Strokes attributable to subcortical infarcts have been increasing recently in elderly patients. To gain insight how this lesion influences the motor outcome and responds to rehabilitative training, we used circumscribed photothrombotic capsular infarct models on 36 Sprague-Dawley rats (24 experimental and 12 sham-operated). We used 2-deoxy-2-[(18)F]-fluoro-D-glucose-micro positron emission tomography (FDG-microPET) to assess longitudinal changes in resting-state brain activity (rs-BA) and daily single-pellet reaching task (SPRT) trainings to evaluate motor recovery. Longitudinal FDG-microPET results showed that capsular infarct resulted in a persistent decrease in rs-BA in bilateral sensory and auditory cortices, and ipsilesional motor cortex, thalamus, and inferior colliculus (P<0.0025, false discovery rate (FDR) q<0.05). The decreased rs-BA is compatible with diaschisis and contributes to manifest the malfunctions of lesion-specific functional connectivity. In contrast, capsular infarct resulted in increase of rs-BA in the ipsilesional internal capsule, and contralesional red nucleus and ventral hippocampus in recovery group (P<0.0025, FDR q<0.05), implying that remaining subcortical structures have an important role in conducting the recovery process in capsular infarct. The SPRT training facilitated motor recovery only in rats with an incomplete destruction of the posterior limb of the internal capsule (PLIC) (Pearson's correlation, P<0.05). Alternative therapeutic interventions are required to enhance the potential for recovery in capsular infarct with complete destruction of PLIC.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 October 2014; doi:10.1038/jcbfm.2014.178. PMID:25352047
Kim, Donghyeon; Kim, Ra Gyung; Kim, Hyung-Sun; Kim, Jin-Myung; Jun, Sung Chan; Lee, Boreom; Jo, Hang Joon; Neto, Pedro R; Lee, Min-Cheol; Kim, Hyoung-Ihl
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. PMID:24550298
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
Whole brain mapping of stroke patients with large cortical infarcts is not trivial due to the complexity of infarcts' anatomical location and appearance in magnetic resonance image. In this study, we proposed an individualized diffeomorphic mapping framework for solving this problem. This framework is based on our recent work of large deformation diffeomorphic metric mapping (LDDMM) in Du et al. (2011) and incorporates anatomical features, such as sulcal/gyral curves, cortical surfaces, brain intensity image, and masks of infarcted regions, in order to align a normal brain to the brain of stroke patients. We applied this framework to synthetic data and data of stroke patients and validated the mapping accuracy in terms of the alignment of gyral/sulcal curves, sulcal regions, and brain segmentation. Our results revealed that this framework provided comparable mapping results for stroke patients and healthy controls, suggesting the importance of incorporating individualized anatomical features in whole brain mapping of brains with large cortical infarcts. PMID:25278293
Soon, Hock Wei; Qiu, Anqi
In 15 patients with internal carotid artery (ICA) dissections, patterns of brain infarctions visible on CT were categorized according to a pathogenetically oriented classification system. This differentiated ischemic brain damage due to low flow from thromboembolic infarctions. Simultaneously, cerebral hemodynamic reserve was evaluated by means of both CO2-dependent vasomotor reactivity and HMPAO- and 99 mTc-RBC-SPECT. Six out of 11 patients
Cornelius Weiller; Wolfgang Müllges; E. Bernd Ringelstein; Udalrich Buell; Werner Reiche
We used single photon emission computed tomography (SPECT) in brain perfusion imaging to study the changes of regional cerebral blood flow (rCBF) and cerebral function in brain infarction patients treated with intravascular laser irradiation of blood (ILIB). 17 of 35 patients with brain infarction were admitted to be treated by ILIB on the base of standard drug therapy, and SPECT brain perfusion imaging was performed before and after ILIB therapy with self-comparison. The results were analyzed in quantity with brain blood flow function change rate (BFCR%) model. Effect of ILIB during the therapy process in the other 18 patients were also observed. In the 18 patients, SPECT indicated an improvement of rCBF (both in focus and in total brain) and cerebral function after a 30 min-ILIB therapy. And the 17 patients showed an enhancement of total brain rCBF and cerebral function after ILIB therapy in comparison with that before, especially for the focus side of the brain. The enhancement for focus itself was extremely obvious with a higher significant difference (P<0.0001). The mirror regions had no significant change (P>0.05). BFCR% of foci was prominently higher than that of mirror regions (P<0.0001). In conclusion, the ILIB therapy can improve rCBF and cerebral function and activate brain cells of patients with brain infarction. The results denote new evidence of ILIB therapy for those patients with cerebral ischemia.
Xiao, Xue-Chang; Dong, Jia-Zheng; Chu, Xiao-Fan; Jia, Shao-Wei; Liu, Timon C.; Jiao, Jian-Ling; Zheng, Xi-Yuan; Zhou, Ci-Xiong
The purpose of this study was to investigate the correlation between platelet aggregability and silent brain infarcts. The study subjects were 445 people (264 men, 181 women; mean age, 53 ± 14 years) with no neurologic signs, history of brain tumor, trauma, cerebrovascular disease, or antiplatelet medications. Adenosine diphosphate (ADP)-induced platelet aggregation was measured by the aggregation-size analytic method. Platelet aggregability was classified into 9 classes. The presence of headache/vertigo, hypertension, diabetes mellitus, hyperlipidemia, or smoking was elicited by questioning or blood sampling. A head MRI scan was performed, and if marked atherosclerosis or obvious stenosis in the intracranial vessels was detected, it was defined as a positive MRA finding. Silent brain infarcts were detected in 26.3% of subjects. Hyperaggregability defined as that above class 6, 7, and 8 was present in 43.8%, 30.8%, and 15.7% of subjects, respectively. The risk factors for silent brain infarcts by multiple logistic regression analysis were aging, hypertension, positive MRA findings, and hyperaggregability. Platelet ADP hyperaggregability might be a risk factor for silent brain infarcts. PMID:22308263
Ono, Kenichiro; Arimoto, Hirohiko; Shirotani, Toshiki
It is important to detect the site and size of infarction volume in stroke patients. An automatic method for segmenting brain infarction lesion from diffusion weighted magnetic resonance (MR) images of patients has been developed. The method uses an integrated approach which employs image processing techniques based on anisotropic filters and atlas-based registration techniques. It is a multi-stage process, involving first images preprocessing, then global and local registration between the anatomical brain atlas and the patient, and finally segmentation of infarction volume based on region splitting and merging and multi-scale adaptive statistical classification. The proposed multi-scale adaptive statistical classification model takes into account spatial, intensity gradient, and contextual information of the anatomical brain atlas and the patient. Application of the method to diffusion weighted imaging (DWI) scans of twenty patients with clinically determined infarction was carried out. It shows that the method got a satisfied segmentation even in the presence of radio frequency (RF) inhomogeneities. The results were compared with lesion delineations by human experts, showing the identification of infarction lesion with accuracy and reproducibility.
Li, Wu; Tian, Jie
–28) there were 108 infarct "non-expansion” voxels and 113 infarct "expansion” voxels (of which 80 were “complete expansion” and 33 “partial expansion” voxels). Brain choline concentration increased for each change in expansion category from "non-expansion", via...
Karaszewski, B.; Thomas, R.G.R.; Chappell, F.M.; Armitage, P.A.; Carpenter, T.K.; Lymer, G.K.S.; Dennis, M.S.; Marshall, I.; Wardlaw, J.M.
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. PMID:23444303
Stefansdottir, Hrafnhildur; Arnar, David O.; Aspelund, Thor; Sigurdsson, Sigurdur; Jonsdottir, Maria K.; Hjaltason, Haukur; Launer, Lenore J.; Gudnason, Vilmundur
Cerebral infarcts initially showing as markedly hyperintense on magnetic resonance (MR)T2-weighted images decreased in intensity and became nearly isointense to normal brain tissue in subsequent MR studies. This MR fogging was observed in 7 (23%) out of 31 cases of cortical infarct and 4 (20%) out of 20 cases of perforator infarct in the second to sixth weeks of the
R. Asato; R. Okumura; Y. Miki; J. Konishi
Although it is thought that the major factor responsible for cell damage is reactive oxygen species (ROS), our recent studies have shown that acrolein is more toxic than ROS. Thus, the relative importance of acrolein and ROS in cell damage during brain infarction was compared using photochemically induced thrombosis model mice. The levels of acrolein-conjugated albumin, and of 4-hydroxynonenal (HNE)-conjugated albumin and 8-OHdG were evaluated as indicators of damage produced by acrolein and ROS, respectively. The increase in acrolein-conjugated albumin was much greater than the increase in HNE-conjugated albumin or 8-OHdG, suggesting that acrolein is more strongly involved in cell damage than ROS during brain infarction. It was also shown that infarction led more readily to RNA damage than to DNA or phospholipid damage. As a consequence, polyamines were released from RNA, and acrolein was produced from polyamines, especially from spermine by spermine oxidase. Production of acrolein from spermine by spermine oxidase was clarified using spermine synthase-deficient Gy mice and transglutaminase 2-knockout mice, in which spermine content is negligible or spermidine/spermine N(1)-acetyltransferase activity is elevated. PMID:21187074
Saiki, Ryotaro; Park, Hyerim; Ishii, Itsuko; Yoshida, Madoka; Nishimura, Kazuhiro; Toida, Toshihiko; Tatsukawa, Hideki; Kojima, Soichi; Ikeguchi, Yoshihiko; Pegg, Anthony E; Kashiwagi, Keiko; Igarashi, Kazuei
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
Silent brain infarct and white matter lesions are common radiological findings associated with the risk of clinical stroke and dementia; however, our understanding of their underlying pathophysiology and risk factors remains limited. This study aimed to determine whether assessment of retinal microvascular abnormalities could provide prognostic information regarding the risk of brain infarct and white matter lesions on magnetic resonance imaging. This study is based on a subset of 810 middle-aged persons without clinical stroke or baseline magnetic resonance imaging infarct enrolled in the Atherosclerosis Risk in Communities Brain Magnetic Resonance Imaging Study, a prospective, population-based study. Participants had a baseline magnetic resonance imaging brain examination and retinal photography in 1993–1995, and returned for a repeat magnetic resonance imaging examination in 2004–2006. Magnetic resonance images were graded for presence of any cerebral infarct, infarct with lacunar characteristics and white matter lesions according to standardized protocols. Retinal photographs were graded for presence of retinopathy lesions and retinal arteriolar abnormalities following a standardized protocol. Over a median follow-up of 10.5 years, 164 (20.2%) participants developed cerebral infarct, 131 (16.2%) developed lacunar infarct, 182 (24.2%) developed new white matter lesions and 49 (6.1%) had evidence of white matter lesion progression. After adjusting for age, gender, race, cardiovascular risk factors and carotid intima-media thickness, retinopathy was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval 1.42–5.60) and lacunar infarct (odds ratio 3.19; 95% confidence interval: 1.56–6.50). Retinal arteriovenous nicking was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval: 1.66–4.76), lacunar infarct (odds ratio 2.48; 95% confidence interval: 1.39–4.40) and white matter lesion incidence (odds ratio 2.12; 95% confidence interval: 1.18–3.81) and progression (odds ratio 2.22; 95% confidence interval: 1.00–5.88). In conclusion, retinal microvascular abnormalities are associated with emergence of subclinical magnetic resonance imaging brain infarcts and white matter lesions, independent of shared risk factors. Retinal vascular imaging may offer a non-invasive tool to investigate the pathogenesis and natural history of cerebral small-vessel disease. PMID:20519327
Cheung, Ning; Mosley, Thomas; Islam, Amirul; Kawasaki, Ryo; Sharrett, A. Richey; Klein, Ronald; Coker, Laura H.; Knopman, David S.; Shibata, Dean K.; Catellier, Diane
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. PMID:24086572
Lin, Xiaojie; Miao, Peng; Wang, Jixian; Yuan, Falei; Guan, Yongjing; Tang, Yaohui; He, Xiaosong; Wang, Yongting; Yang, Guo-Yuan
Background Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI-infarct, in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods Using 2.2 million genotyped and imputed SNPs, each study performed cross-sectional genome-wide association analysis of MRI-infarct using age and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance weighted meta-analysis, including 9401 participants with mean age 69.7, 19.4% of whom had ?1 MRI-infarct. Results The most significant association was found with rs2208454 (minor allele frequency: 20%), located in intron 3 of MACRO Domain Containing 2 gene and in the downstream region of Fibronectin Leucine Rich Transmembrane Protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI-infarcts: odds ratio=0.76, 95% confidence interval=0.68–0.84, p=4.64×10?7. Highly suggestive associations (p<1.0×10?5) were also found for 22 other SNPs in linkage disequilibrium (r2>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 African-American participants, although 4 SNPs within 200kb from rs2208454 were associated with MRI-infarcts in African-American sample. Conclusions This first community-based, genome-wide association study on covert MRI-infarcts uncovered novel associations. Although replication of the association with top SNP failed, possibly due to insufficient power, results in the African American sample are encouraging, and further efforts at replication are needed. PMID:20044523
Debette, Stephanie; Bis, Joshua C.; Fornage, Myriam; Schmidt, Helena; Ikram, M. Arfan; Sigurdsson, Sigurdur; Heiss, Gerardo; Struchalin, Maksim; Smith, Albert V.; van der Lugt, Aad; DeCarli, Charles; Lumley, Thomas; Knopman, David S.; Enzinger, Christian; Eiriksdottir, Gudny; Koudstaal, Peter J.; DeStefano, Anita L.; Psaty, Bruce M.; Dufouil, Carole; Catellier, Diane J.; Fazekas, Franz; Aspelund, Thor; Aulchenko, Yurii S.; Beiser, Alexa; Rotter, Jerome I.; Tzourio, Christophe; Shibata, Dean K.; Tscherner, Maria; Harris, Tamara B.; Rivadeneira, Fernando; Atwood, Larry D.; Rice, Kenneth; Gottesman, Rebecca F.; van Buchem, Mark A.; Uitterlinden, Andre G.; Kelly-Hayes, Margaret; Cushman, Mary; Zhu, Yicheng; Boerwinkle, Eric; Gudnason, Vilmundur; Hofman, Albert; Romero, Jose R.; Lopez, Oscar; van Duijn, Cornelia M.; Au, Rhoda; Heckbert, Susan R.; Wolf, Philip A.; Mosley, Thomas H.; Seshadri, Sudha; Breteler, Monique M.B.; Schmidt, Reinhold; Launer, Lenore J.; Longstreth, WT
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
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.
Shaposhnikov, Dmitry; Revich, Boris; Gurfinkel, Yuri; Naumova, Elena
To understand the pathophysiology of ischemic stroke, in vivo imaging of the brain tissue viability and related spreading depolarization is crucial. In the infarct core, impairment of energy metabolism causes anoxic depolarization (AD), which considerably increases energy consumption, accelerating irreversible neuronal damage. In the peri-infarct penumbra region, where tissue is still reversible despite limited blood flow, peri-infarct depolarization (PID) occurs, exacerbating energy deficit and hence expanding the infarct area. We previously showed that light-scattering signal, which is sensitive to cellular/subcellular structural integrity, was correlated with AD and brain tissue viability in a rat hypoxia-reoxygenation model. In the present study, we performed transcranial NIR diffuse reflectance imaging of the rat brain during middle cerebral artery (MCA) occlusion and examined whether the infarct core and PIDs can be detected. Immediately after occluding the left MCA, light scattering started to increase focally in the occlusion site and a bright region was generated near the occlusion site and spread over the left entire cortex, which was followed by a dark region, showing the occurrence of PID. The PID was generated repetitively and the number of times of occurrence in a rat ranged from four to ten within 1 hour after occlusion (n=4). The scattering increase in the occlusion site was irreversible and the area with increased scattering expanded with increasing the number of PIDs, indicating an expansion of the infarct core. These results suggest the usefulness of NIR diffuse reflectance signal to visualize spatiotemporal changes in the infarct area and PIDs.
Kawauchi, Satoko; Nishidate, Izumi; Nawashiro, Hiroshi; Sato, Shunichi
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
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
EEGs from 16 patients with stroke in three different stages of evolution were recorded. EEG sources were calculated every 0.39 Hz by frequency domain VARETA. The main source was within the delta band in 2 out of 4 chronic patients, and in 67% of the patients in the acute or subacute stages when edema (cytotoxic or vasogenic) was present. Moreover, all patients showed abnormal activity in the theta band. Sources of abnormal activity in cortical or corticosubcortical infarcts were located in the cortex, surrounding the lesion. At the site of the infarct, a decrease of EEG power was observed. Sources of abnormal theta power coincided with edema and/or ischemic penumbra. PMID:11056837
Fernández-Bouzas, A; Harmony, T; Fernández, T; Silva-Pereyra, J; Valdés, P; Bosch, J; Aubert, E; Casián, G; Otero Ojeda, G; Ricardo, J; Hernández-Ballesteros, A; Santiago, E
Ultrasound-mediated microbubble thrombolysis (UMT) was performed in a middle cerebral artery occlusion model in rats to evaluate possible effects upon brain infarct volume, apoptosis, IL-6 and TNF-alpha levels, and disruption of the blood-brain barrier (BBB). The results show that infarct volume was significantly reduced (p<0.04) in the microbubble + ultrasound (MB + US) group as compared to control animals. The levels of IL-6 and TNF-alpha concentrations, as markers of tissue damage, were not significantly different. In trypan blue treated animals, no additional BBB disruption was observed for the UMT group. Likewise, there was no increase in apoptotic cell death outside the infarction area in animals treated with MB + US. The results demonstrate that UMT does not have a harmful effect upon ischemic stroke in a middle cerebral artery occlusion model of the rat. The significant reduction in brain infarction following insonation with ultrasound and microbubbles suggests a novel neuroprotective effect in ischemic stroke.
Fatar, M.; Griebe, M.; Stroick, M.; Kern, R.; Hennerici, M.; Meairs, S.
Previous studies have shown that proliferation of endogenous neural precursor cells cannot alone compensate for the damage to neurons and axons. From the perspective of neural plasticity, we observed the effects of functional electrical stimulation treatment on endogenous neural precursor cell proliferation and expression of basic fibroblast growth factor and epidermal growth factor in the rat brain on the infarct side. Functional electrical stimulation was performed in rat models of acute middle cerebral artery occlusion. Simultaneously, we set up a placebo stimulation group and a sham-operated group. Immunohistochemical staining showed that, at 7 and 14 days, compared with the placebo group, the numbers of nestin (a neural precursor cell marker)-positive cells in the subgranular zone and subventricular zone were increased in the functional electrical stimulation treatment group. Western blot assays and reverse-transcription PCR showed that total protein levels and gene expression of epidermal growth factor and basic fibroblast growth factor were also upregulated on the infarct side. Prehensile traction test results showed that, at 14 days, prehension function of rats in the functional electrical stimulation group was significantly better than in the placebo group. These results suggest that functional electrical stimulation can promote endogenous neural precursor cell proliferation in the brains of acute cerebral infarction rats, enhance expression of basic fibroblast growth factor and epidermal growth factor, and improve the motor function of rats. PMID:25206808
Xiang, Yun; Liu, Huihua; Yan, Tiebin; Zhuang, Zhiqiang; Jin, Dongmei; Peng, Yuan
The physiologic properties of the normal cellular prion protein (PrP(C)) have not been established fully, although recent evidence showed its upregulation in cerebral ischaemia. Using patients, animal models, and in vitro studies we aimed to identify in detail the expression and localization of PrP(C) in ischemic stroke. Patients in acute phase of ischaemic stroke had increased plasma levels of circulating PrP(C) as compared to healthy age- and gender-matched controls (3.1 +/- 1.4 vs. 1.9 +/- 0.7 ng/ml, P = 0.002). Immunohistochemistry showed increased expression of PrP(C) in the soma of peri-infarcted neurones as well as in the endothelial cells (EC) of micro-vessels and inflammatory cells in peri-infarcted brain tissue from patients who survived for 2-34 days after an initial stroke. The same pattern was repeated 1-48 hr after MCAO. RT-PCR showed increased gene expression of PrP(C) by human foetal neurons (HFN) after 12 hr of oxygen glucose deprivation (OGD), which remained increased after 24 hr reperfusion. Western blotting confirmed that protein expression was similarly upregulated, and fluorescent labeling showed a notable increase in peri-nuclear and axonal PrP(C) staining intensity. Increased plasma PrP(C) seems to reflect endogenous expression in acute stroke-affected brain tissue. Increased cellular expression in peri-infarcted regions may influence hypoxia-induced cell damage, although the effects on EC survival and angiogenesis remain to be elucidated. PMID:17149767
Mitsios, Nicholas; Saka, Mohamad; Krupinski, Jerzy; Pennucci, Roberta; Sanfeliu, Coral; Miguel Turu, Marta; Gaffney, John; Kumar, Pat; Kumar, Shant; Sullivan, Matthew; Slevin, Mark
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
The cause and pathogenesis of gastroschisis are uncertain. We report the autopsy and placental pathology of a stillbirth at 20 gestational weeks, in which gastroschisis was accompanied by destructive lesions in the cerebral cortex and brainstem, as well as cardiac calcification, consistent with ischemic injury during the 2nd trimester. An important potential underlying mechanism explaining the fetal abnormalities is the presence of infarcts in the placenta, indicative at this gestational age of maternal vascular underperfusion. The association of gastroschisis with ischemic lesions in the brain, heart, and placenta in this case supports the concept that gastroschisis, at least in some instances, may result from vascular event(s) causing disruption of the fetal abdominal wall and resulting in the extrusion of the abdominal organs, as well as hypoxic–ischemic brain and cardiac injury. PMID:23895144
Folkerth, Rebecca D.; Habbe, Donald M.; Boyd, Theonia K.; McMillan, Kristin; Gromer, Jessica; Sens, Mary Ann; Elliott, Amy J.
Patients with middle cerebral artery (MCA) infarction accompanied by MCA occlusion with or without internal carotid artery (ICA) occlusion have a poor prognosis, as a result of brain cell damage caused by both the infarction and by space-occupying and life-threatening edema formation. Multiple treatments can reduce the likelihood of edema formation, but tend to show limited efficacy. Decompressive hemicraniectomy with duroplasty has been promising for improving functional outcomes and reducing mortality, particularly improved functional outcomes can be achieved with early decompressive surgery. Therefore, identifying patients at risk for developing fatal edema is important and should be performed as early as possible. Sixty-four patients diagnosed with major MCA infarction with MCA occlusion within 8hours of symptom onset were retrospectively reviewed. Early clinical, laboratory, and computed tomography angiography (CTA) parameters were analyzed for malignant brain edema (MBE). Twenty of the 64 patients (31%) had MBE, and the clinical outcome was poor (3month modified Rankin Scale >2) in 95% of them. The National Institutes of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early Computed Tomography Score, Clot Burden Score, and Collateral Score (CS) showed statically significant differences in both groups. Multivariable analyses adjusted for age and sex identified the independent predictors of MBE: NIHSS score >18 (odds ratio [OR]: 4.4, 95% confidence interval [CI]: 1.2-16.0, p=0.023) and CS on CTA <2 (OR: 7.28, 95% CI: 1.7-30.3,p=0.006). Our results provide useful information for selecting patients in need of aggressive treatment such as decompressive surgery. PMID:25510537
Kim, Hoon; Jin, Seon Tak; Kim, Young Woo; Kim, Seong Rim; Park, Ik Seong; Jo, Kwang Wook
Silent brain infarcts (SBIs) are detected by neuroimaging in approximately 20% of elderly patients in population-based studies. Limited evidence is available for hypertensives at low cardiovascular risk countries. Investigating Silent Strokes in Hypertensives: a Magnetic Resonance Imaging Study (ISSYS) is aimed to assess the prevalence and risk factors of SBIs in a hypertensive Mediterranean population. This is a cohort study in randomly selected hypertensives, aged 50 to 70 years old, and free of clinical stroke and dementia. On baseline, all participants underwent a brain magnetic resonance imaging to assess prevalence and location of silent infarcts, and data on vascular risk factors, comorbidities, and the presence of subclinical cardiorenal damage (left ventricular hypertrophy and microalbuminuria) were collected. Multivariate analyses were performed to determine SBIs associated factors. A total of 976 patients (49.4% men, mean age 64 years) were enrolled, and 163 SBIs were detected in 99 participants (prevalence 10.1%; 95% CI, 8.4%-12.2%), most of them (64.4%) located in the basal ganglia and subcortical white matter. After adjustment, besides age and sex, microalbuminuria and increasing total cardiovascular risk (assessed by the Framingham-calibrated for Spanish population risk function) were independently associated with SBIs. Male sex increased the odds of having SBIs in 2.5 as compared with females. Our results highlight the importance of considering both global risk assessment and sex differences in hypertension and may be useful to design future preventive interventions of stroke and dementia. PMID:24958500
Delgado, Pilar; Riba-Llena, Iolanda; Tovar, José L; Jarca, Carmen I; Mundet, Xavier; López-Rueda, Antonio; Orfila, Francesc; Llussà, Judit; Manresa, Josep M; Alvarez-Sabín, José; Nafría, Cristina; Fernández, José L; Maisterra, Olga; Montaner, Joan
A central difficulty of brain modelling is to span the range of spatio-temporal scales from synapses to the whole brain. This paper overviews results from a recent model of the generation of brain electrical activity that incorporates both basic microscopic neurophysiology and large-scale brain anatomy to predict brain electrical activity at scales from a few tenths of a millimetre to the whole brain. This model incorporates synaptic and dendritic dynamics, nonlinearity of the firing response, axonal propagation and corticocortical and corticothalamic pathways. Its relatively few parameters measure quantities such as synaptic strengths, corticothalamic delays, synaptic and dendritic time constants, and axonal ranges, and are all constrained by independent physiological measurements. It reproduces quantitative forms of electroencephalograms seen in various states of arousal, evoked response potentials, coherence functions, seizure dynamics and other phenomena. Fitting model predictions to experimental data enables underlying physiological parameters to be inferred, giving a new non-invasive window into brain function that complements slower, but finer-resolution, techniques such as fMRI. Because the parameters measure physiological quantities relating to multiple scales, and probe deep structures such as the thalamus, this will permit the testing of a range of hypotheses about vigilance, cognition, drug action and brain function. In addition, referencing to a standardized database of subjects adds strength and specificity to characterizations obtained. PMID:16087447
Robinson, P. A; Rennie, C. J; Rowe, D. L; O'Connor, S. C; Gordon, E
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. PMID:22886394
Toung, Thomas J. K.; Gottschalk, Allan; Mirski, Marek A.; Koehler, Raymond C.
Sonolysis is a new therapeutic option for the acceleration of arterial recanalization. The aim of this study was to confirm risk reduction of brain infarction during endarterectomy (CEA) and stenting (CAS) of the internal carotid artery (ICA) using sonolysis with continuous transcranial Doppler (TCD) monitoring by diagnostic 2 MHz probe, additional interest was to assess impact of new brain ischemic lesions on cognitive functions. Methods: All consecutive patients 1/ with ICA stenosis >70%, 2/ indicated to CEA or CAS, 3/ with signed informed consent, were enrolled to the prospective study during 17 months. Patients were randomized into 2 groups: Group 1 with sonolysis during intervention and Group 2 without sonolysis. Neurological examination, assessment of cognitive functions and brain magnetic resonance imaging (MRI) were performed before and 24 hours after intervention in all patients. Occurrence of new brain infarctions (including infarctions >0.5 cm3), and the results of Mini-Mental State Examination, Clock Drawing and Verbal Fluency tests were statistically evaluated using T-test. Results: 97 patients were included into the study. Out of the 47 patients randomized to sonolysis group (Group 1) 25 underwent CEA (Group 1a) and 22 CAS (Group 1b). Out of the 50 patients randomized to control group (Group 2), 22 underwent CEA (Group 2a) and 28 CAS (Group 2b). New ischemic brain infarctions on follow up MRI were found in 14 (29.8%) patients in Group 1-4 (16.0%) in Group 1a and 10 (45.5%) in Group 1b. In Group 2, new ischemic brain infarctions were found in 18 (36.0%) patients-6 (27.3%) in Group 2a and 12 (42.9%) in Group 2b (p>0.05 in all cases). New ischemic brain infarctions >0.5 cm3 were found in 4 (8.5 %) patients in Group 1 and in 11 (22.0 %) patients in Group 2 (p= 0.017). No significant differences were found in cognitive tests results between subgroups (p>0.05 in all tests). Conclusion: Sonolysis seems to be effective in the prevention of large ischemic brain infarctions during CEA and CAS.
Kuliha, Martin; Školoudík, David; Martin Roubec, Martin; Herzig, Roman; Procházka, Václav; Jonszta, Tomáš; Kraj?a, Jan; Czerný, Dan; Hrbá?, Tomáš; Otáhal, David; Langová, Kate?ina
This thesis integrates hardware development, data analysis, and mathematical modeling to facilitate our understanding of brain cognition. Exploration of these brain mechanisms requires both structural and functional knowledge ...
Lin, Fa-Hsuan, 1972-
Stroke is the second leading cause of death in the world and in South Korea. Ischemic stroke and silent brain infarction (SBI) are complex, multifactorial diseases influenced by multiple genetic and environmental factors. Moderately elevated plasma homocysteine levels are a major risk factor for vascular diseases, including stroke and SBI. Folate and vitamin B12 are important regulators of homocysteine metabolism. Reduced folate carrier (RFC), a bidirectional anion exchanger, mediates folate delivery to a variety of cells. We selected three known RFC-1 polymorphisms (-43C>T, 80A>G, 696T>C) and investigated their relationship to cerebral infarction in the Korean population. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze associations between the three RFC-1 polymorphisms, disease status, and folate and homocysteine levels in 584 ischemic stroke patients, 353 SBI patients, and 505 control subjects. The frequencies of the RFC-1 -43TT, 80GG, and 696CC genotypes differed significantly between the stroke and control groups. The RFC-1 80A>G substitution was also associated with small artery occlusion and SBI. In a gene-environment analysis, the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms in the ischemic stroke group had combined effects with all environmental factors. In summary, we found that the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms may be risk factors for ischemic stroke. PMID:25659099
Cho, Yunkyung; Kim, Jung O; Lee, Jeong Han; Park, Hye Mi; Jeon, Young Joo; Oh, Seung Hun; Bae, Jinkun; Park, Young Seok; Kim, Ok Joon; Kim, Nam Keun
Stroke is the second leading cause of death in the world and in South Korea. Ischemic stroke and silent brain infarction (SBI) are complex, multifactorial diseases influenced by multiple genetic and environmental factors. Moderately elevated plasma homocysteine levels are a major risk factor for vascular diseases, including stroke and SBI. Folate and vitamin B12 are important regulators of homocysteine metabolism. Reduced folate carrier (RFC), a bidirectional anion exchanger, mediates folate delivery to a variety of cells. We selected three known RFC-1 polymorphisms (-43C>T, 80A>G, 696T>C) and investigated their relationship to cerebral infarction in the Korean population. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze associations between the three RFC-1 polymorphisms, disease status, and folate and homocysteine levels in 584 ischemic stroke patients, 353 SBI patients, and 505 control subjects. The frequencies of the RFC-1 -43TT, 80GG, and 696CC genotypes differed significantly between the stroke and control groups. The RFC-1 80A>G substitution was also associated with small artery occlusion and SBI. In a gene-environment analysis, the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms in the ischemic stroke group had combined effects with all environmental factors. In summary, we found that the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms may be risk factors for ischemic stroke. PMID:25659099
Cho, Yunkyung; Kim, Jung O; Lee, Jeong Han; Park, Hye Mi; Jeon, Young Joo; Oh, Seung Hun; Bae, Jinkun; Park, Young Seok; Kim, Ok Joon; Kim, Nam Keun
Background Cerebral infarction is a commonly observed radiological finding in the absence of corresponding, clinical symptomatology, the so-called silent brain infarction (SBI). SBIs are a relatively new consideration as improved imaging has facilitated recognition of their occurrence. However, the true incidence, prevalence and risk factors associated with SBI remain controversial. Methods Systematic searches of the Medline and EMBASE databases from 1946 to December 2013 were performed to identify original studies of population-based adult cohorts derived from community surveys and routine health screening that reported the incidence and prevalence of magnetic resonance imaging (MRI)-determined SBI. Results The prevalence of SBI ranges from 5% to 62% with most studies reported in the 10% to 20% range. Longitudinal studies suggest an annual incidence of between 2% and 4%. A strong association was seen to exist between epidemiological estimates of SBI and age of the population assessed. Hypertension, carotid stenosis, chronic kidney disease and metabolic syndrome all showed a strong association with SBI. Heart failure, coronary artery disease, hyperhomocysteinemia and obstructive sleep apnea are also likely of significance. However, any association between SBI and gender, ethnicity, tobacco or alcohol consumption, obesity, dyslipidemia, atrial fibrillation and diabetes mellitus remains unclear. Conclusions SBI is a remarkably common phenomenon and endemic among older people. This systematic review supports the association of a number of traditional vascular risk factors, but also highlights disparities between clinically apparent and silent strokes, potentially suggesting important differences in pathophysiology and warranting further investigation. PMID:25012298
Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet lining the blood-brain barrier. AQP4 deletion in mice is associated with improved outcomes in global cerebral ischemia produced by transient carotid artery occlusion, and focal cerebral ischemia produced by permanent middle cerebral artery occlusion (MCAO). Here, we investigated the consequences of 1-h transient MCAO produced by intraluminal suture blockade followed by 23h of reperfusion. In nine AQP4(+/+) and nine AQP4(-/-) mice, infarct volume was significantly reduced by an average of 39±4% at 24h in AQP4(-/-) mice, cerebral hemispheric edema was reduced by 23±3%, and Evans Blue extravasation was reduced by 31±2% (mean±SEM). Diffusion-weighted magnetic resonance imaging showed greatest reduction in apparent diffusion coefficient around the occlusion site after reperfusion, with remarkably lesser reduction in AQP4(-/-) mice. The reduced infarct volume in AQP4(-/-) mice following transient MCAO supports the potential utility of therapeutic AQP4 inhibition in stroke. PMID:25449874
Yao, Xiaoming; Derugin, Nikita; Manley, Geoffrey T; Verkman, A S
The present study established a mouse model of cerebral infarction by middle cerebral artery occlusion, and monitored the effect of 25 ?g/kg leukemia inhibitory factor and (or) basic fibroblast growth factor administration 2 hours after model establishment. Results showed that following administration, the number of endogenous neural stem cells in the infarct area significantly increased, malondialdehyde content in brain tissue homogenates significantly decreased, nitric oxide content, glutathione peroxidase and superoxide dismutase activity significantly elevated, and mouse motor function significantly improved as confirmed by the rotarod and bar grab tests. In particular, the effect of leukemia inhibitory factor in combination with basic fibroblast growth factor was the most significant. Results indicate that leukemia inhibitory factor and basic fibroblast growth factor can improve the microenvironment after cerebral infarction by altering free radical levels, improving the quantity of endogenous neural stem cells, and promoting neurological function of mice with cerebral infarction.
