bluuebunny/crossref_metadata_2025 huggingface dataset:
Analytical solutions for tsunami runup on a plane beach: single waves,N-waves and transient waves
Authors: MADSEN PER A. , SCHÄFFER HEMMING A.
Published: February 2010

In the literature it has so far been common practice to consider solitary waves andN-waves (composed of solitary waves) as the appropriate model of tsunamis approaching the shoreline. Unfortunately, this approach is based on a tie between the nonlinearity and the horizontal length scale (or duration) of the wave, which is not realistic for geophysical tsunamis. To resolve this problem, we first derive analytical solutions to the nonlinear shallow-water (NSW) equations for the runup/rundown of single waves, where the duration and the wave height can be specified separately. The formulation is then extended to cover leading depressionN-waves composed of a superposition of positive and negative single waves. As a result the temporal variations of the runup elevation, the associated velocity and breaking criteria are specified in terms of polylogarithmic functions. Finally, we consider incoming transient wavetrains generated by monopole and dipole disturbances in the deep ocean. The evolution of these wavetrains, while travelling a considerable distance over a constant depth, is influenced by weak dispersion and is governed by the linear Korteweg–De Vries (KdV) equation. This process is described by a convolution integral involving the Airy function. The runup on the plane sloping beach is then determined by another convolution integral involving the incoming time series at the foot of the slope. A good agreement with numerical model results is demonstrated.
Viscous stability properties of a Lamb–Oseen vortex in a stratified fluid
Authors: RIEDINGER XAVIER , LE DIZÈS STÉPHANE , MEUNIER PATRICE
Published: February 2010

In this work, we analyse the linear stability of a frozen Lamb–Oseen vortex in a fluid linearly stratified along the vortex axis. The temporal stability properties of three-dimensional normal modes are obtained under the Boussinesq approximation with a Chebychev collocation spectral code for large ranges of Froude numbers and Reynolds numbers (the Schmidt number being fixed to 700). A specific integration technique in the complex plane is used in order to apply the condition of radiation at infinity. For large Reynolds numbers and small Froude numbers, we show that the vortex is unstable with respect to all non-axisymmetrical waves. The most unstable mode is however always a helical radiative mode (m = 1) which resembles either a displacement mode or a ring mode. The displacement mode is found to be unstable for all Reynolds numbers and for moderate Froude numbers (F ~ 1). The radiative ring mode is by contrast unstable only for large Reynolds numbers above 104 and is the most unstable mode for large Froude numbers (F > 2). The destabilization of this mode for large Froude numbers is shown to be associated with a resonance mechanism which is analysed in detail. Analyses of the scaling and of the spatial structure of the different unstable modes are also provided.
Sharp-interface limit of the Cahn–Hilliard model for moving contact lines
Authors: YUE PENGTAO , ZHOU CHUNFENG , FENG JAMES J.
Published: February 2010

Diffuse-interface models may be used to compute moving contact lines because the Cahn–Hilliard diffusion regularizes the singularity at the contact line. This paper investigates the basic questions underlying this approach. Through scaling arguments and numerical computations, we demonstrate that the Cahn–Hilliard model approaches a sharp-interface limit when the interfacial thickness is reduced below a threshold while other parameters are fixed. In this limit, the contact line has a diffusion length that is related to the slip length in sharp-interface models. Based on the numerical results, we propose a criterion for attaining the sharp-interface limit in computing moving contact lines.
Quantitative measurement of the lifetime of localized turbulence in pipe flow
Authors: KUIK D. J. , POELMA C. , WESTERWEEL J.
Published: February 2010

Transition to turbulence in a pipe is characterized by the increase of the characteristic lifetimes of localized turbulent spots (‘puffs’) with increasing Reynolds number (Re). Previous experiments are based on visualization or indirect measurements of the lifetime probability. Here we report quantitative direct measurements of the lifetimes based on accurate pressure measurements combined with laser Doppler anemometry (LDA). The characteristic lifetime is determined directly from the lifetime probability. It is shown that the characteristic lifetime does not diverge at finite Re, and follows an exponential scaling for the observed range 1725 ≤ Re ≤ 1955. Over this small Re range the lifetime increases over four orders of magnitude. The results show that the puff velocity is not constant, and the rapid disintegration of puffs occurs within 20–70 pipe diameters.
Toward an interpretation of dynamic neural activity in terms of chaotic dynamical systems
Authors: Tsuda Ichiro
Published: February 2010

Using the concepts of chaotic dynamical systems, we present an interpretation of dynamic neural activity found in cortical and subcortical areas. The discovery of chaotic itinerancy in high-dimensional dynamical systems with and without a noise term has motivated a new interpretation of this dynamic neural activity, cast in terms of the high-dimensional transitory dynamics among “exotic” attractors. This interpretation is quite different from the conventional one, cast in terms of simple behavior on low-dimensional attractors. Skarda and Freeman (1987) presented evidence in support of the conclusion that animals cannot memorize odor without chaotic activity of neuron populations. Following their work, we study the role of chaotic dynamics in biological information processing, perception, and memory. We propose a new coding scheme of information in chaos-driven contracting systems we refer to as Cantor coding. Since these systems are found in the hippocampal formation and also in the olfactory system, the proposed coding scheme should be of biological significance. Based on these intensive studies, a hypothesis regarding the formation of episodic memory is given.
MAYA HETERARCHY AS INFERRED FROM CLASSIC-PERIOD PLAZA PLANS
Authors: Becker Marshall Joseph
Published: February 2010

