bluuebunny/crossref_metadata_2025 huggingface dataset:
Austrians versus Market Socialists
Authors: Huerta de Soto Jesús
Published: December 2015

In this chapter, the position of market socialists is critically analyzed from the Austrian point of view. First, the definition of socialism is introduced, based on the concept of institutional coercion acting on Kirznerian entrepreneurship. Second is a review of the different aspects of the theorem of the impossibility of socialism, as it was originally developed by Mises and Hayek. Then market socialism is defined and studied, along with the main contributions of its sponsors. A special analytical treatment is provided on the classical model of market socialism from Oskar Lange and its main perpetuators during the twentieth century. Finally, the chapter analyzes the implicit contradiction of market socialism which also affects its most modern varieties and authors. The conclusion is that the position of market socialists is naive and paradoxical.
The Capital-Using Economy
Authors: Lewin Peter , Baetjer Howard
Published: December 2015

Capital theory is fundamental to everything else in Austrian economics. It lies at its core, implicit in discussions of monetary policy, the business cycle, the entrepreneur, and the subjectivity of value and expectations. Prior to the Keynesian revolution, it was capital theory for which the Austrian school was most known among mainstream economists. With the advent of Keynesian macroeconomics, interest in capital theory all but disappeared. But it has recently been the subject of increasing attention. After a brief overview of the main ideas in Austrian capital theory (ACT) from its origins and extensions through the middle of the last century, this chapter notes this rekindled interest and surveys recent applications, including its connection to complexity studies, management studies, entrepreneurship, and macroeconomic policy.
Capital-Based Macroeconomics
Authors: Cochran John P.
Published: December 2015

The recent revival of boom-bust business cycles and the worldwide slow recovery from 2009–2012 has renewed interest in the analysis of a money-production economy developed by Keynes and capital-structure-based Austrian macroeconomics developed by Hayek, Mises, Rothbard, and, most recently, Garrison. Both approaches identify time, money, banking, financial markets, interest, and investment as the major sources of coordination failure leading to recession or depression. When compared with single-aggregate modern macroeconomic models, both Keynes’s and the Austrians’ models, with their lower level of aggregation, provide a better understanding of how an economy goes wrong, However, the chapter argues that Keynes’s model is flawed because it lacks a capital-structure foundation. Keynesian macroeconomic policy is generally unnecessary and, if applied consistently, destabilizes the economy. Austrian economics and its capital-based macroeconomics provide better guidance on cause, recovery, and, more important, prevention.
Models of Decision Making under Risk and Uncertainty
Authors: Pleskac Timothy J. , Diederich Adele , Wallsten Thomas S.
Published: December 2015

Formal models have a long and important history in the study of human decision-making. They have served as normative standards against which to compare real choices, as well as precise descriptions of actual choice behavior. This chapter begins with an overview of the historical development of decision theory and rational choice theory and then reviews how models have been used in their normative and descriptive capacities. Models covered include prospect theory, rank- and sign-dependent utility theories and their descendants, as well as cognitive models of human decision-making like Decision Field Theory and the Leaky Competing Accumulator Model, which are based on basic psychological principles rather than assumptions of rationality.
Quantum Models of Cognition and Decision
Authors: Busemeyer Jerome R. , Wang Zheng , Pothos Emmanuel
Published: December 2015

Quantum probability theory provides a new formalism for constructing probabilistic and dynamic systems of cognition and decision. The purpose of this chapter is to introduce psychologists to this fascinating theory. This chapter is organized into six sections. First, some of the basic psychological principles supporting a quantum approach to cognition and decision are summarized; second, some notations and definitions needed to understand quantum probability theory are presented; third, a comparison of quantum and classical probability theories is presented; fourth, quantum probability theory is used to account for some paradoxical findings in the field of human probability judgments; fifth, a comparison of quantum and Markov dynamic theories is presented; and finally, a quantum dynamic model is used to account for some puzzling findings of decision-making research. The chapter concludes with a summary of advantages and disadvantages of a quantum probability theoretical framework for modeling cognition and decision.
Pea seed-borne mosaic virus: Stability and Wind-Mediated Contact Transmission in Field Pea
Authors: Congdon B. S. , Coutts B. A. , Renton M. , Jones R. A. C.
Published: December 2015