Huang, Weihui; Li, Yadan; Lin, Yufeng; Ye, Xue; Zang, Dawei
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
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. PMID:19272172
Chang, Yi; Hsieh, Cheng-Ying; Peng, Zi-Aa; Yen, Ting-Lin; Hsiao, George; Chou, Duen-Suey; Chen, Chien-Ming; Sheu, Joen-Rong
Fifty-six consecutive elderly ( > or = 65 years) patients, admitted for acute stroke to a geriatric department were included in the study and underwent CT scanning. Functional status was graded according to the modified Rankin scale. Three patients had primary intra-cerebral haemorrhage, 22 deep hemispheric infarct, 17 had anterior circulation cortical infarcts, five had posterior circulation infarcts and in nine the CT scan was normal. Stroke risk factors were equally distributed among the different CT scan groups, and all three larger groups had similar rates of non-neurological major complications including death (41%). However, independence in ADL (Rankin 0-2) was observed in 72% of deep infarct survivors, but only 15% of the cortical infarct group (p = 0.00018). For the normal scan group, functional recovery was intermediate. In the cortical infarct group patients with an infarct of > or = 50 mm mean diameter (five cases) should worse functional recovery than did eight patients with small infarcts. The mean difference between pre- and post-stroke Rankin score (DR) was 3.4 for the larger infarct patients and 1.9 for the smaller infarct group (p = 0.027). Pearson correlation revealed a direct relationship between the infarction size and DR (p = 0.039). Such a relationship was not observed for the deep hemispheric group. PMID:8588543
Beloosesky, Y; Streifler, J Y; Burstin, A; Grinblat, J
Mouse surgical models are important tools for evaluating mechanisms of human cardiac disease. The clinically relevant comorbidities of hypertension and ischaemia have not been explored in mice. We have developed a surgical approach that combines transverse aortic constriction and distal left anterior coronary ligation (MI) to produce a gradual and predictable progression of adverse left ventricular (LV) remodelling that leads to heart failure (HF). Mice received either sham, MI alone, transverse aortic constriction alone or HF surgery. Infarct size and LV remodelling were evaluated by serial 2-D echocardiograms. Transverse aortic constriction gradients were measured by the Doppler velocity-time integral ratio between constricted and proximal aortic velocities. At 4 weeks, hearts were weighed and analysed for histology and brain natriuretic peptide, a molecular marker of HF. Echocardiographic analysis of segmental wall motion scores showed similarly small apical infarct sizes in the MI and HF groups at day 1 postsurgery. MI alone showed little change in infarct size over 4 weeks (0.26 ± 0.02 to 0.27 ± 0.04, P = 0.77); however, HF mice showed infarct expansion (0.25 ± 0.06 to 0.39 ± 0.09, P < 0.05). HF mice also showed LV remodelling with increases in LV volumes (1 day = 36.5 ± 5.2 mL, 28 days = 89.1 ± 16.0 mL) versus no significant changes in the other groups. Furthermore, systolic function progressively deteriorated in the HF group only (ejection fraction, 1 day = 55.6 ± 3.6%, 28 days = 17.6 ± 4.1%, P < 0.05) with an increase of brain natriuretic peptide by 3.5-fold. This surgical model of pressure overload in the setting of a small infarction causes progressive deterioration of cardiac structural and functional properties, and provides a clinically relevant tool to study adverse LV remodelling and heart failure. PMID:25311547
Weinheimer, Carla J; Lai, Ling; Kelly, Daniel P; Kovacs, Attila
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. PMID:24782647
Wu, Ri-Han; Feng, Chao; Xu, Yu; Hua, Ting; Liu, Xue-Yuan; Fang, Min
CD18 integrins mediate leucocyte adhesion to vascular endothelium. This represents the initial step in inflammatory cell infiltration following myocardial necrosis. The current studyassessed whether the expression of these rapidly activated and readily measured adhesion receptors on circulating neutrophils would reflect the extent of cardiac damage in a rabbit model of acute myocardial infarction. Myocardial ischaemia\\/infarction was induced in anaesthetised adult
Graham Hillis; Pamela Taggart; William Dalsey; Antoinette Mangione; Xin-Liang Ma
Background Although free radicals have been reported to play a role in the expansion of ischemic brain lesions, the effect of free radical scavengers is still under debate. In this study, the temporal profile of ischemic stroke lesion sizes was assessed for more than one year to evaluate the effect of edaravone which might reduce ischemic damage. Methods We sequentially enrolled acute ischemic stroke patients, who admitted between April 2003 and March 2004, into the edaravone(-) group (n = 83) and, who admitted between April 2004 and March 2005, into the edaravone(+) group (n = 93). Because, edaravone has been used as the standard treatment after April 2004 in our hospital. To assess the temporal profile of the stroke lesion size, the ratio of the area [T2-weighted magnetic resonance images (T2WI)/iffusion-weighted magnetic resonance images (DWI)] were calculated. Observations on T2WI were continued beyond one year, and observational times were classified into subacute (1-2 months after the onset), early chronic (3-6 month), late chronic (7-12 months) and old (?13 months) stages. Neurological deficits were assessed by the National Institutes of Health Stroke Scale upon admission and at discharge and by the modified Rankin Scale at 1 year following stroke onset. Results Stroke lesion size was significantly attenuated in the edaravone(+) group compared with the edaravone(-) group in the period of early and late chronic observational stages. However, this reduction in lesion size was significant within a year and only for the small-vessel occlusion stroke patients treated with edaravone. Moreover, patients with small-vessel occlusion strokes that were treated with edaravone showed significant neurological improvement during their hospital stay, although there were no significant differences in outcome one year after the stroke. Conclusion Edaravone treatment reduced the volume of the infarct and improved neurological deficits during the subacute period, especially in the small-vessel occlusion strokes. PMID:21447190
BACKGROUND: Intravenous transplantation has been regarded as a most safe method in stem cell therapies. There is evidence showing the homing of bone marrow stem cells (BMSCs) into the injured sites, and thus these cells can be used in the treatment of acute myocardial infarction (MI). This study aimed to investigate the effect of intravenous and epicardial transplantion of BMSCs on myocardial infarction size in a rabbit model. METHODS: A total of 60 New Zealand rabbits were randomly divided into three groups: control group, epicardium group (group I) and ear vein group (group II). The BMSCs were collected from the tibial plateau in group I and group II, cultured and labeled. In the three groups, rabbits underwent thoracotomy and ligation of the middle left anterior descending artery. The elevation of ST segment >0.2 mV lasting for 30 minutes on the lead II and III of electrocardiogram suggested successful introduction of myocardial infarction. Two weeks after myocardial infarction, rabbits in group I were treated with autogenous BMSCs at the infarct region and those in group II received intravenous transplantation of BMSCs. In the control group, rabbits were treated with PBS following thoracotomy. Four weeks after myocardial infarction, the heart was collected from all rabbits and the infarct size was calculated. The heart was cut into sections followed by HE staining and calculation of infarct size with an image system. RESULTS: In groups I and II, the infarct size was significantly reduced after transplantation with BMSCs when compared with the control group (P<0.05). However, there was no significant difference in the infarct size between groups I and II (P>0.05). CONCLUSION: Transplantation of BMSCs has therapeutic effect on MI. Moreover, epicardial and intravenous transplantation of BMSCs has comparable therapeutic efficacy on myocardial infarction. PMID:25215138
Ji, Li-li; Long, Xiao-feng; Tian, Hui; Liu, Yu-fei
Periodontal disease is a predictor of stroke and cognitive impairment. The association between the number of lost teeth (an indicator of periodontal disease) and silent infarcts and cerebral white matter changes on brain CT was investigated in community-dwelling adults without dementia or stroke. Dental examination and CT were performed in 438 stroke- and dementia-free subjects older than 50 yr (mean age, 63 ± 7.9 yr), who were recruited for an early health check-up program as part of the Prevention of Stroke and Dementia (PRESENT) project between 2009 and 2010. In unadjusted analyses, the odds ratio (OR) for silent cerebral infarcts and cerebral white matter changes for subjects with 6-10 and > 10 lost teeth was 2.3 (95% CI, 1.38-4.39; P = 0.006) and 4.2 (95% CI, 1.57-5.64; P < 0.001), respectively, as compared to subjects with 0-5 lost teeth. After adjustment for age, education, hypertension, diabetes mellitus, hyperlipidemia, and smoking, the ORs were 1.7 (95% CI, 1.08-3.69; P = 0.12) and 3.9 (95% CI, 1.27-5.02; P < 0.001), respectively. These findings suggest that severe tooth loss may be a predictor of silent cerebral infarcts and cerebral white matter changes in community-dwelling, stroke- and dementia-free adults. PMID:23772160
Minn, Yang-Ki; Park, Hyunyoung; Cheong, Jin-Sung; Yang, Hyunduk; Lee, Sungik; Do, Seung-Yeon; Kang, Ji-Sook
Our objective was to investigate the effect of cilostazol in acute therapy for small vessel stroke patients. The neurologic deficits in some patients of small vessel brain infarction will progress even if a patient takes immediate medical treatments including aspirin or other antiplatelet drugs. In Japan, cilostazol, presenting not only the antiplatelet effect but also the arteriole dilation, is used for treatment of ischemic stroke. In this study, acute stroke patients with small vessel occlusion were treated with cilostazol instead of aspirin in the conventional medication after 2010. Therefore, patients between April 2007 and March 2009 were classified into the conventional group (group-con, n=220), and patients between April 2010 and March 2012 were classified into the cilostazol group (group-cilo, n=230). Enrolled patients were classified into lacunar infarction (LI) and branch atheromatous disease. Progressing stroke was defined as the increase of National Institutes of Health Stroke Scale score of 2 or more within 48 hours. The clinical outcome was assessed by the modified Rankin Scale (mRS) score at 1 month. As the result, the significant reduction in progressing stroke was dominant in the LI of brainstem (P=.01). The length of hospital stay was significantly shorter in the group-cilo compared with the group-con (18.6 and 21.2 days, P=.03). Moreover, mRS score at 1 month was significantly lower in the group-cilo than the group-con (1.9 and 2.3, P=.03). In conclusion, cilostazol reduced the risk of early neurologic deterioration of patients with small vessel brain infarction. It is eagerly desired to conduct a large randomized control trial. PMID:24513481
Nakase, Taizen; Sasaki, Masahiro; Suzuki, Akifumi
Cerebral ischemic injury activates a robust inflammatory response, exacerbating neurological deficit. Several brain specific microRNA (miRNA) molecules have been reported to mediate functioning of the immune system, referred to as NeurimmiR. We aimed to explore possible associations between serum miRNA levels and stroke severity and their involvement in the regulation of inflammatory responses after stroke. Blood samples were obtained from 31 patients with acute ischemic stroke and 11 healthy controls. We evaluated infarct volume using diffusion weighted imaging and neurological deficit using the National Institutes of Health Stroke Scale. Serum levels of three NeurimmiR, miR-124, miR-9 and miR-219 were detected by real-time polymerase chain reaction and serum levels of metalloproteinase-9 (MMP-9), a proinflammation marker in brain injury, were examined by enzyme-linked immunosorbent assay. We found that serum miR-124 was significantly decreased within 24hours after stroke onset and serum miR-9 was decreased in patients with larger stroke. There were no significant changes in serum miR-219. Both serum miR-124 and miR-9 levels within 24hours were negatively correlated with infarct volume and plasma high-sensitivity C-reactive protein levels. All three NeurimmiR negatively correlated with MMP-9 levels. Our preliminary findings indicate that serum miR-124, miR-9 and miR-219 are suppressed in acute ischemic stroke thus facilitating neuroinflammation and brain injury. PMID:25257664
Liu, Yanping; Zhang, Junjian; Han, Rongfei; Liu, Hanxing; Sun, Dong; Liu, Xuan
Vertebral artery (VA) injuries usually accompany cervical trauma. Although these injuries are commonly asymptomatic, some result in vertebrobasilar infarction. The symptoms of VA occlusion have been reported to usually manifest within 24 hours after trauma. The symptoms of bilateral VA occlusions seem to be more severe and seem to occur with shorter latencies than those of unilateral occlusions. A 48-year-old man had a C3-4 fracture-dislocation with spinal cord compression that resulted from a traffic accident. After surgery, his initial quadriparesis gradually improved. However, he complained of sudden headache and dizziness on the 5th postoperative day. His motor weakness was abruptly aggravated. Radiologic evaluation revealed an infarction in the occipital lobe and cerebellum. Cerebral angiography revealed complete bilateral VA occlusion. We administered anticoagulation therapy. After 6 months, his weakness had only partially improved. This case demonstrates that delayed infarction due to bilateral VA occlusion can occur at latencies as long as 5 days. Thus, we recommend that patients with cervical traumas that may be accompanied by bilateral VA occlusion should be closely observed for longer than 5 days. PMID:25328652
Jang, Donghwan; Kim, Choonghyo; Lee, Seung Jin
Cyclosporin is an immunosuppressant that has recently been proposed as a treatment to prevent reperfusion injury in acute myocardial infarction (MI). We aimed to determine the overall efficacy of cyclosporin in experimental studies of acute reperfused MI. We conducted a systematic review and stratified meta-analysis of published studies describing the efficacy of cyclosporin in experimental models of acute reperfused MI. We included all in vivo publications of cyclosporin where infarct size was measured. A literature search identified 29 potential studies of which 20 fulfilled the eligibility criteria. In these studies (involving four species of animals), cyclosporin reduced myocardial infarct size by a standardized mean (95% confidence interval) difference of ?1.60 (?2.17, ?1.03) compared with controls. Cyclosporin failed to demonstrate a convincing benefit in studies involving pigs. Despite this observation, the overall efficacy of cyclosporin did not differ across species (P= 0.358). The dose of cyclosporin given did not affect final infarct size (P= 0.203). Funnel plots of these data suggested heterogeneity among the studies. Cyclosporin had variable effects on infarct size compared with placebo. Cyclosporin had no effect on myocardial infarct size in swine, raising a question over the potential cardioprotective effects of cyclosporin in man. PMID:21950961
Lim, WY; Messow, CM; Berry, C
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
Gas embolism occurs commonly in cardiac and vascular surgery and decompression sickness. The goals of this study were to develop a new in vivo rat model of cerebrovascular arterial gas embolism and to determine the effects of exogenous surfactants on resultant brain infarct volume and accompanying long-term neurological dysfunction using the model. Unilateral cerebral arterial gas embolism was induced in Sprague Dawley rats, including groups receiving intravenous Pluronic F-127 (PF-127) and Oxycyte perflourocarbon surfactant pretreatment. Magnetic resonance imaging (MRI) was performed at 24 and 72 h postembolism to determine infarct volume. The elevated body swing test (EBST), limb-placement test, proprioception forelimb and hindlimb tests, whisker tactile test, and Morris Water Maze test were performed to assess motor behavior, somatosensory deficit, and spatial cognitive function out to 29 days after embolization. A stable stroke model was developed with MRI examination revealing infarction in the ipsilateral cerebral hemisphere. Gas embolized rats had significant cognitive and sensorimotor dysfunction, including approximately threefold increase in Morris Water Maze latency time, ?20% left-sided biasing in EBST performance, 0.5 to 1.5 (mean) point score elevations in the proprioception and whisker tactile tests, and 3.0 point (mean) elevation in the limb-placement test, all of which were persistent throughout the postembolic period. Surfactant prophylaxis with either PF-127 or Oxycyte rendered stroke undetectable by MRI scanning and markedly reduced the postembolic deficits in both cognitive and sensorimotor performance in treated rats, with normalization of EBST and whisker tactile tests within 7 days. PMID:23845977
Armstead, Stephen C.
Recently, a noninvasive method for determining regional myocardial contractility, using an animal-specific finite element (FE) model-based optimization, was developed to study a sheep with anteroapical infarction (Sun et al., 2009, "A Computationally Efficient Formal Optimization of Regional Myocardial Contractility in a Sheep With Left Ventricular Aneurysm," ASME J. Biomech. Eng., 131(11), p. 111001). Using the methodology developed in the previous study (Sun et al., 2009, "A Computationally Efficient Formal Optimization of Regional Myocardial Contractility in a Sheep With Left Ventricular Aneurysm," ASME J. Biomech. Eng., 131(11), p. 111001), which incorporates tagged magnetic resonance images, three-dimensional myocardial strains, left ventricular (LV) volumes, and LV cardiac catheterization pressures, the regional myocardial contractility and stress distribution of a sheep with posterobasal infarction were investigated. Active material parameters in the noninfarcted border zone (BZ) myocardium adjacent to the infarct (T(max_B)), in the myocardium remote from the infarct (T(max_R)), and in the infarct (T(max_I)) were estimated by minimizing the errors between FE model-predicted and experimentally measured systolic strains and LV volumes using the previously developed optimization scheme. The optimized T(max_B) was found to be significantly depressed relative to T(max_R), while T(max_I) was found to be zero. The myofiber stress in the BZ was found to be elevated, relative to the remote region. This could cause further damage to the contracting myocytes, leading to heart failure. PMID:21428685
Wenk, Jonathan F; Sun, Kay; Zhang, Zhihong; Soleimani, Mehrdad; Ge, Liang; Saloner, David; Wallace, Arthur W; Ratcliffe, Mark B; Guccione, Julius M
Relationship of Left Atrial Global Peak Systolic Strain with Left Ventricular Diastolic Dysfunction and Brain Natriuretic Peptide Level in Patients Presenting with Non-ST Elevation Myocardial Infarction
Background In patients presenting with non-ST elevation myocardial infarction, we investigated the relationship of left atrial deformational parameters evaluated by 2-dimensional speckle tracking imaging (2D-STI) with conventional echocardiographic diastolic dysfunction parameters and brain natriuretic peptide level. Material/Methods We enrolled 74 non-ST segment elevation myocardial infarction patients who were treated with percutaneous coronary intervention and 58 healthy control subjects. Non-ST segment elevation myocardial infarction patients had echocardiographic examination 48 h after the percutaneous coronary intervention procedure and venous blood samples were drawn simultaneously. In addition to conventional echocardiographic parameters, left atrial strain curves were obtained for each patient. Average peak left atrial strain values during left ventricular systole were measured. Results BNP values were higher in non-ST segment elevation myocardial infarction patients compared to controls. Mean left atrium peak systolic global longitudinal strain in Group 2 (the control group) was higher than in the non-ST segment elevation myocardial infarction group. Left atrium peak systolic global longitudinal strain was significantly correlated with left ventricular ejection fraction. There was a significant inverse correlation between left atrium peak systolic global longitudinal strain and brain natriuretic peptide level, left atrium volume maximum, and left atrium volume minimum. Conclusions Our study shows that Left atrium peak systolic global longitudinal strain values decreased consistently with deteriorating systolic and diastolic function in non-ST segment elevation myocardial infarction patients treated with percutaneous coronary intervention. Left atrium peak systolic global longitudinal strain measurements may be helpful as a complimentary method to evaluate diastolic function in this patient population. PMID:25338184
De?irmenci, Hüsnü; Bak?rc?, Eftal Murat; Demirta?, Levent; Duman, Hakan; Hamur, Hikmet; Ceyhun, Gökhan; Topal, Ergün
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. PMID:24367790
Spata, Tyler; Bobek, Daniel; Whitson, Bryan A.; Parthasarathy, Sampath; Mohler, Peter J.; Higgins, Robert S. D.; Kilic, Ahmet
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. PMID:23965746
Mehta, Rupal I; Ivanova, Svetlana; Tosun, Cigdem; Castellani, Rudy J; Gerzanich, Volodymyr; Simard, J Marc
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. PMID:23965746
Mehta, Rupal I.; Ivanova, Svetlana; Tosun, Cigdem; Castellani, Rudy J.; Gerzanich, Volodymyr
Background The cardiac regenerative potential of newly developed therapies is traditionally evaluated in rodent models of surgically induced myocardial ischemia. A generally accepted key parameter for determining the success of the applied therapy is the infarct size. Although regarded as a gold standard method for infarct size estimation in heart ischemia, histological planimetry is time-consuming and highly variable amongst studies. The purpose of this work is to contribute towards the standardization and simplification of infarct size assessment by providing free access to a novel semi-automated software tool. The acronym MIQuant was attributed to this application. Methodology/Principal Findings Mice were subject to permanent coronary artery ligation and the size of chronic infarcts was estimated by area and midline-length methods using manual planimetry and with MIQuant. Repeatability and reproducibility of MIQuant scores were verified. The validation showed high correlation (rmidline length?=?0.981; rarea?=?0.970 ) and agreement (Bland-Altman analysis), free from bias for midline length and negligible bias of 1.21% to 3.72% for area quantification. Further analysis demonstrated that MIQuant reduced by 4.5-fold the time spent on the analysis and, importantly, MIQuant effectiveness is independent of user proficiency. The results indicate that MIQuant can be regarded as a better alternative to manual measurement. Conclusions We conclude that MIQuant is a reliable and an easy-to-use software for infarct size quantification. The widespread use of MIQuant will contribute towards the standardization of infarct size assessment across studies and, therefore, to the systematization of the evaluation of cardiac regenerative potential of emerging therapies. PMID:21980376
Esteves, Tiago; de Pina, Maria de Fátima; Guedes, Joana G.; Freire, Ana; Quelhas, Pedro; Pinto-do-Ó, Perpétua
We prospectively studied 26 patients with ischemic stroke within 24 hr, after 2 wk, and after 6 mo with thallium-201-diethyldithiocarbamate single-photon emission computed tomography (SPECT) and neurologic and functional assessments. The admission flow deficits correlated with outcome. The admission and 6-mo scores correlated with clinical conditions at each time. At 2 wk, the flow deficits were smaller and did not correlate with clinical parameters. Nor did the presence or absence of hyperfixation of the radiopharmaceutical. Six months after the infarct, the flow defect had decreased in 9 of 15 patients in whom three serial scans were available, with better clinical improvement than in the remaining six whose flow deficits increased. More patients in the first group had been treated randomly with the calcium-entry blocker flunarizine. SPECT imaging of rCBF within 24 hr after stroke correlates with clinical outcome and condition, whereas rCBF imaging at 2 wk after the stroke shows no clinical correlation. PMID:1848607
Limburg, M; van Royen, E A; Hijdra, A; Verbeeten, B
Functional reorganization forms the critical mechanism for the recovery of function after brain damage. These processes are driven by inherent changes within the central nervous system (CNS) triggered by the insult and further depend on the neural input the recovering system is processing. Therefore these processes interact with not only the interventions a patient receives, but also the activities and behaviors a patient engages in. In recent years, a wide range of research programs has addressed the association between functional reorganization and the spontaneous and treatment-induced recovery. The bulk of this work has focused on upper-limb and hand function, and today there are new treatments available that capitalize on the neuroplasticity of the brain. However, this is only true for patients with mild to moderated impairments; for those with very limited hand function, the basic understanding is much poorer and directly translates into limited treatment opportunities for these patients. The present paper aims to highlight the knowledge gap on severe stroke with a brief summary of the literature followed by a discussion of the challenges involved in the study and treatment of severe stroke and poor long-term outcome. PMID:22548196
Sterr, Annette; Conforto, Adriana Bastos
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
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
Harada, Katsuhiro; Ohwatashi, Akihiko; Kamikawa, Yurie
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
The Silent Cerebral Infarct Multicenter Transfusion (SIT) Trial is a multi-institutional intervention trial in which children with silent cerebral infarcts are randomized to receive either blood transfusion therapy or observation (standard care) for 36 months. The SIT Trial is scheduled to enroll approximately 1,880 children with sickle cell disease from 29 clinical sites in the United States, Canada, UK, and France. Each child undergoes a screening magnetic resonance imaging (MRI) of the brain to detect the presence of silent cerebral infarct-like lesions, a pre-randomization (baseline) MRI and exit MRI to determine if there are new or enlarged cerebral infarcts, using a designated, prospective imaging protocol. The objective of this manuscript is to describe the innovative method used to process and adjudicate imaging studies for an international trial with a primary endpoint that includes neuroimaging. Institution investigators at each site were provided with computer hardware and software for transmission of MRI images that allow them to strip the scans of all personal information and add unique study identifiers. Three neuroradiologists at separate academic centers review MRI studies and determine the presence or absence of silent cerebral infarct-like lesions. Their findings are subsequently placed on web-based case report forms and sent to the Statistical Coordinating Center. The average time from imaging center receipt of the MRI study to the radiology committee report back to the local site is less than two working days. This novel strategy was designed to maximize efficiency and minimize cost of a complex large multicenter trial that depends heavily on neuroimaging for entry criteria and assessment for the primary outcome measures. The technology, process, and expertise used in the SIT Trial can be adapted to virtually any clinical research trial with digital imaging requirements. PMID:18398653
Vendt, Bruce A; McKinstry, Robert C; Ball, William S; Kraut, Michael A; Prior, Fred W; Barton, Bruce; Casella, James F; DeBaun, Michael R
Current efforts to reduce prehospital cardiac mortality focus more on deployment of specially equipped ambulances than on reduction of patient or ambulance delays. To evaluate this strategy, we needed to find a method that would isolate the separate effects of patient delay, ambulance delay, and the resuscitative capability of the ambulance. Using published data, we have generated a mathematical model of death from ventricular fibrillation following myocardial infarction that shows the relationship among these three factors. Analyses based on the model indicate that the potential life saving impact of a defibrillation-equipped ambulance is severely limited due to typical patient response patterns. If the ambulance arrives ten minutes after the onset of infarction, defibrillation capabilities will reduce prehospital mortality from 6 percent to 2 percent. After a more typical delay of 60 minutes, the mortality rises sharply to 13 percent for an unequipped ambulance. With a delay of this length, defibrillation capabilities reduce mortality only to about 12 percent. PMID:521294
Cretin, S; Willemain, T R
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
Brain temperature is elevated in acute ischemic stroke, especially in the ischemic penumbra (IP). We attempted to investigate the dynamic evolution of brain temperature in different ischemic regions in a monkey model of middle cerebral artery occlusion. The brain temperature of different ischemic regions was measured with proton magnetic resonance spectroscopy (1H MRS), and the evolution processes of brain temperature were compared among different ischemic regions. We found that the normal (baseline) brain temperature of the monkey brain was 37.16°C. In the artery occlusion stage, the mean brain temperature of ischemic tissue was 1.16°C higher than the baseline; however, this increase was region dependent, with 1.72°C in the IP, 1.08°C in the infarct core, and 0.62°C in the oligemic region. After recanalization, the brain temperature of the infarct core showed a pattern of an initial decrease accompanied by a subsequent increase. However, the brain temperature of the IP and oligemic region showed a monotonously and slowly decreased pattern. Our study suggests that in vivo measurement of brain temperature could help to identify whether ischemic tissue survives. PMID:23091367
Sun, Zhihua; Zhang, Jing; Chen, Yingmin; Zhang, Yunting; Zhang, Xuejun; Guo, Hong; Yu, Chunshui
The time course of cardiac sympathetic nerve activity (CSNA) following acute myocardial infarction (MI) is unknown. We therefore undertook serial direct recordings of CSNA, arterial blood pressure (MAP) and heart rate (HR) in 11 conscious sheep before and after MI, and compared them with 10 controls. Conscious CSNA recordings were taken daily from electrodes glued into the thoracic cardiac nerves. Infarction was induced under pethidine and diazepam analgesia by applying tension to a coronary suture. MI size was assessed by left ventricular planimetry (%) at postmortem, peak troponin T and brain natriuretic peptide levels (BNP). Baroreflex slopes were assessed daily using phenylephrine-nitroprusside ramps. The mean infarcted area was 14.4 +/- 2.9%, troponin T 1.88 +/- 0.39 microg l(-1) and BNP 8.4 +/- 1.3 pmol l(-1). There were no differences in haemodynamic parameters or CSNA between groups at baseline. MAP and HR remained constant following MI. CSNA burst frequency increased from baseline levels of 55.8 +/- 7.1 bursts min(-1) to levels of 77.5 +/- 8.7 bursts min(-1) at 2 h post-MI, and remained elevated for 2 days (P < 0.001). CSNA burst area also increased and was sustained for 7 days following MI (P= 0.016). Baroreflex slopes for pulse interval and CSNA did not change. CSNA increases within 1 h of the onset of MI and is sustained for at least 7 days. The duration of this response may be longer because the recording fields decrease with time. This result is consistent with a sustained cardiac excitatory sympathetic reflex. PMID:15774526
Jardine, D L; Charles, C J; Ashton, R K; Bennett, S I; Whitehead, M; Frampton, C M; Nicholls, M G
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
Summary BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors after acute myocardial infarction (MI) prevent heart failure and\\u000a recurrent ischemic events. Our aim was to evaluate the effect of ramipril on N-terminal pro-brain natriuretic peptide (NT-proBNP)\\u000a and on markers of hemostasis, including plasminogen-activator-inhibitor-1 (PAI-1), von Willebrand factor (vWF), factor VIII\\u000a (FVIII) and fibrinogen, in patients after acute MI, with emphasis on those over 55
Lower mean hemoglobin (HGB) levels are associated with unfavorable outcome after spontaneous subarachnoid hemorrhage (SAH). Currently, there is no cutoff level for mean HGB levels associated with unfavorable outcome. This study was conducted to evaluate a threshold for mean HGB concentrations after SAH, and to observe the relation to outcome. The medical records of 702 patients with spontaneous SAH were reviewed. Predictors of outcome were proved by univariate analysis. Predictors with p<0.1 were included in a multivariate binary logistic regression model. Cutoff points for mean HGB levels were calculated by receiver operating characteristic curve analysis. Mean HGB was 11.9g/dl (±standard deviation [SD] 1.7g/dl) in patients with favorable outcome compared to 10.8g/dl (±SD 1.1g/dl) in patients with unfavorable outcome (p<0.001). The highest Youden's index value was found for a HGB cutoff at 11.1g/dl. In a binary logistic regression model, predictors of unfavorable outcome were identified as an initially high Hunt-Hess grade (odds ratio [OR]: 7.7; 95% confidence interval [CI]: 4.4-13.4; p<0.001), cerebral infarction on a CT scan during hospital stay (OR: 3.8; 95% CI: 2.0-7.3; p<0.001), rebleeding during the hospital stay (OR: 3.5; 95% CI: 1.6-8.0; p=0.002), mean HGB concentration <11.1g/dl (OR: 3.3; 95% CI: 2.0-5.3; p<0.001), and hydrocephalus (OR: 2.3; 95% CI: 1.4-3.7; p=0.001). In conclusion, a mean HGB concentration <11.1g/dl during the hospital stay was associated with unfavorable outcome after acute SAH. PMID:25533213
Stein, Marco; Brokmeier, Lisa; Herrmann, Johannes; Scharbrodt, Wolfram; Schreiber, Vanessa; Bender, Michael; Oertel, Matthias F
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. PMID:24330751
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. PMID:24456675
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
Stroke is a severe neurological disorder characterized by the abrupt loss of blood circulation into the brain resulting into wide ranging brain and behavior abnormalities. The present study was designed to evaluate molecular mechanism by which sesamin (SES) induces neuroprotection in mouse model of ischemic stroke. The results of this study demonstrate that SES treatment (30mg/kgbwt) significantly reduced infarction volume, lipid per-oxidation, cleaved-caspase-3 activation, and increased GSH activity following MCAO in adult male mouse. SES treatment also diminished iNOS and COX-2 protein expression, and significantly restored SOD activity and protein expression level in the ischemic cortex of the MCAO animals. Furthermore, SES treatment also significantly reduced inflammatory and oxidative stress markers including Iba1, Nox-2, Cox-2, peroxynitrite compared to placebo MCAO animals. Superoxide radical production, as studied by DHE staining method, was also significantly reduced in the ischemic cortex of SES treated compared to placebo MCAO animals. Likewise, downstream effects of superoxide free radicals i.e. MAPK/ERK and P38 activation was also significantly attenuated in SES treated compared to placebo MCAO animals. In conclusion, these results suggest that SES induces significant neuroprotection, by ameliorating many signaling pathways activated/deactivated following cerebral ischemia in adult mouse. PMID:25316624
Ahmad, Saif; Elsherbiny, Nehal M; Haque, Rizwanul; Khan, M Badruzzaman; Ishrat, Tauheed; Shah, Zahoor A; Khan, Mohammad M; Ali, Mehboob; Jamal, Arshad; Katare, Deepshikha Pande; Liou, Gregory I; Bhatia, Kanchan
Human brain functional networks are embedded in anatomical space and have topological properties--small-worldness, modularity, fat-tailed degree distributions--that are comparable to many other complex networks. Although a sophisticated set of measures is available to describe the topology of brain networks, the selection pressures that drive their formation remain largely unknown. Here we consider generative models for the probability of a functional connection (an edge) between two cortical regions (nodes) separated by some Euclidean distance in anatomical space. In particular, we propose a model in which the embedded topology of brain networks emerges from two competing factors: a distance penalty based on the cost of maintaining long-range connections; and a topological term that favors links between regions sharing similar input. We show that, together, these two biologically plausible factors are sufficient to capture an impressive range of topological properties of functional brain networks. Model parameters estimated in one set of functional MRI (fMRI) data on normal volunteers provided a good fit to networks estimated in a second independent sample of fMRI data. Furthermore, slightly detuned model parameters also generated a reasonable simulation of the abnormal properties of brain functional networks in people with schizophrenia. We therefore anticipate that many aspects of brain network organization, in health and disease, may be parsimoniously explained by an economical clustering rule for the probability of functional connectivity between different brain areas. PMID:22467830
Vértes, Petra E; Alexander-Bloch, Aaron F; Gogtay, Nitin; Giedd, Jay N; Rapoport, Judith L; Bullmore, Edward T
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
A PROPOSITIONAL REPRESENTATION MODEL OF ANATOMICAL AND FUNCTIONAL BRAIN DATA Pablo MATURANA as a methodological tool to examine brain network organization, topology and complex dynamics, as well brain data and neuropsychological assessments linked to the functions explored in these assessments
Paris-Sud XI, UniversitÃ© de
A compact physiologically based mean-field formulation of brain dynamics is proposed to model observed brain activity and electroencephalographic (EEG) signals. In contrast to existing formulations, which are more detailed and complicated, our model is described by a single second-order delay differential equation that encapsulates salient aspects of the physiology. The model captures essential features of activity mediated by fast corticocortical connections and delayed feedbacks via extracortical pathways and external stimuli. In the linear regime, these features can be simply expressed by three coefficients derived from the properties of these physiological pathways and explicit nonlinear approximations are also derived. This compact model successfully reproduces the main features of experimental EEG's and the predictions of previous models, including resonance peaks in EEG spectra and nonlinear dynamics. As an illustration, key features of the dynamics of epileptic seizures are shown to be reproduced by the model. Due to its compact form, the model will facilitate insight into nonlinear brain dynamics via standard nonlinear techniques and will guide analysis and investigation of more complex models. It is thus a useful tool for analyzing complex brain activity, especially when it exhibits low-dimensional dynamics. PMID:17500726
Kim, J W; Robinson, P A
A compact physiologically based mean-field formulation of brain dynamics is proposed to model observed brain activity and electroencephalographic (EEG) signals. In contrast to existing formulations, which are more detailed and complicated, our model is described by a single second-order delay differential equation that encapsulates salient aspects of the physiology. The model captures essential features of activity mediated by fast corticocortical connections and delayed feedbacks via extracortical pathways and external stimuli. In the linear regime, these features can be simply expressed by three coefficients derived from the properties of these physiological pathways and explicit nonlinear approximations are also derived. This compact model successfully reproduces the main features of experimental EEG’s and the predictions of previous models, including resonance peaks in EEG spectra and nonlinear dynamics. As an illustration, key features of the dynamics of epileptic seizures are shown to be reproduced by the model. Due to its compact form, the model will facilitate insight into nonlinear brain dynamics via standard nonlinear techniques and will guide analysis and investigation of more complex models. It is thus a useful tool for analyzing complex brain activity, especially when it exhibits low-dimensional dynamics.
Kim, J. W.; Robinson, P. A.
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
While baseline N-terminal brain natriuretic peptide (NT-proBNP) is useful in the prognosis of acute ST-elevation myocardial infarction (STEMI), it is unclear whether a relationship exists between serial NT-proBNP, reperfusion success, and prognosis. We prospectively defined a NT-proBNP analysis in the WEST (Which Early ST-elevation myocardial infarction Therapy) trial that enrolled 304 acute STEMI patients. NT-proBNP (pg/mL) was measured at baseline prior to treatment (n=258) and 72 to 96 h (n=247) and 30 days (n=221) after treatment (Delta NT-proBNP=72 h value - the baseline NT-proBNP). Reperfusion success was measured by ST-segment resolution at 180 min, infarct size by peak creatine kinase (CK) during the first 24 h, and QRS score at discharge (QRSd). The primary endpoint was a 30 day clinical composite. The ability of either baseline NT-proBNP or Delta NT-proBNP to predict the primary endpoint was compared using single-variable logistic regression and the c-statistic. Median (interquartile range) NT-proBNP in pg/mL was 87 (39-316) at baseline, 864 (338-1857) at 72 h, and 585 (264-1212) at 30 days. ST resolution was inversely correlated with Delta NT-proBNP (r=-0.23, p=0.002) and 30 day NT-proBNP (30 day NT-proBNP 1016, 828, and 397 for <30%, 30%-70%, >or=70% STR, respectively, p<0.001). Infarct size was correlated with Delta NT-proBNP by CK (r=0.41, p<0.001) and QRSd (r=0.31, p<0.001); the 30 day NT-proBNP relationship was similar for CK (r=0.48, p<0.001) and QRSd (p=0.003). The baseline NT-proBNP was associated with an increased 30-day composite endpoint (Q1, 19%; Q2, 20%; Q3, 15%; Q4, 38%; p=0.03 for trend) as was Delta NT-proBNP (Q1, 16%; Q2, 18%; Q3, 19%; Q4, 37%; p=0.009 for trend). The c-statistic for baseline, 72 to 96 h, and Delta NT-proBNP was 0.59, 0.61, and 0.62 for the 30-day composite and 0.64, 0.62, and 0.62 for the 90-day composite, respectively. Delta NT-proBNP clearly predicts short-term adverse cardiac events and is superior to baseline NT-proBNP, but similar to the 72 to 96 h NT-proBNP in predicting clinical events after STEMI. This likely reflects the variability in NT-proBNP at presentation and the ability to integrate subsequent important physiologic sequelae of STEMI such as reperfusion and infarct size. PMID:17487257
Ezekowitz, Justin A; Théroux, Pierre; Welsh, Robert; Bata, Iqbal; Webb, John; Armstrong, Paul W
Computational Modeling of Brain Dynamics during Repetitive Head Motions Igor Szczyrba School motions in traumatic scenarios that are as- sociated with severe brain injuries. Our results are based on the linear Kelvin-Voigt brain injury model, which treats the brain matter as a viscoelastic solid, and on our
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
1. This study examined whether endothelin-1 (ET-1) reduces infarct size in a rabbit model of acute coronary artery occlusion (60 min) and reperfusion (120 min). In addition, we investigated whether the observed cardioprotective effect of ET-1 was due to the activation of ATP-sensitive potassium (KATP) channels by using two selective antagonists, glibenclamide and sodium 5-hydroxydecanoate (5-HD). 2. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 2 h of reperfusion was 55 +/- 4% (n = 11). ET-1 (0.3 nmol kg-1), administered as a bolus injection into the left ventricle, had no effect on infarct size (62 +/- 2%, n = 4). A lower dose of ET-1 (0.03 nmol kg-1) resulted in a significant reduction in infarct size (infarct size 43 +/- 3%; P < 0.05, n = 16). The higher dose (0.3 nmol kg-1), but not the lower dose of ET-1 caused a significant rise in blood pressure, pressure rate index and hence, myocardial oxygen consumption. 3. The reduction in infarct size afforded by ET-1 (0.03 nmol kg-1) was abolished by pretreatment of rabbits with the KATP channel inhibitors, glibenclamide (0.3 mg kg-1) and 5-HD (5 mg kg-1), (infarct size 59 +/- 3 and 63 +/- 4% respectively; n = 4-9). 4. We propose that ET-1 reduces infarct size by opening KATP channels. PMID:8590976
Hide, E. J.; Piper, J.; Thiemermann, C.