Recognition of architectural patterning among groups of structures at lowland Maya sites dating from the Classic period provides insights into the ways that residences and ritual complexes were organized. Each structured group arrangement, or Plaza Plan (PP), reveals an architectural grammar that provides the database enabling us to predict urban as well as rural settlement patterns. Wide variations in sizes among examples of residential PPs suggests that heterarchy was an important aspect of Classic Maya society. Examination of PP2 at Tikal indicates that a heterarchic pattern of organization existed. Heterarchy may relate to the fragility of the structure of lowland Maya kingship, and this may explain the gradual demise of states during the Terminal Classic and Postclassic periods and their replacement by re-emergent Maya chiefdoms.
Franco and Hitler: The Myth of Hendaye 1940
Authors: Preston Paul
Published: February 2010

The Hitler/Franco encounter at Hendaye in October 1940 was a central myth of Francoist propaganda. Allegedly, faced with threats and blandishments to force Spain into war on the Axis side, Franco coolly stood his ground and thereby secured Spanish neutrality. However, there is little evidence that Hitler did threaten Franco. His purpose in travelling to Hendaye, and to Montoire where he met Laval and Pétain, was to compare the relative cost of closer relationships with Spain and Vichy France. Far from cleverly holding off Hitler, Franco was disappointed that the meeting foundered. Germany's need to maintain good relations with Vichy ensured that Hitler could not meet Franco's price for belligerence, the dismemberment of the French North African empire.
War and Social History: Britain and the Home Front during the Second World War
Authors: Harris Jose
Published: February 2010

This article reviews interpretations of the history of British society during the Second World War. Traditionally the Second World War has been viewed as a period of outstanding national unity and social solidarity, and the social arrangements of wartime have been seen as a unique catalyst of administrative ‘collectivism’ and the growth of the ‘welfare state’. More recent historiography has presented a more diffuse picture, emphasising the elements of continuing diversity and conflict in British society during the war period, and the importance of more long-term social trends that were shared by all western European countries.
Witness Seminar on the Origins and Early Development of the Eurobond Market
Authors: Burk Kathleen
Published: February 2010

This is the transcript of an oral history seminar in which those involved in the early years of the market during the late 1960s described and analysed their experiences. The session began with a short historical overview.
Italian Journals: A User's Guide
Authors: Morris Jonathan
Published: February 2010

A review of Italian journals dealing with contemporary European history suggests that there have been notable improvements in the standards of Italian historiography in the last decade. This reflects the continued success of Quaderni Storici, the challenge of new periodicals established since the late 1970s, and the response of more established journals to the changed nature of the Italian political contest.
Matrix Metalloproteinase-9 Mediates Hypoxia-Induced Vascular Leakage in the Brain via Tight Junction Rearrangement
Authors: Bauer Alexander T , Bürgers Heinrich F , Rabie Tamer , Marti Hugo H
Published: February 2010

Blood–brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48 h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.
Overexpression of Heat Shock Protein 27 Reduces Cortical Damage after Cerebral Ischemia
Authors: van der Weerd Louise , Tariq Akbar Mohammed , Aron Badin Romina , Valentim Lauren M , Thomas David L , Wells Dominic J , Latchman David S , Gadian David G , Lythgoe Mark F , de Belleroche Jackie S
Published: February 2010

Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of central nervous system insults, functioning as a protein chaperone, an antioxidant, and through inhibition of cell death pathways. We have used transgenic mice overexpressing HSP27 (HSP27tg) to examine the role of HSP27 in cerebral ischemia, using model of permanent middle cerebral artery occlusion (MCAO). Infarct size was evaluated using multislice T2-weighted anatomical magnetic resonance imaging (MRI) after 24 h. A significant reduction of 30% in infarct size was detected in HSP27tg animals compared with wild-type (WT) littermates. To gain some insight into the mechanisms contributing to cell death and its attenuation by HSP27, we monitored the effect of induction of c-jun and ATF3 on tissue survival in MCAO and their effects on the expression of endogenous mouse HSP25 and HSP70. It is important that, the c-jun induction seen at 4 h tended to be localized to regions that were salvageable in HSP27tg mice but became infarcted in WT animals. Our results provide support for the powerful neuroprotective effects of HSP27 in cerebral ischemia.
Ischemic Preconditioning Regulates Expression of microRNAs and a Predicted Target, MeCP2, in Mouse Cortex
Authors: Lusardi Theresa A , Farr Carol D , Faulkner Craig L , Pignataro Giuseppe , Yang Tao , Lan Jingquan , Simon Roger P , Saugstad Julie A
Published: February 2010