Pea seed-borne mosaic virus (PSbMV) stability in sap and its contact transmission between field pea plants were investigated in glasshouse experiments. When infective leaf sap was kept at room temperature and inoculated to plants in the absence of abrasive, it was still highly infective after 6 h and low levels of infectivity remained after 30 h. PSbMV was transmitted from infected to healthy plants by direct contact when leaves were rubbed against each other. It was also transmitted when intertwining healthy and PSbMV-infected plants were blown by a fan to simulate wind. When air was blown on plants kept at 14 to 20°C, contact transmission of PSbMV occurred consistently and the extent of transmission was enhanced when plants were dusted with diatomaceous earth prior to blowing. In contrast, when plants were kept at 20 to 30°C, blowing rarely resulted in transmission. No passive contact transmission occurred when healthy and infected plants were allowed to intertwine together. This study demonstrates that PSbMV has the potential to be transmitted by contact when wind-mediated wounding occurs in the field. This may play an important role in the epidemiology of the virus in field pea crops, especially in situations where contact transmission expands initial crop infection foci before aphid arrival.
Brain Incorporation of [11C]Arachidonic Acid in Young Healthy Humans Measured with Positron Emission Tomography
Authors: Giovacchini Giampiero , Chang Michael C. J. , Channing Michael A. , Toczek Maria , Mason Alicja , Bokde Arun L. W. , Connolly Catherine , Vuong Bik-Kee , Ma Ying , Der Margaret G. , Doudet Doris J. , Herscovitch Peter , Eckelman William C. , Rapoport Stanley I. , Carson Richard E.
Published: December 2015

Arachidonic acid (AA) is an important second messenger involved in signal transduction mediated by phospholipase A2. The goal of this study was to establish an in vivo quantitative method to examine the role of AA in this signaling process in the human brain. A simple irreversible uptake model was derived from rat studies and modified for positron emission tomography (PET) to quantify the incorporation rate K*of [11C]AA into brain. Dynamic 60-minute three-dimensional scans and arterial input functions were acquired in 8 young healthy adults studied at rest. Brain radioactivity was corrected for uptake of the metabolite [11C]CO2. K* and cerebral blood volume ( Vb) were estimated pixel-by-pixel and were calculated in regions of interest. K* equaled 5.6 ± 1.2 and 2.6 ± 0.5 μL · min−1 · mL−1 in gray and white matter, respectively. K* and Vb values were found to be unchanged with data analysis periods from 20 to 60 minutes. Thus, PET can be used to obtain quantitative images of the incorporation rate K* of [11C]AA in the human brain. As brain incorporation of labeled AA has been shown in awake rats to be increased by pharmacological activation associated with phospholipase A2-signaling, PET and [11C]AA may be useful to measure signal transduction in the human brain.
STAT1 is Activated in Neurons after Ischemia and Contributes to Ischemic Brain Injury
Authors: Takagi Yasushi , Harada Jun , Chiarugi Alberto , Moskowitz Michael A.
Published: December 2015

Signal transducers and activators of transcription (STAT) proteins are a family of transcription factors that play a crucial role in growth and differentiation in a variety of cell types. Among them, STAT1, which is expressed in the brain and directly activated by reactive oxygen species, participates in the regulation of cytokine-signaling and cellular responses, particularly to interferon-γ. Very little, however, is known about the importance of STAT1 during brain injury. The authors found that STAT1 was phosphorylated at tyrosine701 and serine727 and translocated into neuronal nuclei within hours after middle cerebral artery occlusion. At later time points, STAT1 immunoreactivity colocalized with TUNEL-positive neurons, thereby suggesting a role in cell death. In mice genetically deficient in STAT1 expression, the volume of ischemic brain injury was reduced, neurologic deficits were less severe, and TUNEL-positive neurons were also less numerous compared with wild-type mice. STAT1-knockout mice showed increased phosphorylated Akt and decreased pro-***caspase-3 cleavage. Major strain differences in phosphorylated STAT3 or cyclooxygenase-2 protein expression were not found after ischemia. These results indicate that STAT1 is activated and translocated within ischemic neurons and may contribute to brain injury by regulating transcription and phosphorylation of proteins related to apoptosis and cell death.
Mouse Hippocampal Organotypic Tissue Cultures Exposed to In Vitro “Ischemia” Show Selective and Delayed CA1 Damage that is Aggravated by Glucose
Authors: Rytter Anna , Cronberg Tobias , Asztély Fredrik , Nemali Sailasree , Wieloch Tadeusz
Published: December 2015