Mathematical models of varying complexity have proved useful in fitting and interpreting regional cardiac displacements obtained from imaging methods such as ultrasound speckle tracking or MRI tagging. Simpler models, such as the classic thick-walled cylinder model of the left ventricle (LV), can be solved quickly and are easy to implement, but they ignore regional geometric variations and are difficult to adapt to the study of regional pathologies like myocardial infarctions. Complex, anatomically accurate finite-element models work well, but are computationally intensive and require specialized expertise to implement. We developed a kinematic model that offers a compromise between these two traditional approaches, assuming only that displacements in the left ventricle are polynomial functions of initial position and that the myocardium is nearly incompressible, while allowing myocardial motion to vary spatially as would be expected in an ischemic or dyssynchronous LV. Model parameters were determined using an objective function with adjustable weights to account for confidence in individual displacement components and desired strength of the incompressibility constraint. The model accurately represented the motion of both normal and infarcted mouse LVs during the cardiac cycle, with normalized root mean square errors in predicted deformed positions of 8.2 ± 2.3% and 7.4 ± 2.1% for normal and infarcted hearts, respectively. PMID:25542490
Lin, Dan; French, Brent A; Xu, Yaqin; Hossack, John A; Holmes, Jeffrey W
An endovascular model of focal brain ischemia in rats with controlled duration of reperfusion of 1h has been studied. The reliability of experimental model for localization and volume of ischemic lesion (basal ganglia, hippocampus, parietal-temporal regions; the volume of lesion focus on MRI T2-weighted image (T2-WI) in the first day after brain ischemia 146.4 +/- 44.7 mm3) has been worked out. We conducted the clinical monitoring including assessment of neurological deficit, behavioral tests and performed MRI of the brain on 1st, 5th and 10-17th days after the occlusion of middle cerebral artery (MCA), including regimes of diffusion-weighted image (DWI) and T2-WI, and carried out a histological study of the brain. The regress of neurological deficit was seen on the 14th day after surgery. Behavioral tests revealed the reduction of movement activity of animals in the case group 7 days after the MCA occlusion. Compared to the first day after surgery, the decrease of volume lesion focus on DWI and T2-WI was observed on the 5th day (p < 0.05) as well, with the following decrease to the 10-14th days. The histological picture in the lesion foci corresponded to the brain infarction on the 5th and 14th days after surgery. PMID:19894303
Skvortsova, V I; Iarygin, V N; Pirogov, Iu A; Gubski?, L V; Iarygin, K N; Tairova, R T; Uchevatkin, A A; Glushkova, T G
A low-dimensional, compact brain model has recently been developed based on physiologically based mean-field continuum formulation of electric activity of the brain. The essential feature of the new compact model is a second order time-delayed differential equation that has physiologically plausible terms, such as rapid corticocortical feedback and delayed feedback via extracortical pathways. Due to its compact form, the model facilitates insight into complex brain dynamics via standard linear and nonlinear techniques. The model successfully reproduces many features of previous models and experiments. For example, experimentally observed typical rhythms of electroencephalogram (EEG) signals are reproduced in a physiologically plausible parameter region. In the nonlinear regime, onsets of seizures, which often develop into limit cycles, are illustrated by modulating model parameters. It is also shown that a hysteresis can occur when the system has multiple attractors. As a further illustration of this approach, power spectra of the model are fitted to those of sleep EEGs of two subjects (one with apnea, the other with narcolepsy). The model parameters obtained from the fittings show good matches with previous literature. Our results suggest that the compact model can provide a theoretical basis for analyzing complex EEG signals.
Kim, J. W.; Shin, H.-B.; Robinson, P. A.
Background Polymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model. Methods In anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis. Results ADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data. Conclusions ADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability. PMID:20875134
In the last decade typical signs of spinal cord ischemia have been reported. Confirming and supporting signs of acute ischemic\\u000a myelomalacia are vertebral body infarction and the pathognomonic contrast enhancement of the cauda equina in the course of\\u000a the disease. Moreover, bone infarction strongly indicates the proximal occlusion and the level of the affected segmental artery.\\u000a Cartilaginous disc embolism, embolism
Michael Mull; Armin Thron
High incidences of myocardial infarction associated with high morbidity and mortality, are a major concern and economic burden on industrialized nations. Persistent ?-adrenergic receptor stimulation with isoproterenol leads to the development of oxidative stress, myocardial inflammation, thrombosis, platelet aggregation and calcium overload, which ultimately cause myocardial infarction. Therapeutic agents that are presently employed for the prevention and management of myocardial infarction are beta-blockers, antithrombotics, thrombolytics, statins, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers, calcium channel blockers and nitrovasodilators. In spite of effective available interventions, the mortality rate of myocardial infarction is progressively increasing. Thus, there has been a regular need to develop effective therapies for the prevention and management of this insidious disease. In this review, the authors give an overview of the consequences of isoproterenol in the pathogenesis of cardiac disorders and various therapeutic possibilities to prevent these disorders. PMID:24817146
Garg, Monika; Khanna, Deepa
Modelling of Brain Consciousness based on Collaborative Adaptive Filters Ling Lia, , Yili Xiaa of Technology, Japan c Laboratory for Advanced Brain Signal Processing, RIKEN Brain Science Institute, Saitama method for the discrimination between discrete states of brain con- sciousness is proposed, achieved
Kent, University of
Doppler Ultrasound Driven Biomechanical Model of the Brain for Intraoperative Brain of the target is essential to reduce mor- bidity during brain tumor removal interventions. Yet, image-guided neu- rosurgery faces an important issue for large skull openings where brain soft-tissues can exhibit large
Paris-Sud XI, UniversitÃ© de
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
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. PMID:21760967
Yu, Xinge; Li, Yang V
Myocardial infarction (MI) significantly alters the structure and function of the heart. As abnormal strain may drive heart failure and the generation of arrhythmias, we used computational methods to simulate a left ventricle with an MI over the course of a heartbeat to investigate strains and their potential implications to electrophysiology. We created a fully coupled finite element model of myocardial electromechanics consisting of a cellular physiological model, a bidomain electrical diffusion solver, and a nonlinear mechanics solver. A geometric mesh built from magnetic resonance imaging (MRI) measurements of an ovine left ventricle suffering from a surgically induced anteroapical infarct was used in the model, cycled through the cardiac loop of inflation, isovolumic contraction, ejection, and isovolumic relaxation. Stretch-activated currents were added as a mechanism of mechanoelectric feedback. Elevated fiber and cross fiber strains were observed in the area immediately adjacent to the aneurysm throughout the cardiac cycle, with a more dramatic increase in cross fiber strain than fiber strain. Stretch-activated channels decreased action potential (AP) dispersion in the remote myocardium while increasing it in the border zone. Decreases in electrical connectivity dramatically increased the changes in AP dispersion. The role of cross fiber strain in MI-injured hearts should be investigated more closely, since results indicate that these are more highly elevated than fiber strain in the border of the infarct. Decreases in connectivity may play an important role in the development of altered electrophysiology in the high-stretch regions of the heart. PMID:22058157
Wall, Samuel T; Guccione, Julius M; Ratcliffe, Mark B; Sundnes, Joakim S
BackgroundPreterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury.MethodsC57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining.ResultsHI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model.ConclusionsWe have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury. PMID:25187205
Albertsson, Anna-Maj; Bi, Dan; Duan, Luqi; Zhang, Xiaoli; Leavenworth, Jianmei W; Qiao, Lili; Zhu, Changlian; Cardell, Susanna; Cantor, Harvey; Hagberg, Henrik; Mallard, Carina; Wang, Xiaoyang
Ongoing basic molecular analyses are being performed in mice, and a simple long-surviving murine model of myocardial infarction (MI) would be very useful in this regard. Although a few studies have induced MI in mice by coronary artery ligation, the induction involves a complex technique and has a relatively high mortality rate. In addition, the identification of the basic pathological sequence is essential to the interpretation of experimental results. We developed a simple technique for the induction of MI in mice and examined qualitative and quantitative conventional microscopic findings during the pathological evolution over a 28-day observation period. Male BALB/c mice weighing approximately 25-30 g were anesthetized and then ventilated with a positive pressure ventilator. The heart was exposed by thoracotomy. Left coronary artery occlusion was performed by thermocoagulation using a thermocoagulation knife at the level of the tip of the left atrium. After establishing this surgical method, we used it to induce MI in 71 mice. The operative and postoperative mortality rates of this model were 5.6% (4/71) and 12.6% (9/71), respectively. In 3 (5.2%) of the 58 surviving mice, the area of infarct was not sufficient. The infarct area in the remaining 55 mice was 40 +/- 9% of the entire perimeter of the left ventricle. Conventional microscopic examinations with hematoxylin-eosin and Masson-trichrome staining disclosed that all of the characteristic histopathological features of MI occurred 1-2 days earlier than those in rats. Our surgical technique provides a sufficient infarct area, with an acceptable mortality rate. The present study clarified the histopathological sequence in this long surviving murine MI model. PMID:10326655
Kumashiro, H; Kusachi, S; Moritani, H; Ohnishi, H; Nakahama, M; Uesugi, T; Ayada, Y; Nunoyama, H; Tsuji, T
Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F-18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI. PMID:25552881
Sim, Doo Sun; Jeong, Myung Ho; Song, Ho Chun; Kim, Jahae; Chong, Ari; Bom, Hee Seung; Jeong, In Seok; Oh, Sang Gi; Kim, Jong Min; Park, Dae Sung; Kim, Jung Ha; Lim, Kyung Seob; Kim, Min Suk; Ryu, Shi Hyun; Kim, Hyun Kuk; Kim, Sung Soo; Jang, Su Young; Cho, Jae Yeong; Jeong, Hae Chang; Lee, Ki Hong; Park, Keun Ho; Yoon, Nam Sik; Yoon, Hyun Ju; Kim, Kye Hun; Hong, Young Joon; Park, Hyung Wook; Kim, Ju Han; Ahn, Youngkeun; Cho, Jeong Gwan; Park, Jong Chun; Kang, Jung Chaee
Differences in cognitive aging rates among mammals suggest that the pace of brain aging is geneticallyReview Cognitive aging as an extension of brain development: A model linking learning, brain plasticity, and neurodegeneration Joa~o Pedro de Magalha~es a,*, Anders Sandberg b a Department of Genetics
de MagalhÃ£es, JoÃ£o Pedro
In this study, we evaluate the effect of HO-1 upregulation on blood pressure and cardiac function in the new model of infarct spontaneous hypertensive rats (ISHR). Male spontaneous hypertensive rats (SHR) at 13 weeks (n = 40) and age-matched male Wistar (WT) rats (n = 20) were divided into six groups: WT (sham + normal saline (NS)), WT (sham + Co(III) Protoporphyrin IX Chloride (CoPP)), SHR (myocardial infarction (MI) + NS), SHR (MI + CoPP), SHR (MI + CoPP + Tin Mesoporphyrin IX Dichloride (SnMP)), SHR (sham + NS); CoPP 4.5 mg/kg, SnMP 15 mg/kg, for six weeks, one/week, i.p., n = 10/group. At the sixth week, echocardiography (UCG) and hemodynamics were performed. Then, blood samples and heart tissue were collected. Copp treatment in the SHR (MI + CoPP) group lowered blood pressure, decreased infarcted area, restored cardiac function (left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), +dp/dt(max), (-dp/dt(max))/left ventricular systolic pressure (LVSP)), inhibited cardiac hypertrophy and ventricular enlargement (downregulating left ventricular end-systolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and heart weight/body weight (HW/BW)), lowered serum CRP, IL-6 and Glu levels and increased serum TB, NO and PGI2 levels. Western blot and immunohistochemistry showed that HO-1 expression was elevated in the SHR (MI + CoPP) group, while co-administration with SnMP suppressed the benefit functions mentioned above. In conclusion, HO-1 upregulation can lower blood pressure and improve post-infarct cardiac function in the ISHR model. These functions may be involved in the inhibition of inflammation and the ventricular remodeling process and in the amelioration of glucose metabolism and endothelial dysfunction. PMID:23358254
Chen, Tian-Meng; Li, Jian; Liu, Lin; Fan, Li; Li, Xiao-Ying; Wang, Yu-Tang; Abraham, Nader G; Cao, Jian
In this study, we evaluate the effect of HO-1 upregulation on blood pressure and cardiac function in the new model of infarct spontaneous hypertensive rats (ISHR). Male spontaneous hypertensive rats (SHR) at 13 weeks (n = 40) and age-matched male Wistar (WT) rats (n = 20) were divided into six groups: WT (sham + normal saline (NS)), WT (sham + Co(III) Protoporphyrin IX Chloride (CoPP)), SHR (myocardial infarction (MI) + NS), SHR (MI + CoPP), SHR (MI + CoPP + Tin Mesoporphyrin IX Dichloride (SnMP)), SHR (sham + NS); CoPP 4.5 mg/kg, SnMP 15 mg/kg, for six weeks, one/week, i.p., n = 10/group. At the sixth week, echocardiography (UCG) and hemodynamics were performed. Then, blood samples and heart tissue were collected. Copp treatment in the SHR (MI + CoPP) group lowered blood pressure, decreased infarcted area, restored cardiac function (left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), +dp/dtmax, (?dp/dtmax)/left ventricular systolic pressure (LVSP)), inhibited cardiac hypertrophy and ventricular enlargement (downregulating left ventricular end-systolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and heart weight/body weight (HW/BW)), lowered serum CRP, IL-6 and Glu levels and increased serum TB, NO and PGI2 levels. Western blot and immunohistochemistry showed that HO-1 expression was elevated in the SHR (MI + CoPP) group, while co-administration with SnMP suppressed the benefit functions mentioned above. In conclusion, HO-1 upregulation can lower blood pressure and improve post-infarct cardiac function in the ISHR model. These functions may be involved in the inhibition of inflammation and the ventricular remodeling process and in the amelioration of glucose metabolism and endothelial dysfunction. PMID:23358254
Chen, Tian-meng; Li, Jian; Liu, Lin; Fan, Li; Li, Xiao-ying; Wang, Yu-tang; Abraham, Nader G.; Cao, Jian
Ultrasound bio-microscopy was used to measure hemodynamic changes in the left main coronary artery after myocardial infarction (MI), and its usefulness in estimating infarct size was evaluated. MI was induced by left anterior descending artery ligation. Diastolic peak velocity (Vd), mean flow velocity (Vmean) and the velocity-time integral (VTI) were measured 2 and 6 h after MI. Serum troponin I levels were assayed 2, 6 and 12 h after MI. At 2 h, Vmean and VTI significantly differed between mice that underwent low and high left anterior descending artery ligation; Vd, Vmean and VTI were correlated with infarct size (r = -0.557, -0.693 and -0.672, respectively; all p < 0.01). Infarct size was more strongly correlated with 2-h ultrasound bio-microscopy measurements than with 2-h serum troponin I level. Measurement of coronary artery blood flow by ultrasound bio-microscopy may be useful for early estimation of infarct size in mice. PMID:23993171
Su, Rui-Juan; Zhang, Jun-Meng; Li, Rong-Juan; Sun, Yan; Jiang, Bo; Ma, Ning; Li, Zhi-An; Luo, Xiang-Hong; Song, Li; Xue, Jing-Li; Wang, Zheng; Yang, Ya
Cultured Brain Microvessel Endothelial Cells as In Vitro Models of the Blood-Brain Barrier Yoshinobu Takakura, Kenneth L. Audus, and Ronald T. Borchardt INTRODUCTION A central nervous system (CNS) site of action generally requires that, following...). These systems afford an opportunity to look at bidirectional transendothelial movement (transfer from brain to blood and that from blood to brain) of solutes across the BBB in vitro since, at least for primary cultures of bovine microvessel endothelial cells...
Takakura, Yoshinobu; Audus, Kenneth L.; Borchardt, Ronald T.
Numerical Modeling of Brain Dynamics in Traumatic Situations - Impulsive Translations Martin to establishing brain injury tolerance cri- teria for Diffuse Axonal Injuries (DAI) . However, these equations-Stokes equations with a term that describes elastic media, i.e., we model the brain's dynamics in traumatic
Construction of Anatomically Correct Models of Mouse Brain Networks 1 B. H. McCormick a, W. Koh a Y and Public Health, Texas A&M University, 4458 TAMU, College Station, TX 77843-4458 Abstract The Mouse Brain Web, a federated database, provides for the construction of anatomically correct models of mouse brain
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. PMID:24062923
Providência, Rui; Paiva, Luís; Caetano, Francisca; Almeida, Inês; Gomes, Pedro; Marques, António Leitão
The pervasive nature of handedness across human history and cultures is a salient consequence of brain lateralization. This paper presents evidence that provides a structure for understanding the motor control processes that give rise to handedness. According to the Dynamic Dominance Model, the left hemisphere (in right handers) is proficient for processes that predict the effects of body and environmental dynamics, while the right hemisphere is proficient at impedance control processes that can minimize potential errors when faced with unexpected mechanical conditions, and can achieve accurate steady-state positions. This model can be viewed as a motor component for the paradigm of brain lateralization that has been proposed by Rogers et al. (MacNeilage et al., 2009) that is based upon evidence from a wide range of behaviors across many vertebrate species. Rogers proposed a left-hemisphere specialization for well-established patterns of behavior performed in familiar environmental conditions, and a right hemisphere specialization for responding to unforeseen environmental events. The dynamic dominance hypothesis provides a framework for understanding the biology of motor lateralization that is consistent with Roger's paradigm of brain lateralization. PMID:25339923
Sainburg, Robert L.
The present state of medical care for heart attacks, or acute myocardial infarction (AMI), clearly indicates that rapidly and expeditiously seeking definitive medical care will reduce morbidity and prevent mortality. Despite the clearly established advantages of rapid AMI treatment, the time from the onset of acute symptoms of AMI to definitive medical care is often prolonged and individuals with a
Angelo A. Alonzo; Nancy R. Reynolds
The extraction of the brain portion of a neurological image is often necessary prior to tissue segmentation or image registration. While MR Imaging studies on the rat have gained much interest lately, an automatic and robust rat brain extraction tool is still lacking. In this paper, we present a deformable surface model-based rat brain extraction method which extends the popular
Jiehua Li; Xiaofeng Liu; Jiachen Zhuo; Rao P. Gullapalli; Jason M. Zara
Brain shift poses a significant challenge to accurate image-guided neurosurgery. To this end, finite element (FE) brain models have been developed to estimate brain motion during these procedures. The significance of the brain-skull boundary conditions (BCs) for accurate predictions in these models has been explored in dynamic impact and inertial rotation injury computational simulations where the results have shown that the brain mechanical response is sensitive to the type of BCs applied. We extend the study of brain-skull BCs to quasi-static brain motion simulations which prevail in neurosurgery. Specifically, a frictionless brain-skull BC using a contact penalty method master-slave paradigm is incorporated into our existing deformation forward model (forced displacement method). The initial brain-skull gap (CSF thickness) is assumed to be 2mm for demonstration purposes. The brain surface nodes are assigned as either fixed (at bottom along the gravity direction), free (at brainstem), with prescribed displacement (at craniotomy) or as slave nodes potentially in contact with the skull (all the remaining). Each slave node is assigned a penalty parameter (?=5) such that when the node penetrates the rigid body skull inner-surface (master surface), a contact force is introduced proportionally to the penetration. Effectively, brain surface nodes are allowed to move towards or away from the cranium wall, but are ultimately restricted from penetrating the skull. We show that this scheme improves the model's ability to represent the brain-skull interface.
Ji, Songbai; Liu, Fenghong; Roberts, David; Hartov, Alex; Paulsen, Keith
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
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
This paper presents a general statistical framework for modeling deformable object. This model is devoted being used in digital brain atlases. We first present a numerical modeling of brain sulci. We present also a method to characterize the high inter-individual variability of basic cortical structures on which the description of the cerebral cortex is based. The aimed applications use numerical modeling of brain sulci to assist non-linear registration of human brains by inter-individual anatomical matching or to better compare neuro-functional recordings performed on a series of individuals. The utilization of these methods is illustrated using a few examples.
Barillot, Christian; Le Goualher, Georges; Hellier, Pierre; Gibaud, Bernard
Background Evidence from a canine experimental acute myocardial infarction (MI) model shows that until the seventh week after MI the relationship between stellate ganglionic nerve and vagal nerve activities (SGNA/VNA) progressively increases. Objective We evaluated how autonomic nervous system activity influences temporal myocardial repolarization dispersion at this period. Methods We analyzed autonomic nerve activity as well as QT and RR variability from recordings previously obtained in 9 dogs. From a total 48 short-term electrocardiographic segments, 24 recorded before and 24 seven weeks after experimentally-induced MI, we obtained three indices of temporal myocardial repolarization dispersion: QTe (from q wave T to wave end), QTp (from q wave to T wave peak) and Te (from T wave peak to T wave end) variability index (QTeVI, QTpVI, TeVI). We also performed a heart rate variability power spectral analysis on the same segments. Results After MI, all the QT variables increased QTeVI (median [interquartile range]) (from - 1.76[0.82] to ?1.32[0.68]), QTeVI (from ?1.90[1.01] to ?1.45[0.78]) and TeVI (from ?0.72[0.67] to ?0.22[1.00]), whereas all RR spectral indexes decreased (p<0.001 for all). Distinct circadian rhythms in QTeVI (p<0.05,) QTpVI (p<0.001) and TeVI (p<0.05) appeared after MI with circadian variations resembling that of SGNA/VNA. The morning QTpVI and TeVI acrophases approached the SGNA/VNA acrophase. Conversely, the evening QTeVI acrophase coincided with another SGNA/VNA peak. After MI, regression analysis detected a positive relationship between SGNA/VNA and TeVI (R2: 0.077; ?: 0.278; p< 0.001). Conclusion Temporal myocardial repolarization dispersion shows a circadian variation after MI reaching its peak at a time when sympathetic is highest and vagal activity lowest. PMID:24120873
Piccirillo, Gianfranco; Moscucci, Federica; D’Alessandro, Gaetana; Pascucci, Matteo; Rossi, Pietro; Han, Seongwook; Chen, Lan S; Lin, Shien-Fong; Chen, Peng-Sheng; Magrì, Damiano
Cell delivery via the retrograde coronary route boasts less vessel embolism, myocardial injury, and arrhythmogenicity when compared with those via antegrade coronary administration or myocardial injection. However, conventional insertion into the coronary sinus and consequent bleeding complication prevent its application in small animals. To overcome the complication of bleeding, we described a modified coronary retroinfusion technique via the jugular vein route in rats with myocardial infarction (MI). A flexible wire with a bent end was inserted into the left internal jugular vein and advanced slowly along the left superior vena cava. Under direct vision, the wire was run into the left cardiac vein by rotating the wire and changing the position of its tip. A fine tube was then advanced along the wire to the left cardiac vein. This modified technique showed less lethal hemorrhage than the conventional technique. Retroinfusion via transjugular catheter enabled efficient fluid or cell dissemination to the majority areas of the free wall of the left ventricle, covering the infarcted anterior wall. In conclusion, transjugular cardiac vein catheterization may make retrocoronary infusion a more safe and practical route for delivering cell, drug, and gene therapy into the infarcted myocardium of rats. PMID:23903054
Huang, Zheyong; Shen, Yunli; Zhu, Hongmin; Xu, Jianfeng; Song, Yanan; Hu, Xinying; Shuning, Zhang; Yang, Xiangdong; Sun, Aijun; Qian, Juying; Ge, Junbo
This paper describes the process in which complex lesion geometries (specified by computer generated perfusion defects) are incorporated in the description of nonlinear FE mechanical models used for specifying the motion of the left ventricle (LV) in the 4D XCAT phantom to simulate gated cardiac image data. An image interrogation process was developed to define the elements in the LV mesh as ischemic or infarcted based upon the values of sampled intensity levels of the perfusion maps. For every element of the FE mesh, intensity values were determined for each of the interior integration points and the average element intensity levels were determined. The elements with average intensity values below a user-controlled threshold were defined as ischemic or infarcted depending upon the model being defined. For the infarction model cases, the thresholding and interrogation process were repeated in order to define a border zone (BZ) surrounding the infarction. This methodology was evaluated using perfusion maps created by the Perfusion CArdiac-Torso (PCAT) phantom an extension of the 4D XCAT phantom. The PCAT was used to create 3D perfusion maps representing 90% occlusions at 4 locations (left anterior descending segments 6 and 9, left circumflex segment 11, right coronary artery segment 1) in the coronary tree. The volumes and shapes of the defects defined in the FE mechanical models were compared with perfusion maps produced by the PCAT. The models were incorporated into the XCAT phantom. The mechanical models showed distinct changes due to the addition of regions of ischemia and infarction. The volumes of the ischemic/infarcted regions of the models were nearly identical to those volumes obtained from the images and were highly correlated (R2 = 0.99). PMID:25367177
Veress, Alexander I; Fung, George S K; Lee, Taek-Soo; Tsui, Benjamin M W; Segars, Paul W; Gullberg, Grant T
Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It is characterized by fluid retention, shortness of breath, and fatigue, in particular on exertion. Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. Ischemic heart disease is the main cause of heart failure. Ventricular remodelling refers to changes in structure, size, and shape of the left ventricle. This architectural remodelling of the left ventricle is induced by injury (e.g., myocardial infarction), by pressure overload (e.g., systemic arterial hypertension or aortic stenosis), or by volume overload. Since ventricular remodelling affects wall stress, it has a profound impact on cardiac function and on the development of heart failure. A model of permanent ligation of the left anterior descending coronary artery in mice is used to investigate ventricular remodelling and cardiac function post-myocardial infarction. This model is fundamentally different in terms of objectives and pathophysiological relevance compared to the model of transient ligation of the left anterior descending coronary artery. In this latter model of ischemia/reperfusion injury, the initial extent of the infarct may be modulated by factors that affect myocardial salvage following reperfusion. In contrast, the infarct area at 24 hr after permanent ligation of the left anterior descending coronary artery is fixed. Cardiac function in this model will be affected by 1) the process of infarct expansion, infarct healing, and scar formation; and 2) the concomitant development of left ventricular dilatation, cardiac hypertrophy, and ventricular remodelling. Besides the model of permanent ligation of the left anterior descending coronary artery, the technique of invasive hemodynamic measurements in mice is presented in detail. PMID:25489995
Muthuramu, Ilayaraja; Lox, Marleen; Jacobs, Frank; De Geest, Bart
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. PMID:22435060
Ziegler, Gabriel; Dahnke, Robert; Gaser, Christian
Model-based autosegmentation of brain structures in the honeybee using statistical shape models K University of Berlin, 2 Zuse Institute, Berlin Surface-based brain atlases like the Honeybee Brain Atlas (www-Dimensional Average-Shape atlas of the honeybee brain and its applications. JCN 492(1):1-19. 2 Lamecker et.al. (2004
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. PMID:24137186
YUE, XIA; YU, HONGSHENG; LIN, XIALU; LIU, KUI; WANG, XIN; ZHOU, FEI; ZHAO, JINSHUN; ZOU, BAOBO
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).
Archibald J. Fobbs Jr.
The clinical manifestation of acute corpus callosum (CC) infarction is lack of specificity and complex, so it is easily missed diagnosis and misdiagnosis in the early stage. The present study aims to describe the clinical features of the acute CC infarction. In this study, 25 patients with corpus callosum infarction confirmed by the brain MRI/DWI and the risk factors were summarized. Patients were classified into genu infarction (3 cases), body infarction (4cases), body and genu infarction (4 cases), body and splenium infarction (1 case), splenium infarction (13 cases) according to lesion location. Clinical manifestation and prognosis were analyzed among groups. The results indicated that CC infarction in patients with high-risk group accounted for 72%, moderate-risk group accounted for 20%, low-risk group (8%). The main risk factors are carotid intimal thickening or plaque formation, hypertension, hyperlipidemia, cerebral artery stenosis, and so on. The CC infarction often merged with other parts infarction, and splenium infarction had the highest incidence, the clinical symptoms in the body infarction which can appear typical signs and symptoms, but in other parts infarction which always merged many nerve defect symptoms. The body infarction prognosis is poor; the rest parts of infarction are more favorable prognosis. In conclusion, CC infarction has the highest incidence in the stroke of high-risk group; neck color Doppler and TCD examination can be found as early as possible to explore the pathogenic factors. Prognosis is usually much better by treatment according to the location and risk factors. PMID:25197390
Yang, Li-Li; Huang, Yi-Ning; Cui, Zhi-Tang
. We introduce a Hierarchical Collaborative CoEvolutionary (HCCE) approach to design autonomous, yet cooperating agents. Thus, partial brain models consisting of many substructures can be designed. Replication of agents. The HCCE is appropriately designed to support systematic modelling of brain structures, able
Activity of matrix metalloproteinase-9 increases following cerebral ischemia/reperfusion, and is associated with cerebral microvascular permeability, blood-brain barrier destruction, inflammatory cell infiltration and brain edema. Matrix metalloproteinase-9 also likely participates in thrombolysis. A rat model of middle cerebral artery infarction was established by injecting autologous blood clots into the internal carotid artery. At 3 hours following model induction, urokinase was injected into the caudal vein. Decreased neurological severity score, reduced infarct volume, and increased expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 were observed in the cerebral cortex 24 hours after urokinase thrombolysis. These results suggest that urokinase can suppress damage in the acute-early stage of cerebral infarction.
Song, Yuqiang; Zou, Hongli; Wang, Guofeng; Yang, Hongxia; Xie, Zhaohong; Bi, Jianzhong
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
The arrhythmogenic effects of endothelin-1 (ET-1) are mediated via ETA-receptors, but the role of ETB-receptors is unclear.\\u000a We examined the pathophysiologic role of ETB-receptors on ventricular tachyarrhythmias (VT\\/VF) during myocardial infarction\\u000a (MI). MI was induced by coronary ligation in two animal groups, namely in wild-type (n = 63) and in ETB-receptor-deficient (n = 61) rats. Using a telemetry recorder, VT\\/VF episodes were evaluated during
Dimitrios L. Oikonomidis; Dimitrios G. Tsalikakis; Giannis G. Baltogiannis; Alexandros T. Tzallas; Xanthi Xourgia; Maria G. Agelaki; Aikaterini J. Megalou; Andreas Fotopoulos; Apostolos Papalois; Zenon S. Kyriakides; Theofilos M. Kolettis
Direct intracardiac cell injection for heart repair is hindered by numerous limitations including: cell death, poor spreading of the injected cells, arrhythmia, needle injury, etc. Tissue-engineered cell sheet implantation has the potential to overcome some of these limitations. We evaluated whether the transplantation of a muscle-derived stem cell (MDSC) sheet could improve the regenerative capacity of MDSCs in a chronic model of myocardial infarction. MDSC sheet-implanted mice displayed a reduction in left ventricle (LV) dilation and sustained LV contraction compared with the other groups. The MDSC sheet formed aligned myotubes and produced a significant increase in capillary density and a reduction of myocardial fibrosis compared with the other groups. Hearts transplanted with the MDSC sheets did not display any significant arrhythmias and the donor MDSC survival rate was higher than the direct myocardial MDSC injection group. MDSC sheet implantation yielded better functional recovery of chronic infarcted myocardium without any significant arrhythmic events compared with direct MDSC injection, suggesting this cell sheet delivery system could significantly improve the myocardial regenerative potential of the MDSCs. PMID:23319053
Sekiya, Naosumi; Tobita, Kimimasa; Beckman, Sarah; Okada, Masaho; Gharaibeh, Burhan; Sawa, Yoshiki; Kormos, Robert L; Huard, Johnny
A multitude of stem cell types has been extensively studied and used for myocardial regenerative therapy. Amongst these endothelial progenitor cells form a promising source. In our present study, we investigated a one-staged approach for isolation and application of autologous endothelial progenitor cells in a pig model of myocardial infarction. Endothelial progenitor cell isolation was performed by immediately preprocedural bone marrow aspiration and consecutive positive selection by aptamer-based magnetic cell sorting. Animals were divided in three groups receiving endothelial progenitor cells, saline, or no intramyocardial injection respectively. Postprocedural follow-up consisted of weekly echocardiographic evaluations. Postmortem histological analysis after four weeks focused on detection of transplanted PKH26-positive endothelial progenitor cells and neovascularization within the infarcted myocardium. A significant difference in left ventricular ejection fraction could not be shown between the three groups. PKH26-stained endothelial progenitor cells could be found in the endothelial progenitor cells transplanted group, although detection was scarce. Large-sized capillaries were found to be significantly more in endothelial progenitor cells treated myocardium. The one-stage approach of endothelial progenitor cells isolation and application presented herein offers a new therapeutic concept. Even though a beneficial impact on myocardial function could not be assessed, increased neovascularization may indicate positive effects on remodeling processes. Being able to harvest endothelial progenitor cells right before application provides a wider scope of action in urgent cases. PMID:25494449
Haller, Christoph; Sobolewska, Bianka; Schibilsky, David; Avci-Adali, Meltem; Schlensak, Christian; Wendel, Hans-Peter; Walker, Tobias
Health disparities by socioeconomic status (SES) exist for many outcomes, including patients' subjective health status after myocardial infarction (MI). The Reserve Capacity Model (RCM), a theoretical means to understand such disparities, was tested to examine the possible mediating effects of cognitive-emotional factors on the association between SES and health status. Data from 2,348 post-MI patients in PREMIER were used. Indicators of SES were collected during hospitalization via personal interviews, while participants completed measures of stress and reserves at 1 month, depressive symptoms at 6 months, and health status at 1 year through telephone interviews. Structural equation model results provide partial support for the RCM, as cognitive-emotional factors partially mediated the association between SES and mental health status. For physical health status, results supported direct rather than indirect effects of SES. Findings suggest psychosocial interventions with patients of low SES will have their greatest effects on appraisals of psychological health status. PMID:25022863
Bennett, Kymberley K; Buchanan, Donna M; Jones, Philip G; Spertus, John A
During neurosurgery, nonrigid brain deformation may affect the reliability of tissue localization based on preoperative images. To provide accurate surgical guidance in these cases, preoperative images must be updated to reflect the intraoperative brain. This can be accomplished by warping these preoperative images using a biomechanical model. Due to the possible complexity of this deformation, intraoperative information is often required to guide the model solution. In this paper, a linear elastic model of the brain is developed to infer volumetric brain deformation associated with measured intraoperative cortical surface displacement. The developed model relies on known material properties of brain tissue, and does not require further knowledge about intraoperative conditions. To provide an initial estimation of volumetric model accuracy, as well as determine the model’s sensitivity to the specified material parameters and surface displacements, a realistic brain phantom was developed. Phantom results indicate that the linear elastic model significantly reduced localization error due to brain shift, from >16 mm to under 5 mm, on average. In addition, though in vivo quantitative validation is necessary, preliminary application of this approach to images acquired during neocortical epilepsy cases confirms the feasibility of applying the developed model to in vivo data. PMID:22562728
DeLorenzo, Christine; Papademetris, Xenophon; Staib, Lawrence H.; Vives, Kenneth P.; Spencer, Dennis D.; Duncan, James S.
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)
We describe four patients with cerebral infarction and 99mTc-hexamethylpropyleneamine oxime (HMPAO) hyperfixation in distributions corresponding to the infarctions seen at CT and/or MR imaging. Increased HMPAO extraction due to hyperpermeability across the blood-brain barrier and increased retention due to reduced back diffusion of the tracer probably accounted for the increased fractional fixation in infarcts seen in our patients. PMID:9403452
Shintani, S; Tsuruoka, S; Shiigai, T
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. PMID:22114497
Binsalamah, Ziyad Mohammed; Paul, Arghya; Khan, Afshan Afsar; Prakash, Satya; Shum-Tim, Dominique
SUMMARY Autophagy is a homeostatic, carefully regulated, and dynamic process for intracellular recycling of bulk proteins, aging organelles, and lipids. Autophagy occurs in all tissues and cell types, including the brain and neurons. Alteration in the dynamics of autophagy has been observed in many diseases of the central nervous system. Disruption of autophagy for an extended period of time results in accumulation of unwanted proteins and neurodegeneration. However, the role of enhanced autophagy after acute brain injury remains undefined. Established mouse models of brain injury will be valuable in clarifying the role of autophagy after brain injury, and are the topic of discussion in this review. PMID:19879944
Au, Alicia K.; Bayir, Hülya; Kochanek, Patrick M.; Clark, Robert S. B.
The no-reflow phenomenon occurs when an epicardial coronary artery is reopened following myocardial infarction, but portions of the intramural microvasculature fail to reperfuse. One potential mechanism for this is the presence of fibrin tactoids. In addition, some recent studies have suggested that dabigatran treatment may be associated with increased incidence of myocardial infarction. Our aim was to investigate the effect on myocardial infarct size and no-reflow in an acute model of ischemia/reperfusion. Anesthetized, open-chest rabbits were randomly assigned to receive dabigatran (Dab, 0.5 mg/kg bolus + infusion, 0.15 mg/kg/h, IV, n = 11) or vehicle (Veh, n = 11) 15 m before a 30-m coronary artery occlusion and during 2.5 h of the 3 h reperfusion procedure. At the end of the reperfusion period, infarct size (% risk zone) and no-reflow defect were measured. The ischemic risk zone (% of left ventricle) was similar in groups, 24 % in Dab and 25 % in Veh. Necrosis was neither reduced nor increased by Dab treatment; expressed as a percentage of the risk region, infarct size was 30 ± 4 % in Dab and 28 ± 5 % in Veh, p = 0.76. The extent of no-reflow was comparable, expressed either as a percent of the risk region (19 ± 3 %, Dab and 18 ± 3 %, Veh) or as a percent of the necrotic zone (67 ± 8 % Dab and 65 ± 10 % Veh). Dab treatment had no effect on heart rate or blood pressure. Dabigatran treatment did not prevent or ameliorate the no-reflow phenomenon, suggesting that fibrin does not play a major role in the development of microvascular obstruction. Dabigatran did not exacerbate myocardial infarct size. PMID:25017632
Hale, Sharon L; Kloner, Robert A
Large animal models of heart failure are essential in preclinical device testing. In sheep, catheter-based coil embolization of the left anterior descending and diagonal artery provides a minimally invasive and reproducible model of myocardial infarction (MI). Although widely used, this model has historically been plagued with a 30% mortality rate, both in the literature and in our own experience. Our study endeavored to decrease the mortality rate by targeting the most common cause of death, intractable arrhythmias, during creation of the ovine MI model. To this end, we evaluated 2 methods of managing perioperative antiarrhythmic therapy and cardiopulmonary resuscitation during model creation. The first group of sheep was managed at the discretion of the individual operator, whereas the second group was treated according to a standardized protocol that included mandatory pretreatment with amiodarone. Sheep experiencing life-threatening arrhythmias, most commonly ventricular fibrillation, were either resuscitated according to operator-driven instructions or the standardized protocol. By comparing these 2 treatment groups, we have shown that using a standardized protocol is advantageous in reducing mortality associated with the ovine MI model. Since implementing the standardized protocol, our laboratory has lowered the expected mortality rate to 10% during catheter-based induction of ovine MI and has greatly reduced the number of animals required for study needs. In addition, the standardized protocol has proven beneficial in training new staff members. By implementing this standardized method of model management, the outcomes of model creation have been optimized. PMID:23849412
Dardenne, Adrienne; Fernandez, Carlos; Wagner, Alyssa; Milewski, Krzysztof; Ordanes, Diane R; Mount, Patricia A; Cheng, Yanping; Yi, Geng-Hua; Conditt, Gerard B; Tellez, Armando; Kaluza, Greg L; Granada, Juan F; Feeney, William P
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.
