedure to determine the aqueous boundary layer (ABL) thickness and the paracellular parameters: porosity-pathlength (dual-pore model), pore radius, and water channel electrostatic potential. The refined parameters were then used to transform the P(e) values into the transendothelial permeability (P(c)) values. Porcine BMEC mono-culture models showed tight junctions comparable to those reported in several Caco-2 studies. Bovine cultures were somewhat leakier. In the human primary cultured cell and the hCMEC/D3 cell line data, IVIVC based on P(e) values has r(2) = 0.14. With transformed permeability values, r(2) = 0.58. Comparable improvements were found in the other species data. By using the in vitro transendothelial P(c) values in place of the apparent P(e) values, IVIVC can be dramatically improved. PMID:21514381
Avdeef, Alex
Epileptic Seizures after Thromboembolic Cerebral Infarcts: A Positron Emission Tomographic Study
In the present positron emission tomographic (PET) study regional blood flow and oxygen metabolism were compared in the infarcted and remote brain areas of two comparable groups of patients with a thromboembolic infarct the territory of the middle cerebral artery. One group of patients had developed postinfarction seizures. PET scan showed a more decreased regional blood flow (rCBF) and oxygen
J. De Reuck; D. Decoo; L. Algoed; P. Boon; G. Van Maele; I. Lemahieu; K. Strijckmans; P. Goethals
Parallel optimization of tumor model parameters for fast registration of brain tumor images
NASA Astrophysics Data System (ADS)
The motivation of this work is to register MR brain tumor images with a brain atlas. Such a registration method can make possible the pooling of data from different brain tumor patients into a common stereotaxic space, thereby enabling the construction of statistical brain tumor atlases. Moreover, it allows the mapping of neuroanatomical brain atlases into the patient's space, for segmenting brains and thus facilitating surgical or radiotherapy treatment planning. However, the methods developed for registration of normal brain images are not directly applicable to the registration of a normal atlas with a tumor-bearing image, due to substantial dissimilarity and lack of equivalent image content between the two images, as well as severe deformation or shift of anatomical structures around the tumor. Accordingly, a model that can simulate brain tissue death and deformation induced by the tumor is considered to facilitate the registration. Such tumor growth simulation models are usually initialized by placing a small seed in the normal atlas. The shape, size and location of the initial seed are critical for achieving topological equivalence between the atlas and patient's images. In this study, we focus on the automatic estimation of these parameters, pertaining to tumor simulation. In particular, we propose an objective function reflecting feature-based similarity and elastic stretching energy and optimize it with APPSPACK (Asynchronous Parallel Pattern Search), for achieving significant reduction of the computational cost. The results indicate that the registration accuracy is high in areas around the tumor, as well as in the healthy portion of the brain.
Zacharaki, Evangelia I.; Hogea, Cosmina S.; Shen, Dinggang; Biros, George; Davatzikos, Christos
National Technical Information Service (NTIS)
Several goals were achieved during this period of 9 months, both in the experimental laboratory and in patients with acute myocardial infarction. (1) A study of the effects of aprotinin administration on myocardial ischemic injury, subsequent necrosis and...
E. Braunwald
3D brain atlas reconstructor service--online repository of three-dimensional models of brain structures.
Brain atlases are important tools of neuroscience. Traditionally prepared in paper book format, more and more commonly they take digital form which extends their utility. To simplify work with different atlases, to lay the ground for developing universal tools which could abstract from the origin of the atlas, efforts are being made to provide common interfaces to these atlases. 3D Brain Atlas Reconstructor service (3dBARs) described here is a repository of digital representations of different brain atlases in CAF format which we recently proposed and a repository of 3D models of brain structures. A graphical front-end is provided for creating and viewing the reconstructed models as well as the underlying 2D atlas data. An application programming interface (API) facilitates programmatic access to the service contents from other websites. From a typical user's point of view, 3dBARs offers an accessible way to mine publicly available atlasing data with a convenient browser based interface, without the need to install extra software. For a developer of services related to brain atlases, 3dBARs supplies mechanisms for enhancing functionality of other software. The policy of the service is to accept new datasets as delivered by interested parties and we work with the researchers who obtain original data to make them available to the neuroscience community at large. The functionality offered by the 3dBARs situates it at the core of present and future general atlasing services tying it strongly to the global atlasing neuroinformatics infrastructure. PMID:23943281
Majka, Piotr; Kowalski, Jakub M; Chlodzinska, Natalia; Wójcik, Daniel K
Cooling for Acute Ischemic Brain Damage (COOL AID) An Open Pilot Study of Induced Hypothermia in Acute Ischemic Stroke
Background and Purpose—Hypothermia is effective in improving outcome in experimental models of brain infarction. We studied the feasibility and safety of hypothermia in patients with acute ischemic stroke treated with thrombolysis. Methods—An open study design was used. All patients presented with major ischemic stroke (National Institutes of Health Stroke Scale (NIHSS) score .15) within 6 hours of onset. After informed
Derk W. Krieger; Michael A. De Georgia; Alex Abou-Chebl; John C. Andrefsky; Cathy A. Sila; Irene L. Katzan; Marc R. Mayberg; Anthony J. Furlan
Head and brain response to blast using sagittal and transverse finite element models.