Oxygen and glucose deprivation (OGD) in cell cultures is generally studied in a medium, such as artificial cerebrospinal fluid (CSF), with an ion composition similar to that of the extracellular fluid of the normal brain (2 to 4 mmol/L K+, 2 to 3 mmol/L Ca2+; pH 7.4). Because the distribution of ions across cell membranes dramatically shifts during ischemia, the authors exposed mouse organotypic hippocampal tissue cultures to OGD in a medium, an ischemic cerebrospinal fluid, with an ion composition similar to the extracellular fluid of the brain during ischemia in vivo (70 mmol/L K+, 0.3 mmol/L Ca2+; pH 6.8). In ischemic CSF, OGD induced a selective and delayed cell death in the CA1 region, as assessed by propidium iodide uptake. Cell death was glutamate receptor dependent since blockade of the N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors mitigated cell damage. Hyperglycemia aggravates ischemic brain damage in vivo, whereas in vitro glucose in artificial CSF prevents oxygen deprivation-induced damage. The authors demonstrate that glucose in ischemic CSF significantly exacerbates cell damage after oxygen deprivation. This new model of in vitro “ischemia” can be useful in future studies of the mechanisms and treatment of ischemic cell death, including studies using genetically modified mice.
High Glycogen Levels in Brains of Rats with Minimal Environmental Stimuli: Implications for Metabolic Contributions of Working Astrocytes
Authors: Cruz Nancy F. , Dienel Gerald A.
Published: December 2015

The concentration of glycogen, the major brain energy reserve localized mainly in astrocytes, is generally reported as about 2 or 3 μmol/g, but sometimes as high as 3.9 to 8 μmol/g, in normal rat brain. The authors found high but very different glycogen levels in two recent studies in which glycogen was determined by the routine amyloglucosidase procedure in 0.03N HCl digests either of frozen powders (4.8 to 6 μmol/g) or of ethanol-insoluble fractions (8 to 12 μmol/g). To evaluate the basis for these discrepant results, glycogen was assayed in parallel extracts of the same samples. Glycogen levels in ethanol extracts were twice those in 0.03N HCl digests, suggesting incomplete enzyme inactivation even with very careful thawing. The very high glycogen levels were biologically active and responsive to physiologic and pharmacological challenge. Glycogen levels fell after brief sensory stimulation, and metabolic labeling indicated its turnover under resting conditions. About 95% of the glycogen was degraded under in vitro ischemic conditions, and its “carbon equivalents” recovered mainly as glc, glc-P, and lactate. Resting glycogen stores were reduced by about 50% by chronic inhibition of nitric oxide synthase. Because neurotransmitters are known to stimulate glycogenolysis, stress or sensory activation due to animal handling and tissue-sampling procedures may stimulate glycogenolysis during an experiment, and glycogen lability during tissue sampling and extraction can further reduce glycogen levels. The very high glycogen levels in normal rat brain suggest an unrecognized role for astrocytic energy metabolism during brain activation.
Generalized Sensory Stimulation of Conscious Rats Increases Labeling of Oxidative Pathways of Glucose Metabolism When the Brain Glucose–Oxygen Uptake Ratio Rises
Authors: Dienel Gerald A. , Wang Robert Y. , Cruz Nancy F.
Published: December 2015