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
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
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. PMID:23442172
Schirner, Michael; McIntosh, Anthony R.; Jirsa, Viktor K.
The zebrafish (Danio rerio) is rapidly becoming a popular model organism in pharmacogenetics and neuropharmacology. Both larval and adult zebrafish are currently used to increase our understanding of brain function, dysfunction, and their genetic and pharmacological modulation. Here we review the developing utility of zebrafish in the analysis of complex brain disorders (including, for example, depression, autism, psychoses, drug abuse and cognitive disorders), also covering zebrafish applications towards the goal of modeling major human neuropsychiatric and drug-induced syndromes. We argue that zebrafish models of complex brain disorders and drug-induced conditions have become a rapidly emerging critical field in translational neuropharmacology research. PMID:24412421
Kalueff, Allan V.; Stewart, Adam Michael; Gerlai, Robert
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
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 FITC-Dextran 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).
Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J.
Surgical navigation systems are used intraoperatively to help the surgeon to ascertain her or his position and to guide tools\\u000a within the patient frame with respect to registered structures of interest in the preoperative images. However, these systems\\u000a are subject to inaccuracy caused by intraoperative brain movement (brain shift) since they assume that the intracranial structures\\u000a are rigid. Experiments show
Oskar M. Skrinjar; Dennis D. Spencer; James S. Duncan
Little is known about the cardioprotective effects against heart failure (HF), the effects on differentiation of bone marrow-derived mononuclear cell (BMMNC), and the biocompatibility of BMMNC-seeded biodegradable poly-glycolide-co-caprolactone (PGCL) scaffolds in a myocardial infarction (MI) animal model. This study hypothesized that implantation of a BMMNC-seeded PGCL scaffold into the epicardial surface in a rat MI model would be biocompatible, induce
Hainan Piao; Jin-Sook Kwon; Shuguang Piao; Ju-Hee Sohn; Yeong-Shin Lee; Jang-Whan Bae; Kyung-Kuk Hwang; Dong-Woon Kim; Oju Jeon; Byung-Soo Kim; Young-Bae Park; Myeong-Chan Cho
In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.
Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood
Three-dimensional finite models for the monkey, baboon, and human brains have been developed and are described. Isoparametric brick elements and membrane elements represent the soft tissue and partitioning internal folds of dura, respectively. By specifying the finite element mesh on the skull inner surface, the irregular shape of the brain is generated. Each model is subjected to the same skull acceleration to investigate response relationships between species. Important dynamic response differences are revealed by comparing the computed intracranial pressures. Experimentally derived head injury data are correlated with model dynamic responses. Using the baboon and monkey models, brain injury tests are simulated and model response measures are compared to produced injury. Using the human model, computed stresses are compared to intracranial pressures measured in cadaver impact tests. PMID:623576
Ward, C C; Nikravesh, P E; Thompson, R B
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
The study of information-processing adaptations in the brain is controversial, in part because of disputes about the form such adaptations might take. Many psychologists assume that adaptations come in two kinds, specialized and general-purpose. Specialized mechanisms are typically thought of as innate, domain-specific, and isolated from other brain systems, whereas generalized mechanisms are developmentally plastic, domain-general, and interactive. However, if brain mechanisms evolve through processes of descent with modification, they are likely to be heterogeneous, rather than coming in just two kinds. They are likely to be hierarchically organized, with some design features widely shared across brain systems and others specific to particular processes. Also, they are likely to be largely developmentally plastic and interactive with other brain systems, rather than canalized and isolated. This article presents a hierarchical model of brain specialization, reviewing evidence for the model from evolutionary developmental biology, genetics, brain mapping, and comparative studies. Implications for the search for uniquely human traits are discussed, along with ways in which conventional views of modularity in psychology may need to be revised. PMID:22723350
Barrett, H. Clark
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
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
The use of conducting gels to mimic brain and other tissues is of increasing interest in the development of new medical devices. Currently, there are few such models that can be utilized at physiologic temperatures. In this work, the conductivities of agar, agarose and gelatin gels were manipulated by varying NaCl concentration from 0–1 mg/ml. The AC conductivity was measured at room and physiological temperatures (37°C) in the 100–500 Hz frequency range. Conductivity (?) was nearly independent of frequency but increased linearly with NaCl concentration and was higher at physiological temperatures in these gels. A formula for predicting conductivity as a function of NaCl concentration was derived for each gel type. The overall goal is to develop a ‘brain gel model’, for studying low frequency electrical properties of the brain and other tissues at physiological temperatures. PMID:23139442
Kandadai, Madhuvanthi A.; Raymond, Jason L.; Shaw, George J.
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
\\u000a In spite of all efforts, patients diagnosed with highly malignant brain tumors (gliomas), continue to face a grim prognosis.\\u000a Achieving significant therapeutic advances will also require a more detailed quantitative understanding of the dynamic interactions\\u000a among tumor cells, and between these cells and their biological microenvironment. Data-driven computational brain tumor models\\u000a have the potential to provide experimental tumor biologists with
Zhihui Wang; Thomas S. Deisboeck
In spite of all efforts, patients diagnosed with highly malignant brain tumors (gliomas), continue to face a grim prognosis.\\u000a Achieving significant therapeutic advances will also require a more detailed quantitative understanding of the dynamic interactions\\u000a among tumor cells, and between these cells and their biological microenvironment. Data-driven computational brain tumor models\\u000a have the potential to provide experimental tumor biologists with
Zhihui Wang; Thomas S. Deisboeck
To examine the preventive and therapeutic effects of ginsenoside Rb1 for neural injury during cerebral infarction, we used a middle cerebral artery occlusion (MCAO) model in rats to investigate the effects of ginsenoside Rb1 with Edaravone as a control. Ginsenoside Rb1 was given to the rats by intragastric administration either before or after the MCAO surgery to study its preventive and therapeutic effects. Ginsenoside Rb1-treated rats had a smaller infarct volume than the positive control. Interleukin-1 (IL-1), brain-derived neurotrophic factor (BDNF), tumor necrosis factor-? (TNF-?), neurofilament (NF) and growth associated protein-43 (GAP-43) were measured to determine brain damage and the recovery of nerves. These findings suggest that ginsenoside Rb1 has neuroprotective effects in rats, and the protection efficiency is higher than Edaravone. The protective mechanism is different from Edaravone. The preventive ability of ginsenoside Rb1 is higher than its repair ability in neuroprotection in vivo. PMID:23548124
Jiang, Zhou; Wang, Yuhui; Zhang, Xiaoyun; Peng, Tao; Lu, Yun; Leng, Jianchun; Xie, Quan
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.
Digital three-dimensional models, besides representing helpful didactic tools, play an important role in the analysis of brain function and development. The fundamental idea of this approach is that patterns of neural connectivity and activity, pathological lesions, or gene expression are transferred into a single in silico structure: the digital atlas model. This article focuses on recent and ongoing work to build digital models of the developing Drosophila brain, which is formed by an invariant set of approximately 100 neural lineages. Lineages represent key elements in the emerging models of the fly brain: aside from their common origin, which is reflected in the shared expression of numerous developmental control genes, neurons belonging to a given lineage share many morphological characters, including axonal projection and dendritic arborization.
Volker Hartenstein and colleagues (University of California at Los Angeles; )
A 2-day-old boy had hemi-convulsion and diagnosed as having neonatal infarction. Brain MRI was performed on the day after the day of onset. Abnormal finding were noted on diffusion weighted imaging, but not on T1 and T2 weighted imaging. During the first few days of life, it is difficult to demonstrate neonatal brain infarction by T1 and T2 weighted imaging. Diffusion weighted imaging is useful for the early diagnosis of neonatal infarction. PMID:16026098
Okamoto, Kentaro; Fukuda, Mitsumasa
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. PMID:24139652
D’Angelo, Egidio; Solinas, Sergio; Garrido, Jesus; Casellato, Claudia; Pedrocchi, Alessandra; Mapelli, Jonathan; Gandolfi, Daniela; Prestori, Francesca
Three-dimensional (3D) modeling of medical images is a critical part of surgical simulation. In this paper, we focus on the magnetic resonance (MR) images denoising for brain modeling reconstruction, and exploit a practical solution. We attempt to remove the noise existing in the MR imaging signal and preserve the image characteristics. A wavelet-based adaptive curve shrinkage function is presented in spherical coordinates system. The comparative experiments show that the denoising method can preserve better image details and enhance the coefficients of contours. Using these denoised images, the brain 3D visualization is given through surface triangle mesh model, which demonstrates the effectiveness of the proposed method.
Zhao, De-xin; Liu, Peng-jie; Zhang, De-gan
Aims There are few data comparing the fate of multipotent progenitor cells (MPCs) used in cardiac cell therapy after myocardial infarction (MI). To document in vivo distribution of MPCs delivered by intracoronary (IC) injection. Methods and results Using an anterior MI swine model, near-infrared (NIR) fluorescence was used for in vivo tracking of labelled MPCs [mesenchymal stromal (MSCs), bone marrow mononuclear (BMMNCs), and peripheral blood mononuclear (PBMNCs)] cells early after IC injection. Signal intensity ratios (SIRs) of injected over non-injected (reference) zones were used to report NIR fluorescence emission. Following IC injection, significant differences in mean SIR were documented when MSCs were compared with BMMNCs [1.28 ± 0.10 vs. 0.77 ± 0.11, P < 0.001; 95% CI (0.219, 0.805), respectively] or PBMNCs [1.28 ± 0.10 vs. 0.80 ± 0.14, P = 0.005; 95% CI (0.148, 0.813), respectively]. Differences were maintained during the 60 min tracking period, with only the MSC-injected groups continuously emitting NIR fluorescence (SIR>1). This is correlated with greater cell retention for MSCs relative to mononuclear cells. However, there was evidence of MSC-related vessel plugging in some swine. Conclusion Our in vivo NIR fluorescence findings suggest that MPC distribution and retention immediately after intracoronary delivery vary depending on cell population and could potentially impact the clinical efficacy of cardiac cell therapy. PMID:19687154
Ly, Hung Q.; Hoshino, Kozo; Pomerantseva, Irina; Kawase, Yoshiaki; Yoneyama, Ryuichi; Takewa, Yoshiaki; Fortier, Annik; Gibbs-Strauss, Summer L.; Vooght, Carrie; Frangioni, John V.; Hajjar, Roger J.
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.
SUMMARY Brain ischemia, also termed cerebral ischemia, is a condition in which there is insufficient blood flow to the brain to meet metabolic demand, leading to tissue death (cerebral infarction) due to poor oxygen supply (cerebral hypoxia). Our group is interested in the protective effects of neuropeptides for alleviating brain ischemia, as well as the underlying mechanisms of their action. The present study was initiated to investigate molecular responses at the level of gene expression in ischemic brain tissue. To achieve this, we used a mouse permanent middle cerebral artery occlusion (PMCAO) model in combination with high-throughput DNA microarray analysis on an Agilent microarray platform. Briefly, the right (ipsilateral) and left (contralateral) hemispheres of PMCAO model mice were dissected at two time points, 6 and 24 hours post-ischemia. Total RNA from the ischemic (ipsilateral) hemisphere was subjected to DNA microarray analysis on a mouse whole genome 4x44K DNA chip using a dye-swap approach. Functional categorization using the gene ontology (GO, MGD/AMIGO) of numerous changed genes revealed expression pattern changes in the major categories of cellular process, biological regulation, regulation of biological process, metabolic process and response to stimulus. Reverse-transcriptase PCR (RT-PCR) analysis on randomly selected highly up- or downregulated genes validated, in general, the microarray data. Using two time points for this analysis, major and minor trends in gene expression and/or functions were observed in relation to early- and late-response genes and differentially regulated genes that were further classified into specific pathways or disease states. We also examined the expression of these genes in the contralateral hemisphere, which suggested the presence of bilateral effects and/or differential regulation. This study provides the first ischemia-related transcriptome analysis of the mouse brain, laying a strong foundation for studies designed to elucidate the mechanisms regulating ischemia and to explore the neuroprotective effects of agents such as target neuropeptides. PMID:22015461
Hori, Motohide; Nakamachi, Tomoya; Rakwal, Randeep; Shibato, Junko; Nakamura, Keisuke; Wada, Yoshihiro; Tsuchikawa, Daisuke; Yoshikawa, Akira; Tamaki, Keiji; Shioda, Seiji
Apolipoprotein E (apoE) is the primary apolipoprotein synthesized in the brain in response to injury with known neuroprotective effects exerted through antioxidant, antiinflammatory, antiexcitotoxic, and neurotrophic mechanisms. We have previously demonstrated that COG1410, an apoE mimetic peptide, exerts neuroprotective and antiinflammatory effects in a murine model of traumatic brain injury (TBI). As in TBI, ischemia-reperfusion injury is a component of acute stroke, which displays a pharmacogenetic association with the APOE4 gene. Using an intraluminal middle cerebral occlusion (MCAO) model in rats, we found that a single intravenous injection of COG1410 at 120 min post-MCAO significantly improved vestibulomotor function, decreased poststroke locomotor asymmetry, and decreased infarct volume of the ipsilateral hemisphere. These results support further exploration of a novel apoE-mimetic peptide, COG1410, as a therapeutic treatment for stroke. PMID:18803296
Tukhovskaya, Elena A; Yukin, Alexey Yu; Khokhlova, Oksana N; Murashev, Arkady N; Vitek, Michael P
1 Researcher Kidney Modeling molecular dockingBrain Analysis Visualization e-Research Platform User Environment Globus Condor Alchemi UNICORE XGrid PBS ResearcherResearcher Kidney Modeling molecular docking Computer Servers Virtual Organization Grid Host Environment Globus Condor Alchemi UNICORE XGrid PBS Kidney
Chapter 18 Experimental Models of Anxiety for Drug Discovery and Brain Research Peter C. Hart confronta- tion), these phenotypes have clear utility in testing the effects of psychotropic drugs fully characterize drug effects or a mutant mouse pheno- type. The use of a single model
Kalueff, Allan V.
The human brain and skull are three dimensional (3D) anatomical structures with complex surfaces. However, medical images are often two dimensional (2D) and provide incomplete visualization of structural morphology. To overcome this loss in dimension, we developed and validated a freely available, semi-automated pathway to build 3D virtual reality (VR) and hand-held, stereolithograph models. To evaluate whether surface visualization in 3D was more informative than in 2D, undergraduate students (n?=?50) used the Gillespie scale to rate 3D VR and physical models of both a living patient-volunteer's brain and the skull of Phineas Gage, a historically famous railroad worker whose misfortune with a projectile tamping iron provided the first evidence of a structure-function relationship in brain. Using our processing pathway, we successfully fabricated human brain and skull replicas and validated that the stereolithograph model preserved the scale of the VR model. Based on the Gillespie ratings, students indicated that the biological utility and quality of visual information at the surface of VR and stereolithograph models were greater than the 2D images from which they were derived. The method we developed is useful to create VR and stereolithograph 3D models from medical images and can be used to model hard or soft tissue in living or preserved specimens. Compared to 2D images, VR and stereolithograph models provide an extra dimension that enhances both the quality of visual information and utility of surface visualization in neuroscience and medicine. PMID:17971879
Kelley, Daniel J.; Farhoud, Mohammed; Meyerand, M. Elizabeth; Nelson, David L.; Ramirez, Lincoln F.; Dempsey, Robert J.; Wolf, Alan J.; Alexander, Andrew L.; Davidson, Richard J.
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. PMID:22146068
Introduction: Despite advancements in medicine leading to a marked decline in mortality due to acute myocardial infarction (MI), mortality due to post-MI heart failure (HF) remains high. Left ventricular (LV) remodeling is important in the pathogenesis of HF following MI. Previous reports investigating iron overload in anemia and chronic liver cirrhosis suggest that excess iron exhibits cell toxicity in multiple organ systems. During acute MI, ischemia/reperfusion (I/R) injury caused by temporary coronary ischemia results in massive necrosis followed by fibrosis. Previous reports studying tissue injury demonstrated that iron accumulation suppresses wound healing and exacerbates tissue injury in other organs. However, the role of iron in scar formation and LV remodeling is not well characterized. Methods: To address this, we investigated iron, transferrin, and fibrosis in heart tissue sections after I/R injury, and potential cytotoxic effects of iron in the form of FeCl3 on HL-1 and H9C2 cardiomyocytes. Mice underwent surgical I/R injury using left anterior descending coronary ligation to induce 30-minute transient ischemia. The hearts were harvested 1 week later and prepared for histological assays. Results: Masson's trichrome staining revealed fibrosis from the anterior to posterior wall in the mid-myocardium. Perl's iron staining revealed non-transferrin bound iron localized in scar tissue at anterior and posterior aspects of the heart. Immunohistochemistry found ferritin localization to areas of fibrosis, specifically in the extracellular fluid of mid-myocardium and intracellular fluid of fibroblasts and surrounding cardiomyocytes. While iron was undetectable in iron stains of sham operated mice, more than 50 cells were positive with the iron stain in I/R group. Image J (NIH) showed increased anti-ferritin staining in the I/R group compared to sham controls (more than a four-fold increase). To further investigate this, HL-1 and H9C2 cardiomyocytes were cultured with doses of 1 µM to 1 mM FeCl3 for 24 hours, and cell death was analyzed with Live/Dead Cell Viability Assay (Invitrogen). Treatment greater than 100 µM decreased cell viability, and significant cell death (n=6, P<.05) was observed in cardiomyocytes exposed to 50 µM FeCl3 or more, and that excess iron leads to cell death. Conclusions: These results suggest that iron accumulation may play a role in cardiac cell death and fibrosis in ventricular myofiber remodeling after I/R injury. Taken together, excess iron in MI may induce cell death, leading to LV remodeling following I/R injury. Understanding the role of iron accumulation in the heart could develop new therapeutic strategies for treating multiple heart diseases including HF.
Higa, Jason K; Matsui, Takashi
\\u000a Traumatic brain injury (TBI) represents a major burden on health care worldwide. In the US, TBI accounts for 435,000 emergency\\u000a department visits, 37,000 hospital admissions, and approximately 2,500 deaths each year. Of the patients affected, 48% are\\u000a impaired by chronic physical, cognitive, and psychosocial deficits. While aggressive early rehabilitation improves function\\u000a (Cowen et al. Arch Phys Med Rehabil 76:797–803, 1995;
Peter A. Walker; Nathan D. Allison
In an open-chest porcine model, we examined whether myocardial pharmacological conditioning at the time of reperfusion with low-dose insulin or insulin-like growth factor 2 (IGF2), not affecting serum glucose levels, could reduce infarct size and improve functional recovery. Two groups of anaesthetized pigs with either 60 or 40 min. of left anterior descending artery occlusion (total n = 42) were randomized to receive either 0.9% saline, insulin or IGF2 infusion for 15 min., starting 5 min. before a 180-min. reperfusion period. Repeated fluorescent microsphere injections were used to confirm ischaemia and reperfusion. Area at risk and infarct size was determined with Evans blue and triphenyltetrazolium chloride staining. Local myocardial function was evaluated with multi-layer radial tissue Doppler strain and speckle-tracking strain from epicardial echocardiography. Western blotting and TUNEL staining were performed to explore apoptosis. Infarct size did not differ between treatment groups and was 56.7 ± 6.8%, 49.7 ± 9.6%, 56.2 ± 8.0% of area at risk for control, insulin and IGF2 group, respectively, in the 60-min. occlusion series. Corresponding values were 45.6 ± 6.0%, 48.4 ± 7.2% and 34.1 ± 5.8% after 40-min. occlusion. Global and local cardiac function did not differ between treatment groups. No differences related to treatment could be found in myocardial tissue cleaved caspase-3 content or the degree of TUNEL staining. Reperfusion therapy with low-dose insulin or with IGF2 neither reduced infarct size nor improved function in reperfused myocardium in this in vivo porcine model. PMID:24751184
Salminen, Pirjo-Riitta; Dahle, Geir Olav; Moen, Christian Arvei; Wergeland, Anita; Jonassen, Anne Kristin; Haaverstad, Rune; Matre, Knut; Grong, Ketil
Large-scale white matter pathways crisscrossing the cortex create a complex pattern of connectivity that underlies human cognitive function. Generative mechanisms for this architecture have been difficult to identify in part because little is known in general about mechanistic drivers of structured networks. Here we contrast network properties derived from diffusion spectrum imaging data of the human brain with 13 synthetic network models chosen to probe the roles of physical network embedding and temporal network growth. We characterize both the empirical and synthetic networks using familiar graph metrics, but presented here in a more complete statistical form, as scatter plots and distributions, to reveal the full range of variability of each measure across scales in the network. We focus specifically on the degree distribution, degree assortativity, hierarchy, topological Rentian scaling, and topological fractal scaling--in addition to several summary statistics, including the mean clustering coefficient, the shortest path-length, and the network diameter. The models are investigated in a progressive, branching sequence, aimed at capturing different elements thought to be important in the brain, and range from simple random and regular networks, to models that incorporate specific growth rules and constraints. We find that synthetic models that constrain the network nodes to be physically embedded in anatomical brain regions tend to produce distributions that are most similar to the corresponding measurements for the brain. We also find that network models hardcoded to display one network property (e.g., assortativity) do not in general simultaneously display a second (e.g., hierarchy). This relative independence of network properties suggests that multiple neurobiological mechanisms might be at play in the development of human brain network architecture. Together, the network models that we develop and employ provide a potentially useful starting point for the statistical inference of brain network structure from neuroimaging data. PMID:24675546
Klimm, Florian; Bassett, Danielle S; Carlson, Jean M; Mucha, Peter J
Large-scale white matter pathways crisscrossing the cortex create a complex pattern of connectivity that underlies human cognitive function. Generative mechanisms for this architecture have been difficult to identify in part because little is known in general about mechanistic drivers of structured networks. Here we contrast network properties derived from diffusion spectrum imaging data of the human brain with 13 synthetic network models chosen to probe the roles of physical network embedding and temporal network growth. We characterize both the empirical and synthetic networks using familiar graph metrics, but presented here in a more complete statistical form, as scatter plots and distributions, to reveal the full range of variability of each measure across scales in the network. We focus specifically on the degree distribution, degree assortativity, hierarchy, topological Rentian scaling, and topological fractal scaling—in addition to several summary statistics, including the mean clustering coefficient, the shortest path-length, and the network diameter. The models are investigated in a progressive, branching sequence, aimed at capturing different elements thought to be important in the brain, and range from simple random and regular networks, to models that incorporate specific growth rules and constraints. We find that synthetic models that constrain the network nodes to be physically embedded in anatomical brain regions tend to produce distributions that are most similar to the corresponding measurements for the brain. We also find that network models hardcoded to display one network property (e.g., assortativity) do not in general simultaneously display a second (e.g., hierarchy). This relative independence of network properties suggests that multiple neurobiological mechanisms might be at play in the development of human brain network architecture. Together, the network models that we develop and employ provide a potentially useful starting point for the statistical inference of brain network structure from neuroimaging data. PMID:24675546
Klimm, Florian; Bassett, Danielle S.; Carlson, Jean M.; Mucha, Peter J.
Following a myocardial infarction (MI), increases in plasma angiotensin II may activate central nervous system (CNS) pathways and thereby peripheral mechanisms (eg, sympathetic activity and the circulating/cardiac renin-angiotensin-aldosterone system ). Plasma angiotensin II may directly activate CNS pathways through the subfornical organ and chronically enhance activity by way of a neuromodulatory system. The latter involves an increase in CNS aldosterone-causing "ouabain" release (eg, from magnocellular neurons of the supraoptic and paraventricular nuclei). "Ouabain" may lower membrane potential, thereby enhancing activity of angiotensinergic pathways. The resulting increases in sympathetic activity, and circulating/cardiac RAAS contributes to progressive left ventricular remodeling and dysfunction after MI and can be largely prevented by central administration of a blocker for any of the components of this neuromodulatory system. These new insights into the crucial role of the CNS may lead to new therapeutic approaches for the prevention of heart failure after MI with minimal peripheral adverse effects. PMID:19486591
Huang, Bing S; Leenen, Frans H H
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.
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.
Recent reports indicate that elevating DNA glycosylase/AP lyase repair enzyme activity offers marked cytoprotection in cultured cells and a variety of injury models. In this study, we measured the effect of EndoIII, a fusion protein construct that traffics Endonuclease III, a DNA glycosylase/AP lyase, to the mitochondria, on infarct size in a rat model of myocardial ischemia/reperfusion. Open-chest, anesthetized rats were subjected to 30 min of occlusion of a coronary artery followed by 2 h of reperfusion. An intravenous bolus of EndoIII, 8 mg/kg, just prior to reperfusion reduced infarct size from 43.8 ± 1.4 % of the risk zone in control animals to 24.0 ± 1.3 % with no detectable hemodynamic effect. Neither EndoIII's vehicle nor an enzymatically inactive EndoIII mutant (K120Q) offered any protection. The magnitude of EndoIII's protection was comparable to that seen with the platelet aggregation inhibitor cangrelor (25.0 ± 1.8 % infarction of risk zone). Because loading with a P2Y12 receptor blocker to inhibit platelets is currently the standard of care for treatment of acute myocardial infarction, we tested whether EndoIII could further reduce infarct size in rats treated with a maximally protective dose of cangrelor. The combination reduced infarct size to 15.1 ± 0.9 % which was significantly smaller than that seen with either cangrelor or EndoIII alone. Protection from cangrelor but not EndoIII was abrogated by pharmacologic blockade of phosphatidylinositol-3 kinase or adenosine receptors indicating differing cellular mechanisms. We hypothesized that EndoIII protected the heart from spreading necrosis by preventing the release of proinflammatory fragments of mitochondrial DNA (mtDNA) into the heart tissue. In support of this hypothesis, an intravenous bolus at reperfusion of deoxyribonuclease I (DNase I) which should degrade any DNA fragments escaping into the extracellular space was as protective as EndoIII. Furthermore, the combination of EndoIII and DNase I produced additive protection. While EndoIII would maintain mitochondrial integrity in many of the ischemic cardiomyocytes, DNase I would further prevent mtDNA released from those cells that EndoIII could not save from propagating further necrosis. Thus, our mtDNA hypothesis would predict additive protection. Finally to demonstrate the toxicity of mtDNA, isolated hearts were subjected to 15 min of global ischemia. Infarct size doubled when the coronary vasculature was filled with mtDNA fragments during the period of global ischemia. To our knowledge, EndoIII and DNase are the first agents that can both be given at reperfusion and add to the protection of a P2Y12 blocker, and thus should be effective in today's patient with acute myocardial infarction. PMID:25595210
Yang, Xi-Ming; Cui, Lin; White, James; Kuck, Jamie; Ruchko, Mykhaylo V; Wilson, Glenn L; Alexeyev, Mikhail; Gillespie, Mark N; Downey, James M; Cohen, Michael V
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. PMID:24742302
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.
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 PMID:23874160
Basu, Sanjay; Glantz, Stanton; Bitton, Asaf; Millett, Christopher
Nothobranchius furzeri has emerged as a new fish model for neurobiological and age research over recent years, due to the exceptionally short lifespan, age-dependent cognitive/behavioral decline, expression of age-related biomarkers. The growing interest in this teleost has raised the need to construct an atlas of the whole brain of N. furzeri. The study has been carried out on adult specimens belonging to the long lived strain, originating from Mozambique and named MZM 04/10. In the atlas, the external features of brain, images of sections stained with luxol fast bleu/violet and schematic drawings of the most representative sections are showed. The identification and description of brain structures has been carried out on methodological and hodological studies. Comparative analyses have revealed remarkable and peculiar neuroanatomical characteristics of N. furzeri brain architecture. Thus, a comprehensive whole brain atlas of N. furzeri has been constructed aiming to provide a baseline for structural and functional future experiments on this emerging model organism. PMID:23408644
Paeoniflorin, a component in Paeonia lactiflora Pall, inhibits nuclear factor-kappaB expression in chronic hypoperfusion rat and has anti-inflammatory properties. Therefore, the aim of the present study was to investigate the effect of paeoniflorin on cerebral infarct, and the involvement of anti-inflammation. We established an animal model of cerebral infarct by occluding both the common carotid arteries and the right middle cerebral artery for 90 min, followed by reperfusion of 24 hours. The ratios of cerebral infarction area to total brain area, and neuro-deficit score were used as an index to observe the effects of paeoniflorin on cerebral infarct. ED1 (mouse anti rat CD68), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecular-1 (ICAM-1), myeloperoxidase (MPO) immunostaining and apoptotic cells in the cerebral infarction region also were studied. The results indicated that both pre-treatment and post-treatment with paeoniflorin reduced the ratio of cerebral infarction area; pre-treatment with paeoniflorin also reduced the neurological deficit score. The counts of ED1, IL-1beta, TNF-alpha, ICAM-1 of microvessels and MPO immunoreactive cells and apoptotic cells were increased in the cerebral infarction region; however, these increases were reduced by Paeoniflorin pre-treatment. In conclusion, Paeoniflorin reduced cerebral infarct and neurological deficit in ischemia-reperfusion injured rats, suggesting that paeoniflorin may have a similar effect in humans and might be a suitable treatment for stroke. Paeoniflorin reduced cerebral infarct, at least in part, involves the anti-inflammatory properties. PMID:20128044
Tang, Nou-Ying; Liu, Chung-Hsiang; Hsieh, Ching-Tou; Hsieh, Ching-Liang
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.
of Engineering, Dartmouth College, Hanover, NH 03755, USA 2 Department of Computer Science, Dartmouth College-based models. The technique involves six basic steps: 1. from pre-operative MRI scans, generate a FEM mesh of brain deformations. The project is funded by the National Institute of Neurological Disorders and Stroke
A model of associative memory for time varying spatial patterns is proposed and simulated on a digital computer. This is a network composed of many neuron-like elements, and shows an ability for associative memory similar to that of the brain.
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.
Background. There are several reports that engrafted mesenchymal stem cells (MSCs) stimulate angiogenesis in the ischemic heart, but the mechanism remains con- troversial. We hypothesize that transplantation of MSCs enhances vascular regeneration through a paracrine action. Methods. A transmural myocardial infarction was cre- ated by ligation of the left anterior descending coronary artery in rats. Those with an ejection fraction
Yao Liang Tang; Qiang Zhao; Xinyu Qin; Leping Shen; Leilei Cheng; Junbo Ge; M. Ian Phillips
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
Alexander I. Veress; William Paul Segars; Benjamin M. W. Tsui; Grant T. Gullberg
Background Optimal fluid resuscitation strategy following combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remain controversial and the effect of resuscitation infusion speed on outcome is not well known. We have previously reported that bolus infusion of fresh frozen plasma (FFP) protects the brain compared with bolus infusion of 0.9% normal saline (NS). We now hypothesize reducing resuscitation infusion speed through a stepwise infusion speed increment protocol using either FFP or NS would provide neuroprotection compared with a high speed resuscitation protocol. Methods 23 Yorkshire swine underwent a protocol of computer controlled TBI and 40% hemorrhage. Animals were left in shock (mean arterial pressure of 35 mmHg) for two hours prior to resuscitation with bolus FFP (n?=?5, 50 ml/min) or stepwise infusion speed increment FFP (n?=?6), bolus NS (n?=?5, 165 ml/min) or stepwise infusion speed increment NS (n?=?7). Hemodynamic variables over a 6-hour observation phase were recorded. Following euthanasia, brains were harvested and lesion size as well as brain swelling was measured. Results Bolus FFP resuscitation resulted in greater brain swelling (22.36?±?1.03% vs. 15.58?±?2.52%, p?=?0.04), but similar lesion size compared with stepwise resuscitation. This was associated with a lower cardiac output (CO: 4.81?±?1.50 l/min vs. 5.45?±?1.14 l/min, p?=?0.03). In the NS groups, bolus infusion resulted in both increased brain swelling (37.24?±?1.63% vs. 26.74?±?1.33%, p?=?0.05) as well as lesion size (3285.44?±?130.81 mm3 vs. 2509.41?±?297.44 mm3, p?=?0.04). This was also associated with decreased cardiac output (NS: 4.37?±?0.12 l/min vs. 6.35?±?0.10 l/min, p?0.01). Conclusions In this clinically relevant model of combined TBI and HS, stepwise resuscitation protected the brain compared with bolus resuscitation. PMID:25116886
Modern, very sensitive, and noninvasive devices (strain-gauges, accelerometers, etc) detect deformations and motions in the order of a few microns. The observation that the rise in intracranial pressure produces measurable suture strain suggests that noninvasive determination of mechanical parameters in the intracranial cavity, such as density, velocity, pressure, energy, and their time rates, is clearly possible. Based on the above premise, and utilizing the concept of representative elementary volume (REV), this paper presents the conceptual part of a theory that defines the mechanical behavior of the brain and skull under various conditions. The systematic review of brain tissue mechanics leads to a continuum model of a mixed stress-displacement boundary value type, which defines the dynamics of the visco-elastic brain tissue in mathematical terms. PMID:3598115
Karni, Z; Ivan, L P; Bear, J
Cerebral injuries can trigger stress-related cardiomyopathy. The extent of cerebral injury and the involvement of the insular cortex influence the incidence and extent of myocardial injury (MI), and drugs with proven neuroprotective and cardioprotective properties such as levosimendan might be beneficial. This hypothesis was addressed in a rat model of transient middle cerebral artery occlusion. Transient brain ischemia was induced for 60 min by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats. Treatment with levosimendan (24 µg/kg) was started briefly before reperfusion. Hemodynamic parameters were recorded and cerebral and MI quantified after 24 h. Levosimendan treatment significantly reduced cerebral infarct size in the cortex, but not in the striatal and insular regions. However, its effects on survival (28 vs. 45 %), incidence of MI (8 vs. 33 %) as indicated by a troponin I (sTnI) threshold of 4.8 µg/L and large insular infarcts of ?10 mm(3) (23 vs. 50 %) failed to reach statistical significance. Blood pressure demonstrated significant differences related to insular infarct size during reperfusion. Levosimendan demonstrated no relevant effects on markers of MI (sTnI = 1.5 ± 2.8 vs. 5.3 ± 7.2 µg/L, P = 0.121). Insular infarct size could be identified as the only predictor of MI (odds ratio = 1.86, P = 0.037). In conclusion, the current investigation confirmed insular infarct size as a predictor of MI and source of hemodynamic compromise, but failed to demonstrate an effect of levosimendan on MI trigged by brain ischemia. A hardly protectable insular region might explain this. PMID:25262586
Bleilevens, C; Roehl, A B; Zoremba, N; Tolba, R; Rossaint, R; Hein, M
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. PMID:22110762
Taheri, Saeid; Shi, Honglian
A 74-year-old man was surgically treated owing to incarcerated right inguinal hernia. Following surgery, he developed a focal hemorrhagic testicular infarct localized in the anterior pole of the right testis. The cause of the infarct seemed to bei either thrombosis or compression by edema of the veins draining the testis. PMID:3727192
Nistal, M; Palacios, J; Regadera, J; Paniagua, R
The clinical features, treatment, and outcome were reviewed for 48 patients with a haematoma and 71 patients with an infarct in the posterior fossa in order to develop a rational plan of management. Clinical features alone were insufficient to make a diagnosis in about half of the series. Patients with a haematoma were referred more quickly to the neurosurgical unit, were more often in coma, and more often had CT evidence of brain stem compression and acute hydrocephalus. Ultimately, 75% of the patients with a haematoma required an operation. By contrast, most patients with an infarct were managed successfully conservatively. Early surgical management in both cerebellar haemorrhage and infarct (either external ventricular drainage or evacuation of the lesion), associated with early presentation and CT signs of brain stem compression and acute hydrocephalus, led to a good outcome in most patients. Of the patients with cerebellar haematoma initially treated by external drainage, over half subsequently required craniectomy and evacuation of the lesion; but, in some cases, this failed to reverse the deterioration. In patients with a cerebellar infarct, external drainage was more often successful. The guidelines, findings, and recommendations for future management of patients with posterior fossa stroke are discussed. Images PMID:7673958
Mathew, P; Teasdale, G; Bannan, A; Oluoch-Olunya, D
Uncovering the roles of neural feedback in the brain is an active area of experimental research. In songbirds, the telencephalic premotor nucleus HVC receives neural feedback from both forebrain and brain stem areas. Here we present a computational model of birdsong sequencing that incorporates HVC and associated nuclei and builds on the model of sparse bursting presented in our preceding companion paper. Our model embodies the hypotheses that 1) different networks in HVC control different syllables or notes of birdsong, 2) interneurons in HVC not only participate in sparse bursting but also provide mutual inhibition between networks controlling syllables or notes, and 3) these syllable networks are sequentially excited by neural feedback via the brain stem and the afferent thalamic nucleus Uva, or a similar feedback pathway. We discuss the model's ability to unify physiological, behavioral, and lesion results and we use it to make novel predictions that can be tested experimentally. The model suggests a neural basis for sequence variations, shows that stimulation in the feedback pathway may have different effects depending on the balance of excitation and inhibition at the input to HVC from Uva, and predicts deviations from uniform expansion of syllables and gaps during HVC cooling. PMID:19553477
Gibb, Leif; Gentner, Timothy Q.; Abarbanel, Henry D. I.