Mild traumatic brain injury caused by blast exposure from Improvised Explosive Devices has become increasingly prevalent in modern conflicts. To investigate head kinematics and brain tissue response in blast scenarios, two solid hexahedral blast-head models were developed in the sagittal and transverse planes. The models were coupled to an Arbitrary Lagrangian-Eulerian model of the surrounding air to model blast-head interaction, for three blast load cases (5 kg C4 at 3, 3.5 and 4 m). The models were validated using experimental kinematic data, where predicted accelerations were in good agreement with experimental tests, and intracranial pressure traces at four locations in the brain, where the models provided good predictions for frontal, temporal and parietal, but underpredicted pressures at the occipital location. Brain tissue response was investigated for the wide range of constitutive properties available. The models predicted relatively low peak principal brain tissue strains from 0.035 to 0.087; however, strain rates ranged from 225 to 571 s-1. Importantly, these models have allowed us to quantify expected strains and strain rates experienced in brain tissue, which can be used to guide future material characterization. These computationally efficient and predictive models can be used to evaluate protection and mitigation strategies in future analysis. PMID:24293124
Singh, Dilaver; Cronin, Duane S; Haladuick, Tyler N
Association of Cardiac Annular / Valvular Calcification with Brain Findings on Magnetic Resonance Imaging in Community Dwelling Older Adults: the Cardiovascular Health Study
Objective The objective of this study is to investigate the association of mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVSc) with covert magnetic resonance imaging (MRI)-defined brain infarcts. Background Clinically silent brain infarcts defined by MRI are associated with increased risk of cognitive decline, dementia, and future overt stroke. Left sided cardiac valvular / annular calcifications are suspected as risk factors for clinical ischemic stroke. Methods 2,680 Cardiovascular Health Study participants without clinical history of stroke or transient ischemic attack underwent both brain MRI (1992–93) and echocardiography (1994–95). Results The mean age of the participants was 74.5 years ± 4.8 and 39.3% were men. The presence of any annular / valvular calcification (either MAC or AAC or AVSc), MAC alone, or AAC alone were significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, HDL-cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular / valve calcification remained associated with covert brain infarcts [RR 1.24 (95% CI 1.05, 1.47)]. The degree of annular / valvular calcification severity showed a direct relation with the presence of covert MRI findings. Conclusion Left-sided cardiac annular / valvular calcification are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening on the progression of annular / valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk of cognitive impairment and future stroke.
Rodriguez, Carlos J.; Bartz, Traci M.; Longstreth, W.T.; Kizer, Jorge R.; Barasch, Eddy; Lloyd-Jones, Donald M.; Gottdiener, John S.
Aetiological considerations and risk factors for multi-infarct dementia.
One hundred and seventy five multi-infarct dementia (MID) patients were evaluated for risk factors for stroke as well as for the types of cerebrovascular lesions that were present. The incidence of associated risk factors for stroke were as follows: hypertension (66%), heart disease (47%), cigarette smoking (37%), diabetes mellitus (20%), moderate alcohol consumption (19%) and hyperlipidaemia (21%). The most frequently occurring type of lesions were multiple lacunar infarctions of the brain (43%). These were combined with other types of stroke in an additional 21%. Atherosclerotic occlusive disease of the carotid and vertebrobasilar arteries occurred alone in 18% and was associated with other types of stroke in another 25%. Embolic cerebral infarctions were present alone in 8% and were combined with other types of stroke in 15%. MID was more frequent in men (62%) than women (p less than 0.002). Mean bihemispheric gray matter cerebral blood flow (CBF) values showed a fluctuating course and when results were pooled and compared between different types of MID, extracranial occlusive disease and/or multiple lacunar infarctions resulted in lowest CBF values. The location of cerebral infarctions was more importantly related to cognitive impairments than was the total volume of infarcted brain. Mortality rates among 125 MID patients followed for 31 months has been 5%. Correct clinical classification of the types of cerebrovascular lesions was confirmed in three necropsied cases.