Interpretation of functional metabolic brain images requires understanding of metabolic shifts in working brain. Because the disproportionately higher uptake of glucose compared with oxygen (“aerobic glycolysis”) during sensory stimulation is not fully explained by changes in levels of lactate or glycogen, metabolic labeling by [6-14C]glucose was used to evaluate utilization of glucose during brief brain activation. Increased labeling of tricarboxylic acid cycle–derived amino acids, mainly glutamate but also γ-aminobutyric acid, reflects a rise in oxidative metabolism during aerobic glycolysis. The size of the glutamate, lactate, alanine, and aspartate pools changed during stimulation. Brain lactate was derived from blood-borne glucose and its specific activity was twice that of alanine, revealing pyruvate compartmentation. Glycogen labeling doubled during recovery compared with rest and activation; only 4% to 8% of the total 14C was recovered in lactate plus glycogen. Restoration of glycogen levels was slow, and diversion of glucose from oxidative pathways to restore its level could cause a prolonged reduction of the global O2/glucose uptake ratio. The rise in the brain glucose–oxygen uptake ratio during activation does not simply reflect an upward shift of glycolysis under aerobic conditions; instead, it involves altered fluxes into various (oxidative and biosynthetic) pathways with different time courses.
Glutathione Peroxidase-1 Contributes to the Neuroprotection Seen in the Superoxide Dismutase-1 Transgenic Mouse in Response to Ischemia/Reperfusion Injury
Authors: Crack Peter J. , Taylor Juliet M. , de Haan Judy B. , Kola Ismail , Hertzog Paul , Iannello Rocco C.
Published: December 2015

The authors hypothesized that glutathione peroxidase-1 (Gpx-1) contributes to the neuroprotection seen in the superoxide dismutase-1 transgenic (Sod-1 tg) mouse. To investigate this hypothesis, they crossed the Gpx-1 -/- mouse with the Sod-1 tg and subjected the cross to a mouse model of ischemia/reperfusion. Two hours of focal cerebral ischemia followed by 24 hours of reperfusion was induced via intraluminal suture. The Sod-1 tg/Gpx-1 -/- cross exhibited no neuroprotection when infarct volume was measured; indeed, infarct volume increased in the Sod-1 tg/Gpx-1 -/- cross compared with the wild-type mouse. Our results suggest that Gpx-1 plays an important regulatory role in the protection of neural cells in response to ischemia/reperfusion injury.
Estimation of Cerebral Perfusion Reserve by Blood Oxygenation Level—Dependent Imaging: Comparison with Single-Photon Emission Computed Tomography
Authors: Shiino Akihiko , Morita Yasuo , Tsuji Atsushi , Maeda Kengo , Ito Ryuta , Furukawa Akira , Matsuda Masayuki , Inubushi Toshiro
Published: December 2015

Measurement of cerebrovascular reserve capacity predicts the risk of ischemic insult in patients with major vessel occlusion. Blood oxygenation level-dependent (BOLD) imaging has the potential to estimate reserve capacity of the cerebral circulation noninvasively based on changes in the signal that reflect differences in the magnetic susceptibility of intravascular oxyhemoglobin and deoxyhemoglobin. The authors examined the feasibility of using the BOLD technique to assess cerebrovascular reserve capacity in patients with cerebrovascular occlusive disease by comparing results with an established method of measuring CBF. Ten patients with severe or complete occlusion of the internal carotid artery were compared with 17 healthy subjects to evaluate regional differences and identify variables that indicate a change in the BOLD signal. Dilation of cerebral vessels was induced by breath holding, and the R2* change was examined with gradient-echo, echo-planar imaging. Before measuring the regional change in the BOLD signal, actual timing of “activated” and “rest” periods was corrected by shifting the phase of a sine-wave template to obtain the largest correlation coefficient. Percent signal change was calculated on a pixel-by-pixel basis and was compared with CBF measured by single-photon emission computed tomography (SPECT) before and after acetazolamide challenge. The degree of impairment and the distribution of impaired areas detected by the BOLD study correlated with the results of SPECT. Overall sensitivity and specificity of the BOLD technique by visual inspection were 100% and 98.4%, respectively. A negative response (decreased CBF) frequently was observed in areas of exhausted reserve capacity, suggesting that a “steal” phenomenon exists. The percent change and the ΔCBF were well correlated ( P < 0.01). The mean percent change in most areas of impaired reserve capacity was more than 2 SD below the mean values in healthy subjects. The present method of semiquantitative BOLD analysis can be used to create a map of the cerebral hemodynamic state. Furthermore, the development of reliable, generally accessible techniques for evaluating cerebral hemodynamics opens the door for clinical studies to monitor and treat patients with compromised reserve. This study is an attempt to develop such analysis.
Matching Gene Expression with Hypometabolism after Cerebral Ischemia in the Nonhuman Primate
Authors: Chuquet Julien , Benchenane Karim , Liot Géraldine , Fernández-Monreal Mónica , Toutain Jérôme , Blanchet Sophie , Eveno Eric , Auffray Charles , Piétu Geneviève , Buisson Alain , Touzani Omar , MacKenzie Eric T. , Vivien Denis
Published: December 2015