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
Penetrating traumatic brain injury (pTBI) has been difficult to model in small laboratory animals, such as rats or mice. Previously, we have established a non-fatal, rat model for pTBI using a modified air-rifle that accelerates a pellet, which hits a small probe that then penetrates the experimental animal’s brain. Knockout and transgenic strains of mice offer attractive tools to study biological reactions induced by TBI. Hence, in the present study, we adapted and modified our model to be used with mice. The technical characterization of the impact device included depth and speed of impact, as well as dimensions of the temporary cavity formed in a brain surrogate material after impact. Biologically, we have focused on three distinct levels of severity (mild, moderate, and severe), and characterized the acute phase response to injury in terms of tissue destruction, neural degeneration, and gliosis. Functional outcome was assessed by measuring bodyweight and motor performance on rotarod. The results showed that this model is capable of reproducing major morphological and neurological changes of pTBI; as such, we recommend its utilization in research studies aiming to unravel the biological events underlying injury and regeneration after pTBI. PMID:25374559
Cernak, Ibolja; Wing, Ian D.; Davidsson, Johan; Plantman, Stefan
SUMMARY Neural stem cells in the subventricular zone (SVZ) of the adult mammalian forebrain are a potential source of neurons for neural tissue repair after brain insults such as ischemic stroke and traumatic brain injury (TBI). Recent studies show that neurogenesis in the ventricular zone (VZ) of the adult zebrafish telencephalon has features in common with neurogenesis in the adult mammalian SVZ. Here, we established a zebrafish model to study injury-induced neurogenesis in the adult brain. We show that the adult zebrafish brain possesses a remarkable capacity for neuronal regeneration. Telencephalon injury prompted the proliferation of neuronal precursor cells (NPCs) in the VZ of the injured hemisphere, compared with in the contralateral hemisphere. The distribution of NPCs, viewed by BrdU labeling and ngn1-promoter-driven GFP, suggested that they migrated laterally and reached the injury site via the subpallium and pallium. The number of NPCs reaching the injury site significantly decreased when the fish were treated with an inhibitor of ?-secretase, a component of the Notch signaling pathway, suggesting that injury-induced neurogenesis mechanisms are at least partly conserved between fish and mammals. The injury-induced NPCs differentiated into mature neurons in the regions surrounding the injury site within a week after the injury. Most of these cells expressed T-box brain protein (Tbr1), suggesting they had adopted the normal neuronal fate in this region. These results suggest that the telencephalic VZ contributes to neural tissue recovery following telencephalic injury in the adult zebrafish, and that the adult zebrafish is a useful model for regenerative medicine. PMID:22028327
Kishimoto, Norihito; Shimizu, Kohei; Sawamoto, Kazunobu
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
Valid sensitive animal models are crucial for understanding the pathobiology of complex human disorders, such as anxiety, autism, depression and schizophrenia, which all have the 'spectrum' nature. Discussing new important strategic directions of research in this field, here we focus i) on cross-species validation of animal models, ii) ensuring their population (external) validity, and iii) the need to target the interplay between multiple disordered domains. We note that optimal animal models of brain disorders should target evolutionary conserved 'core' traits/domains and specifically mimic the clinically relevant inter-relationships between these domains. PMID:24384129
Stewart, Adam Michael; Kalueff, Allan V
ObjectiveTo describe the range of early recovery patterns seen in children admitted for inpatient rehabilitation after traumatic brain injury and to build simple predictive models of expected recovery.Patients103 consecutive paediatric admissions to a neurological rehabilitation facility after closed head injury.MethodsChildren's recoveries were defined by repeated scores on the WeeFIM (a validated paediatric measure of functional independence) assembled into recovery trajectories.
Rob J Forsyth; Cynthia F Salorio; James R Christensen
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. PMID:19003488
Gerth, Sabrina; Vasishth, Shravan
The human brain and skull are three dimensional (3D) anatomical structures with complex surfaces. However, medical images are often two dimensional (2D) and provide incomplete visualization of structural morphology. To overcome this loss in dimension, we developed and validated a freely available, semi-automated pathway to build 3D virtual reality (VR) and hand- held, stereolithograph models. To evaluate whether surface visualization
Daniel J. Kelley; Mohammed Farhoud; M. Elizabeth Meyerand; David L. Nelson; Lincoln F. Ramirez; Robert J. Dempsey; Alan J. Wolf; Andrew L. Alexander; Richard J. Davidson
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.
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. PMID:24066038
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
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
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
A probabilistic deformable model for the representation of brain structures is described. The statistically learned deformable model represents the relative location of head (skull and scalp) and brain surfa- ces in Magnetic Resonance Images (MRIs) and accommodates their sig- nicant variability across dierent individuals. The head and brain surfa- ces of each volume are parameterized by the amplitudes of the
Christophoros Nikou; Fabrice Heitz; Jean-paul Armspach
Abstract. A probabilistic deformable model for the representation of brain structures is described. The statistically learned deformable model represents the relative location of head (skull and scalp) and brain surfa- ces in Magnetic Resonance Images (MRIs) and accommodates,their sig- nicant variability across dierent individuals. The head and brain surfa- ces of each volume are parameterized by the amplitudes of the
Christophoros Nikou; Fabrice Heitz; Jean-paul Armspach; Gloria Bueno
Functional Representation of Human Embryo Brain Models Roman Durikovic Silvester Czanner Hirofumi embryo brain is organic and has many folds that are difficult to model or animate with conventional metamorphosis during the growth of some human embryo organs, partic- ularly brain and stomach. Popular methods
Categories and Functional Units: An Infinite Hierarchical Model for Brain Activations Danial present a model that describes the structure in the responses of different brain areas to a set of stimuli encodes the relationship between brain activations and fMRI time courses. A variational inference
Predictive Modeling of fMRI Brain States using Functional Canonical Correlation Analysis S Abstract. We present a novel method for predictive modeling of human brain states from functional for prediction of naturalistic stimuli from unknown fMRI data shows that the method nds highly predictive brain
Design and Integration of Partial Brain Models Using Hierarchical Cooperative CoEvolution Michail and integrating brain-inspired artificial cognitive sys- tems. Specifically, we introduce a new computational framework for modelling partial brain areas following a coevolutionary agent-based approach. Properly for
To exploit the advantages of using rabbits for cardiac imaging research and to tackle the technical obstacles, efforts have been made under the framework of a doctoral research program. In this overview article, by cross-referencing the current literature, we summarize how we have developed a preclinical cardiac research platform based on modified models of reperfused myocardial infarction (MI) in rabbits; how the in vivo manifestations of cardiac imaging could be closely matched with those ex vivo macro- and microscopic findings; how these imaging outcomes could be quantitatively analyzed, validated and demonstrated; and how we could apply this cardiac imaging platform to provide possible solutions to certain lingering diagnostic and therapeutic problems in experimental cardiology. In particular, tissue components in acute cardiac ischemia have been stratified and characterized, post-infarct lipomatous metaplasia (LM) as a common but hardly illuminated clinical pathology has been identified in rabbit models, and a necrosis avid tracer as well as an anti-ischemic drug have been successfully assessed for their potential utilities in clinical cardiology. These outcomes may interest the researchers in the related fields and help strengthen translational research in cardiovascular diseases. PMID:25392822
Feng, Yuanbo; Bogaert, Jan; Oyen, Raymond
Numerical grid generation is used to provide a framework for brain and neuron visualization. Smoothing spline surfaces are fit to contour data to generate 3D solid model reconstruction of brain tissues. Finite element methods are then used...
Batte, David Allan
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
The Impact of Trimetazidine Treatment on Left Ventricular Functions and Plasma Brain Natriuretic Peptide Levels in Patients with Non-ST Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention
Background and Objectives The aim of this study was to investigate the impact of treatment with oral trimetazidine (TMZ) applied before and after percutaneous coronary interventions (PCI) on short-term left ventricular functions and plasma brain natriuretic peptide (BNP) levels in patients with non-ST segment elevation myocardial infarction (NSTEMI) undergoing PCI. Subjects and Methods The study included 45 patients who were undergoing PCI with the diagnosis of NSTEMI. The patients were randomized into two groups. The first group (n=22) of the patients hospitalized with the diagnosis of NSTEMI was given conventional therapy plus 60 mg TMZ just prior to PCI. Treatment with TMZ was continued for one month after the procedure. TMZ treatment was not given to the second group (n=23). Echocardiography images were recorded and plasma BNP levels were measured just prior to the PCI and on the 1st and 30th days after PCI. Results The myocardial performance index (MPI) was greater in the second group (p=0.02). In the comparison of BNP levels, they significantly decreased in both of the groups during the 30-day follow-up period (29.0±8 and 50.6±33, p<0.01 respectively). However, decreasing of BNP levels was higher in the group administered with TMZ. The decrease of left ventriclular end-diastolic volume was observed in all groups at 30 days after intervention, but was higher in the group administered with TMZ (p=0.01). Conclusion Trimetazidine treatment commencing prior to PCI and continued after PCI in patients with NSTEMI provides improvements in MPI, left ventricular end diastolic volume and a decrease in BNP levels. PMID:23964292
Karakelleo?lu, ?ule; Gündo?du, Fuat; Ta?, Muhammed Hakan; Kaya, Ahmet; Duman, Hakan; De?irmenci, Hüsnü; Hamur, Hikmet; ?im?ek, Ziya
Proteomics and systems biology have significantly contributed to biomarker discovery in the field of brain injury. This study utilized 2D-DIGE-PMF-MS as a preliminary screen to detect biomarkers in a rat model of penetrating ballistic-like brain injury (PBBI). Brain-specific systems biology analysis of brain tissue identified 386 proteins having a fold change of more than 2, of which 321 proteins were increased and 65 were decreased 24 h after PBBI compared to sham controls. The majority of upregulated proteins were cytoskeletal (10.5%), nucleic acid binding (9.3%), or kinases (8.9%). Most proteins were involved in protein metabolism (22.7%), signal transduction (20.4%), and development (9.6%). Pathway analysis indicated that these proteins were involved in neurite outgrowth and cell differentiation. Semiquantitative Western blotting of 6, 24, 48, and 72 h after PBBI indicated ubiquitin carboxyl-terminal hydrolase isozyme L1 (a proposed traumatic brain injury biomarker in human clinical trials), tyrosine hydroxylase, and syntaxin-6 were found to be consistently elevated in brain tissue and cerebral spinal fluid after PBBI compared to sham controls. Combining proteomics and brain-specific systems biology can define underlying mechanisms of traumatic brain injury and provide valuable information in biomarker discovery that, in turn, may lead to novel therapeutic targets. PMID:23161467
Boutté, Angela M; Yao, Changping; Kobeissy, Firas; May Lu, Xi-Chun; Zhang, Zhiqun; Wang, Kevin K; Schmid, Kara; Tortella, Frank C; Dave, Jitendra R
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 (8.4×10³/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
Objective To evaluate the potential protective affects of Epo on left ventricular (LV) function and remodeling after acute myocardial\\u000a infarction (MI).\\u000a \\u000a \\u000a \\u000a Methods Epo was injected into the peritoneum of male Wistar rats (250 g) during 6 weeks post induction of MI. Rats were divided into\\u000a five groups: MI treated with single high dose (MT1, 5,000 U\\/kg, n?=?10), single high dose (5,000 U\\/kg) and repeated high doses
Itsik Ben-Dor; Britta Hardy; Shmuel Fuchs; Ella Kaganovsky; Ehud Kadmon; Alex Sagie; Raymond Coleman; Mali Mansur; Boaz Politi; Abigail Fraser; Daniela Harell; Elimelech Okon; Alexander Battler; Moti Haim
We report a case of cerebellar infarction originating from vertebral artery stenosis caused by a hypertrophied uncovertebral joint. A 38-year-old male patient presented with sudden onset of headache, dizziness, and dysarthria. The brain MR image showed acute infarction in the right cerebellar hemisphere in the territory of the posterior inferior cerebellar artery (PICA) and superior cerebellar artery (SCA). The MR
Jong Mun Choi; Hyeok Jin Hong; Suk Ki Chang; Sung Han Oh
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. PMID:24991402
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
One of the criteria defining mild traumatic brain injury (mTBI) in humans is a loss of consciousness lasting for less than 30 min. mTBI can result in long-term impairment of cognition and behavior. In rats, the length of time it takes a rat to right itself after injury is considered to be an analog for human return to consciousness. This study characterized a rat mild brain blast injury (mBBI) model defined by a righting response reflex time (RRRT) of more than 4 min but less than 10 min. Assessments of motor coordination relying on beam-balance and foot-fault assays and reference memory showed significant impairment in animals exposed to mBBI. This study's hypothesis is that there are inflammatory outcomes to mTBI over time that cause its deleterious effects. For example, mBBI significantly increased brain levels of interleukin (IL)-1? and tumor necrosis factor-? (TNF?) protein. There were significant inflammatory responses in the cortex, hippocampus, thalamus, and amygdala 6 hr after mBBI, as evidenced by increased levels of the inflammatory markers associated with activation of microglia and macrophages, ionized calcium binding adaptor 1 (IBA1), impairment of the blood-brain barrier, and significant neuronal losses. There were significant increases in phosphorylated Tau (p-Tau) levels, a putative precursor to the development of neuroencephalopathy, as early as 6 hr after mBBI in the cortex and the hippocampus but not in the thalamus or the amygdala. There was an apparent correlation between RRRTs and p-Tau protein levels but not IBA1. These results suggest potential therapies for mild blast injuries via blockade of the IL-1? and TNF? receptors. © 2014 Wiley Periodicals, Inc. PMID:25410497
Perez-Polo, J R; Rea, H C; Johnson, K M; Parsley, M A; Unabia, G C; Xu, G-Y; Prough, D; DeWitt, D S; Spratt, H; Hulsebosch, C E
the number of neurons in the human brain, found that the length of simulated signaling pathway can to characterize signaling in small-world networks with large but bounded numbers of nodes, as in human brainsA computational model for signaling pathways in bounded small-world networks corresponding to brain
ANALYZING IMAGING BIOMARKERS FOR TRAUMATIC BRAIN INJURY USING 4D MODELING OF LONGITUDINAL MRI Bo and treatment efficacy in patients with traumatic brain injury (TBI). To our knowledge, the identification, School of Computing, Brain Injury Research Center, University of Utah University of California at Los
SEGMENTATION OF PATIENT SPECIFIC MEG/EEG SKULL, SCALP, AND BRAIN MODELS FROM MRI Belma Dogdas California, LA, CA 90089-2564 ABSTRACT We present an automated method for segmenting skull, scalp, and brain and morphology to produce a scalp mask. The brain and scalp masks provide boundaries between which the skull must
Leahy, Richard M.
Aligning context-based statistical models of language with brain activity during reading Leila for incoming words given the context. On the other hand, brain imaging studies have sug- gested that during reading, the brain (a) continu- ously builds a context from the successive words and every time
recently which allow for uncertainty yet still capture the first order effects associated with brain the procedure for modeling the dural septa and study the effect of those membranes on subsurface brain shift-rigid deformation of brain tissue caused by gravity, edema, hyperosmotic drugs administered prior to surgery
Miga, Michael I.
INCORPORATION OF A LANGUAGE MODEL INTO A BRAIN COMPUTER INTERFACE BASED SPELLER THROUGH HMMs Ã?ada, 34956 Istanbul, Turkey ABSTRACT Brain computer interface (BCI) research deals with the problem control and may be unable to communicate. The idea of brain-computer interfaces (BCIs) involves
Uncued Brain-Computer Interfaces: a Variational Hidden Markov Model of Mental State Dynamics CÃ©dric Brain- Computer Interfaces based on motor imagery. Our algorithm aims at ltering the continuous classier that the combination of our algorithm with a dynamic classier yields the best results. 1 Introduction Brain-Computer
Paris-Sud XI, UniversitÃ© de
Use of digitalis in myocardial infarction is controversial. To determine the efficacy and toxic threshold, serial infusions of 3 ?g/kg per min of acetyl-strophanthidin were given to six intact conscious dogs 24 hr before and 1 hr, 2 days, and 7 days after myocardial infarction induced by inflation of a balloon cuff implanted on the left anterior descending coronary artery. Within 1 hr after myocardial infarction, heart rate increased by 28%. Left ventricular end-diastolic pressure increased from 7 to 20 mm Hg, and stroke volume decreased by 25%. At this time acetylstrophanthidin caused no beneficial hemodynamic change, 1 wk later, the heart rate and left ventricular end-diastolic pressure had declined toward normal but remained elevated. At this time, acetylstrophanthidin lowered left ventricular end-diastolic pressure by 25%, and increased the stroke volume and cardiac output by 25% and 21% respectively, without any change in heart rate or aortic pressure. Tolerance to acetylstrophanthidin, defined as appearance of ventricular tachycardia, declined the 1st hr after myocardial infarction by 24% (P<0.05) from the control level of 43 ±4 ?g/kg (SEM), but subsequently returned to control. Thus, immediately after myocardial infarction, tolerance to acetylstrophanthidin was reduced, and left ventricular failure was not ameliorated. 1 wk later in the healing phase of myocardial infarction, tolerance to acetylstrophanthidin returned to normal and left ventricular performance was improved by this drug. The study suggests a limited therapeutic role for digitalis in the treatment of left ventricular failure in the acute phase immediately after myocardial infarction, but beneficial effects may occur in the healing phase 1 wk later. PMID:5411786
Kumar, Raj; Hood, William B.; Joison, Julio; Gilmour, David P.; Norman, John C.; Abelmann, Walter H.
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.
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.
We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0??m pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, ?v?3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion. PMID:25692137
Rizzo, A.; Vasco, C.; Girgenti, V.; Fugnanesi, V.; Calatozzolo, C.; Canazza, A.; Salmaggi, A.; Rivoltini, L.; Morbin, M.; Ciusani, E.
Well-characterized in vivo and in vitro models exist for the study of ischaemia- and infarction-related ventricular fibrillation (VF). In rats in vivo, VF appears to occur in distinct acute ischaemia- (early) and infarction-related (late) phases. Interestingly, isolated buffer-perfused rat hearts do not develop late VF. This raises the possibility that unidentified components of the blood may be responsible for late VF. We thus sought to characterize an isolated blood-perfused rat heart in order to investigate the possible influence of blood components on arrhythmias arising from ischaemia and infarction. Hearts, excised from male Wistar rats, were perfused in the Langendorff mode with blood from support rats (male Wistar, 350–430 g) via an extracorporeal circuit. Perfused hearts underwent left coronary artery occlusion for 240 min or a sham procedure (n=10 group?1). Only 10% of ischaemic hearts developed late VF (90–240 min). Tissue myeloperoxidase activity (an index of neutrophil accumulation) increased during ischaemia from 0.017±0.004 (six fresh hearts) to 0.056±0.005 units mg protein?1 (P<0.05) at 240 min, but values were similar in sham hearts (0.083±0.013). Likewise, the decline (?1 vs 240 min of ischaemia shown) in circulating total white blood cells from 6.8±0.5 to 1.9±0.2×103 ?l?1 and in platelets from 441±32 to 274±16×103 ?l?1 (both P<0.05) was similar in time-matched sham hearts (data not shown). Surprisingly, only 10% of ischaemic hearts developed early VF (0–90 min), although the incidence of early ventricular tachycardia was 100% in these hearts (P<0.05 vs sham hearts). Blood K+ values were normal (hyperkalaemia suppresses VF). Although late VF was absent in blood-perfused hearts, it would be premature to conclude from this that late VF is not mediated by blood components. This is because the similar neutrophil accumulation in ischaemic and sham hearts, the decline in numbers of circulating blood components, and the unexpected paucity of early VF all question the validity of the model. PMID:12429582
Clements-Jewery, Hugh; Hearse, David J; Curtis, Michael J
Acute myocardial infarction is being recognized as a spectrum of clinical subsets. This appreciation has been brought about to a large degree by the development of several new tools that can be applied clinically to aid in evaluation of patients with acute infarction, and in some cases to provide short and long-term prognostic information. In the realm of noninvasive methods, several tests utilizing radiopharmaceuticals and scintillation cameras have emerged and are rapidly becoming reliable diagnostic parameters in patients with coronary disease and infarction. Technetium 99m (stannous) pyrophosphate (TcPYP) scintigraphy, one of the first of these techniques to find clinical use, has been shown to be an accurate indicator of acute transmural myocardial infarction and provides added sensitivity and specificity to the diagnosis. Increased diagnostic accuracy, the dimension of visible localization and the potential for infarct sizing promise physicians better understanding of a patient's clinical presentation and a more rational approach to management. ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 5.Figure 6.Figure 7.Figure 8.Figure 10.Figure 11.Figure 12.Figure 13. PMID:339549
Werner, Jeffrey A.; Botvinick, Elias H.; Shames, David M.; Parmley, William W.
Objective(s): Some histopathological alterations take place in the ischemic regions following brain ischemia. Recent studies have demonstrated some neuroprotective roles of crocin in different models of experimental cerebral ischemia. Here, we investigated the probable neuroprotective effects of crocin on the brain infarction and histopathological changes after transient model of focal cerebral ischemia. Materials and Methods: Experiment was performed in four groups of rats (each group; n=8), sham, control ischemia and ischemia treated rats. Transient focal cerebral ischemia was induced by 80 min middle cerebral artery occlusion (MCAO) followed by 24 hr reperfusion. Crocin, at doses 50 and 80 mg/kg, was injected at the beginning of ischemia (IP injection). Neurologic outcome (Neurological Deficit Score, NDS scale), infarct volume (TTC staining) and histological studies were assessed 24 hr after termination of MCAO. Results: Treatment with crocin, at doses 50 and 80 mg/kg, significantly reduced the cortical infarct volume by 48% and 60%, and also decreased striatal infarct volume by 45% and75%, respectively. Crocin at two different doses significantly improved the NDS of ischemic rats. At histological evaluation, crocin, at dose 80 mg/kg more than 50 mg/kg, decreased the number of eosinophilic (prenecrotic) neurons and reduced the fiber demyelination and axonal damage in ischemic regions. Conclusion: Our findings indicated that crocin effectively reduces brain ischemia-induced injury and improves neurological outcomes. Crocin also is a potent neuroprotective factor that can be able to prevent histopathological alterations following brain ischemia. PMID:25691932
Sarshoori, Javad Raouf; Asadi, Mohammad Hossien; Mohammadi, Mohammad Taghi
Purpose Simplified models of non-monoexponential diffusion signal decay are of great interest to study the basic constituents of complex diffusion behaviour in tissues. The latebra, a unique structure uniformly present in the yolk of avian eggs, exhibits a non-monoexponential diffusion signal decay. This model is more complex than simple phantoms based on differences between water and lipid diffusion, but is also devoid of microscopic structures with preferential orientation or perfusion effects. Methods Diffusion scans with multiple b-values were performed on a clinical 3 Tesla system in raw and boiled chicken eggs equilibrated to room temperature. Diffusion encoding was applied over the ranges 5–5,000 and 5–50,000 s/mm2. A low read-out bandwidth and chemical shift was used for reliable lipid/water separation. Signal decays were fitted with exponential functions. Results The latebra, when measured over the 5–5,000 s/mm2 range, exhibited independent of preparation clearly biexponential diffusion, with diffusion parameters similar to those typically observed in in-vivo human brain. For the range 5–50,000 s/mm2 there was evidence of a small third, very slow diffusing water component. Conclusion The latebra of the avian egg contains membrane structures, which may explain a deviation from a simple monoexponential diffusion signal decay, which is remarkably similar to the deviation observed in brain tissue. PMID:24105853
Maier, Stephan E.; Mitsouras, Dimitris; Mulkern, Robert V.
The detailed knowledge about the contribution of immunoproteasome to the neuroinflammation in ischemic stroke is still not available. The immunoreactivity of low molecular mass peptide 2 (LMP2) and low molecular mass peptide 7 (LMP7) was evident in the ipsilateral ischemic cerebral cortex and striatum following transient middle cerebral artery occlusion (MCAO). Both LMP2 and LMP7 increased as early as 4?h after the MCAO, further increased at 24?h, peaked at 72?h and decreased 7 days later. LMP2 and LMP7 were mainly present in astrocytes and microglia/macrophage cells, respectively. LMP2 knockdown by shRNA (short hairpin RNA) markedly reduced the levels of LMP2 and LMP7 protein and caused 75.5 and 78.6% decrease in the caspase-like (C-L) and chymotrypsin-like (CT-L) activities, respectively. Compared with cont-shRNA group (39.7%, infarction volumes/total ipsilateral hemisphere), the infarction volumes were reduced to 22.5% in LMP2-shRNA group. Additionally, LMP2 knockdown significantly reduced activated astrocytes and microglia, the expression nuclear factor kappa B (NF-?B) p65, tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) and caused less accumulation of ischemia-induced protein ubiquitination compared with MG132. These findings demonstrate that inhibition of LMP2 significantly attenuates inflammatory reaction and offers neuroprotection against focal cerebral ischemia in rats, suggesting that selective immunoproteasome inhibitors may be a promising strategy for stroke treatment. PMID:25633295
Chen, X; Zhang, X; Wang, Y; Lei, H; Su, H; Zeng, J; Pei, Z; Huang, R
During ischemic stroke, occlusion of the cerebrovasculature causes neuronal cell death (infarction), but naturally occurring genetic factors modulating infarction have been difficult to identify in human populations. In a surgically induced mouse model of ischemic stroke, we have previously mapped Civq1 to distal chromosome 7 as a quantitative trait locus determining infarct volume. In this study, genome-wide association mapping using 32 inbred mouse strains and an additional linkage scan for infarct volume confirmed that the size of the infarct is determined by ancestral alleles of the causative gene(s). The genetically isolated Civq1 locus in reciprocal recombinant congenic mice refined the critical interval and demonstrated that infarct size is determined by both vascular (collateral vessel anatomy) and non-vascular (neuroprotection) effects. Through the use of interval-specific SNP haplotype analysis, we further refined the Civq1 locus and identified integrin alpha L (Itgal) as one of the causative genes for Civq1. Itgal is the only gene that exhibits both strain-specific amino acid substitutions and expression differences. Coding SNPs, a 5-bp insertion in exon 30b, and increased mRNA and protein expression of a splice variant of the gene (Itgal-003, ENSMUST00000120857), all segregate with infarct volume. Mice lacking Itgal show increased neuronal cell death in both ex vivo brain slice and in vivo focal cerebral ischemia. Our data demonstrate that sequence variation in Itgal modulates ischemic brain injury, and that infarct volume is determined by both vascular and non-vascular mechanisms. PMID:24130503
Keum, Sehoon; Lee, Han Kyu; Chu, Pei-Lun; Kan, Matthew J.; Huang, Min-Nung; Gallione, Carol J.; Gunn, Michael D.; Lo, Donald C.; Marchuk, Douglas A.
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
To better understand the complexity of the brain-pituitary-gonad axis (BPG) in fish, we developed a biologically based pharmacodynamic model capable of accurately predicting the normal functioning of the BPG axis in salmon. This first-generation model consisted of a set of 13 equations whose formulation was guided by published values for plasma concentrations of pituitary- (FSH, LH) and ovary- (estradiol, 17a,20b-dihydroxy-4-pregnene-3-one) derived hormones measured in Coho salmon over an annual spawning period. In addition, the model incorporated pertinent features of previously published mammalian models and indirect response pharmacodynamic models. Model-based equations include a description of gonadotropin releasing hormone (GnRH) synthesis and release from the hypothalamus, which is controlled by environmental variables such as photoperiod and water temperature. GnRH stimulated the biosynthesis of mRNA for FSH and LH, which were also influenced by estradiol concentration in plasma. The level of estradiol in the plasma was regulated by the oocytes, which moved along a maturation progression. Estradiol was synthesized at a basal rate and as oocytes matured, stimulation of its biosynthesis occurred. The BPG model can be integrated with toxico-genomic, -proteomic data, allowing linkage between molecular based biomarkers and reproduction in fish.
Kim, Jonghan; Hayton, William L.; Schultz, Irv R.
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
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
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.
The brain is a truly fascinating structure! It controls the body and allows everyone to think, learn, speak, move, feel, remember, and experience emotions. Although the brain is a single organ, it is very complex and has several regions, each having a specific function. These functionally diverse regions work together to allow for coordination of…
Demetrikopoulos, Melissa K.; Pecore, John; Rose, Jordan D.; Fobbs, Archibald J., Jr.; Johnson, John I.; Carruth, Laura L.
MULTIVARIATE MODELING OF LONGITUDINAL MRI IN EARLY BRAIN DEVELOPMENT WITH CONFIDENCE MEASURES Neda. Our proposed method estimates non- linear models of growth trajectories for individual subjects mixed effects modeling (NLME) where multimodal changes are described using Gompertz functions
To determine the infarct affinity of a low molecular weight contrast agent, Gd(ABE-DTTA), during the subacute phase of myocardial 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 Descending (LAD) coronary artery with an angioplasty balloon. DE-MRI images with Gd(ABE-DTTA) were obtained on days 4, 14, and 28 after MI. Control DE-MRI by Gd(DTPA) was carried out on day 27. T2-TSE images were acquired on day 3, 13 and 27. Triphenyltetrazolium chloride (TTC) histomorphometry validated postmortem the existence of infarct. Gd(ABE-DTTA) highlighted the infarct on day 4, but not at all on day 14 or on day 28, following MI. On day 4, the mean ± SD signal intensity (SI) of infarcted myocardium in the presence of Gd(ABE-DTTA) significantly differed from that of healthy myocardium (45 ± 6.0 vs. 10 ± 5.0, P < 0.05), but it did not on day 14 (11 ± 9.4 vs. 10 ± 5.7, P = NS), nor on day 28 (7 ± 1.5 vs. 7 ± 2.4, P = NS). The mean ± SD signal intensity enhancement (SIE) induced by Gd(ABE-DTTA) was 386 ± 165% on day 4, significantly different from mean SIE on day 14 (9 ± 20%), and from mean SIE on day 28 (12 ± 18%), following MI (P < 0.05). The last two mean values did not differ significantly (P = NS) from each other. As control, Gd(DTPA) was used and it did highlight the infarct on day 27, inducing a mean SIE value of 312 ± 40%. The mean SIE on day 3, 13, or 27 did not vary significantly (P = NS) on the T2-TSE images (114 ± 41%, 123 ± 41%, and 150 ± 79%, respectively). Post mortem, the existence of infarcts was confirmed by TTC staining. The infarct affinity of Gd(ABE-DTTA) vanishes in the subacute phase of scar healing, allowing its use for infarct age differentiation early on, immediately following the acute phase. PMID:21336553
Kirschner, Robert; Varga-Szemes, Akos; Simor, Tamas; Suranyi, Pal; Kiss, Pal; Ruzsics, Balazs; Brott, Brigitta C.; Elgavish, Ada
For the 3D brain MRI parameterized statistical model segmentation method, the pre-processing method of brain image is brought forward for the model. First the DWM(directional weighted median) filter and Gaussian template are used to de-noise the brain MRI image. Then the Laplacian operator is used to sharpen the image, and the Robert operator is used to realize the edge detection,
Wang Xing-ce; Xu Feng; Leng Chang; Zhou Ming-quan; Wu Zhong-ke; Liu Xin-yu
Objective. Deep brain stimulation (DBS) near the pedunculopontine nucleus (PPN) has been posited to improve medication-intractable gait and balance problems in patients with Parkinson's disease. However, clinical studies evaluating this DBS target have not demonstrated consistent therapeutic effects, with several studies reporting the emergence of paresthesia and oculomotor side effects. The spatial and pathway-specific extent to which brainstem regions are modulated during PPN-DBS is not well understood. Approach. Here, we describe two computational models that estimate the direct effects of DBS in the PPN region for human and translational non-human primate (NHP) studies. The three-dimensional models were constructed from segmented histological images from each species, multi-compartment neuron models and inhomogeneous finite element models of the voltage distribution in the brainstem during DBS. Main Results. The computational models predicted that: (1) the majority of PPN neurons are activated with -3 V monopolar cathodic stimulation; (2) surgical targeting errors of as little as 1 mm in both species decrement activation selectivity; (3) specifically, monopolar stimulation in caudal, medial, or anterior PPN activates a significant proportion of the superior cerebellar peduncle (up to 60% in the human model and 90% in the NHP model at -3 V) (4) monopolar stimulation in rostral, lateral or anterior PPN activates a large percentage of medial lemniscus fibers (up to 33% in the human model and 40% in the NHP model at -3 V) and (5) the current clinical cylindrical electrode design is suboptimal for isolating the modulatory effects to PPN neurons. Significance. We show that a DBS lead design with radially-segmented electrodes may yield improved functional outcome for PPN-DBS.
Zitella, Laura M.; Mohsenian, Kevin; Pahwa, Mrinal; Gloeckner, Cory; Johnson, Matthew D.
... prevent and treat them. NIH Patient Recruitment for Spinal Cord Infarction Clinical Trials At NIH Clinical Center Throughout the U.S. and Worldwide NINDS Clinical Trials Organizations Column1 Column2 ... National Spinal Cord Injury Association 75-20 Astoria Blvd Suite ...
CX3CR1 (fractalkine receptor) is important for sustaining normal microglial activity in the brain. Lack of CX3CR1 reportedly results in neurotoxic microglial phenotype in disease models. The objective of this study was to test the hypothesis that the absence of CX3CR1 worsens the outcome in cerebral ischemia. We observed significantly smaller (56%) infarcts and blood–brain barrier damage in CX3CR1-deficient (CX3CR1?\\/?) animals
Ádám Dénes; Szilamér Ferenczi; József Halász; Zsuzsanna Környei; Krisztina J Kovács
CX3CR1 (fractalkine receptor) is important for sustaining normal microglial activity in the brain. Lack of CX3CR1 reportedly results in neurotoxic microglial phenotype in disease models. The objective of this study was to test the hypothesis that the absence of CX3CR1 worsens the outcome in cerebral ischemia. We observed significantly smaller (56%) infarcts and blood-brain barrier damage in CX3CR1-deficient (CX3CR1\\/) animals
Szilamer Ferenczi; J ozsef Halasz; Zsuzsanna Kornyei
The focal brain ischemia with disturbance of cerebral venous drainage often lead to brain edema and hemorrhagic infarction and make mortality and morbidity worse. So we tried to make sure of this fact using a middle cerebral artery (MCA) occlusion model in adult cat. The MCA was exposed by the transorbital approach and temporally obstructed by Zen's clip. We divided the animals into two groups of eight cats. One group is only MCA occlusion group (sham group) and the other in MCA occlusion with disturbance of venous drainage (VRD group). We ligated bilateral external jugular vein (EJV) and internal jugular vein (IJV) and injected embolic sources from the left EJV to obstruct the venous system of cat brain. The pressure of superior sagittal sinus was increased up to 18.7 +/- 5.3 mmHg by this method. A cranial window was made above the ectosylvian gyrus, which has poor anastomosis. The reactivity of pial arteriole and regional cerebral blood flow (rCBF) were observed through the window. And histological brain examination was also performed. The result was that the reactivity of pial arterioles was severely disturbed in VRD group. The area of cerebral infarction and edema were also significantly expanded in VRD group. Considering from these facts, when the venous drainage was disturbed, cerebral perfusion pressure relatively decrease. Because of the decrease in cerebral perfusion pressure, cerebral infarction and edema probably expand to the area so called penumbra. PMID:1419337
Miyamoto, K; Tsujimoto, S; Tominaga, M; Takeshima, T; Morimoto, T; Tsunoda, S; Sakaki, T
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 develop a detailed model consisting of multiple structures. Two types of atlas model were generated employing different mesh types and biomechanical properties suited for various applications. The developed model was able to capture the detailed anatomy of the brain and reflect the application-dependant biomechanical behaviour based on material modelling of brain tissue under surgical intervention.
Gao, Chunping; Eng Hock Tay, Francis; Nowinski, Wieslaw L.
Introduction To date, most animal studies of myocardial ischemia have used open-chest models with direct surgical coronary artery ligation. We aimed to develop a novel, percutaneous, minimally-invasive, closed-chest model of experimental myocardial infarction (EMI) in the New Zealand White rabbit and compare it with the standard open-chest surgical model in order to minimize local and systemic side-effects of major surgery. Methods New Zealand White rabbits were handled in conformity with the "Guide for the Care and Use of Laboratory Animals" and underwent EMI under intravenous anesthesia. Group A underwent EMI with an open-chest method involving surgical tracheostomy, a mini median sternotomy incision and left anterior descending (LAD) coronary artery ligation with a plain suture, whereas Group B underwent EMI with a closed-chest method involving fluoroscopy-guided percutaneous transauricular intra-arterial access, superselective LAD catheterization and distal coronary embolization with a micro-coil. Electrocardiography (ECG), cardiac enzymes and transcatheter left ventricular end-diastolic pressure (LVEDP) measurements were recorded. Surviving animals were euthanized after 4 weeks and the hearts were harvested for Hematoxylin-eosin and Masson-trichrome staining. Results In total, 38 subjects underwent EMI with a surgical (n = 17) or endovascular (n = 21) approach. ST-segment elevation (1.90 ± 0.71 mm) occurred sharply after surgical LAD ligation compared to progressive ST elevation (2.01 ± 0.84 mm;p = 0.68) within 15-20 min after LAD micro-coil embolization. Increase of troponin and other cardiac enzymes, abnormal ischemic Q waves and LVEDP changes were recorded in both groups without any significant differences (p > 0.05). Infarct area was similar in both models (0.86 ± 0.35 cm in the surgical group vs. 0.92 ± 0.54 cm in the percutaneous group;p = 0.68). Conclusion The proposed model of transauricular coronary coil embolization avoids thoracotomy and major surgery and may be an equally reliable and reproducible platform for the experimental study of myocardial ischemia. PMID:22330077
Objective. To explore the mechanism of cardioprotective effects of Chinese medicine, Yiqi Huoxue recipe, in rats with myocardial infarction- (MI-) induced heart failure. Methods. Male Sprague-Dawley rats underwent left anterior descending artery (LAD) ligation or sham operation. The surviving MI rats were divided randomly into three groups: MI (5?mL/kg/d NS by gavage), MI + Metoprolol Tartrate (MT) (12?mg/kg/d MT by gavage), and MI + Yiqi Huoxue (5?mL/kg recipe by gavage). And the sham operation rats were given 5?mL/kg/d normal saline. Treatments were given on the day following surgery for 4 weeks. Then rats were detected for heart structure and function by transthoracic echocardiography. Apoptosis in heart tissues was detected by TUNEL staining. To determine whether the endoplasmic reticulum (ER) stress response pathway is included in the cardioprotective function of the recipe, ER stress related proteins such as GRP78 and caspase-12 were examined. Results. Yiqi Huoxue recipe attenuated heart function injury, reversed histopathological damage, alleviated myocardial apoptosis and inhibited ER stress in MI rats. Conclusion. All the results suggest that Yiqi Huoxue recipe improves the injured heart function maybe through inhibition of ER stress response pathway, which is a promising target in therapy for heart failure. PMID:24864159
Lou, Li-Xia; Zhang, Dong-Mei; Wu, Sheng-Xian; Gao, Yong-Hong; Nie, Bo; Zhao, Ming-Jing; Lv, Xi-Ying; Jin, Qiu-Shuo; Zhao, Yi-Zhou; Wang, Shuo-Ren; Chai, Li-Min
A Computational Model for Lesion Dynamics in Multiple Sclerosis of the Brain Krishna Mohan, T. R was to evaluate a physically motivated network model for lesion formation in the brain. The parsimonious network and death leading to neuro-degeneration and, ii) generation of alarm signals by the damaged cells that lead
A probabilistic deformable model for the representation of multiple brain structures is described. The statistically learned deformable model represents the relative location of different anatomical surfaces in brain magnetic resonance images (MRIs) and accommodates their significant variability across different individuals. The surfaces of each anatomical structure are parameterized by the amplitudes of the vibration modes of a deformable spherical mesh.