Meyer, J S; McClintic, K L; Rogers, R L; Sims, P; Mortel, K F
Brain Slices as Models for Neurodegenerative Disease and Screening Platforms to Identify Novel Therapeutics
Recent improvements in brain slice technology have made this biological preparation increasingly useful for examining pathophysiology of brain diseases in a tissue context. Brain slices maintain many aspects of in vivo biology, including functional local synaptic circuitry with preserved brain architecture, while allowing good experimental access and precise control of the extracellular environment, making them ideal platforms for dissection of molecular pathways underlying neuronal dysfunction. Importantly, these ex vivo systems permit direct treatment with pharmacological agents modulating these responses and thus provide surrogate therapeutic screening systems without recourse to whole animal studies. Virus or particle mediated transgenic expression can also be accomplished relatively easily to study the function of novel genes in a normal or injured brain tissue context. In this review we will discuss acute brain injury models in organotypic hippocampal and co-culture systems and the effects of pharmacological modulation on neurodegeneration. The review will also cover the evidence of developmental plasticity in these ex vivo models, demonstrating emergence of injury-stimulated neuronal progenitor cells, and neurite sprouting and axonal regeneration following pathway lesioning. Neuro-and axo-genesis are emerging as significant factors contributing to brain repair following many acute and chronic neurodegenerative disorders. Therefore brain slice models may provide a critical contextual experimental system to explore regenerative mechanisms in vitro.
Cho, Seongeun; Wood, Andrew; Bowlby, Mark R
Quantitative imaging methods for the development and validation of brain biomechanics models.
Rapid deformation of brain tissue in response to head impact or acceleration can lead to numerous pathological changes, both immediate and delayed. Modeling and simulation hold promise for illuminating the mechanisms of traumatic brain injury (TBI) and for developing preventive devices and strategies. However, mathematical models have predictive value only if they satisfy two conditions. First, they must capture the biomechanics of the brain as both a material and a structure, including the mechanics of brain tissue and its interactions with the skull. Second, they must be validated by direct comparison with experimental data. Emerging imaging technologies and recent imaging studies provide important data for these purposes. This review describes these techniques and data, with an emphasis on magnetic resonance imaging approaches. In combination, these imaging tools promise to extend our understanding of brain biomechanics and improve our ability to study TBI in silico. PMID:22655600
Bayly, Philip V; Clayton, Erik H; Genin, Guy M
Quantitative Imaging Methods for the Development and Validation of Brain Biomechanics Models
Rapid deformation of brain tissue in response to head impact or acceleration can lead to numerous pathological changes, both immediate and delayed. Modeling and simulation hold promise for illuminating the mechanisms of traumatic brain injury (TBI) and for developing preventive devices and strategies. However, mathematical models have predictive value only if they satisfy two conditions. First, they must capture the biomechanics of the brain as both a material and a structure, including the mechanics of brain tissue and its interactions with the skull. Second, they must be validated by direct comparison with experimental data. Emerging imaging technologies and recent imaging studies provide important data for these purposes. This review describes these techniques and data, with an emphasis on magnetic resonance imaging approaches. In combination, these imaging tools promise to extend our understanding of brain biomechanics and improve our ability to study TBI in silico.
Bayly, Philip V.; Clayton, Erik H.; Genin, Guy M.
Novel Brain Arteriovenous Malformation Mouse Models for Type 1 Hereditary Hemorrhagic Telangiectasia
Endoglin (ENG) is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM) than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng2fl/2fl mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng2fl/2fl mice: R26CreER (all cell types after tamoxifen treatment), SM22?-Cre (smooth muscle and endothelial cell) and LysM-Cre (lysozyme M-positive macrophage). An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) was injected into the brain to induce focal angiogenesis. We found that SM22?-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.