Preconditioning describes the ischemic stimulus that triggers an endogenous, neuroprotective response that protects the brain during a subsequent severe ischemic injury, a phenomenon known as ‘tolerance’. Ischemic tolerance requires new protein synthesis, leads to genomic reprogramming of the brain's response to subsequent ischemia, and is transient. MicroRNAs (miRNAs) regulate posttranscriptional gene expression by exerting direct effects on messenger RNA (mRNA) translation. We examined miRNA expression in mouse cortex in response to preconditioning, ischemic injury, and tolerance. The results of our microarray analysis revealed that miRNA expression is consistently altered within each group, but that preconditioning was the foremost regulator of miRNAs. Our bioinformatic analysis results predicted that preconditioning-regulated miRNAs most prominently target mRNAs that encode transcriptional regulators; methyl-CpG binding protein 2 (MeCP2) was the most prominent target. No studies have linked MeCP2 to preconditioning or tolerance, yet miR-132, which regulates MeCP2 expression, is decreased in preconditioned cortex. Downregulation of miR-132 is consistent with our finding that preconditioning ischemia induces a rapid increase in MeCP2 protein, but not mRNA, in mouse cortex. These studies reveal that ischemic preconditioning regulates expression of miRNAs and their predicted targets in mouse brain cortex, and further suggest that miRNAs and MeCP2 could serve as effectors of ischemic preconditioning-induced tolerance.
Functional Brain Abnormalities Localized in 55 Chronic Tinnitus Patients: Fusion of SPECT Coincidence Imaging and MRI
Authors: Farhadi Mohammad , Mahmoudian Saeid , Saddadi Fariba , Karimian Ali Reza , Mirzaee Mohammad , Ahmadizadeh Majid , Ghasemikian Khosro , Gholami Saeid , Ghoreyshi Esmaeel , Beyty Saeid , Shamshiri Ahmadreza , Madani Sedighe , Bakaev Valery , Moradkhani Seddighe , Raeisali Gholamreza
Published: February 2010

Tinnitus is often defined as the perception of sounds or noise in the absence of any external auditory stimuli. The pathophysiology of subjective idiopathic tinnitus remains unclear. The aim of this study was to investigate the functional brain activities and possible involved cerebral areas in subjective idiopathic tinnitus patients by means of single photon emission computerized tomography (SPECT) coincidence imaging, which was fused with magnetic resonance imaging (MRI). In this cross-sectional study, 56 patients (1 subject excluded) with subjective tinnitus and 8 healthy controls were enrolled. After intravenous injection of 5 mCi F18-FDG (fluorodeoxyglucose), all subjects underwent a brain SPECT coincidence scan, which was then superimposed on their MRIs. In the eight regions of interest (middle temporal, inferotemporal, medial temporal, lateral temporal, temporoparietal, frontal, frontoparietal, and parietal areas), the more pronounced values were represented in medial temporal, inferotemporal, and temporoparietal areas, which showed more important proportion of associative auditory cortices in functional attributions of tinnitus than primary auditory cortex. Brain coincidence SPECT scan, when fused on MRI is a valuable technique in the assessment of patients with tinnitus and could show the significant role of different regions of central nervous system in functional attributions of tinnitus.
Neurovascular Coupling in Rat Brain Operates Independent of Hemoglobin Deoxygenation
Authors: Lindauer Ute , Leithner Christoph , Kaasch Heike , Rohrer Benjamin , Foddis Marco , Füchtemeier Martina , Offenhauser Nikolas , Steinbrink Jens , Royl Georg , Kohl-Bareis Matthias , Dirnagl Ulrich
Published: February 2010

Recently, a universal, simple, and fail-safe mechanism has been proposed by which cerebral blood flow (CBF) might be coupled to oxygen metabolism during neuronal activation without the need for any tissue-based mechanism. According to this concept, vasodilation occurs by local erythrocytic release of nitric oxide or ATP wherever and whenever hemoglobin is deoxygenated, directly matching oxygen demand and supply in every tissue. For neurovascular coupling in the brain, we present experimental evidence challenging this view by applying an experimental regime operating without deoxy-hemoglobin. Hyperbaric hyperoxygenation (HBO) allowed us to prevent hemoglobin deoxygenation, as the oxygen that was physically dissolved in the tissue was sufficient to support oxidative metabolism. Regional CBF and regional cerebral blood oxygenation were measured using a cranial window preparation in anesthetized rats. Hemodynamic and neuronal responses to electrical forepaw stimulation or cortical spreading depression (CSD) were analyzed under normobaric normoxia and during HBO up to 4 ATA (standard atmospheres absolute). Inconsistent with the proposed mechanism, during HBO, CBF responses to functional activation or CSD were unchanged. Our results show that activation-induced CBF regulation in the brain does not operate through the release of vasoactive mediators on hemoglobin deoxygenation or through a tissue-based oxygen-sensing mechanism.
Agmatine Attenuates Brain Edema through Reducing the Expression of Aquaporin-1 after Cerebral Ischemia
Authors: Kim Jae Hwan , Lee Yong Woo , Park Kyung Ah , Lee Won Taek , Lee Jong Eun
Published: February 2010