Christophoros Nikou; Gloria Bueno; Fabrice Heitz; Jean-Paul Armspach
Early studies on the modeling of electromagnetic (EM) field interactions with the human head have shown that induced current densities in the brain depend on both tissue geometry and its conductive properties. However, no head model of sufficient complexity for studying the physics of induced brain activation has been developed which provides well-defined smooth boundaries between tissues of different conductivities
Ming Chen; David J. Mogul
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 is used is appropriately designed to support system- atic modelling of brain structures, able to reproduce bi- ological
This study aims to monitor how the change of cell survival of transplanted adipose-derived stem cells (ADSCs) responds to myocardial infarction (MI) via the hexadecyl-4-(124)I-iodobenzoate ((124)I-HIB) mediated direct labeling method in vivo. Stem cells have shown the potential to improve cardiac function after MI. However, monitoring of the fate of transplanted stem cells at target sites is still unclear. Rat ADSCs were labeled with (124)I-HIB, and radiolabeled ADSCs were transplanted into the myocardium of normal and MI model. In the group of (124)I-HIB-labeled ADSC transplantation, in vivo imaging was performed using small-animal positron emission tomography (PET)/computed tomography (CT) for 9days. Twenty-one days post-transplantation, histopathological analysis and apoptosis assay were performed. ADSC viability and differentiation were not affected by (124)I-HIB labeling. In vivo tracking of the (124)I-HIB-labeled ADSCs was possible for 9 and 3days in normal and MI model, respectively. Apoptosis of transplanted cells increased in the MI model compared than that in normal model. We developed a direct labeling agent, (124)I-HIB, and first tried to longitudinally monitor transplanted stem cell to MI. This approach may provide new insights on the roles of stem cell monitoring in living bodies for stem cell therapy from pre-clinical studies to clinical trials. PMID:25446095
Kim, Min Hwan; Woo, Sang-Keun; Lee, Kyo Chul; An, Gwang Il; Pandya, Darpan; Park, Noh Won; Nahm, Sang-Soep; Eom, Ki Dong; Kim, Kwang Il; Lee, Tae Sup; Kim, Chan Wha; Kang, Joo Hyun; Yoo, Jeongsoo; Lee, Yong Jin
While diffusion MRI promises an insight into white matter microstructure in vivo, the axonal pathways that connect different brain regions together can only partially be segmented using current methods. Here we present ...
Piatkowski, Jakub Przemyslaw
Each year in the US, ?1.5 million people sustain a traumatic brain injury (TBI). Victims of TBI can suffer from chronic post-TBI symptoms, such as sensory and motor deficits, cognitive impairments including problems with memory, learning, and attention, and neuropsychiatric symptoms such as depression, anxiety, irritability, aggression, and suicidal rumination. Although partially associated with the site and severity of injury, the biological mechanisms associated with many of these symptoms – and why some patients experience differing assortments of persistent maladies – are largely unknown. The use of animal models is a promising strategy for elucidation of the mechanisms of impairment and treatment, and learning, memory, sensory, and motor tests have widespread utility in rodent models of TBI and psychopharmacology. Comparatively, behavioral tests for the evaluation of neuropsychiatric symptomatology are rarely employed in animal models of TBI and, as determined in this review, the results have been inconsistent. Animal behavioral studies contribute to the understanding of the biological mechanisms by which TBI is associated with neurobehavioral symptoms and offer a powerful means for pre-clinical treatment validation. Therefore, further exploration of the utility of animal behavioral tests for the study of injury mechanisms and therapeutic strategies for the alleviation of emotional symptoms are relevant and essential. PMID:24109476
Malkesman, Oz; Tucker, Laura B.; Ozl, Jessica; McCabe, Joseph T.
Treatment of arteriovenous malformations (AVMs) of the brain often requires the injection of a liquid embolic material to reduce blood flow through the malformation. The type of the liquid and the location of injection have to be carefully planned in a pre-operative manner. We introduce a new model of the interaction of liquid embolic materials with blood for the simulation of their propagation and solidification in the AVM. Solidification is mimicked by an increase of the material's viscosity. Propagation is modelled by using the concept of two-fluids modelling and that of scalar transport. The method is tested on digital phantoms and on one anatomically derived patient AVM case. Simulations showed that intuitive behaviour of the two-fluid system can be confirmed and that two types of glue propagation through the malformation can be reproduced. Distinction between the two types of propagation could be used to identify fistulous and plexiform compartments composing the AVM and to characterize the solidification of the embolic material in them. PMID:22056793
Orlowski, Piotr; Summers, Paul; Noble, J Alison; Byrne, James; Ventikos, Yiannis
plays a key role in pathogenesis of anxiety and depression. Animal models of these disorders are widely. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 5. Expanding beyond anxiety and depression: focus on obsessions, compulsions and impulsivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6. Modeling other relevant brain disorders
Kalueff, Allan V.
Toward the goal of understanding the human brain function, we have developed a web-based human brain functional mapping knowledge base (HBFMKB) system to mining human brain-function association model from vast Medline abstracts. Since nomenclature and relationships among cognitive functions have no consensus yet, we use rule-based natural language processing methods to extract behavioral task and cognitive function and do n-gram
Mei-Yu Hsiao; Der-Yow Chen; Jyh-Horng Chen
Cerebral edema forms in the early hours of ischemic stroke by processes involving increased transport of Na and Cl from blood into brain across an intact blood–brain barrier (BBB). Our previous studies provided evidence that the BBB Na–K–Cl cotransporter is stimulated by the ischemic factors hypoxia, aglycemia, and arginine vasopressin (AVP), and that inhibition of the cotransporter by intravenous bumetanide greatly reduces edema and infarct in rats subjected to permanent middle cerebral artery occlusion (pMCAO). More recently, we showed that BBB Na/H exchanger activity is also stimulated by hypoxia, aglycemia, and AVP. The present study was conducted to further investigate the possibility that a BBB Na/H exchanger also participates in edema formation during ischemic stroke. Sprague-Dawley rats were subjected to pMCAO and then brain edema and Na content assessed by magnetic resonance imaging diffusion-weighed imaging and magnetic resonance spectroscopy Na spectroscopy, respectively, for up to 210?minutes. We found that intravenous administration of the specific Na/H exchange inhibitor HOE-642 significantly decreased brain Na uptake and reduced cerebral edema, brain swelling, and infarct volume. These findings support the hypothesis that edema formation and brain Na uptake during the early hours of cerebral ischemia involve BBB Na/H exchanger activity as well as Na–K–Cl cotransporter activity. PMID:23149557
O'Donnell, Martha E; Chen, Yi-Je; Lam, Tina I; Taylor, Kelleen C; Walton, Jeffrey H; Anderson, Steven E
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
We propose a minimalistic model of the anesthetized brain in order to study the generation of rhythms observed in electroencephalograms (EEGs) recorded from anesthetized humans. We propose that non-neuronal brain cells-astrocytes-play an important role in brain dynamics and that oscillation-based models may provide a simple way to study such dynamics. The model is capable of replicating the main features (i.e. slow and alpha oscillations) observed in EEGs. In addition, this model suggests that astrocytes are integral to the generation of slow EEG (˜0.7 Hz) rhythms. By including astrocytes in the model we take a first step towards investigating the interaction of the brain and cardiovasular system which are primarily connected via astrocytes. The model also illustrates that rich nonlinear dynamics can arise from basic oscillatory "building blocks" and therefore complex systems may be modelled in an uncomplicated way.
Hansard, T.; Hale, A. C.; Stefanovska, A.
Objective: Striatocapsular infarction is an uncommon form of deep hemispheric strokes. We analyzed the clinical presentation of this stroke to determine its core features and neurological outcome. Material and methods: This prospective, observational, short-term longitudinal study was carried out from November 1, 2009 to October 30, 2011 in the department of neurology, Sulaimaniya general teaching hospital, Iraq and involved 13 consecutive Kurdish patients who were diagnosed with striatocapsular infarction radiologically; all patients underwent routine blood tests, resting 12-lead ECG, transthoracic echocardiography, and urgent non-contrast CT brain scanning at the time of admission. All patients were reassessed clinically after 3 months. Results: Nine patients (69%) were females and 7 patients (53%) were older than 50 years of age. Infarction of the right lenticular nucleus was more common than the left one. Severe flaccid hemiplegia dominated the clinical presentation. Speech and language dysfunction were found in 4 patients (30%) while inattention and neglect were detected in 8 patients (61%). At 3 months, 4 patients were bed-ridden and 4 were wheel-chair bound; dystonia and involuntary movements did not occur. Only the patient with bilateral infarction demonstrated Parkinsonism. Conclusion: Striatocapsular infraction in Iraqi Kurdish patients was more common in females and at the right lenticular nucleus. Hypertension, smoking, and hypercholesterolemia were the commonest risk factors. Dense hemiplegia was the commonest presentation; the functional outcome was poor in the majority. After 3 months of the ischemic event, involuntary movements and dystonia were not seen, and Parkinsonism was found in one patient only. PMID:23322963
Shukir Muhammed Amin, Osama; Aziz Abdullah, Araz; Xaznadar, Amanj; Shaikhani, Mohammad
Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01–0.03?min?1. Finally, the model suggests that infusion over a short duration (20–60?min) should be employed along with single-sonication or multiple-sonication at 10?min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration.
Nhan, Tam; Burgess, Alison; Lilge, Lothar; Hynynen, Kullervo
We discuss the theory and practice of applying independent component analysis (ICA) to electroencephalographic (EEG) data. ICA blindly decomposes multi-channel EEG data into maximally independent component processes (ICs) that typically express either particularly brain generated EEG activities or some type of non-brain artifacts (line or other environmental noise, eye blinks and other eye movements, or scalp or heart muscle activity).
Julie Onton; Scott Makeig
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
Pabitra N. Sen; Peter J. Bassery
Objectives: We sought to identify critical components of myocardial infarction (MI) including area at risk (AAR), MI-core and salvageable zone (SZ) by using cardiac magnetic resonance imaging (cMRI) and multifunctional stainings in rabbits. Materials and Methods: Fifteen rabbits received 90-min coronary artery (CA) ligation and reopening to induce reperfused MI. First-pass perfusion weighted imaging (PWI90') was performed immediately before CA reperfusion. Necrosis avid dye Evans blue (EB) was intravenously injected for later MI-core detection. One-day later, cMRI with T2-weighted imaging (T2WI), PWI24h and delayed enhancement (DE) T1WI was performed at a 3.0T clinical scanner. The heart was excised and CA was re-ligated with aorta infused by red-iodized-oil (RIO). The heart was sliced into 3-mm sections for digital radiography (DR), histology and planimetry with myocardial salvage index (MSI) and perfusion density rate (PDR) calculated. Results: There was no significant difference between MI-cores defined by DE-T1WI and EB-staining (31.13±8.55% vs 29.80±7.97%; p=0.74). The AAR was defined similarly by PWI90' (39.93±9.51%), RIO (38.82±14.41%) and DR (38.17±15.98%), underestimated by PWI24h (36.44±5.31%), but overestimated (p<0.01) by T2WI (56.93±8.87%). Corresponding MSI turned out to be 24.17±9.5% (PWI90'), 21.97±9.41% (DR) and 22.68±9.65% (RIO), which were significantly (p<0.01) higher and lower than that with PWI24h (15.15±7.34%) and T2WI (45.52±7.5%) respectively. The PDR differed significantly (p<0.001) between normal myocardium (350.6±33.1%) and the AAR (31.2±15%), suggesting 11-times greater blood perfusion in normal myocardium over the AAR. Conclusion: The introduced rabbit platform and new staining techniques together with the use of a 3.0T clinical scanner for cMRI enabled visualization of MI components and may contribute to translational cardiac imaging research for improved theranostic management of ischemic heart disease. PMID:24396513
Feng, Yuanbo; Chen, Feng; Ma, Zhanlong; Dekeyzer, Frederik; Yu, Jie; Xie, Yi; Cona, Marlein Miranda; Oyen, Raymond; Ni, Yicheng
Eleven patients with large cerebellar infarctions were admitted recently to our service. Eight of them showed evidence of hydrocephalus on the CT scan examination. Five were treated with controlled external ventricular drainage and six were managed conservatively. One death, most likely due to progressive brainstem infarction, occurred. The outcome was favorable in the other patients. It is suggested that prompt treatment of the acute obstructive hydrocephalus may obviate the need for posterior fossa decompression in patients with massive cerebellar infarction. PMID:6658959
Khan, M; Polyzoidis, K S; Adegbite, A B; McQueen, J D
\\u000a Intra-operative images acquired during brain surgery do not provide sufficient detail to confidently locate brain internal\\u000a structures that have been identified in high-resolution pre-operative images. However, the pre-operative images can be warped\\u000a to the intra-operative position of brain using predicted deformation field. While craniotomy-induced brain shift deformation\\u000a can be accurately computed using patient-specific finite element models in real-time, accurate segmentation
Jiajie Ma; Adam Wittek; Benjamin Zwick; Grand R. Joldes; Simon K. Warfield; Karol Miller
Brain scans were abnormal in 2 of 6 patients with cerebral "Moyamoya" disease. The spatial and temporal scan patterns were analogous to those described in conventional cerebral infarction. Cerebral infarction due to emboli resulting from mural thrombi may explain the uptake of radioisotope. None of the scans was abnormal in 4 adult patients in which the disease was complicated by subarachnoid hemorrhage. PMID:1163721
Mori, H; Maeda, T; Suzuki, Y; Hisada, K; Inoue, M
Human investigators instinctively segment medical images into their anatomical components, drawing upon prior knowledge of anatomy to overcome image artifacts, noise, and lack of tissue contrast. The authors describe: 1) the development and use of a brain tissue probability model for the segmentation of multiple sclerosis (MS) lesions in magnetic resonance (MR) brain images, and 2) an empirical comparison of
Micheline Kamber; Rajjan Shinghal; D. L. Collins; Gordon S. Francis; Alan C. Evans
3D Ultrasound as Sparse Data for Intraoperative Brain Deformation Model Karen E. Lunna , Alex Hitchcock Medical Center; d Norris Cotton Cancer Center ABSTRACT During neurosurgery, intraoperative brain shift compromises the accuracy of image guided techniques. We are investigating the use of ultrasound
Miga, Michael I.
Treatment of myocardial infarction (MI) with adipose-derived stem cells (ASCs) has produced promising results. Cyclosporine A (CsA) inhibits apoptosis by preventing the opening of mitochondrial permeability transition pores. A CsA nanoparticle emulsion (CsA-NP) has lower toxicity and higher efficiency as compared to CsA. In this study, we hypothesized that a combination of ASCs and CsA-NP would enhance the therapeutic efficiency in a swine MI model. MI was induced in pig hearts by occlusion of the left anterior descending artery. The animals that survived MI were divided into four groups and 1 week later received intracoronary ASCs (ASCs, n=6), intracoronary culture media in combination with CsA-NP (CsA-NP, n=6), intracoronary ASCs in combination with CsA-NP (ASCs + CsA-NP, n=6), or remained untreated (control, n=4). Animals were sacrificed 8 weeks later and were evaluated for cardiac function by delayed-enhanced magnetic resonance imaging and immunohistopathology. We observed that the left ventricular ejection fraction (LVEF) was significantly increased in the ASCs + CsA-NP group, compared to the CsA-NP group (53.6%±2.4% versus 48.6%±1.5%, P<0.05), and the ASCs group (53.6%±2.4% versus 48.3%±1.8%, P<0.05). More importantly, the infarct size was significantly smaller in the ASCs + CsA-NP group as compared to the CsA-NP group (6.2±1.7 cm3 versus 9.1±3.4 cm3, P<0.05) and the ASCs group (6.2±1.7 cm3 versus 7.5±0.6 cm3, P<0.05). These findings were further confirmed by analysis of the expression of cardiomyocyte markers, myosin heavy chain (?-actinin) and troponin T. In addition, the CsA-NP + ASCs treatment promoted neovascularization (P<0.05) and inhibited cardiomyocyte apoptosis (P<0.01) compared to the control group. This study demonstrates that CsA-NP enhanced the therapeutic benefits of ASCs transplantation for MI. PMID:24376353
Yin, Qiaoxiang; Pei, Zhiyong; Wang, Heng; Zhao, Yusheng
With the advent of neuroimaging techniques, it becomes feasible to explore the structure-function relationships in the brain. When the brain is not involved in any cognitive task or stimulated by any external output, it preserves important activities which follow well-defined spatial distribution patterns. Understanding the self-organization of the brain from its anatomical structure, it has been recently suggested to model the observed functional pattern from the structure of white matter fiber bundles. Different models which study synchronization (e.g., the Kuramoto model) or global dynamics (e.g., the Ising model) have shown success in capturing fundamental properties of the brain. In particular, these models can explain the competition between modularity and specialization and the need for integration in the brain. Graphing the functional and structural brain organization supports the model and can also highlight the strategy used to process and organize large amount of information traveling between the different modules. How the flow of information can be prevented or partially destroyed in pathological states, like in severe brain injured patients with disorders of consciousness or by pharmacological induction like in anaesthesia, will also help us to better understand how global or integrated behavior can emerge from local and modular interactions. PMID:25276772
Das, T K; Abeyasinghe, P M; Crone, J S; Sosnowski, A; Laureys, S; Owen, A M; Soddu, A
With the advent of neuroimaging techniques, it becomes feasible to explore the structure-function relationships in the brain. When the brain is not involved in any cognitive task or stimulated by any external output, it preserves important activities which follow well-defined spatial distribution patterns. Understanding the self-organization of the brain from its anatomical structure, it has been recently suggested to model the observed functional pattern from the structure of white matter fiber bundles. Different models which study synchronization (e.g., the Kuramoto model) or global dynamics (e.g., the Ising model) have shown success in capturing fundamental properties of the brain. In particular, these models can explain the competition between modularity and specialization and the need for integration in the brain. Graphing the functional and structural brain organization supports the model and can also highlight the strategy used to process and organize large amount of information traveling between the different modules. How the flow of information can be prevented or partially destroyed in pathological states, like in severe brain injured patients with disorders of consciousness or by pharmacological induction like in anaesthesia, will also help us to better understand how global or integrated behavior can emerge from local and modular interactions. PMID:25276772
Das, T. K.; Abeyasinghe, P. M.; Crone, J. S.; Sosnowski, A.; Laureys, S.; Owen, A. M.; Soddu, A.
Key requirements for cardiac tissue engineering include the maintenance of cell viability and function and the establishment of a perfusable vascular network in millimeters thick and compact cardiac constructs upon implantation. We investigated if these requirements can be met by providing an intrinsic vascularization stimulus (via sustained action of VEGF secreted at a controlled rate by transduced myoblasts) to a cardiac patch engineered under conditions of effective oxygen supply (via medium flow through channeled elastomeric scaffolds seeded with neonatal cardiomyocytes). We demonstrate that this combined approach resulted in increased viability, vascularization and functionality of the cardiac patch. After implantation in a mouse model of myocardial infarction, VEGF-expressing patches displayed significantly improved engraftment, survival and differentiation of cardiomyocytes, leading to greatly enhanced contractility as compared to controls not expressing VEGF. Controlled VEGF expression also mediated the formation of mature vascular networks, both within the engineered patches and in the underlying ischemic myocardium. We propose that this combined cell-biomaterial approach can be a promising strategy to engineer cardiac patches with intrinsic and extrinsic vascularization potential. PMID:23083931
Marsano, Anna; Maidhof, Robert; Luo, Jianwen; Fujikara, Kana; Konofagou, Elisa E; Banfi, Andrea; Vunjak-Novakovic, Gordana
Animal stroke models suggest that valproate has multiple neuroprotective mechanisms against ischemic brain damage. This study investigated whether valproate improves functional recovery in patients with acute middle cerebral artery (MCA) infarction. This was an open-label controlled trial. Three to 24 hours after acute MCA infarction, patients were assigned to either the valproate group (n = 17) or the non-valproate group (n = 17). The valproate group received intravenous valproate (400 mg) at enrollment, and then every 12 hours for three days, followed by oral valproate (500 mg) every 12 hours for three months. Neurological function, laboratory data, and brain magnetic resonance imaging were examined at stroke onset, and at two-week and three-month follow-up. No significant differences were observed between the groups with regard to demographics or baseline characteristics. All patients were elderly, had a high pretreatment score on the NIH stroke scale (NIHSS), and slow stroke lesion growth with a final large infarct volume at two-week follow-up. At the three-month follow-up, functional outcome between pre- and post-treatment had improved significantly in the valproate group (NIHSS, p = 0.004; modified Rankin scale (mRS), p = 0.007; Barthel index (BI), p = 0.001). No such improvement was noted in the NIHSS or mRS for the non-valproate group, though mild improvement was seen on the BI (p = 0.022). This open-label trial is the first to demonstrate that valproate treatment markedly improves functional outcome in patients with acute MCA infarction.
Lee, Jiunn-Tay; Chou, Chung-Hsing; Cho, Nai-Yu; Sung, Yueh-Feng; Yang, Fu-Chi; Chen, Cheng-Yu; Lai, Yu-Hua; Chiang, Chun-I; Chu, Chi-Ming; Lin, Jiann-Chyun; Hsu, Yaw-Don; Hong, Jau-Shyong; Peng, Giia-Sheun; Chuang, De-Maw
The role of microglia in healthy brains is just beginning to receive notice. Recent studies have revealed that these phagocytic cells control the patterning and wiring of the developing central nervous system (CNS) by regulating, amongst many other processes, programmed cell death, activity-dependent synaptic pruning and synapse maturation. Microglia also play important roles in the mature brain and have demonstrated effects on behavior. Converging evidence from human and mouse studies together raise questions as to the role of microglia in disorders of brain development such as autism, schizophrenia or obsessive-compulsive disorder. In this review, we summarize a number of major findings regarding the role of microglia in brain development and highlight some key questions and avenues for future study. PMID:25463024
Bilimoria, Parizad M; Stevens, Beth
), 26 autism spectrum disorder (ASD) and 11 pediatric control (PedCon) children ob- tained through Learning #12;Figure 1: Schematic diagram of proposed functional brain network filtration framework using
Chung, Moo K.
Connectivity analysis focuses on the interaction between brain regions. Such relationships inform us about patterns of neural communication and may enhance our understanding of neurological disorders. This thesis proposes ...
Venkataraman, Archana, Ph. D. Massachusetts Institute of Technology
Since the beginning of the military conflicts in Iraq and Afghanistan, there have been over 250,000 diagnoses of traumatic brain injury (TBI) in the U.S. military, with the majority of incidents caused by improvised explosive ...
Nyein, Michelle K. (Michelle Kyaw)
Background Infarct of the anterior spinal artery is the most common subtype of spinal cord infarct, and is characterized by bilateral motor deficits with spinothalamic sensory deficits. We experienced a case with atypical anterior-spinal-artery infarct that presented with bilateral hand weakness but without sensory deficits. Case Report A 29-year-old man presented with sudden neck pain and bilateral weakness of the hands. Magnetic resonance imaging (MRI) of the brain did not reveal any lesion. His motor symptoms improved rapidly except for mild weakness in his left wrist and fingers. Magnetic resonance angiography showed proximal occlusion of the left vertebral artery; a spine MRI revealed left cervical cord infarction. Conclusions Bilateral or unilateral hand weakness can be the sole symptom of a cervical cord infarct. PMID:24829605
Kim, Min-Ji; Jang, Mi-Hee; Choi, Mi-Song; Kang, Suk Yun; Kim, Joo Yong; Kwon, Ki-Han; Kang, Ik-Won
Clinicoradiological correlations observed in patients with small cortical infarctions have supported somatotopic representation of different parts of body areas in primary motor cortex. However, isolated shoulder weakness because of infarction in precentral gyrus has rarely been described. We report an 80-year-old woman with isolated shoulder palsy because of cortical ischemic infarction in the base of the left precentral gyrus as confirmed by brain magnetic resonance imaging. In our patient, cardiogenic embolism or Trousseau syndrome associated with lung cancer was considered the cause of ischemic infarction. Physicians should consider small cortical infarction, when a patient complains of sudden onset of shoulder weakness without pain. In line with the previous reports, a responsible cortical lesion in our patient corresponded to motor shoulder area in the motor homunculus reported to be located more medially to the hand area. PMID:24008130
Kawasaki, Akiko; Suzuki, Keisuke; Takekawa, Hidehiro; Kokubun, Norito; Yamamoto, Masanari; Asakawa, Yohei; Okamura, Madoka; Hirata, Koichi
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.
Brain Computer Interfaces (BCIs) enable one to control peripheral ICT and robotic devices by processing brain activity on-line.\\u000a The potential usefulness of BCI systems, initially demonstrated in rehabilitation medicine, is now being explored in education,\\u000a entertainment, intensive workflow monitoring, security, and training. Ethical issues arising in connection with these investigations\\u000a are triaged taking into account technological imminence and pervasiveness of
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. PMID:24520391
Choi, Eun-Jung; Chen, Wanqiu; Jun, Kristine; Arthur, Helen M.; Young, William L.; Su, Hua
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. PMID:24358300
Zhang, Qiaoli; Ding, Yingxue; Yao, Yanqing; Yu, Yang; Yang, Lijun; Cui, Hong
Versican, a large chondroitin sulfate proteoglycan, plays a role in conditions such as wound healing and tissue remodelling. To test the hypothesis that versican expression is transiently upregulated and plays a role in the infarcted heart, we examined its expression in a rat model of myocardial infarction. Northern blot analysis demonstrated increased expression of versican mRNA. Quantitative real-time RT-PCR analysis
Kenichi Toeda; Keigo Nakamura; Satoshi Hirohata; Omer F. Hatipoglu; Kadir Demircan; Hitoshi Yamawaki; Hiroko Ogawa; Shozo Kusachi; Yasushi Shiratori; Yoshifumi Ninomiya
Some recent developments of the dissipative quantum model of brain arereported. In particular, the time-dependent frequency case is considered withits implications on the different life-times of the collective modes.
Alfinito, E; Alfinito, Eleonora; Vitiello, Giuseppe
Some recent developments of the dissipative quantum model of brain are reported. In particular, the time-dependent frequency case is considered with its implications on the different life-times of the collective modes.
Eleonora Alfinito; Giuseppe Vitiello
PurposeDamage to normal tissue is a limiting factor in clinical radiotherapy (RT). We tested the hypothesis that the presence of tumor alters the response of normal tissues to irradiation using a rat in situ brain tumor model.
Janice A. Zawaski; M. Waleed Gaber; Omaima M. Sabek; Christy M. Wilson; Christopher D. Duntsch; Thomas E. Merchant
The prediction of brain extracellular fluid (ECF) concentrations in human is a potentially valuable asset during drug development as it can provide the pharmacokinetic input for pharmacokinetic-pharmacodynamic models. This study aimed to compare two translational modelling approaches that can be applied at the preclinical stage of development in order to simulate human brain ECF concentrations. A population-PBPK model of the central nervous system was developed based on brain microdialysis data, and the model parameters were translated to their corresponding human values to simulate ECF and brain tissue concentration profiles. In parallel, the PBPK modelling software Simcyp was used to simulate human brain tissue concentrations, via the bottom-up prediction of brain tissue distribution using two different sets of mechanistic tissue composition-based equations. The population-PBPK and bottom-up approaches gave similar predictions of total brain concentrations in both rat and human, while only the population-PBPK model was capable of accurately simulating the rat ECF concentrations. The choice of PBPK model must therefore depend on the purpose of the modelling exercise, the in vitro and in vivo data available and knowledge of the mechanisms governing the membrane permeability and distribution of the drug. PMID:25044007
Ball, Kathryn; Bouzom, François; Scherrmann, Jean-Michel; Walther, Bernard; Declèves, Xavier
Patients with Alzheimer's disease and multi-infarct dementia were studied with scans using fluorodeoxyglucose tagged with fluorine 18. The rates of glucose metabolism were calculated. Patients with Alzheimer's dementia showed decreased metabolism in all areas of the brain but with preferential sparing of the primary motor and sensory cortex. Patients with multi-infarct dementia also had global reductions in glucose metabolic rates when compared with normal control subjects, but the areas of hypometabolism were focal and asymmetric.
Benson, D.F.; Kuhl, D.E.; Hawkins, R.A.; Phelps, M.E.; Cummings, J.L.; Tsai, S.Y.
We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs(-/-) mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs(-/-) mice as early as 4months after the surgery. The 2/3NX triple NOSs(-/-) mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1? (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs(-/-) mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin-angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs(-/-) mouse is a new experimentally useful model of AMI. Renin-angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1?-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model. PMID:25265498
Uchida, Taro; Furuno, Yumi; Tanimoto, Akihide; Toyohira, Yumiko; Arakaki, Kumiko; Kina-Tanada, Mika; Kubota, Haruaki; Sakanashi, Mayuko; Matsuzaki, Toshihiro; Noguchi, Katsuhiko; Nakasone, Junko; Igarashi, Tomonori; Ueno, Susumu; Matsushita, Masayuki; Ishiuchi, Shogo; Masuzaki, Hiroaki; Ohya, Yusuke; Yanagihara, Nobuyuki; Shimokawa, Hiroaki; Otsuji, Yutaka; Tamura, Masahito; Tsutsui, Masato
Hydrocephalus is an entity which embraces a variety of diseases whose final result is the enlarged size of cerebral ventricular system, partially or completely. The physiopathology of hydrocephalus lies in the dynamics of circulation of cerebrospinal fluid (CSF). The consequent CSF stasis in hydrocephalus interferes with cerebral and ventricular system development. Children and adults who sustain congenital or acquired brain injury typically experience a diffuse insult that impacts many areas of the brain. Development and recovery after such injuries reflects both restoration and reorganization of cognitive functions. Classic examples were already reported in literature. This suggests the presence of biological mechanisms associated with resilient adaptation of brain networks. We will settle a link between the notable modifications to neurophysiology secondary to hydrocephalus and the ability of neuronal tissue to reassume and reorganize its functions. PMID:22232589
de Oliveira, Matheus Fernandes; Pinto, Fernando Campos Gomes; Nishikuni, Koshiro; Botelho, Ricardo Vieira; Lima, Alessandra Moura; Rotta, José Marcus
Blast-related traumatic brain injury is the most prevalent injury for combat personnel seen in the current conflicts in Iraq and Afghanistan, yet as a research community,we still do not fully understand the detailed etiology and pathology of this injury. Finite element (FE) modeling is well suited for studying the mechanical response of the head and brain to blast loading. This paper details the development of a FE head and brain model for blast simulation by examining both the dilatational and deviatoric response of the brain as potential injury mechanisms. The levels of blast exposure simulated ranged from 50 to 1000 kPa peak incident overpressure and 1–8 ms in positive-phase duration, and were comparable to real-world blast events. The frontal portion of the brain had the highest pressures corresponding to the location of initial impact, and peak pressure attenuated by 40–60% as the wave propagated from the frontal to the occipital lobe. Predicted brain pressures were primarily dependent on the peak overpressure of the impinging blast wave, and the highest predicted brain pressures were 30%less than the reflected pressure at the surface of blast impact. Predicted shear strain was highest at the interface between the brain and the CSF. Strain magnitude was largely dependent on the impulse of the blast, and primarily caused by the radial coupling between the brain and deforming skull.The largest predicted strains were generally less than 10%,and occurred after the shock wave passed through the head.For blasts with high impulses, CSF cavitation had a large role in increasing strain levels in the cerebral cortex and periventricular tissues by decoupling the brain from the skull. Relating the results of this study with recent experimental blast testing suggest that a rate-dependent strain-based tissue injury mechanism is the source primary blast TBI. PMID:22298329
Panzer, Matthew B; Myers, Barry S; Capehart, Bruce P; Bass, Cameron R
Nowadays, transgenic mice are a common tool to study brain abnormalities in neurological disorders. These studies usually rely on neuropathological examinations, which have a number of drawbacks, including the risk of artefacts introduced by fixation and dehydration procedures. Here we present 3D Fast Spin Echo Magnetic Resonance Imaging (MRI) in combination with 2D and 3D segmentation techniques as a powerful tool to study brain anatomy. We set up MRI of the brain in mouse models for the fragile X syndrome (FMR1 knockout) and Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH) syndrome (L1CAM knockout). Our major goal was to determine qualitative and quantitative differences in specific brain structures. MRI of the brain of fragile X and CRASH patients has revealed alterations in the size of specific brain structures, including the cerebellar vermis and the ventricular system. In the present MRI study of the brain from fragile X knockout mice, we have measured the size of the brain, cerebellum and 4th ventricle, which were reported as abnormal in human fragile X patients, but found no evidence for altered brain regions in the mouse model. In CRASH syndrome, the most specific brain abnormalities are vermis hypoplasia and abnormalities of the ventricular system with some degree of hydrocephalus. With the MRI study of L1CAM knockout mice we found vermis hypoplasia, abnormalities of the ventricular system including dilatation of the lateral and the 4th ventricles. These subtle abnormalities were not detected upon standard neuropathological examination. Here we proved that this sensitive MRI technique allows to measure small differences which can not always be detected by means of pathology.
Verhoye, Marleen; Sijbers, Jan; Kooy, R. F.; Reyniers, E.; Fransen, E.; Oostra, B. A.; Willems, Peter; Van der Linden, Anne-Marie
Objective: Adiponectin is a hormone that is mainly secreted by fat cells. Adiponectin has anti-inflammatory and anti-atherosclerotic effects, and a protective effect against ischemic brain injury, but the level of expression of adiponectin in brain tissue is unknown. In the current study, a mouse model of transient cerebral ischemia was used to determine the level of expression of adiponectin in ischemic brain tissue. Methods: Sixty CD-1 mice underwent transient middle cerebral artery occlusion. The level of expression of adiponectin in mouse brain tissues 1 hour, 4 hours, 1 day, 3 days, and 7 days, after cerebral ischemia/reperfusion injury were determined using a real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry. Results: The level of expression of adiponectin in mouse ischemic brain tissues increased after cerebral ischemia/reperfusion injury and was higher in the central area of ischemia than in the peripheral area. The level of expression of adiponectin occurred only in vascular endothelial cells. There was no significant change in the level of expression of adiponectin mRNA in brain tissue pre- and post-ischemia/reperfusion injury. Conclusion: After cerebral ischemia/reperfusion injury, adiponectin accumulated in the vascular endothelial cells of ischemic brain tissues, and non-endogenous adiponectin was generated. Circulating adiponectin accumulated in ischemic brain tissues through its role in adhering to damaged vascular endothelial cells.
Shen, Lin-Hui; Miao, Jie; Zhao, Ya-Jie; Zhao, Yong-Ju; Liang, Wei
Carbon monoxide is formed as a result of combustion of any carbon compound and can lead to hypoxia in many organs including the brain and the heart. Carbon monoxide poisoning in the United States is the leading cause of the fatal poisonings. In this study we present a case with no-known accompanying disease in the light of literature where myocardial infarction was developed as a result of carbon monoxide poisoning.
Gonullu, Hayriye; Karadas, Sevdegul; Aydin, Irfan; Vuruskan, Ertan
In the late 1990s, the Korea Ministry of Education and Human Resources, in response to concern over the relatively low standing of the nation's universities and researchers, launched the Brain Korea 21 program BK21). BK21 seeks to make Korean research universities globally competitive and to produce more high-quality researchers in Korea. It…
Seong, Somi; Popper, Steven W.; Goldman, Charles A.; Evans, David K.