To correlate brain metabolic status with the molecular events during cerebral ischemia, a cDNA array was performed after positron emission tomography scanning in a model of focal cerebral ischemia in baboons. Cluster analysis for the expression of 74 genes allowed the identification of 4 groups of genes. In each of the distinct groups, the authors observed a marked inflection in the pattern of gene expression when the CMRo2 was reduced by 48% to 66%. These patterns of coordinated modifications in gene expression could define molecular checkpoints for the development of an ischemic infarct and a molecular definition of the penumbra.
Upregulation of Haptoglobin in Reactive Astrocytes after Transient Forebrain Ischemia in Rats
Authors: Lee Mun-Yong , Kim Seong Yun , Choi Jeong-Sun , Lee Il-Ha , Choi Yun-Sik , Jin Jong Youl , Park Seon-Joo , Sung Ki-Wug , Chun Myung-Hoon , Kim In-Sook
Published: December 2015

Immunohistochemistry for haptoglobin (Hp) in the postischemic hippocampus demonstrated an immunoreactivity visible one day after reperfusion and continuing to increase until 14 days after ischemia. The immunoreactivity was most prominent in CA1 and the dentate hilar region, especially in cells with astroglial morphology. Double immunofluorescence histochemistry confirmed colocalization of the Hp and glial fibrillary acidic protein. Furthermore, a reverse transcription-polymerase chain reaction study confirmed an elevated Hp mRNA level in the postischemic hippocampus. The Hp gene expression was also upregulated in C6 and A-172 glioblastoma cell lines after H2O2 treatment. These findings suggest that Hp is synthesized in reactive astrocytes in response to ischemia-reperfusion injury.
Differences in the Extent of Primary Ischemic Damage between Middle Cerebral Artery Coagulation and Intraluminal Occlusion Models
Authors: Kanemitsu Hideaki , Nakagomi Tadayoshi , Tamura Akira , Tsuchiya Teruaki , Kono Go , Sano Keiji
Published: December 2015

The authors studied the differences between heat-shock/stress protein 70 (hsp70) gene expression and protein synthesis in the unilateral middle cerebral artery (MCA) microsurgical direct occlusion (Tamura's) model and the unilateral intraluminal occlusion model. In Tamura's model, expression of hsp70 mRNA and HSP70 protein and decreased protein synthesis were detected in the ischemic areas, including the ipsilateral cortex and caudate. These phenomena, however, were not observed in the areas outside the MCA territory, including the ipsilateral thalamus, hippocampus, and substantia nigra. These results were consistent among the experimental rats. In the intraluminal occlusion model, however, induction of both hsp70 mRNA and HSP70 protein and impairment of protein synthesis were noted in the areas outside the MCA territory, including the ipsilateral thalamus, hypothalamus, hippocampus, and substantia nigra, as well as in the MCA territory, including the ipsilateral cortex and caudate. These results were not consistent among the experimental rats. These different results might be due to widespread damage resulting from internal carotid artery (ICA) occlusion in the intraluminal occlusion model. Accordingly, the authors suggest that this model be called an ICA occlusion model, rather than a pure MCA occlusion model.
Direct Visualization of Trapped Erythrocytes in Rat Brain after Focal Ischemia and Reperfusion
Authors: Liu Shimin , Connor John , Peterson Steven , Shuttleworth C. William , Liu Ke Jian
Published: December 2015