Brain edema is frequently shown after cerebral ischemia. It is an expansion of brain volume because of increasing water content in brain. It causes to increase mortality after stroke. Agmatine, formed by the decarboxylation of L-arginine by arginine decarboxylase, has been shown to be neuroprotective in trauma and ischemia models. The purpose of this study was to investigate the effect of agmatine for brain edema in ischemic brain damage and to evaluate the expression of aquaporins (AQPs). Results showed that agmatine significantly reduced brain swelling volume 22 h after 2 h middle cerebral artery occlusion in mice. Water content in brain tissue was clearly decreased 24 h after ischemic injury by agmatine treatment. Blood–brain barrier (BBB) disruption was diminished with agmatine than without. The expressions of AQPs-1 and -9 were well correlated with brain edema as water channels, were significantly decreased by agmatine treatment. It can thus be suggested that agmatine could attenuate brain edema by limitting BBB disruption and blocking the accumulation of brain water content through lessening the expression of AQP-1 after cerebral ischemia.
Glial Dysfunction in Abstinent Methamphetamine Abusers
Authors: Sailasuta Napapon , Abulseoud Osama , Harris Kent C , Ross Brian D
Published: February 2010

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized 13C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects ( P>0.1). However, glial 13C-bicarbonate production rate from [1-13C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamine-addicted women (methamphetamine 0.04 μmol/g per min ( N=5) versus controls 0.11 μmol/g per min ( N=5), P=0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous 13C MRS methods may determine ‘cause and effect’ between glial failure and neuronal injury.
Early Nonischemic Oxidative Metabolic Dysfunction Leads to Chronic Brain Atrophy in Traumatic Brain Injury
Authors: Xu Yueqiao , McArthur David L , Alger Jeffry R , Etchepare Maria , Hovda David A , Glenn Thomas C , Huang Sungcheng , Dinov Ivo , Vespa Paul M
Published: February 2010

Chronic brain atrophy after traumatic brain injury (TBI) is a well-known phenomenon, the causes of which are unknown. Early nonischemic reduction in oxidative metabolism is regionally associated with chronic brain atrophy after TBI. A total of 32 patients with moderate-to-severe TBI prospectively underwent positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) within the first week and at 6 months after injury. Regional lobar assessments comprised oxidative metabolism and glucose metabolism. Acute MRI showed a preponderance of hemorrhagic lesions with few irreversible ischemic lesions. Global and regional chronic brain atrophy occurred in all patients by 6 months, with the temporal and frontal lobes exhibiting the most atrophy compared with the occipital lobe. Global and regional reduction in cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose were observed. The extent of metabolic dysfunction was correlated with the total hemorrhage burden on initial MRI ( r=0.62, P=0.01). The extent of regional brain atrophy correlated best with CMRO2 and CBF. Lobar values of OEF were not in the ischemic range and did not correlate with chronic brain atrophy. Chronic brain atrophy is regionally specific and associated with regional reductions in oxidative brain metabolism in the absence of irreversible ischemia.
A Systematic Review and Meta-Analysis of Erythropoietin in Experimental Stroke
Authors: Jerndal Mikael , Forsberg Kalle , Sena Emily S , Macleod Malcolm R , O'Collins Victoria E , Linden Thomas , Nilsson Michael , Howells David W
Published: February 2010

Erythropoietin (EPO) has shown promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also to promote regeneration after stroke. Here, we report a systematic review and meta-analysis of the efficacy of EPO in animal models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral outcome. Nineteen studies involving 346 animals for infarct size and 425 animals for neurobehavioral outcome met our inclusion criteria. Erythropoietin improved infarct size by 30.0% (95% CI: 21.3 to 38.8) and neurobehavioral outcome by 39.8% (33.7 to 45.9). Studies that randomized to treatment group or that blinded assessment of outcome showed lower efficacy. Erythropoietin was tested in animals with hypertension in no studies reporting infarct size and in 7.5% of the animals reporting neurobehavioral outcome. These findings show efficacy for EPO in experimental stroke, but when the impact of common sources of bias are considered, this efficacy falls, suggesting we may be overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works best would be beneficial.
High-Affinity Dopamine D2/D3 PET Radioligands 18F-Fallypride and 11C-FLB457: A Comparison of Kinetics in Extrastriatal Regions Using a Multiple-Injection Protocol
Authors: Vandehey Nicholas T , Moirano Jeffrey M , Converse Alexander K , Holden James E , Mukherjee Jogesh , Murali Dhanabalan , Nickles R Jerry , Davidson Richard J , Schneider Mary L , Christian Bradley T
Published: February 2010