A flexible graphics system for displaying functional and anatomic data on arbitrary collections of surfaces on or within the brain is presented. The system makes it possible to show complex, convoluted surfaces with the shading cues necessary to understand their shapes; to vary viewpoint, object position, illumination, and perspective easily; to show multiple-objects in one view, with or without transparency,
Bradley A. Payne; Arthur W. Toga
This paper presents a brain based biometrics methodology using local global (L-G) and stochastic Petri net (SPN) graphs. In particular, today's most used lying detection systems (polygraph) are based on blood pressure under certain psychological conditions and have been proven inadequate and inaccurate for determining if a person is saying the truth or not. The main reason behind this inaccuracy
Nikolaos G. Bourbakis; S. Makrogiannis
Background and Purpose—Intravenously delivered human umbilical cord blood cells (HUCBC) have been previously shown to improve functional recovery of stroked rats. To extend these findings, we examined the behavioral recovery and stroke infarct volume in the presence of increasing doses of HUCBC after permanent middle cerebral artery occlusion (MCAO). Methods—Rats were subjected to MCAO and allowed to recover for 24
Martina Vendrame; Jordan Cassady; Jennifer Newcomb; Tanya Butler; Keith R. Pennypacker; Tanja Zigova; Cyndy Davis Sanberg; Paul R. Sanberg; Alison E. Willing
Quantitative evaluation of brain hemodynamics and metabolism, particularly the relationship between brain function and oxygen utilization, is important for understanding normal human brain operation as well as pathophysiology of neurological disorders. It can also be of great importance for evaluation of hypoxia within tumors of the brain and other organs. A fundamental discovery by Ogawa and co-workers of the BOLD (Blood Oxygenation Level Dependent) contrast opened a possibility to use this effect to study brain hemodynamic and metabolic properties by means of MRI measurements. Such measurements require developing theoretical models connecting MRI signal to brain structure and functioning and designing experimental techniques allowing MR measurements of salient features of theoretical models. In our review we discuss several such theoretical models and experimental methods for quantification brain hemodynamic and metabolic properties. Our review aims mostly at methods for measuring oxygen extraction fraction, OEF, based on measuring blood oxygenation level. Combining measurement of OEF with measurement of CBF allows evaluation of oxygen consumption, CMRO2. We first consider in detail magnetic properties of blood – magnetic susceptibility, MR relaxation and theoretical models of intravascular contribution to MR signal under different experimental conditions. Then, we describe a “through-space” effect – the influence of inhomogeneous magnetic fields, created in the extravascular space by intravascular deoxygenated blood, on the MR signal formation. Further we describe several experimental techniques taking advantage of these theoretical models. Some of these techniques - MR susceptometry, and T2-based quantification of oxygen OEF – utilize intravascular MR signal. Another technique – qBOLD – evaluates OEF by making use of through-space effects. In this review we targeted both scientists just entering the MR field and more experienced MR researchers interested in applying advanced BOLD-based techniques to study brain in health and disease. PMID:22927123
Yablonskiy, Dmitriy A.; Sukstanskii, Alexander L.; He, Xiang
Recent studies have demonstrated the feasibility of transcranial High Intensity Focused Ultrasound (HIFU) therapy in the brain using adaptive focusing techniques. However, the complexity of the procedures imposes to provide an accurate targeting, monitoring and control of this emerging therapeutic modality in order to ensure the safety of the treatment and avoid potential damaging effects of ultrasound on healthy tissues. For these purposes, a complete workflow and setup for HIFU treatment under Magnetic Resonance (MR) guidance is proposed and implemented in rats. For the first time, tissue displacements induced by the acoustic radiation force are detected in vivo in brain tissues and measured quantitatively using motion-sensitive MR sequences. Such a valuable target control prior to treatment assesses the quality of the focusing pattern in situ and enables to estimate the acoustic intensity at focus. This MR-Acoustic radiation force imaging is then correlated with conventional MR-Thermometry sequences which are used to follow the temperature changes during the HIFU therapeutic session. Last, pre and post treatment Magnetic Resonance Elastography (MRE) datasets are acquired and evaluated as a new potential way to non invasively control the stiffness changes due to the presence of thermal necrosis. As a proof of concept, MRguided HIFU is performed in vitro in turkey breast samples and in vivo in transcranial rat brain experiments. The experiments are conducted using a dedicated MR compatible HIFU setup in a high field MRI scanner (7T). Results obtained on rats confirmed that both the MR localization of the US focal point and the pre and post HIFU measurement of the tissue stiffness, together with temperature control during HIFU are feasible and valuable techniques for an efficient monitoring of HIFU in the brain. Brain elasticity appears to be more sensitive to the presence of oedema than to tissue necrosis. PMID:20019400
Larrat, Benoît; Pernot, Mathieu; Aubry, Jean-François; Dervishi, Elvis; Sinkus, Ralph; Seilhean, Danielle; Marie, Yannick; Boch, Anne-Laure; Fink, Mathias; Tanter, Mickaël
Despite recent progress on brain connectivity modeling using neuroimaging data such as fMRI, most current approaches assume that brain connectivity networks have time-invariant topology/coefficients. This is clearly problematic as the brain is inherently nonstationary. Here, we present a time-varying model to investigate the temporal dynamics of brain connectivity networks. The proposed method allows for abrupt changes in network structure via a fused least absolute shrinkage and selection operator (LASSO) scheme, as well as recovery of time-varying networks with smoothly changing coefficients via a weighted regression technique. Simulations demonstrate that the proposed method yields improved accuracy on estimating time-dependent connectivity patterns when compared to a static sparse regression model or a weighted time-varying regression model. When applied to real resting-state fMRI datasets from Parkinson's disease (PD) and control subjects, significantly different temporal and spatial patterns were found to be associated with PD. Specifically, PD subjects demonstrated reduced network variability over time, which may be related to impaired cognitive flexibility previously reported in PD. The temporal dynamic properties of brain connectivity in PD subjects may provide insights into brain dynamics associated with PD and may serve as a potential biomarker in future studies. PMID:25252272
Liu, Aiping; Chen, Xun; McKeown, Martin J; Wang, Z Jane
The KIV (K-4) model is based on biological attributes found in the limbic system of a salamander. Higher forms of organisms including humans have a limbic system which incorporates the sensory cortex, hippocampus and entorhinal cortex\\/ amygdala of the brain. The KIV model has been used successfully for classification and prediction tasks. We propose the use of the KIV model
Mark H. Myers; Robert Kozma
intervals around the aver- age trajectory. This is accomplished using non-linear mixed effects modelingMULTIVARIATE MODELING OF LONGITUDINAL MRI IN EARLY BRAIN DEVELOPMENT WITH CONFIDENCE MEASURES Neda and DTI (Dif- fusion Tensor Imaging) using multivariate nonlinear mixed effect modeling of temporal
We show that in the dissipative quantum model of brain the time-dependence ofthe frequencies of the electrical dipole wave quanta leads to the dynamicalorganization of the memories in space (i.e. to their localization in more orless diffused regions of the brain) and in time (i.e. to their longer orshorter life-time). The life-time and the localization in domains of the memorystates also depend on internal parameters and on the number of links that thebrain establishes with the external world. These results agree with thephysiological observations of the dynamic formation of neural circuitry whichgrows as brain develops and relates to external world.
This paper presents a new fully automatic model-based segmentation algorithm, which combines level-set methods to model the shape of brain structures and their variation with active appearance modeling to generate images that are used to drive the segmentation. The new algorithm incorporates multi-modality images to improve the segmentation performance and the recursive least square (RLS) algorithm is adopted to minimize the difference between test image and the one synthesized from the shape and appearance modeling. When compared with manual segmentation, the 2D and 3D experiments demonstrate that the new algorithm is computationally efficient and robust and is promising for automatic segmentation of the lateral ventricles. PMID:17466538
Hu, Shiyan; Collins, D Louis
Identification of myocardial infarction (MI) by imaging is critical for clinical management of ischemic heart disease. Iodine-123-labeled hypericin (¹²³I-Hyp) is a new potent infarct avid agent. We sought to compare target selectivity and organ distribution between ¹²³I-Hyp and the myocardial perfusion agent, technetium-99m-labeled hexakis [2-methoxy isobutyl isonitrile] ((99m)Tc-Sestamibi) in rabbits with acute MI. Hypericin was radiolabeled with I using iodogen as oxidant, and (99m)Tc-Sestamibi was prepared from a commercial kit and radioactive sodium pertechnetate. Rabbits (n = 6) with 24-hour-old MI received ¹²³I-Hyp intravenously and received (99m)Tc-Sestamibi 9 hours later. They were studied by dual-isotope simultaneous acquisition micro single photon emission computed tomography/computed tomography (DISA-?SPECT/CT), tissue gamma counting (TGC), autoradiography, and histology. After purification, ¹²³I-Hyp was obtained with radiochemical purity around 99%. DISA-?SPECT/CT images showed ¹²³I-Hyp retention in infarcted but not in normal myocardium. By TGC, accumulation values reached 1.175 ± 0.096 percentage of injected dose per gram (%ID/g) and 0.028 ± 0.007%ID/g in infarcted myocardium and normal myocardium with high tracer concentration in liver, intestines, and gallbladder. (99m)Tc-Sestamibi was prepared with radiochemical purity over 95%. DISA-?SPECT/CT showed no accumulation in MI and high initial radioactivity levels in normal myocardium that were rapidly cleared as confirmed by TGC (0.011 ± 0.003%ID/g). Liver and intestines were clearly visualized. By TGC, gallbladder and kidneys show moderate (99m)Tc-Sestamibi uptake. The selectivity of ¹²³I-Hyp for infarcted myocardium and (99m)Tc-Sestamibi for normal myocardium was confirmed. ¹²³I-Hyp distribution in rabbits is characterized by hepatobiliary excretion. (99m)Tc-Sestamibi undergoes hepatorenal elimination. PMID:23714775
Cona, Marlein M; Feng, Yuanbo; Li, Yue; Chen, Feng; Vunckx, Kathleen; Zhou, Lin; Van Slambrouck, Katrien; Rezaei, Ahmadreza; Gheysens, Olivier; Nuyts, Johan; Verbruggen, Alfons; Oyen, Raymond; Ni, Yicheng
Buyang Huanwu decoction (BYHWD) is a well-known and canonical Chinese medicine formula from “Correction on Errors in Medical Classics” in Qing dynasty. Here, we show that BYHWD could alleviate the ventricular remodeling induced by left anterior descending (LAD) artery ligation in rats. BYHWD treatment (18?g/kg/day) decreased heart weight/body weight (HW/BW), left ventricle (LV) dimension at end diastole (LVDd) and increased LV ejection fraction (LVEF) and LV fractional shortening (LVFS) significantly compared to model group at the end of 12 weeks. The collagen volume of BYHWD group was more significantly decreased than that of model group. Proteomic analysis showed that atrial natriuretic factor (ANF) was downregulated; heat shock protein beta-6 (HSPB6) and peroxiredoxin-6 (PRDX6) were upregulated in BYHWD-treated group among successfully identified proteins. The apoptotic index (AI) was reduced by BYHWD accompanied by decreased expression of Bax and caspase 3 activity, increased Bcl-2/Bax ratio, and phosphorylation of HSPB6 compared to that of model group. Taken together, these results suggest that BYHWD can alleviate ventricular remodeling induced by LAD artery ligation. The antiremodeling effects of BYHWD are conferred by decreasing AI through affecting multiple targets including increased Bcl-2/Bax ratio and decreased caspase 3 activity that might be via upregulated PRDX6, phosphorylation of HSPB6 and subsequently reduction of ANF. PMID:23049607
Zhou, Ying Chun; Liu, Bin; Li, Ying Jia; Jing, Lin Lin; Wen, Ge; Tang, Jing; Xu, Xin; Lv, Zhi Ping; Sun, Xue Gang
Brain changes due to development and maturation, normal aging, or degenerative disease are continuous, gradual, and variable across individuals. To quantify the individual progression of brain changes, we propose a spatio-temporal methodology based on Hidden Markov Models (HMM), and apply it on four-dimensional structural brain magnetic resonance imaging series of older individuals. First, regional brain features are extracted in order to reduce image dimensionality. This process is guided by the objective of the study or the specific imaging patterns whose progression is of interest, for example, the evaluation of Alzheimer-like patterns of brain change in normal individuals. These regional features are used in conjunction with HMMs, which aim to measure the dynamic association between brain structure changes and progressive stages of disease over time. A bagging framework is used to obtain models with good generalization capability, since in practice the number of serial scans is limited. An application of the proposed methodology was to detect individuals with the risk of developing MCI, and therefore it was tested on modeling the progression of brain atrophy patterns in older adults. With HMM models, the state-transition paths corresponding to longitudinal brain changes were constructed from two completely independent datasets, the Alzheimer Disease Neuroimaging Initiative and the Baltimore Longitudinal Study of Aging. The statistical analysis of HMM-state paths among the normal, progressive MCI, and MCI groups indicates that, HMM-state index 1 is likely to be a predictor of the conversion from cognitively normal to MCI, potentially many years before clinical symptoms become measurable. PMID:24706564
Wang, Ying; Resnick, Susan M; Davatzikos, Christos
Burnett DM, Kolakowsky-Hayner SA, Slater D, Stringer A, Bushnik T, Zafonte R, Cifu DX. Ethnographic analysis of traumatic brain injury patients in the national Model Systems database. Arch Phys Med Rehabil 2003;84:263-7. Objective: To compare demographics, injury characteristics, therapy service and intensity, and outcome in minority versus nonminority patients with traumatic brain injury (TBI). Design: Retrospective analysis. Setting: Twenty medical
Derek M. Burnett; Stephanie A. Kolakowsky-Hayner; Dan Slater; Anthony Stringer; Tamara Bushnik; Ross Zafonte; David X. Cifu
The finite mixture (FM) model is the most commonly used model for statistical segmentation of brain magnetic reso- nance (MR) images because of its simple mathematical form and the piecewise constant nature of ideal brain MR images. However, being a histogram-based model, the FM has an intrinsic limita- tion—no spatial information is taken into account. This causes the FM model
Yongyue Zhang; Michael Brady; Stephen M. Smith
Various strategies have been devised to reduce the clinical consequences of myocardial infarction, including acute medical care, revascularization, stem cell transplantations, and more recently, prevention of cardiomyocyte cell death. Activation of embryonic signaling pathways is a particularly interesting option to complement these strategies and to improve the functional performance and survival rate of cardiomyocytes. Here, we have concentrated on bone morphogenetic protein 2 (BMP-2), which induces ectopic formation of beating cardiomyocytes during development in the mesoderm and protects neonatal cardiomyocytes from ischemia-reperfusion injury. In a mouse model of acute myocardial infarction, an i.v. injection of BMP-2 reduced infarct size in mice when given after left anterior descending artery ligation. Mice treated with BMP-2 are characterized by a reduced rate of apoptotic cardiomyocytes both in the border zone of the infarcts and in the remote myocardium. In vitro, BMP-2 increases the frequency of spontaneously beating neonatal cardiomyocytes and the contractile performance under electrical pacing at 2 Hz, preserves cellular adenosine triphosphate stores, and decreases the rate of apoptosis despite the increased workload. In addition, BMP-2 specifically induced phosphorylation of Smad1/5/8 proteins and protected adult cardiomyocytes from long-lasting hypoxia-induced cellular damage and oxidative stress without activation of the cardiodepressant transforming growth factor-? pathway. Our data suggest that BMP-2 treatment may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by improving the contractility of cardiomyocytes and preventing cardiomyocyte cell death. PMID:23376954
Ebelt, Henning; Hillebrand, Ina; Arlt, Stephan; Zhang, Ying; Kostin, Sawa; Neuhaus, Herbert; Müller-Werdan, Ursula; Schwarz, Elisabeth; Werdan, Karl; Braun, Thomas
Neurologic disorders such as Alzheimer's, Parkinson's disease, and Restless Legs Syndrome involve a loss of brain iron homeostasis. Moreover, iron deficiency is the most prevalent nutritional concern worldwide with many associated cognitive and neural ramifications. Therefore, understanding the mechanisms by which iron enters the brain and how those processes are regulated addresses significant global health issues. The existing paradigm assumes that the endothelial cells (ECs) forming the blood-brain barrier (BBB) serve as a simple conduit for transport of transferrin-bound iron. This concept is a significant oversimplification, at minimum failing to account for the iron needs of the ECs. Using an in vivo model of brain iron deficiency, the Belgrade rat, we show the distribution of transferrin receptors in brain microvasculature is altered in luminal, intracellular, and abluminal membranes dependent on brain iron status. We used a cell culture model of the BBB to show the presence of factors that influence iron release in non-human primate cerebrospinal fluid and conditioned media from astrocytes; specifically apo-transferrin and hepcidin were found to increase and decrease iron release, respectively. These data have been integrated into an interactive model where BBB ECs are central in the regulation of cerebral iron metabolism. PMID:25315861
Simpson, Ian A; Ponnuru, Padmavathi; Klinger, Marianne E; Myers, Roland L; Devraj, Kavi; Coe, Christopher L; Lubach, Gabriele R; Carruthers, Anthony; Connor, James R
Modular architecture has been found in most cortical areas of mammalian brains, but little is known about its evolutionary origin. It has been proposed by several researchers that maximizing information transmission among subsystems can be used as a principle for understanding the development of complex brain networks. In this paper, we study how heterogeneous modules develop in coupled-map networks via a genetic algorithm, where selection is based on maximizing bidirectional information transmission. Two functionally differentiated modules evolved from two homogeneous systems with random couplings, which are associated with symmetry breaking of intrasystem and intersystem couplings. By exploring the parameter space of the network around the optimal parameter values, it was found that the optimum network exists near transition points, at which the incoherent state loses its stability and an extremely slow oscillatory motion emerges. PMID:25124068
Yamaguti, Yutaka; Tsuda, Ichiro
Background Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects a substantial portion of combat veterans and poses serious consequences to long-term health. Consequently, the identification of diagnostic and prognostic blood biomarkers for PTSD is of great interest. Previously, we assessed genome-wide gene expression of seven brain regions and whole blood in a social defeat mouse model subjected to various stress conditions. Results To extract biological insights from these data, we have applied a new computational framework for identifying gene modules that are activated in common across blood and various brain regions. Our results, in the form of modular gene networks that highlight spatial and temporal biological functions, provide a systems-level molecular description of response to social stress. Specifically, the common modules discovered between the brain and blood emphasizes molecular transporters in the blood-brain barrier, and the associated genes have significant overlaps with known blood signatures for PTSD, major depression, and bipolar disease. Similarly, the common modules specific to the brain highlight the components of the social defeat stress response (e.g., fear conditioning pathways) in each brain sub-region. Conclusions Many of the brain-specific genes discovered are consistent with previous independent studies of PTSD or other mental illnesses. The results from this study further our understanding of the mechanism of stress response and contribute to a growing list of diagnostic biomarkers for PTSD. PMID:23962043
We measured regional cerebral blood flow and [123I]iodoamphetamine (IMP) uptake in 16 patients with unilateral brain infarcts during the subacute period (Day 3 to Day 50) and again after 3 months. Our results show that the central and peripheral areas described earlier in the chronic period were already differentiated in the subacute period. The central area presented a short phase of luxury perfusion and a longer phase of IMP hyperfixation. The peripheral area showed both a slight regional cerebral blood flow decrease and an early IMP uptake decrease similar to those previously found in the chronic period. Contralateral regional cerebral blood flow during the subacute period, considered normal, was significantly lower than that during the chronic period. PMID:2784014
Raynaud, C; Rancurel, G; Tzourio, N; Soucy, J P; Baron, J C; Pappata, S; Cambon, H; Mazoyer, B; Lassen, N A; Cabanis, E
Episodic memory is among the cognitive functions that can be affected in the acute phase following mild traumatic brain injury (MTBI). The present study used EEG recordings to evaluate global synchronization and network organization of rhythmic activity during the encoding and recognition phases of an episodic memory task varying in stimulus type (kaleidoscope images, pictures, words, and pseudowords). Synchronization of oscillatory activity was assessed using a linear and nonlinear connectivity estimator and network analyses were performed using algorithms derived from graph theory. Twenty five MTBI patients (tested within days post-injury) and healthy volunteers were closely matched on demographic variables, verbal ability, psychological status variables, as well as on overall task performance. Patients demonstrated sub-optimal network organization, as reflected by changes in graph parameters in the theta and alpha bands during both encoding and recognition. There were no group differences in spectral energy during task performance or on network parameters during a control condition (rest). Evidence of less optimally organized functional networks during memory tasks was more prominent for pictorial than for verbal stimuli. PMID:20863861
Tsirka, Vasso; Simos, Panagiotis G; Vakis, Antonios; Kanatsouli, Kassiani; Vourkas, Michael; Erimaki, Sofia; Pachou, Ellie; Stam, Cornelis Jan; Micheloyannis, Sifis
The therapeutic goal in treating cerebral ischemia is to reduce the extent of brain injury and thus minimize neuro-logical impairment. We examined the effects of p-hydro-xybenzyl alcohol (HBA), an active component of Gastrodia elata Blume, on transient focal cerebral ischemia-induced brain injury with respect to the involvement of protein disulphide isomerase (PDI), nuclear factor-E2-related factor 2 (Nrf2), and neurotrophic factors. All animals were ovariectomized 14 days before ischemic injury. Ischemic injury was induced for 1 h by middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Three days before MCAO, the vehicle-treated and the HBA-treated groups received intramuscular sesame oil and HBA (25 mg/kg BW), respectively. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed decreased infarct volume in the ischemic lesion of HBA-treated animals. HBA pretreatment also promoted functional recovery, as measured by the modified neurological severity score (mNSS; p < 0.05). Moreover, expression of PDI, Nrf2, BDNF, GDNF, and MBP genes increased by HBA treatment. In vitro, H2O2-induced PC12 cell death was prevented by 24 h HBA treatment, but bacitracin, a PDI inhibitor, attenuated this cytoprotective effect in a dose-dependent manner. HBA treatment for 2 h also induced nuclear translocation of Nrf2, possibly activating the intracellular antioxidative system. These results suggest that HBA protects against brain damage by modulating cytoprotective genes, such as Nrf2 and PDI, and neurotrophic factors. PMID:21347705
Kam, Kyung-Yoon; Yu, Seong Jin; Jeong, Nahee; Hong, Jeong Hwa; Anthony Jalin, Angela M. A.; Lee, Sungja; Choi, Yong Won; Lee, Chae Kwan; Kang, Sung Goo
We propose a model of quantum-like (QL) processing of mental information. This model is based on quantum information theory. However, in contrast to models of "quantum physical brain" reducing mental activity (at least at the highest level) to quantum physical phenomena in the brain, our model matches well with the basic neuronal paradigm of the cognitive science. QL information processing is based (surprisingly) on classical electromagnetic signals induced by joint activity of neurons. This novel approach to quantum information is based on representation of quantum mechanics as a version of classical signal theory which was recently elaborated by the author. The brain uses the QL representation (QLR) for working with abstract concepts; concrete images are described by classical information theory. Two processes, classical and QL, are performed parallely. Moreover, information is actively transmitted from one representation to another. A QL concept given in our model by a density operator can generate a variety of concrete images given by temporal realizations of the corresponding (Gaussian) random signal. This signal has the covariance operator coinciding with the density operator encoding the abstract concept under consideration. The presence of various temporal scales in the brain plays the crucial role in creation of QLR in the brain.
Alzheimer's disease is characterized by the accumulation and deposition of plaques of ?-amyloid (A?) peptide in the brain. Given its pivotal role, new therapies targeting A? are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of A? assemblies and evaluated their efficiency in reducing the A? burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood–brain barrier targeting and with phosphatidic acid for A? binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, A? assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble A?1–42 (?33%), assessed by ELISA, and the number and total area of plaques (?34%) detected histologically. Also, brain A? oligomers were reduced (?70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [11C]Pittsburgh compound B (PIB). The reduction of brain A? was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain A? aggregates and promote peptide removal across the blood–brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease. PMID:25319699
Balducci, Claudia; Mancini, Simona; Minniti, Stefania; La Vitola, Pietro; Zotti, Margherita; Sancini, Giulio; Mauri, Mario; Cagnotto, Alfredo; Colombo, Laura; Fiordaliso, Fabio; Grigoli, Emanuele; Salmona, Mario; Snellman, Anniina; Haaparanta-Solin, Merja; Forloni, Gianluigi; Re, Francesca
We show that in the dissipative quantum model of brain the time-dependence of the frequencies of the electrical dipole wave quanta leads to the dynamical organization of the memories in space (i.e. to their localization in more or less diffused regions of the brain) and in time (i.e. to their longer or shorter life-time). The life-time and the localization in domains of the memory states also depend on internal parameters and on the number of links that the brain establishes with the external world. These results agree with the physiological observations of the dynamic formation of neural circuitry which grows as brain develops and relates to external world.
E. Alfinito; G. Vitiello
The Senescence-Accelerated Mouse (SAM) represents a group of inbred mouse strains developed as a model for the study of human aging and age-related diseases. Senescence-prone (SAMP) strains exhibit an early onset of age-related decline in the peripheral immunity such as thymic involution, loss of CD4+ T cells, impaired helper T cell function, decreased antibody-forming capacity, dysfunction of antigen-presenting cells, decreased natural killer activity, increased auto-antibodies, and susceptibility to virus infection. Senescence-prone SAMP10 mice undergo age-related changes in the brain such as brain atrophy, shrinkage and loss of cortical neurons, retraction of cortical neuronal dendrites, loss of dendritic spines, loss of synapses, impaired learning and memory, depressive behavior, accumulation of neuronal DNA damage, neuronal ubiquitinated inclusions, reduced hippocampal cholinergic receptors, decreased neurotrophic factors, decreased hippocampal zinc and zinc transporters, increased sphyngomyelinase, and elevated oxidative-nitrative stress. Recent data indicating increased pro-inflammatory cytokines in the brain of SAMP10 mice are directing investigators toward an integration of immune and neural abnormalities to enhance understanding of the principles of brain aging. We highlight how mouse brain cells adopt cytokine-mediated responses and how SAMP10 mice are defective in these responses. SAMP10 model would be useful to study how age-related disturbances in peripheral immunity have an impact on dysregulation of brain tissue homeostasis, resulting in age-related neurodegeneration. PMID:22396891
Shimada, Atsuyoshi; Hasegawa-Ishii, Sanae
Brain tissue segmentation is important in studying markers in human brain Magnetic Resonance Images (MRI) of patients with diseases such as Multiple Sclerosis (MS). Parametric segmentation approaches typically assume unimodal Gaussian distributions on MRI intensities of individual tissue classes, even in applications on multi-spectral images. However, this assumption has not been rigorously verified especially in the context of MS. In this work, we evaluate the local MRI intensities of both healthy and diseased brain tissues of 21 multi-spectral MRIs (63 volumes in total) of MS patients for adherence to this assumption. We show that the tissue intensities are not uniform across the brain and vary across (anatomical) regions of the brain. Consequently, we show that Gaussian mixtures can better model the multi-spectral intensities. We utilize an Expectation Maximization (EM) based approach to learn the models along with a symmetric Jeffreys divergence criterion to study differences in intensity distributions. The effects of these findings are also empirically verified on automatic segmentation of brains with MS.
Xiao, Yiming; Shah, Mohak; Francis, Simon; Arnold, Douglas L.; Arbel, Tal; Collins, D. Louis
Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents. PMID:23591844
Martínez-Aranda, Antonio; Hernández, Vanessa; Picón, Cristina; Modolell, Ignasi; Sierra, Angels
This study aimed to quantify dynamic structural changes in the brain after subcortical stroke and identify brain areas that contribute to motor recovery of affected limbs. High-resolution structural MRI and neurological examinations were conducted at five consecutive time points during the year following stroke in 10 patients with left hemisphere subcortical infarctions involving motor pathways. Gray matter volume (GMV) was calculated using an optimized voxel-based morphometry technique, and dynamic changes in GMV were evaluated using a mixed-effects model. After stroke, GMV was decreased bilaterally in brain areas that directly or indirectly connected with lesions, which suggests the presence of regional damage in these "healthy" brain tissues in stroke patients. Moreover, the GMVs of these brain areas were not correlated with the Motricity Index (MI) scores when controlling for time intervals after stroke, which indicates that these structural changes may reflect an independent process (such as axonal degeneration) but cannot affect the improvement of motor function. In contrast, the GMV was increased in several brain areas associated with motor and cognitive functions after stroke. When controlling for time intervals after stroke, only the GMVs in the cognitive-related brain areas (hippocampus and precuneus) were positively correlated with MI scores, which suggests that the structural reorganization in cognitive-related brain areas may facilitate the recovery of motor function. However, considering the small sample size of this study, further studies are needed to clarify the exact relationships between structural changes and recovery of motor function in stroke patients. PMID:22431281
Fan, Fengmei; Zhu, Chaozhe; Chen, Hai; Qin, Wen; Ji, Xunming; Wang, Liang; Zhang, Yujin; Zhu, Litao; Yu, Chunshui
The purpose was to examine psychosocial factors that influence the physical activity behaviors of adults with brain injuries. Two differing models, based on Harter's model of self-worth, were proposed to examine the relationship between perceived competence, social support, physical self-worth, affect, and motivation. Adults numbering 384 with…
The paper presents calculations for the electric field and absorbed power density distribution in chick brain tissue inside a test tube, using an off-center spherical model. It is shown that the off-center spherical model overcomes many of the limitations of the concentric spheri...
Computerized medical decision support systems have been a major research topic in recent years. Intelligent computer programs were implemented to aid physicians and other medical professionals in making difficult medical decisions. This report compares three different mathematical models for building a traumatic brain injury (TBI) medical decision support system (MDSS). These models were developed based on a large TBI patient
Yu-Chuan Li; Li Liu; Wen-Ta Chiu; Wen-Shan Jian
Multivariate Nonlinear Mixed Model to Analyze Longitudinal Image Data: MRI Study of Early Brain to any longitudinal data with nonlinear growth patterns that can not easily be modeled by linear methods image data, in which subjects are scanned and measured repeatedly over time, become available
Utah, University of
This paper presents a conceptual model for movement rehabilitation of traumatic brain injury (TBI) using virtual environments. This hybrid model integrates principles from ecological systems theory with recent advances in cognitive neuroscience, and supports a multilevel approach to both assessment and treatment. Performance outcomes at any stage of recovery are determined by the interplay of task, individual, and environmental\\/contextual factors.
Peter H. Wilson; Patrick Thomas; David Shum; Jonathan Duckworth; Mark Gugliemetti; H. Rudolph; N. Mumford; R. Eldridge
Despite considerable investigation in rodent models of traumatic brain injury (TBI), no novel therapy has been successfully translated from bench to bedside. Although well-described limitations of clinical trails may account for these failures, several modeling factors may also contribute to the lack of therapeutic translation from the laboratory to the clinic. Specifically, models of TBI may omit one or more critical, clinically relevant pathophysiologic features. In this invited review article, the impact of the limited incorporation of several important clinical pathophysiologic factors in TBI, namely secondary insults (i.e., hypotension and/or hypoxemia), coma, and aspects of standard neurointensive care monitoring and management strategies (i.e., intracranial pressure [ICP] monitoring and ICP-directed therapies, sedation, mechanical ventilation, and cardiovascular support) are discussed. Comparative studies in rodent and large animal models of TBI (which may, in some cases, represent super models) are also presented. We conclude that therapeutic breakthroughs will likely require a multidisciplinary approach, involving investigation in a range of models, including clinically relevant modifications of established animal models, along with development and application of new innovations in clinical trial design. PMID:11721738
Statler, K D; Jenkins, L W; Dixon, C E; Clark, R S; Marion, D W; Kochanek, P M
Electrical neurostimulation techniques, such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), are increasingly used in the neurosciences, e.g., for studying brain function, and for neurotherapeutics, e.g., for treating depression, epilepsy, and Parkinson’s disease. The characterization of electrical properties of brain tissue has guided our fundamental understanding and application of these methods, from electrophysiologic theory to clinical dosing-metrics. Nonetheless, prior computational models have primarily relied on ex-vivo impedance measurements. We recorded the in-vivo impedances of brain tissues during neurosurgical procedures and used these results to construct MRI guided computational models of TMS and DBS neurostimulatory fields and conductance-based models of neurons exposed to stimulation. We demonstrated that tissues carry neurostimulation currents through frequency dependent resistive and capacitive properties not typically accounted for by past neurostimulation modeling work. We show that these fundamental brain tissue properties can have significant effects on the neurostimulatory-fields (capacitive and resistive current composition and spatial/temporal dynamics) and neural responses (stimulation threshold, ionic currents, and membrane dynamics). These findings highlight the importance of tissue impedance properties on neurostimulation and impact our understanding of the biological mechanisms and technological potential of neurostimulatory methods. PMID:23850466
Wagner, Tim; Eden, Uri; Rushmore, Jarrett; Russo, Christopher J.; Dipietro, Laura; Fregni, Felipe; Simon, Stephen; Rotman, Stephen; Pitskel, Naomi B.; Ramos-Estebanez, Ciro; Pascual-Leone, Alvaro; Grodzinsky, Alan J.; Zahn, Markus; Valero-Cabre, Antoni
Twenty-five patients with clinical and CT findings indicating supratentorial cerebral infarct were prospectively studied with MR. MR examinations were performed between the 3rd and 150th day after stroke. T2-weighted axial images were compared with T1-weighted sequences after i.v. administration of Gd-DTPA. T2-weighted images demonstrated parenchymal lesions in all 25 patients. Postcontrast T1-weighted images, however, displayed pathologic contrast enhancement in only 19 areas of infarction. In 5 of the 25 patients, the use of Gd-DTPA provided additional diagnostic information by demonstrating gyral contrast enhancement as a pattern typical for ischemia. In 2 of the 25 patients, pathologic contrast enhancement was observed in an area that was isointense to the surrounding brain tissue on the T2-weighted images. In one patient, Gd-DTPA improved differentiation between areas of subacute and chronic infarction. At present, in the patient with suspected cerebral infarction, MR imaging after i.v. administration of Gd-DTPA appears recommended when clinical findings and CT are equivocal. PMID:2552531
Henkes, H; Schörner, W; Cordes, M; Sander, B; Schmitz, B; Felix, R
Networks of connections within the human brain have been the subject of intense recent research, yet their topology is still only partially understood. We analyze weighted networks calculated from functional magnetic resonance imaging (fMRI) data acquired during task performance. Expanding previous work in the area, our analysis retains all of the connections between all of the voxels in the full brain fMRI data, computing correlations between approximately 200,000 voxels per subject for 10 subjects. We evaluate the extent to which this rich dataset can be described by existing models of scale-free or exponentially truncated scale-free topology, comparing results across a large number of more complex topological models as well. Our results suggest that the novel “log quadratic” model presented in this paper offers a significantly better fit to networks of functional connections at the voxel level in the human brain.
Ruiz Vargas, E.; Mitchell, D. G. V.; Greening, S. G.; Wahl, L. M.
The multifractal spectrum Dq (Rényi dimensions) is used for the analysis and comparison between the Neuron Axons Network (NAN) of healthy and pathological human brains because it conveys information about the statistics in many scales, from the very rare to the most frequent network configurations. Comparison of the Fractional Anisotropy Magnetic Resonance Images between healthy and pathological brains is performed with and without noise reduction. Modelling the complex structure of the NAN in the human brain is undertaken using the dynamics of the Lorenz model in the chaotic regime. The Lorenz multifractal spectra capture well the human brain characteristics in the large negative q's which represent the rare network configurations. In order to achieve a closer approximation in the positive part of the spectrum (q > 0) two independent modifications are considered: a) redistribution of the dense parts of the Lorenz model's phase space into their neighbouring areas and b) inclusion of additive uniform noise in the Lorenz model. Both modifications, independently, drive the Lorenz spectrum closer to the human NAN one in the positive q region without destroying the already good correspondence of the negative spectra. The modelling process shows that the unmodified Lorenz model in its full chaotic regime has a phase space distribution with high fluctuations in its dense parts, while the fluctuations in the human brain NAN are smoother. The induced modifications (phase space redistribution or additive noise) moderate the fluctuations only in the positive part of the Lorenz spectrum leading to a faithful representation of the human brain axons network in all scales.
Hizanidis, J.; Katsaloulis, P.; Verganelakis, D. A.; Provata, A.
Presently available anatomic atlases provide useful coordinate systems such as the ubiquitous Talairach system but are sorely lacking in both spatial resolution and completeness. An appropriately sampled anatomic specimen can provide the additional detail necessary to accurately localize activation sites as well as provide other structural perspectives such as chemoarchitecture. We collected serial section postmortem anatomic data from several whole human head and brain specimens using a cryosectioning technique. Tissue imaged so that voxel resolution was 200 microns or better at full color. These high resolution datasets along with collections of MR data were placed within a common coordinate system and used to produce a probabilistic representation. This approach represents anatomy within a coordinate system as a probability. Coordinate locations are assigned a confidence limit to describe the likelihood that a given location belongs to an anatomic structure based upon the population of specimens. A variety of warping strategies are discussed to provide statistics on morphometric variability and probability. High dimensional anatomically based warps utilizing sulcal anatomy are described. These data are an important and necessary part of the comprehensive structural and functional analyses that focus on the mapping of the human brain.
Toga, Arthur W.; Thompson, Paul
Introduction The anaesthetic agent propofol (2,6-diisopropylphenol) has been shown to be an effective neuroprotective agent in different in vitro models of brain injury induced by oxygen and glucose deprivation. We examined its neuroprotective properties in an in vitro model of traumatic brain injury. Methods In this controlled laboratory study organotypic hippocampal brain-slice cultures were gained from six- to eight-day-old mice pups. After 14 days in culture, hippocampal brain slices were subjected to a focal mechanical trauma and subsequently treated with different molar concentrations of propofol under both normo- and hypothermic conditions. After 72 hours of incubation, tissue injury assessment was performed using propidium iodide (PI), a staining agent that becomes fluorescent only when it enters damaged cells via perforated cell membranes. Inside the cell, PI forms a fluorescent complex with nuclear DNA. Results A dose-dependent reduction of both total and secondary tissue injury could be observed in the presence of propofol under both normo- and hypothermic conditions. This effect was further amplified when the slices were incubated at 32°C after trauma. Conclusions When used in combination, the dose-dependent neuroprotective effect of propofol is additive to the neuroprotective effect of hypothermia in an in vitro model of traumatic brain injury. PMID:19397790
Rossaint, Jan; Rossaint, Rolf; Weis, Joachim; Fries, Michael; Rex, Steffen; Coburn, Mark
The developing human brain remains one of the few unsolved mysteries of science. Advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. However, the precise role of mechanics throughout this process remains underestimated and poorly understood. Here we show that mechanical stretch plays a crucial role in brain development. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we model the human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing inner core. This approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. We calibrate our model using magnetic resonance images from very preterm neonates. Our model predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the gyrification index, the ratio between the total and exposed surface area, we demonstrate that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. Understanding the mechanisms of cortical folding in the developing human brain has direct implications in the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism.