Choi, Eun-Jung; Chen, Wanqiu; Jun, Kristine; Arthur, Helen M.; Young, William L.; Su, Hua
[Chemotherapy for experimental subarachnoid dissemination model of brain tumor].
Chemotherapy was applied for experimental subarachnoid dissemination model of brain tumor which was established in male Wister-SPF (SLC) rats inoculated intracisternally with 2 X 10(5) C6 rat glioma cells. Nontreated animals died about 24 days after inoculation. Autopsy findings of the animals showed localized or multifocal invasion of the tumor on leptomeninges in cisterna magna, and partially infiltration into the parenchyma of the cerebellum and medulla oblongata. Three days after inoculation, the tumor deposition and proliferation already occurred. Several tumor cell layers were found in the subarachnoid space over the cerebellomedullary surface. Tumor bearing animals were at first treated by single agent. These are ACNU administered intraperitoneally, methotrexate administered intracisternally, and OK-432 administered intraperitoneally. In the next stage, combination of these drugs was applied. ACNU, 3 mg/kg i. p., on Day 3, was effective in elongation of median survival time by 23.6%, statistically significant (P less than 0.02). Methotrexate, 0.25 mg/kg i.th., on Day 3, was also effective in elongation of median survival time by 8.4%, statistically significant (P less than 0.05). OK-432, 0.1 KE/kg i. p., daily, 14 times, from Day 3 to Day 16, was ineffective in elongation of median survival time. Combination of ACNU, methotrexate and OK-432, in the same schedule as described above, produced the longest median survival time of 42.4%, statistically significant (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6585681
Yamashita, T; Shinonaga, M; Ishiwata, Y; Nishimura, S; Murai, M; Kyuma, Y; Kuwabara, T
Optically enhanced blood-brain-barrier crossing of plasmonic-active nanoparticles in preclinical brain tumor animal models
NASA Astrophysics Data System (ADS)
Nanotechnology provides tremendous biomedical opportunities for cancer diagnosis, imaging, and therapy. In contrast to conventional chemotherapeutic agents where their actual target delivery cannot be easily imaged, integrating imaging and therapeutic properties into one platform facilitates the understanding of pharmacokinetic profiles, and enables monitoring of the therapeutic process in each individual. Such a concept dubbed "theranostics" potentiates translational research and improves precision medicine. One particular challenging application of theranostics involves imaging and controlled delivery of nanoplatforms across blood-brain-barrier (BBB) into brain tissues. Typically, the BBB hinders paracellular flux of drug molecules into brain parenchyma. BBB disrupting agents (e.g. mannitol, focused ultrasound), however, suffer from poor spatial confinement. It has been a challenge to design a nanoplatform not only acts as a contrast agent but also improves the BBB permeation. In this study, we demonstrated the feasibility of plasmonic gold nanoparticles as both high-resolution optical contrast agent and focalized tumor BBB permeation-inducing agent. We specifically examined the microscopic distribution of nanoparticles in tumor brain animal models. We observed that most nanoparticles accumulated at the tumor periphery or perivascular spaces. Nanoparticles were present in both endothelial cells and interstitial matrices. This study also demonstrated a novel photothermal-induced BBB permeation. Fine-tuning the irradiating energy induced gentle disruption of the vascular integrity, causing short-term extravasation of nanomaterials but without hemorrhage. We conclude that our gold nanoparticles are a powerful biocompatible contrast agent capable of inducing focal BBB permeation, and therefore envision a strong potential of plasmonic gold nanoparticle in future brain tumor imaging and therapy.