18F-Fallypride and 11C-FLB457 are commonly used PET radioligands for imaging extrastriatal dopamine D2/D3 receptors, but differences in their in vivo kinetics may affect the sensitivity for measuring subtle changes in receptor binding. Focusing on regions of low binding, a direct comparison of the kinetics of 18F-fallypride and 11C-FLB457 was made using a MI protocol. Injection protocols were designed to estimate K1, k2, fND kon, Bmax, and koff in the midbrain and cortical regions of the rhesus monkey. 11C-FLB457 cleared from the arterial plasma faster and yielded a ND space distribution volume ( K1/ k2) that is three times higher than 18F-fallypride, primarily due to a slower k2 (FAL:FLB; k2=0.54 min−1:0.18 min−1). The dissociation rate constant, koff, was slower for 11C-FLB457, resulting in a lower KDapp than 18F-fallypride (FAL:FLB; 0.39 nM:0.13 nM). Specific D2/D3 binding could be detected in the cerebellum for 11C-FLB457 but not 18F-fallypride. Both radioligands can be used to image extrastriatal D2/D3 receptors, with 11C-FLB457 providing greater sensitivity to subtle changes in low-receptor-density cortical regions and 18F-fallypride being more sensitive to endogenous dopamine displacement in medium-to-high-receptor-density regions. In the presence of specific D2/D3 binding in the cerebellum, reference region analysis methods will give a greater bias in BPND with 11C-FLB457 than with 18F-fallypride.
Vascular Endothelial Growth Factor Increases Neurogenesis after Traumatic Brain Injury
Authors: Thau-Zuchman Orli , Shohami Esther , Alexandrovich Alexander G , Leker Ronen R
Published: February 2010

Activation of endogenous stem cells has been proposed as a novel form of therapy in a variety of neurologic disorders including traumatic brain injury (TBI). Vascular endothelial growth factor (VEGF) is expressed in the brain after TBI and serves as a potent activator of angiogenesis and neurogenesis. In this study, we infused exogenous VEGF into the lateral ventricles of mice for 7 days after TBI using mini-osmotic pumps to evaluate the effects on recovery and functional outcome. The results of our study show that VEGF significantly increases the number of proliferating cells in the subventricular zone and in the perilesion cortex. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia and only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF compared with vehicle-treated animals after TBI. Injury size was significantly smaller at 90 days after TBI in VEGF-treated animals, suggesting additional neuroprotective effects of VEGF. In conclusion, VEGF significantly augments neurogenesis and angiogenesis and reduces lesion volumes after TBI. These changes are associated with significant improvement in recovery rates and functional outcome.
Inducing Stroke in Aged, Hypertensive, Diabetic Rats
Authors: Rewell Sarah SJ , Fernandez John A , Cox Susan F , Spratt Neil J , Hogan Lisa , Aleksoska Elena , van Raay Leena , Liberatore Gabriel T , Batchelor Peter E , Howells David W
Published: February 2010

Animal models of ischemic stroke often neglect comorbidities common in patients. This study shows the feasibility of inducing stroke by 2 h of thread occlusion of the middle cerebral artery in aged (56 week old) spontaneously hypertensive rats (SHRs) with both acute (2 weeks) and chronic (36 weeks) diabetes. After modifying the streptozotocin dosing regimen to ensure that old SHRs survived the induction of diabetes, few died after induction of stroke. Induction of stroke is feasible in rats with multiple comorbidities. Inclusion of such comorbid animals may improve translation from the research laboratory to the clinic.
Isoflurane Anesthesia Induced Persistent, Progressive Memory Impairment, Caused a Loss of Neural Stem Cells, and Reduced Neurogenesis in Young, but Not Adult, Rodents
Authors: Zhu Changlian , Gao Jianfeng , Karlsson Niklas , Li Qian , Zhang Yu , Huang Zhiheng , Li Hongfu , Kuhn H Georg , Blomgren Klas
Published: February 2010

Isoflurane and related anesthetics are widely used to anesthetize children, ranging from premature babies to adolescents. Concerns have been raised about the safety of these anesthetics in pediatric patients, particularly regarding possible negative effects on cognition. The purpose of this study was to investigate the effects of repeated isoflurane exposure of juvenile and mature animals on cognition and neurogenesis. Postnatal day 14 (P14) rats and mice, as well as adult (P60) rats, were anesthetized with isoflurane for 35 mins daily for four successive days. Object recognition, place learning and reversal learning as well as cell death and cytogenesis were evaluated. Object recognition and reversal learning were significantly impaired in isoflurane-treated young rats and mice, whereas adult animals were unaffected, and these deficits became more pronounced as the animals grew older. The memory deficit was paralleled by a decrease in the hippocampal stem cell pool and persistently reduced neurogenesis, subsequently causing a reduction in the number of dentate gyrus granule cell neurons in isoflurane-treated rats. There were no signs of increased cell death of progenitors or neurons in the hippocampus. These findings show a previously unknown mechanism of neurotoxicity, causing cognitive deficits in a clearly age-dependent manner.
Annexin A2 Combined with Low-Dose tPA Improves Thrombolytic Therapy in a Rat Model of Focal Embolic Stroke
Authors: Zhu Haihao , Fan Xiang , Yu Zhanyang , Liu Jianxiang , Murata Yoshihiro , Lu Jie , Zhao Song , Hajjar Katherine A , Lo Eng H , Wang Xiaoying
Published: February 2010