Budday, Silvia; Raybaud, Charles; Kuhl, Ellen
Abstract Objective: Neonatal hypoxic-ischemic encephalopathy (HIE) is caused by brain injury that occurs in a developing fetus or infant. Stem cell transplantation can reportedly induce functional recovery in animal models of HIE. Murine neonatal splenocytes are enriched with immature blood stem cells and are used for the investigation of murine models of syngeneic transplantation. The aim of this study was to investigate the therapeutic potential of newborn splenocytes in a murine model of neonatal ischemia-reperfusion brain injury. Methods: C57BL/6N mice (postnatal day 7) underwent right common carotid artery occlusion with an aneurysm clip. Following hypoxic exposure, reperfusion was achieved by unclamping the artery. Newborn splenocytes were transplanted intravenously at 3 weeks after injury. Results: The splenocytes transplanted group tended to show an improvement in behavioral tests, but it was not significantly different compared with the control groups. The transplanted cells were localized in various organs including injured brain tissue over 3 weeks. In the penumbra region of the brain, vascular endothelial growth factor (VEGF) expression was upregulated after transplantation. Conclusions: These results showed that syngeneic transplantation of newborn splenocytes achieved the long-term survival of the grafts and exerted influence the microenvironment in the injured brains of mice. PMID:24939627
Wang, Feifei; Shen, Yuan; Tsuru, Emi; Yamashita, Tatsuyuki; Baba, Nobuyasu; Tsuda, Masayuki; Maeda, Nagamasa; Sagara, Yusuke
The present study assessed the impact of sample size on the power and fit of structural equation modeling applied to functional brain connectivity hypotheses. The data consisted of time-constrained minimum norm estimates of regional brain activity during performance of a reading task obtained with magnetoencephalography. Power analysis was first conducted for an autoregressive model with 5 latent variables (brain regions), each defined by 3 indicators (successive activity time bins). A series of simulations were then run by generating data from an existing pool of 51 typical readers (aged 7.5-12.5 years). Sample sizes ranged between 20 and 1,000 participants and for each sample size 1,000 replications were run. Results were evaluated using chi-square Type I errors, model convergence, mean RMSEA (root mean square error of approximation) values, confidence intervals of the RMSEA, structural path stability, and D-Fit index values. Results suggested that 70 to 80 participants were adequate to model relationships reflecting close to not so close fit as per MacCallum et al.'s recommendations. Sample sizes of 50 participants were associated with satisfactory fit. It is concluded that structural equation modeling is a viable methodology to model complex regional interdependencies in brain activation in pediatric populations. PMID:25435589
Sideridis, Georgios; Simos, Panagiotis; Papanicolaou, Andrew; Fletcher, Jack
Pituitary adenylate-cyclase activating polypeptide (PACAP) has neuroprotective and axonal guidance functions, but the mechanisms behind such actions remain unclear. Previously we examined effects of PACAP (PACAP38, 1 pmol) injection intracerebroventrically in a mouse model of permanent middle cerebral artery occlusion (PMCAO) along with control saline (0.9% NaCl) injection. Transcriptomic and proteomic approaches using ischemic (ipsilateral) brain hemisphere revealed differentially regulated genes and proteins by PACAP38 at 6 and 24 h post-treatment. However, as the ischemic hemisphere consisted of infarct core, penumbra, and non-ischemic regions, specificity of expression and localization of these identified molecular factors remained incomplete. This led us to devise a new experimental strategy wherein, ischemic core and penumbra were carefully sampled and compared to the corresponding contralateral (healthy) core and penumbra regions at 6 and 24 h post PACAP38 or saline injections. Both reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to examine targeted gene expressions and the collapsin response mediator protein 2 (CRMP2) protein profiles, respectively. Clear differences in expression of genes and CRMP2 protein abundance and degradation product/short isoform was observed between ischemic core and penumbra and also compared to the contralateral healthy tissues after PACAP38 or saline treatment. Results indicate the importance of region-specific analyses to further identify, localize and functionally analyse target molecular factors for clarifying the neuroprotective function of PACAP38. PMID:25257527
Hori, Motohide; Nakamachi, Tomoya; Shibato, Junko; Rakwal, Randeep; Tsuchida, Masachi; Shioda, Seiji; Numazawa, Satoshi
Two major vascular pathologies underlie brain damage in patients with disease of small size penetrating brain arteries and arterioles; 1) thickening of the arterial media and 2) obstruction of the origins of penetrating arteries by parent artery intimal plaques. The media of these small vessels may be thickened by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements that accompanies degenerative changes in patients with hypertension and or diabetes or can contain foreign deposits as in amyloid angiopathy and genetically mediated conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These pathological changes lead to 2 different pathophysiologies: 1) brain ischemia in regions supplied by the affected arteries. The resultant lesions are deep small infarcts, most often involving the basal ganglia, pons, thalami and cerebral white matter. And 2) leakage of fluid causing edema and later gliosis in white matter tracts. The changes in the media and adventitia effect metalloproteinases and other substances within the matrix of the vessels and lead to abnormal blood/brain barriers in these small vessels. and chronic gliosis and atrophy of cerebral white matter. PMID:25692102
Objective: To identify global research trends in neuroimaging diagnosis for cerebral infarction using a bibliometric analysis of the Web of Science. Data Retrieval: We performed a bibliometric analysis of data retrieval for neuroimaging diagnosis for cerebral infarction containing the key words “CT, magnetic resonance imaging, MRI, transcranial Doppler, transvaginal color Doppler, digital subtraction angiography, and cerebral infarction” using the Web of Science. Selection Criteria: Inclusion criteria were: (a) peer-reviewed articles on neuroimaging diagnosis for cerebral infarction which were published and indexed in the Web of Science; (b) original research articles and reviews; and (c) publication between 2004–2011. Exclusion criteria were: (a) articles that required manual searching or telephone access; and (b) corrected papers or book chapters. Main Outcome Measures: (1) Annual publication output; (2) distribution according to country; (3) distribution according to institution; (4) top cited publications; (5) distribution according to journals; and (6) comparison of study results on neuroimaging diagnosis for cerebral infarction. Results: Imaging has become the predominant method used in diagnosing cerebral infarction. The most frequently used clinical imaging methods were digital subtraction angiography, CT, MRI, and transcranial color Doppler examination. Digital subtraction angiography is used as the gold standard. However, it is a costly and time-consuming invasive diagnosis that requires some radiation exposure, and is poorly accepted by patients. As such, it is mostly adopted in interventional therapy in the clinic. CT is now accepted as a rapid, simple, and reliable non-invasive method for use in diagnosis of cerebrovascular disease and preoperative appraisal. Ultrasonic Doppler can be used to reflect the hardness of the vascular wall and the nature of the plaque more clearly than CT and MRI. Conclusion: At present, there is no unified standard of classification of cerebral infarction imaging. Detection of clinical super-acute cerebral infarction remains controversial due to its changes on imaging, lack of specificity, and its similarity to a space-occupying lesion. Neuroimaging diagnosis for cerebral infarction remains a highly active area of research and development.
Du, Yan; Yang, Xiaoxia; Song, Hong; Chen, Bo; Li, Lin; Pan, Yue; Wu, Qiong; Li, Jia
This paper proposes a methodology that enables an arbitrary 3-D MRI brain image-volume to be automatically segmented and classified into neuro-anatomical components using multiresolution registration and matching with a novel volumetric brain structure model (VBSM). This model contains both raster and geometric data. The raster component comprises the mean MRI volume after a set of individual volumes of normal volunteers have been transformed to a standardized brain-based coordinate space. The geometric data consists of polyhedral objects representing anatomically important structures such as cortical gyri and deep gray matter nuclei. The method consists of iteratively registering the data set to be segmented to the VBSM using deformations based on local image correlation. This segmentation process is performed hierarchically in scale-space. Each step in decreasing levels of scale refines the fit of the previous step and provides input to the next. Results from phantom and real MR data are presented.
Collins, D. Louis; Peters, Terence M.; Dai, Weiqian; Evans, Alan C.
A new shock model in the rat using hemorrhagic hypotension for production of brain damage is described. Hemorrhagic shock was induced by lowering arterial blood pressure with bleeding. The MABP was maintained at approximately 25 mm Hg, accompanied by isoelectric EEG, and then shed blood was retransfused. At 1 week of recovery, morphological and 45Ca autoradiographic changes were examined. No brain damage was observed in rats after 1 min of isoelectric EEG. Mild neuronal damage in the hippocampal CA1 subfield was seen in some animals after 2 min of isoelectric EEG. Severe and consistent neuronal loss in the hippocampal CA1 subfield was recognized after 3 min of isoelectric EEG. Additional damage was also seen in the dentate hilus and the thalamus in some animals. This model can be used to study the pathophysiology of postshock brain damage and to assess new therapies following shock.
Yamauchi, Y.; Kato, H.; Kogure, K. (Tohoku Univ. School of Medicine, Sendai (Japan))
New genetic models provide better biological mimics of human tumors. The new models can give deeper insight into tumorigenesis and provide better targets for testing therapies. To use the new models most successfully, it is useful to keep in mind limitations that are harder to overcome by genetic manipulation. These include biochemical and anatomical differences between species, as well as differences in scale, both spatial and temporal. Three approaches to new genetic brain tumor models are described in the following articles. This essay provides a context, bringing out both advantages and remaining concerns. Examples are taken from work in brain tumor immunobiology and immunotherapy. The complementarity of different models, and the dichotomy between general principles and model-specific details are stressed. PMID:11718260
Lampson, L A
Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood-brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.220. PMID:25492116
Yemisci, Muge; Caban, Secil; Gursoy-Ozdemir, Yasemin; Lule, Sevda; Novoa-Carballal, Ramon; Riguera, Ricardo; Fernandez-Megia, Eduardo; Andrieux, Karine; Couvreur, Partick; Capan, Yilmaz; Dalkara, Turgay
Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.99, Caco-2 r=0.91 and MDCKII-MDR1 r=0.85). Despite of the substantial differences in the absolute in vitro P(app) values and regardless of the method used (side-by-side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood-brain barrier passage of new drug candidates. PMID:20920560
Hakkarainen, Jenni J; Jalkanen, Aaro J; Kääriäinen, Tiina M; Keski-Rahkonen, Pekka; Venäläinen, Tetta; Hokkanen, Juho; Mönkkönen, Jukka; Suhonen, Marjukka; Forsberg, Markus M
Automatically segmenting anatomical structures from 3D brain MRI images is an important task in neuroimaging. One major challenge is to design and learn effective image models accounting for the large variability in anatomy and data acquisition protocols. A deformable template is a type of generative model that attempts to explicitly match an input image with a template (atlas), and thus, they are robust against global intensity changes. On the other hand, discriminative models combine local image features to capture complex image patterns. In this paper, we propose a robust brain image segmentation algorithm that fuses together deformable templates and informative features. It takes advantage of the adaptation capability of the generative model and the classification power of the discriminative models. The proposed algorithm achieves both robustness and efficiency, and can be used to segment brain MRI images with large anatomical variations. We perform an extensive experimental study on four datasets of T1-weighted brain MRI data from different sources (1,082 MRI scans in total) and observe consistent improvement over the state-of-the-art systems. PMID:23836390
Liu, Cheng-Yi; Iglesias, Juan Eugenio; Tu, Zhuowen
Transcranial magnetic stimulation (TMS) offers the possibility of non-invasive treatment of brain disorders in humans. Studies on animals can allow rapid progress of the research including exploring a variety of different treatment conditions. Numerical calculations using animal models are needed to help design suitable TMS coils for use in animal experiments, in particular, to estimate the electric field induced in animal brains. In this paper, we have implemented a high-resolution anatomical MRI-derived mouse model consisting of 50 tissue types to accurately calculate induced electric field in the mouse brain. Magnetic field measurements have been performed on the surface of the coil and compared with the calculations in order to validate the calculated magnetic and induced electric fields in the brain. Results show how the induced electric field is distributed in a mouse brain and allow investigation of how this could be improved for TMS studies using mice. The findings have important implications in further preclinical development of TMS for treatment of human diseases.
Crowther, L. J.; Hadimani, R. L.; Kanthasamy, A. G.; Jiles, D. C.
Rich clubs arise when nodes that are 'rich' in connections also form an elite, densely connected 'club'. In brain networks, rich clubs incur high physical connection costs but also appear to be especially valuable to brain function. However, little is known about the selection pressures that drive their formation. Here, we take two complementary approaches to this question: firstly we show, using generative modelling, that the emergence of rich clubs in large-scale human brain networks can be driven by an economic trade-off between connection costs and a second, competing topological term. Secondly we show, using simulated neural networks, that Hebbian learning rules also drive the emergence of rich clubs at the microscopic level, and that the prominence of these features increases with learning time. These results suggest that Hebbian learning may provide a neuronal mechanism for the selection of complex features such as rich clubs. The neural networks that we investigate are explicitly Hebbian, and we argue that the topological term in our model of large-scale brain connectivity may represent an analogous connection rule. This putative link between learning and rich clubs is also consistent with predictions that integrative aspects of brain network organization are especially important for adaptive behaviour. PMID:25180309
Vértes, Petra E; Alexander-Bloch, Aaron; Bullmore, Edward T
We hypothesized that appraisal of brain connectivity may shed light on the substrate of the radiologically isolated syndrome (RIS), a term applied to asymptomatic subjects with brain MRI abnormalities highly suggestive of multiple sclerosis. We thus used a multimodal MRI approach on the human brain by modeling measures of microstructural integrity of white matter (WM) tracts with those of functional connectivity (FC) at the level of resting state networks in RIS subjects, demographically matched normal controls (NC), and relapsing-remitting (RR) MS patients, also matched with RIS for brain macrostructural damage (i.e., lesions and atrophy). Compared with NC, in both RIS subjects and MS patients altered integrity of WM tracts was present. However, RIS subjects showed, at a less conservative threshold, lower diffusivities than RRMS patients in distinct cerebral associative, commissural, projection, and cerebellar WM tracts, suggesting a relatively better anatomical connectivity. FC was similar in NC and RIS subjects, even in the presence of important risk factors for MS (spinal cord lesions, oligoclonal bands, and dissemination in time on MRI) and increased in RRMS patients in two clinically relevant networks subserving "processing" (sensorimotor) and "control" (working memory) functions. In RIS, the lack of functional reorganization in key brain networks may represent a model of "functional reserve," which may become upregulated, with an adaptive or maladaptive role, only at a later stage in case of occurrence of clinical deficit. PMID:25589750
Giorgio, Antonio; Stromillo, Maria Laura; De Leucio, Alessandro; Rossi, Francesca; Brandes, Imke; Hakiki, Bahia; Portaccio, Emilio; Amato, Maria Pia; De Stefano, Nicola
Introduction Stem cell therapy can promote good recovery from stroke. Several studies have demonstrated that mesenchymal stem cells (MSC) are safe and effective. However, more information regarding appropriate cell type is needed from animal model. This study was targeted at analyzing the effects in ischemic stroke of acute intravenous (i.v.) administration of allogenic bone marrow- (BM-MSC) and adipose-derived-stem cells (AD-MSC) on functional evaluation results and brain repair markers. Methods Allogenic MSC (2 × 106 cells) were administered intravenously 30 minutes after permanent middle cerebral artery occlusion (pMCAO) to rats. Infarct volume and cell migration and implantation were analyzed by magnetic resonance imaging (MRI) and immunohistochemistry. Function was evaluated by the Rogers and rotarod tests, and cell proliferation and cell-death were also determined. Brain repair markers were analyzed by confocal microscopy and confirmed by western blot. Results Compared to infarct group, function had significantly improved at 24 h and continued at 14 d after i.v. administration of either BM-MSC or AD-MSC. No reduction in infarct volume or any migration/implantation of cells into the damaged brain were observed. Nevertheless, cell death was reduced and cellular proliferation significantly increased in both treatment groups with respect to the infarct group. At 14 d after MSC administration vascular endothelial growth factor (VEGF), synaptophysin (SYP), oligodendrocyte (Olig-2) and neurofilament (NF) levels were significantly increased while those of glial fiibrillary acid protein (GFAP) were decreased. Conclusions i.v. administration of allogenic MSC - whether BM-MSC or AD-MSC, in pMCAO infarct was associated with good functional recovery, and reductions in cell death as well as increases in cellular proliferation, neurogenesis, oligodendrogenesis, synaptogenesis and angiogenesis markers at 14 days post-infarct. PMID:23356495
Bilateral medial medullary infarction (bilateral MMI) is an extremely rare cerebrovascular accident presenting with quadriplegia as the initial symptom and resulting in poor functional prognosis. Diagnosis of bilateral MMI has become possible based on brain MRI findings in recent years, but is still very difficult to diagnose. In the present case, brain MRI was performed 9 hours after the onset, and the infarcted area was detected only by diffusion-weighted MRI. However, changes over time were clearly detected by FLAIR-MRI on days 3, 5 and 7, but it is essential to confirm the disease by DW-MRI in the early stage.The infarct observed on horizontal MRI sections showed the characteristic "heart appearance" sign. For an early diagnosis of bilateral MMI, it is essential to bear in mind that characteristic findings may be obtained by diffusion-weighted MRI. PMID:21318946
Tokuoka, Kentaro; Yuasa, Naoki; Ishikawa, Tatsuya; Takahashi, Michiko; Mandokoro, Hiroyuki; Kitagawa, Yasuhisa; Takagi, Shigeharu
Optimal control of drug delivery to brain tumors for a PDE driven model using the Galerkin finite is used to examine the optimal drug delivery to brain tumors. The PDE driven mathematical model of the treatment, i.e., minimizing the tumor cell density and reducing the side effects of drugs. A distributed
Hanson, Floyd B.
Patterns of recovery from traumatic brain injury (TBI) vary greatly across individuals. Using archival data from the Traumatic Brain Injury Model Systems, recovery of memory following TBI as measured by scores on the Rey Auditory Verbal Learning Test (RAVLT) through 5 years postinjury was examined via mixed-effects modeling. Individual-level variables of age and posttraumatic amnesia duration were significant predictors of
Bong-Chul Chu; Scott Millis; Juan Carlos Arango-Lasprilla; Robin Hanks; Thomas Novack; Tessa Hart
A 52-year-old man presented with a history of sudden onset diplopia. On neurological examination, the only abnormality was a right-sided oculomotor (third nerve) palsy. A brain CT was performed and reported as showing no abnormality. He was discharged to be investigated as an outpatient. He presented 1 month later with a new expressive dysphasia and confusional state. MRI was performed which revealed multiple cerebral infarcts. He was discharged on secondary stroke prevention medication. Six months elapsed, before a transthoracic echocardiogram was performed. This showed a large left atrial myxoma. The patient underwent an emergency resection and made a good postoperative recovery. This case report showed the importance of considering a cardiogenic source of emboli in patients who present with cerebral infarcts. Performing echocardiography early will help to detect treatable conditions such as atrial myxoma, and prevent further complications. PMID:24285802
Kebede, Saba; Edmunds, Eiry; Raybould, Adrian
This paper presents the permeability analysis of neuroactive drugs and correlation with in vivo brain/plasma ratios in a dynamic microfluidic blood-brain barrier (BBB) model. Permeability of seven neuroactive drugs (Ethosuximide, Gabapentin, Sertraline, Sunitinib, Traxoprodil, Varenicline, PF-304014) and trans-endothelial electrical resistance (TEER) were quantified in both dynamic (microfluidic) and static (transwell) BBB models, either with brain endothelial cells (bEnd.3) in monoculture, or in co-culture with glial cells (C6). Dynamic cultures were exposed to 15 dyn/cm(2) shear stress to mimic the in vivo environment. Dynamic models resulted in significantly higher average TEER (respective 5.9-fold and 8.9-fold increase for co-culture and monoculture models) and lower drug permeabilities (average respective decrease of 0.050 and 0.052 log(cm/s) for co-culture and monoculture) than static models; and co-culture models demonstrated higher average TEER (respective 90 and 25% increase for static and dynamic models) and lower drug permeability (average respective decrease of 0.063 and 0.061 log(cm/s) for static and dynamic models) than monoculture models. Correlation of the resultant logP e values [ranging from -4.06 to -3.63 log(cm/s)] with in vivo brain/plasma ratios (ranging from 0.42 to 26.8) showed highly linear correlation (R (2) > 0.85) for all model conditions, indicating the feasibility of the dynamic microfluidic BBB model for prediction of BBB clearance of pharmaceuticals. PMID:25118670
Booth, R; Kim, H
We assess the challenges of studying action and language mechanisms in the brain, both singly and in relation to each other to provide a novel perspective on neuroinformatics, integrating the development of databases for encoding – separately or together – neurocomputational models and empirical data that serve systems and cognitive neuroscience. PMID:24234916
Bonaiuto, James J.; Bornkessel-Schlesewsky, Ina; Kemmerer, David; MacWhinney, Brian; Nielsen, Finn Årup; Oztop, Erhan
The paper provides an overview of neuroinformatics research at Yale University being performed as part of the national Human Brain Project. This research is exploring the integration of multidisciplinary sensory data, using the olfactory system as a model domain. The neuroinformatics activities fall into three main areas: 1) building databases and related tools that support experimental olfactory research at Yale
Perry L Miller; Prakash Nadkarni; Michael Singer; Luis Marenco; Michael Hines; Gordon Shepherd
Patients diagnosed with glioblastoma, the most aggressive form of brain cancer, routinely undergo MRI scanning prior to receiving treatment. Now, an international team of investigators has developed a mathematical modeling technique that can translate the data from pretreatment MRI scans into patient-specific rates of tumor growth and metastasis that may find use in tailoring therapy to meet the needs of each patient.
A mouse line has been developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor [Cell 98 (1999) 427]. These NR1 hypomorphic mice represent an experimental model of reduced NMDA receptor function that may be relevant to the pathophysiology of schizophrenia. To further characterize the neurobiological phenotype resulting from developmental NMDA receptor hypofunction, regional brain
Gary E Duncan; Seiya Miyamoto; Hongbin Gu; Jeffrey A Lieberman; Beverly H Koller; John N Snouwaert
Detection of dynamic brain networks modulated by acupuncture using a graph theory model Lijun Bai acupuncture manipulation have already demonstrated significant modulatory effects on wide limbic of acupuncture, however, knowledge on the organization of such large-scale cortical networks behind the active
Researchers have found that tumor stem cell lines derived directly from human glioblastoma brain tumors are a better model to study the biology and physiology of glioblastomas than are cancer cell lines that have been commonly used in cancer research laboratories.
Brains Rule! Neuroscience Expositions, funded through a National Institute on Drug Abuse Science Education Drug Abuse Partnership Award, has developed a successful model for informal neuroscience education. Each Exposition is a "reverse science fair" in which neuroscientists present short neuroscience teaching modules to students. This study…
Zardetto-Smith, Andrea M.; Mu, Keli; Carruth, Laura L.; Frantz, Kyle J.
CORTICAL SULCI MODEL AND MATCHING FROM 3D BRAIN MAGNETIC RESONANCE IMAGES S Langlois (1) , N maps based on the topography of sulci and gyri. Our work is based on this method and our objective sulci are also necessary relations for sulci identification. Data are issued from 3D MRI images (120x256
Correlations of cognitive functioning with brain activation during a sternberg item recognition paradigm (SIRP) were investigated in patients with schizophrenia and in healthy controls studied at 8 sites. To measure memory scanning times, 4 response time models were fit to SIRP data. The best fitting model assumed exhaustive serial memory scanning followed by self-terminating memory search and involved one intercept parameter to represent SIRP processes not contributing directly to memory scanning. Patients displayed significantly longer response times with increasing memory load and differed on the memory scanning, memory search, and intercept parameters of the best fitting probability model. Groups differed in the correlation between the memory scanning parameter and linear brain response to increasing memory load within left inferior and left middle frontal gyrus, bilateral caudate, and right precuneus. The pattern of findings in these regions indicated that high scanning capacity was associated with high neural capacity among healthy subjects but that scanning speed was uncoupled from brain response to increasing memory load among schizophrenia patients. Group differences in correlation of the best fitting model's scanning parameter with a quadratic trend in brain response to increasing memory load suggested inefficient or disordered patterns of neural inhibition among individuals with schizophrenia, especially in the left perirhinal and entorhinal cortices. The results show at both cognitive and neural levels that disordered memory scanning contributes to deficient SIRP performance among schizophrenia patients. PMID:19023127
Brown, Gregory G; McCarthy, Gregory; Bischoff-Grethe, Amanda; Ozyurt, Burak; Greve, Doug; Potkin, Steven G; Turner, Jessica A; Notestine, Randy; Calhoun, Vince D; Ford, Judy M; Mathalon, Daniel; Manoach, Dara S; Gadde, Syam; Glover, Gary H; Wible, Cynthia G; Belger, Aysenil; Gollub, Randy L; Lauriello, John; O'Leary, Daniel; Lim, Kelvin O
The mechanism of memory localization in extended domains is described in the framework of the parametric dissipative quantum model of brain. The size of the domains and the capability in memorizing depend on the number of links the system is able to establish with the external world.
The mechanism of memory localization in extended domains is described in the framework of the parametric dissipative quantum model of brain. The size of the domains and the capability in memorizing depend on the number of links the system is able to establish with the external world.
E. Alfinito; G. Vitiello
, mannitol administration, head elevation, and mild hyperventilation. The model is able to replicate observed-Kellie Doctrine which states that total intracranial volume ([brain volume] + [blood volume] + [cerebrospinal compartments include the arterial blood volume, capillary blood volume, venous blood volume, cerebrospinal
Joint T1 and Brain Fiber Log-Demons Registration Using Currents to Model Geometry Viviana Siless1Â´on, ConcepciÂ´on, Chile Abstract. We present an extension of the diffeomorphic Geometric Demons algorithm which the superiority of the Log-domain Geometric Demons over their purely iconic counterparts. Keywords: Registration
Paris-Sud XI, UniversitÃ© de
Quantification of brain structure is important for evaluating changes in brain size with growth and aging and for characterizing neurodegeneration disorders. Previous quantification efforts using ex vivo techniques suffered considerable error due to shrinkage of the cerebrum after extraction from the skull, deformation of slices during sectioning, and numerous other factors. In vivo imaging studies of brain anatomy avoid these problems and allow repetitive studies following progression of brain structure changes due to disease or natural processes. We have developed a methodology for obtaining triangular mesh models of the cortical surface from MRI brain datasets. The cortex is segmented from nonbrain tissue using a 2D region-growing technique combined with occasional manual edits. Once segmented, thresholding and image morphological operations (erosions and openings) are used to expose the regions between adjacent surfaces in deep cortical folds. A 2D region- following procedure is then used to find a set of contours outlining the cortical boundary on each slice. The contours on all slices are tiled together to form a closed triangular mesh model approximating the cortical surface. This model can be used for calculation of cortical surface area and volume, as well as other parameters of interest. Except for the initial segmentation of the cortex from the skull, the technique is automatic and requires only modest computation time on modern workstations. Though the use of image data avoids many of the pitfalls of ex vivo and sectioning techniques, our MRI-based technique is still vulnerable to errors that may impact the accuracy of estimated brain structure parameters. Potential inaccuracies include segmentation errors due to incorrect thresholding, missed deep sulcal surfaces, falsely segmented holes due to image noise and surface tiling artifacts. The focus of this paper is the characterization of these errors and how they affect measurements of cortical surface area and volume.
Klein, Gregory J.; Teng, Xia; Schoenemann, P. T.; Budinger, Thomas F.
Summary The presence of heterotopic brain tissue in the lung is a rare abnormality. The cases reported thus far are usually associated with neural tube defects (NTD). As there are no reports of experimental models of NTD that present this abnormality, the objective of the present study was to develop a surgical method of brain tissue heterotopia in the lung. We used 24 pregnant Swiss mice divided into two groups of 12 animals each, denoted 17GD and 18GD according to the gestational day (GD) when caesarean section was performed to collect the fetuses. Surgery was performed on the 15th GD, one fetus was removed by hysterectomy and its brain tissue was cut into small fragments and implanted in the lung of its litter mates. Thirty-four live fetuses were obtained from the 17GD group. Of these, eight (23.5%) were used as control (C), eight (23.5%) were sham operated (S) and 18 (52.9%) were used for pulmonary brain tissue implantation (PBI). Thirty live fetuses were obtained from the females of the 18GD group. Of these, eight (26.6%) were C, eight (26.6%) S and 14 (46.6%) were used for PBI. Histological examination of the fetal trunks showed implantation of GFAP-positive brain tissue in 85% of the fetuses of the 17GD group and in 100% of those of the 18GD group, with no significant difference between groups for any of the parameters analysed. The experimental model proved to be efficient and of relatively simple execution, showing complete integration of the brain tissue with pulmonary and pleural tissue and thus representing a model that will permit the study of different aspects of cell implantation and interaction. PMID:17877535
Quemelo, Paulo Roberto Veiga; Sbragia, Lourenço; Peres, Luiz Cesar
Central nervous system (CNS) infections in ruminant livestock, such as listeriosis, are of major concern for veterinary and public health. To date, no host-specific in vitro models for ruminant CNS infections are available. Here, we established and evaluated the suitability of organotypic brain-slices of ruminant origin as in vitro model to study mechanisms of Listeria monocytogenes CNS infection. Ruminants are frequently affected by fatal listeric rhombencephalitis that closely resembles the same condition occurring in humans. Better insight into host–pathogen interactions in ruminants is therefore of interest, not only from a veterinary but also from a public health perspective. Brains were obtained at the slaughterhouse, and hippocampal and cerebellar brain-slices were cultured up to 49 days. Viability as well as the composition of cell populations was assessed weekly. Viable neurons, astrocytes, microglia and oligodendrocytes were observed up to 49 days in vitro. Slice cultures were infected with L. monocytogenes, and infection kinetics were monitored. Infected brain cells were identified by double immunofluorescence, and results were compared to natural cases of listeric rhombencephalitis. Similar to the natural infection, infected brain-slices showed focal replication of L. monocytogenes and bacteria were predominantly observed in microglia, but also in astrocytes, and associated with axons. These results demonstrate that organotypic brain-slice cultures of bovine origin survive for extended periods and can be infected easily with L. monocytogenes. Therefore, they are a suitable model to study aspects of host–pathogen interaction in listeric encephalitis and potentially in other neuroinfectious diseases. PMID:22804762
Guldimann, Claudia; Lejeune, Beatrice; Hofer, Sandra; Leib, Stephen L; Frey, Joachim; Zurbriggen, Andreas; Seuberlich, Torsten; Oevermann, Anna
Complete heart block (CHB) developed in 10.3% of patients with acute myocardial infarction (MI). It was more frequent among patients with inferior myocardial infarction compared to anterior myocardial infarction, but the mortality was significantly high among patients with anterior MI who devel oped CHB.A new classification into primary (P) and secondary (S) CHB is suggested by the sequence of events.
M. C. Gupta; M. M. Singh; P. K. Wahal; M. P. Mehrotra; S. K. Gupta
The Brain's ability to integrate information from different modalities (multisensory integration) is fundamental for accurate sensory experience and efficient interaction with the environment: it enhances detection of external stimuli, disambiguates conflict situations, speeds up responsiveness, facilitates processes of memory retrieval and object recognition. Multisensory integration operates at several brain levels: in subcortical structures (especially the Superior Colliculus), in higher-level associative cortices (e.g., posterior parietal regions), and even in early cortical areas (such as primary cortices) traditionally considered to be purely unisensory. Because of complex non-linear mechanisms of brain integrative phenomena, a key tool for their understanding is represented by neurocomputational models. This review examines different modelling principles and architectures, distinguishing the models on the basis of their aims: (i) Bayesian models based on probabilities and realizing optimal estimator of external cues; (ii) biologically inspired models of multisensory integration in the Superior Colliculus and in the Cortex, both at level of single neuron and network of neurons, with emphasis on physiological mechanisms and architectural schemes; among the latter, some models exhibit synaptic plasticity and reproduce development of integrative capabilities via Hebbian-learning rules or self-organizing maps; (iii) models of semantic memory that implement object meaning as a fusion between sensory-motor features (embodied cognition). This overview paves the way to future challenges, such as reconciling neurophysiological and Bayesian models into a unifying theory, and stimulates upcoming research in both theoretical and applicative domains. PMID:25218929
Ursino, Mauro; Cuppini, Cristiano; Magosso, Elisa
The process of the sexual differentiation of the brain represents a valuable model system for the study of the chemical modification of the mammalian brain. Although there are numerous functional and structural sex differences in the adult brain, these are imposed on an essentially feminine or bipotential brain by testicular hormones during a critical phase of perinatal development in the rat. It is suggested that a relatively marked structural sex difference in the rat brain, the sexually dimorphic nucleus of the preoptic area (SDN-POA), is a morphological signature of the permanent or organizational action of estradiol derived from the aromatization of testicular testosterone. The SDN-POA of the male rat is severalfold larger in volume and is composed of more neurons than that of the female. The observation that the mitotic formation of the neurons of the SDN-POA is specifically prolonged has enabled us to identify the time course and pathway of neuronal migration into the nucleus. Study of the development of the SDN-POA suggests that estradiol in the male increases the number of neurons which survive a phase of neuronal death by exerting a neurite growth promoting action and/or a direct neuronotrophic action. Finally, although it is clear that gonadal hormones have dramatic permanent effects on the brain during perinatal development, even after puberty and in adulthood gonadal steroids can alter neuronal structure and, perhaps as a corollary to this, have permanent effects on reproductive function. Although the brain may be most sensitive to gonadal hormones or exogenous chemical factors during perinatal development, such as sensitivity does not appear limited to this period.
Premature babies are particularly vulnerable to brain injury. In this study we focus on cortical brain damage associated with long-term cognitive, behavioral, attentional or socialization deficits in children born preterm. Using a mouse model of preterm birth (PTB), we demonstrated that complement component C5a contributes to fetal cortical brain injury. Disruption of cortical dendritic and axonal cytoarchitecture was observed in PTB-mice. Fetuses deficient in C5aR (-/-) did not show cortical brain damage. Treatment with antibody anti-C5, that prevents generation of C5a, also prevented cortical fetal brain injury in PTB-mice. C5a also showed a detrimental effect on fetal cortical neuron development and survival in vitro. Increased glutamate release was observed in cortical neurons in culture exposed to C5a. Blockade of C5aR prevented glutamate increase and restored neurons dendritic and axonal growth and survival. Similarly, increased glutamate levels - measured by (1)HMRS - were observed in vivo in PTB-fetuses compared to age-matched controls. The blockade of glutamate receptors prevented C5a-induced abnormal growth and increased cell death in isolated fetal cortical neurons. Simvastatin and pravastatin prevented cortical fetal brain developmental and metabolic abnormalities -in vivo and in vitro. Neuroprotective effects of statins were mediated by Akt/PKB signaling pathways. This study shows that complement activation plays a crucial role in cortical fetal brain injury in PTL and suggests that complement inhibitors and statins might be good therapeutic options to improve neonatal outcomes in preterm birth. PMID:24184716
Pedroni, Silvia M A; Gonzalez, Juan M; Wade, Jean; Jansen, Maurits A; Serio, Andrea; Marshall, Ian; Lennen, Ross J; Girardi, Guillermina
Background Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the standard of acute stroke care. Its potential to increase the risk of secondary intracerebral hemorrhage, especially if administered late, has been ascribed to its proteolytic activity that has detrimental effects on blood–brain barrier (BBB) integrity after stroke. FTY720 has been shown to protect endothelial barriers in several disease models such as endotoxin-induced pulmonary edema and therefore is a promising candidate to counteract the deleterious effects of rt-PA. Besides that, every putative neuroprotectant that will be eventually forwarded into clinical trials should be tested in conjunction with rt-PA. Methods We subjected C57Bl/6 mice to 3 h filament-induced tMCAO and postoperatively randomized them into four groups (n?=?18/group) who received the following treatments directly prior to reperfusion: 1) vehicle-treatment, 2) FTY720 1 mg/kg i.p., 3) rt-PA 10 mg/kg i.v. or 4) FTY720 and rt-PA as a combination therapy. We measured functional neurological outcome, BBB disruption by quantification of EB extravasation and MMP-9 activity by gelatin zymography. Results We observed a noticeable increase in mortality in the rt-PA/FTY720 cotreatment group (61%) as compared to the vehicle (33%), the FTY720 (39%) and the rt-PA group (44%). Overall, functional neurological outcome did not differ significantly between groups and FTY720 had no effect on rt-PA- and stroke-induced BBB disruption and MMP-9 activation. Conclusions Our data show that FTY720 does not improve functional outcome and BBB integrity in large hemispheric infarctions, neither alone nor in conjunction with rt-PA. These findings stand in contrast to a recently published study that showed beneficial effects of FTY720 in combination with thrombolysis in a thrombotic model of MCAO leading to circumscript cortical infarctions. They might therefore represent a caveat that the coadministration of these two drugs might lead to excess mortality in the setting of a severe stroke. PMID:24499647
Acute organophosphate and carbamate pesticide poisonings result in adverse cardiac outcomes. The cardiac effects of chronic low-level pesticide exposure have not been studied. The authors analyzed self-reported lifetime use of pesticides reported at enrollment (1993–1997) and myocardial infarction mortality through 2006 and self-reported nonfatal myocardial infarction through 2003 among male pesticide applicators in the Agricultural Health Study. Using proportional hazard models, the authors estimated the association between lifetime use of 49 pesticides and fatal and nonfatal myocardial infarction. There were 476 deaths from myocardial infarction among 54,069 men enrolled in the study and 839 nonfatal myocardial infarctions among the 32,024 participants who completed the follow-up interview. Fatal and nonfatal myocardial infarctions were associated with commonly reported risk factors, including age and smoking. There was little evidence of an association between having used pesticides, individually or by class, and myocardial infarction mortality (e.g., insecticide hazard ratio (HR)?=?0.91, 95% confidence interval (CI): 0.67, 1.24; herbicide HR?=?0.74, 95% CI: 0.49, 1.10) or nonfatal myocardial infarction incidence (e.g., insecticide HR?=?0.85, 95% CI: 0.66, 1.09; herbicide HR?=?0.91, 95% CI: 0.61, 1.36). There was no evidence of a dose response with any pesticide measure. In a population with low risk for myocardial infarctio