Yuan, Hsiangkuo; Wilson, Christy M.; Li, Shuqin; Fales, Andrew M.; Liu, Yang; Grant, Gerald; Vo-Dinh, Tuan
Magnesium in acute myocardial infarction: Overview of available evidence
Despite improvements in the outcome of patients with acute myocardial infarction (MI) during the past three decades, room for improvement exists in elderly patients and in patients who are not candidates for thrombolysis. Animal models suggest that magnesium supplementation before reperfusion reduces infarct size. Statistical analysis of the randomized trials of magnesium in MI reveals a gradient of response. When
Elliott M. Antman
Neurobehavioral abnormalities in a brain-specific NADPH-cytochrome P450 reductase knockout mouse model
The aim of the present study was to test a new hypothesis that brain cytochrome P450 reductase (CPR) and CPR-dependent enzymes play important roles in behavioral performance. A mouse model with brain neuron-specific deletion of the Cpr gene (brain-Cpr-null) was recently generated. Brain-Cpr-null mice and wild-type (WT) littermates were compared in a variety of behavioral assays. Notable differences were found in the exploratory behavior assay: for both males and females, activity in the center of the chamber was significantly higher for brain-Cpr-null than for WT mice on days 2 and 3 of the assay, although no significant difference was found between the two groups in anxiety-like behavior in the elevated zero maze. Furthermore, in the fear-conditioning assay, brain-Cpr-null mice exhibited significantly less activity suppression than did WT controls. This deficit in activity suppression was not accompanied by any difference between WT and brain-Cpr-null mice in nociceptive responses to foot shocks. Abnormal activity suppression was also observed in both male and female brain-Cpr-null mice during the contextual memory test. However, in the Morris water maze assay, the brain-Cpr-null and WT mice were indistinguishable, indicating normal spatial memory in the mutant mice. These data collectively indicate a novel role of the Cpr gene in fear conditioning and memory.
Fang, Cheng; Bolivar, Valerie J.; Gu, Jun; Yang, Weizhu; Zeitlin, Scott O.; Ding, Xinxin
Creating Rat Model for Hypoxic Brain Damage in Neonates by Oxygen Deprivation
Current study explores the feasibility of using a non-surgical method of oxygen deprivation to create Hypoxic brain damage in neonatal rats for medical studies. 7-day-old Sprague Dowley (SD) rats were kept in a container with low oxygen level (8%) for 1.5h. A second group had bilateral cephalic artery ligation before the 1.5h-low oxygen treatment, a method similar to the popular Rice method, to expose the brain to both hypoxic and ischemic situations. Short term neural functions and brain water weights were evaluated 1 day after the hypoxic treatment. Brain pathology and histology were also examined at 1 day and 3 days after the hypoxic treatment. Both groups showed impaired neural functions and increased brain water weight compared to the controls. Histology studies also revealed injuries in the subcortex, hippocampus and lateral ventricle in the brains from both groups. There is no significant difference in the degree of brain damages observed in the two groups. Our work demonstrated that oxygen deprivation alone is sufficient to cause brain damages similar to those seen in Hypoxic-ischemic brain disease (HIBD). Because this method avoids the invasive surgical procedure and therefore reduces the stress and mortality of laboratory animals during the experiment, we recommend it to be the favorable method for creating rat models for HIBD studies.
Zhang, Qiaoli; Ding, Yingxue; Yao, Yanqing; Yu, Yang; Yang, Lijun; Cui, Hong
Clinical characteristics and long-term outcome of patients in whom congestive heart failure develops after thrombolytic therapy for acute myocardial infarction: Development of a predictive model
Ischemic heart disease is the most common cause of congestive heart failure, which often begins after acute myocardial infarction. To better delineate the clinical characteristics and outcomes of patients in whom congestive heart failure develops after acute myocardial infarction in the thrombolytic era, we prospectively evaluated patients enrolled in six of the TAMI trials. The study cohort comprised 1619 consecutive
Christopher M. O'Connor; William R. Hathaway; Eric R. Bates; Jeffrey D. Leimberger; Kristina N. Sigmon; Dean J. Kereiakes; Barry S. George; Joseph K. Samaha; Charles W. Abbottsmith; Richard J. Candela; Eric J. Topol; Robert M. Califf
Computational model of an infant brain subjected to periodic motion simplified modelling and Bayesian sensitivity analysis.
Non-accidental head injury in infants, or shaken baby syndrome, is a highly controversial and disputed topic. Biomechanical studies often suggest that shaking alone cannot cause the classical symptoms, yet many medical experts believe the contrary. Researchers have turned to finite element modelling for a more detailed understanding of the interactions between the brain, skull, cerebrospinal fluid (CSF), and surrounding tissues. However, the uncertainties in such models are significant; these can arise from theoretical approximations, lack of information, and inherent variability. Consequently, this study presents an uncertainty analysis of a finite element model of a human head subject to shaking. Although the model geometry was greatly simplified, fluid-structure-interaction techniques were used to model the brain, skull, and CSF using a Eulerian mesh formulation with penalty-based coupling. Uncertainty and sensitivity measurements were obtained using Bayesian sensitivity analysis, which is a technique that is relatively new to the engineering community. Uncertainty in nine different model parameters was investigated for two different shaking excitations: sinusoidal translation only, and sinusoidal translation plus rotation about the base of the head. The level and type of sensitivity in the results was found to be highly dependent on the excitation type. PMID:22292202
Batterbee, D C; Sims, N D; Becker, W; Worden, K; Rowson, J
From animal model to human brain networking: dynamic causal modeling of motivational systems.