Recent studies showed that soluble annexin A2 dramatically increases tissue plasminogen activator (tPA)-mediated plasmin generation in vitro, and reduces thrombus formation in vivo. Here, we hypothesize that combining annexin A2 with tPA can significantly enhance thrombolysis efficacy, so that lower doses of tPA can be applied in ischemic stroke to avoid neurotoxic and hemorrhagic complications. In vitro activity assays confirmed tPA-specific amplification of plasmin generation by recombinant annexin A2. In a rat focal embolic stroke model, combination therapy with tPA and recombinant annexin A2 protein at 2 h post-ischemia decreased the effective dose required for tPA by four-fold and reduced brain infarction. Combining annexin A2 with tPA also lengthened the time window for thrombolysis. Compared with tPA (10 mg/kg) alone, the combination of annexin A2 (5 mg/kg) plus low-dose tPA (2.5 mg/kg) significantly enhanced fibrinolysis, attenuated mortality, brain infarction, and hemorrhagic transformation, even when administered at 4 h post-ischemia. Combination with recombinant annexin A2, the effective thrombolytic dose of tPA can be decreased. As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy.
Mast Cells as Early Responders in the Regulation of Acute Blood–Brain Barrier Changes after Cerebral Ischemia and Hemorrhage
Authors: Lindsberg Perttu Johannes , Strbian Daniel , Karjalainen-Lindsberg Marja-Liisa
Published: February 2010

The inflammatory response triggered by stroke has been viewed as harmful, focusing on the influx and migration of blood-borne leukocytes, neutrophils, and macrophages. This review hypothesizes that the brain and meninges have their own resident cells that are capable of fast host response, which are well known to mediate immediate reactions such as anaphylaxis, known as mast cells (MCs). We discuss novel research suggesting that by acting rapidly on the cerebral vessels, this cell type has a potentially deleterious role in the very early phase of acute cerebral ischemia and hemorrhage. Mast cells should be recognized as a potent inflammatory cell that, already at the outset of ischemia, is resident within the cerebral microvasculature. By releasing their cytoplasmic granules, which contain a host of vasoactive mediators such as tumor necrosis factor-α, histamine, heparin, and proteases, MCs act on the basal membrane, thus promoting blood–brain barrier (BBB) damage, brain edema, prolonged extravasation, and hemorrhage. This makes them a candidate for a new pharmacological target in attempts to even out the inflammatory responses of the neurovascular unit, and to stabilize the BBB after acute stroke.
Perfusion Pressure-Dependent Recovery of Cortical Spreading Depression is Independent of Tissue Oxygenation over a Wide Physiologic Range
Authors: Sukhotinsky Inna , Yaseen Mohammad A , Sakadžić Sava , Ruvinskaya Svetlana , Sims John R , Boas David A , Moskowitz Michael A , Ayata Cenk
Published: February 2010

Spreading depression (SD) is a slowly propagating wave of transient neuronal and glial depolarization that develops after stroke, trauma and subarachnoid hemorrhage. In compromised tissue, repetitive SD-like injury depolarizations reduce tissue viability by worsening the mismatch between blood flow and metabolism. Although the mechanism remains unknown, SDs show delayed electrophysiological recovery within the ischemic penumbra. Here, we tested the hypothesis that the recovery rate of SD can be varied by modulating tissue perfusion pressure and oxygenation. Systemic blood pressure and arterial pO2 were simultaneously manipulated in anesthetized rats under full physiologic monitoring. We found that arterial hypotension doubled the SD duration, whereas hypertension reduced it by a third compared with normoxic normotensive rats. Hyperoxia failed to shorten the prolonged SD durations in hypotensive rats, despite restoring tissue pO2. Indeed, varying arterial pO2 (40 to 400 mm Hg) alone did not significantly influence SD duration, whereas blood pressure (40 to 160 mm Hg) was inversely related to SD duration in compromised tissue. These data suggest that cerebral perfusion pressure is a critical determinant of SD duration independent of tissue oxygenation over a wide range of arterial pO2 levels, and that hypotension may be detrimental in stroke and subarachnoid hemorrhage, where SD-like injury depolarizations have been observed.
Wide Genetic Variation in the Native Pial Collateral Circulation is a Major Determinant of Variation in Severity of Stroke
Authors: Zhang Hua , Prabhakar Pranay , Sealock Robert , Faber James E
Published: February 2010

Severity of stroke varies widely among individuals. Whether differences in the extent of the native (preexisting) pial collateral circulation exist and contribute to this variability is unknown. We addressed these questions and probed for potential genetic contributions using morphometric analysis of the collateral circulation in 15 inbred mouse strains recently shown to exhibit wide differences in infarct volume. Morphometrics were determined in the unligated left hemisphere (for native collaterals) and ligated right hemisphere (for remodeled collaterals) 6 days after permanent middle cerebral artery (MCA) occlusion. Variation among strains in native collateral number, diameter, MCA, anterior cerebral artery (ACA), and posterior cerebral artery (PCA) tree territories were, respectively: 56-fold, 3-fold, 42%, 56%, and 61%. Collateral length ( P<0.001) and the number of penetrating arterioles branching from them also varied ( P<0.05). Infarct volume correlated inversely with collateral number ( P<0.0001), diameter ( P<0.0001), and penetrating arteriole number ( P<0.05) and directly with MCA territory ( P<0.05). Relative collateral conductance and MCA territory, when factored together, strongly predicted infarct volume ( P<0.0001). Outward remodeling of collaterals in the ligated hemisphere varied ∼3-fold. These data show that the extent of the native pial collateral circulation and collateral remodeling after obstruction vary widely with genetic background, and suggest that this variability, due to natural polymorphisms, is a major contributor to variability in infarct volume.
Dihydropyridine-Insensitive Calcium Currents Contribute to Function of Small Cerebral Arteries
Authors: Kuo Ivana Y , Ellis Anthie , Seymour Victoria AL , Sandow Shaun L , Hill Caryl E
Published: February 2010

Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (CaV1.2) and T-type (CaV3.1 and CaV3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L- and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised ∼20% of current in SMCs of the main arteries and ∼45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.
Cerebral Blood Volume Alterations in the Perilesional Areas in the Rat Brain after Traumatic Brain Injury—Comparison with Behavioral Outcome
Authors: Immonen Riikka , Heikkinen Taneli , Tähtivaara Leena , Nurmi Antti , Stenius Taina-Kaisa , Puoliväli Jukka , Tuinstra Tinka , Phinney Amie L , Van Vliet Bernard , Yrjänheikki Juha , Gröhn Olli
Published: February 2010

In the traumatic brain injury (TBI) the initial impact causes both primary injury, and launches secondary injury cascades. One consequence, and a factor that may contribute to these secondary changes and functional outcome, is altered hemodynamics. The relative cerebral blood volume (CBV) changes in rat brain after severe controlled cortical impact injury were characterized to assess their interrelations with motor function impairment. Magnetic resonance imaging (MRI) was performed 1, 2, 4 h, and 1, 2, 3, 4, 7, and 14 days after TBI to quantify CBV and water diffusion. Neuroscore test was conducted before, and 2, 7, and 14 days after the TBI. We found distinct temporal profile of CBV in the perilesional area, hippocampus, and in the primary lesion. In all regions, the first response was drop of CBV. Perifocal CBV was reduced for over 4 days thereafter gradually recovering. After the initial drop, the hippocampal CBV was increased for 2 weeks. Neuroscore demonstrated severely impaired motor functions 2 days after injury (33% decrease), which then slowly recovered in 2 weeks. This recovery parallelled the recovery of perifocal CBV. CBV MRI can detect cerebrovascular pathophysiology after TBI in the vulnerable perilesional area, which seems to potentially associate with time course of sensory-motor deficit.
Absolute Arterial Cerebral Blood Volume Quantification Using Inflow Vascular-Space-Occupancy with Dynamic Subtraction Magnetic Resonance Imaging
Authors: Donahue Manus J , Sideso Ediri , MacIntosh Bradley J , Kennedy James , Handa Ashok , Jezzard Peter
Published: February 2010

In patients with steno-occlusive disease of the internal carotid artery (ICA), cerebral blood flow may be maintained by autoregulatory increases in arterial cerebral blood volume (aCBV). Therefore, characterizing aCBV may be useful for understanding hemodynamic compensation strategies. A new ‘inflow vascular-space-occupancy with dynamic subtraction (iVASO-DS)’ MRI approach is presented where aCBV (mL blood/100 mL parenchyma) is quantified without contrast agents using the difference between images with and without inflowing blood water signal. The iVASO-DS contrast mechanism is investigated (3.0 T, spatial resolution=2.4 × 2.4 × 5 mm3) in healthy volunteers ( n=8; age=29±5 years), and patients with mild ( n=7; age=72±8 years) and severe ( n=10; age=73±8 years) ICA stenoses. aCBV was quantified in right and left hemispheres in controls, and, alongside industry standard dynamic susceptibility contrast (DSC), contralateral (cont), and ipsilateral (ips) to maximum stenosis in patients. iVASO contrast significantly correlated ( R=0.67, P<0.01) with DSC-CBV after accounting for transit time discrepancies. Gray matter aCBV (mL/100 mL) was 1.60±0.10 (right) versus 1.61±0.20 (left) in controls, 1.59±0.38 (cont) and 1.65±0.37 (ips) in mild stenosis patients, and 1.72±0.18 (cont) and 1.58±0.20 (ips) in severe stenosis patients. aCBV was asymmetric ( P<0.01) in 41% of patients whereas no asymmetry was found in any control. The potential of iVASO-DS for autoregulation studies is discussed in the context of existing hemodynamic literature.
Activation of NR2A Receptors Induces Ischemic Tolerance through CREB Signaling
Authors: Terasaki Yasukazu , Sasaki Tsutomu , Yagita Yoshiki , Okazaki Shuhei , Sugiyama Yukio , Oyama Naoki , Omura-Matsuoka Emi , Sakoda Saburo , Kitagawa Kazuo
Published: February 2010