An organism's behavior is sensitive to different reinforcements in the environment. Based on extensive animal literature, the reinforcement sensitivity theory (RST) proposes three separate neurobehavioral systems to account for such context-sensitive behavior, affecting the tendency to react to punishment, reward, or goal-conflict stimuli. The translation of animal findings to complex human behavior, however, is far from obvious. To examine whether the neural networks underlying humans' motivational processes are similar to those proposed by the RST model, we conducted a functional MRI study, in which 24 healthy subjects performed an interactive game that engaged the different motivational systems using distinct time periods (states) of punishment, reward, and conflict. Crucially, we found that the different motivational states elicited activations in brain regions that corresponded exactly to the brain systems underlying RST. Moreover, dynamic causal modeling of each motivational system confirmed that the coupling strengths between the key brain regions of each system were enabled selectively by the appropriate motivational state. These results may shed light on the impairments that underlie psychopathologies associated with dysfunctional motivational processes and provide a translational validity for the RST. PMID:22623666
Gonen, Tal; Admon, Roee; Podlipsky, Ilana; Hendler, Talma
Neural Mechanisms Linking Mild Traumatic Brain Injury and Anxiety States in an Animal Model.
National Technical Information Service (NTIS)
Previous correlational studies suggest that mild traumatic brain injury (TBI) is associated with an increase in the prevalence of anxiety disorders, including posttraumatic stress disorder (PTSD). By using a relevant animal model, this research demonstrat...
G. Forster M. Watt P. Manzerra
Cotransplantation of human umbilical cord-derived mesenchymal stem cells and umbilical cord blood-derived CD34? cells in a rabbit model of myocardial infarction.
The objective of the study is to investigate the effect of hypoxic preconditioning on the immunomodulatory properties of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and the effect of cotransplantation of hUC-MSCs and human umbilical cord blood (hUCB)-derived CD34(+) cells in a rabbit model of myocardial infarction. hUC-MSCs with or without hypoxic preconditioning by cobalt chloride were plated in a 24-well plate, and then cocultured with hUCB-CD34(+) cells and PBMCs for 96 h at 37 °C in a 5% CO? incubator. For the negative control, hUC-MSCs were omitted. The groups were divided as follows: A1 = HP-MSCs + hUCB-CD34(+) cells + PBMC, A2 = hUC-MSCs + hUCB-CD34(+) cells + PBMC, Negative Control = hUCB-CD34(+) cells + PBMC. Culture supernatants of each group were collected, and the IL-10 and IFN-? levels were measured by ELISA. A rabbit model of MI was established using a modified Fujita method. The animals were then randomized into three groups and received intramyocardial injections of 0.4 ml of PBS alone (n = 8, PBS group), hUC-MSCs in PBS (n = 8, hUC-MSCs group), or hUC-MSCs + CD34(+) cells in PBS (n = 8, Cotrans group), at four points in the infarct border zone. Echocardiography was performed at baseline, 4 weeks after MI induction, and 4 weeks after cell transplantation, respectively. Stem cell differentiation and neovascularization in the infracted area were characterized for the presence of cardiac Troponin I (cTnI) and CD31 by immunohistochemical staining, and the extent of myocardial fibrosis was evaluated by hematoxylin and eosin (H&E) and Masson's trichrome. IFN-? was 27.00 ± 1.11, 14.20 ± 0.81, and 7.22 ± 0.14 pg/ml, and IL-10 was 31.68 ± 3.08, 61.42 ± 1.08, and 85.85 ± 1.80 pg/ml for the Control, A1 and A2 groups, respectively, which indicated that hUCB-CD34(+) cells induced immune reaction of peripheral blood mononuclear cells, whereas both hUC-MSCs and HP-MSCs showed an immunosuppressive effect, which, however, was attenuated by hypoxic preconditioning. The Cotrans group had less collagen deposition in the infarcted myocardium and better heart function than