Previous exposure to a nonlethal ischemic insult protects the brain against subsequent harmful ischemia. N-methyl-D-aspartate (NMDA) receptors are a highly studied target of neuroprotection after ischemia. Recently, NMDA receptor subtypes were implicated in neuronal survival and death. We focused on the contribution of NR2A and cyclic-AMP response element (CRE)-binding protein (CREB) signaling to ischemic tolerance using primary cortical neurons. Ischemia in vitro was modeled by oxygen–glucose deprivation (OGD). Ischemic tolerance was induced by applying 45-mins OGD 24 h before 180-mins OGD. Sublethal OGD also induced cross-tolerance against lethal glutamate and hydrogen peroxide. After sublethal OGD, expression of phosphorylated CREB and CRE transcriptional activity were significantly increased. When CRE activity was inhibited by CREB-S133A, a mutant CREB, ischemic tolerance was abolished. Inhibiting NR2A using NVP-AAM077 attenuated preconditioning-induced neuroprotection and correlated with decreased CRE activity levels. Activating NR2A using bicuculline and 4-aminopiridine induced resistance to lethal ischemia accompanied by elevated CRE activity levels, and this effect was abolished by NVP-AAM077. Elevated brain-derived neurotrophic factor (BDNF) transcriptional activities were observed after sublethal OGD and administration of bicuculline and 4-aminopiridine. NR2A-containing NMDA receptors and CREB signaling have important functions in the induction of ischemic tolerance. This may provide potential novel therapeutic strategies to treat ischemic stroke.
Pretreatment Diffusion- and Perfusion-MR Lesion Volumes Have a Crucial Influence on Clinical Response to Stroke Thrombolysis
Authors: Parsons Mark W , Christensen Soren , McElduff Patrick , Levi Christopher R , Butcher Ken S , De Silva Deidre A , Ebinger Martin , Barber P Alan , Bladin Christopher , Donnan Geoffrey A , Davis Stephen M ,   For the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) Investigators
Published: February 2010

We hypothesized that pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes may have influenced clinical response to thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). In 98 patients randomized to intravenous (IV) tissue plasminogen activator (tPA) or placebo 3 to 6 h after stroke onset, we examined increasing acute DWI and PWI lesion volumes (Tmax—with 2-sec delay increments), and increasing PWI/DWI mismatch ratios, on the odds of both excellent (modified Rankin Scale (mRS): 0 to 1) and poor (mRS: 5 to 6) clinical outcome. Patients with very large PWI lesions (most had internal carotid artery occlusion) had increased odds ratio (OR) of poor outcome with IV-tPA (58% versus 25% placebo; OR=4.13, P=0.032 for Tmax +2-sec volume >190 mL). Excellent outcome from tPA treatment was substantially increased in patients with DWI lesions <18 mL (77% versus 18% placebo, OR=15.0, P<0.001). Benefit from tPA was also seen with DWI lesions up to 25 mL (69% versus 29% placebo, OR=5.5, P=0.03), but not for DWI lesions >25 mL. In contrast, increasing mismatch ratios did not influence the odds of excellent outcome with tPA. Clinical responsiveness to IV-tPA, and stroke outcome, depends more on baseline DWI and PWI lesion volumes than the extent of perfusion–diffusion mismatch.
A Fully Automated Method for Quantitative Cerebral Hemodynamic Analysis Using DSC–MRI
Authors: Bjørnerud Atle , Emblem Kyrre E
Published: February 2010

Dynamic susceptibility contrast (DSC)-based perfusion analysis from MR images has become an established method for analysis of cerebral blood volume (CBV) in glioma patients. To date, little emphasis has, however, been placed on quantitative perfusion analysis of these patients, mainly due to the associated increased technical complexity and lack of sufficient stability in a clinical setting. The aim of our study was to develop a fully automated analysis framework for quantitative DSC-based perfusion analysis. The method presented here generates quantitative hemodynamic maps without user interaction, combined with automatic segmentation of normal-appearing cerebral tissue. Validation of 101 patients with confirmed glioma after surgery gave mean values for CBF, CBV, and MTT, extracted automatically from normal-appearing whole-brain white and gray matter, in good agreement with literature values. The measured age- and gender-related variations in the same parameters were also in agreement with those in the literature. Several established analysis methods were compared and the resulting perfusion metrics depended significantly on method and parameter choice. In conclusion, we present an accurate, fast, and automatic quantitative perfusion analysis method where all analysis steps are based on raw DSC data only.