Partial microcirculatory stasis after cerebral ischemia and reperfusion is a potential factor in delayed cell death. Sometimes described as the “no-reflow” phenomenon, limitations in current detection techniques have left the extent and spatial distribution of the phenomenon undetermined, which has led to some doubt as to its actual existence. The authors describe a new method, based on erythrocyte autofluorescence, that allows the erythrocytes trapped in the microvasculature, and thus blocking recirculation, to be directly visualized. Using this method, the authors have examined the spatial and temporal characteristics of this phenomenon in the rat intraluminal model of cerebral ischemia and reperfusion. Up to 15% of the capillaries in the ischemic penumbra remained occluded at least 2 hours after reperfusion. The amount of capillary bed showing trapped erythrocytes was more severe in the ischemic penumbra region than in the ischemic core. These results indicate that the no-reflow phenomenon may contribute to the developing damage in ischemic penumbra region, leading to additional injury after reperfusion.
Upregulation of Mitochondrial Base-Excision Repair Capability within Rat Brain after Brief Ischemia
Authors: Chen Dexi , Minami Manabu , Henshall David C. , Meller Robert , Kisby Glen , Simon Roger P.
Published: December 2015

The mechanism by which brief episodes of cerebral ischemia confer protection (tolerance) against subsequent prolonged ischemic challenges remains unclear, but may involve upregulation of cell injury repair capability. The mitochondrion is a key site for the regulation of cell death pathways, and damage to mitochondrial genes has been linked to a number of neurologic diseases and aging. Therefore, the authors examined the response of the DNA base excision repair (BER) pathway in rat brain mitochondria after either brief (tolerance-inducing) or prolonged (injury-producing) focal cerebral ischemia. Brief (30-minute) middle cerebral artery occlusion (MCAO) induced mild oxidative mitochondrial DNA damage and initiated a prolonged (up to 72-hour) activation above control levels of the principal enzymes of the mitochondrial BER pathway, including uracil DNA glycosylase, apurinic/apyrimidinic (AP) endonuclease, DNA polymerase-γ, and DNA ligase. In contrast, prolonged (100-minute MCAO) ischemia induced more substantial mitochondrial oxidative DNA damage whereas elevation of BER activity was transient (∼1 hour), declining to less than control levels over the course of 4 to 72 hours. These data reveal the differences in BER capacity after brief or prolonged ischemia, which may contribute to the neuron's ability to resist subsequent ischemic insults.
In Vivo Excitotoxicity Induced by Ouabain, a Na+/K+-ATPase Inhibitor
Authors: Veldhuis Wouter B. , van der Stelt Mario , Delmas Florence , Gillet Brigitte , Veldink Gerrit A. , Vliegenthart Johannes F. G. , Nicolay Klaas , Bär Peter R.
Published: December 2015

The susceptibility of immature rat brain to neurotoxicity of N-methyl-D-aspartate (NMDA) has provided a widely used in vivo paradigm to study excitotoxicity relevant to acute neurodegenerative diseases such as cerebral ischemia. In this study, in vivo excitotoxicity was induced via injection of ouabain (1 mM/0.5 μL), a Na+/K+-ATPase-inhibitor, into neonatal rat brain and compared with NMDA injection. The aim of the study was to induce excitotoxicity secondary to cellular membrane depolarization, thereby more closely mimicking the pathophysiologic processes of ischemia-induced brain injury where NMDA-receptor overstimulation by glutamate follows, not precedes, membrane depolarization. Na+/K+-ATPase-inhibition caused an acute, 40% ± 8% decrease of the apparent diffusion coefficient (ADC) of water, as measured using diffusion-weighted magnetic resonance imaging (MRI), and resulted in infarctlike lesions as measured using T2-weighted MRI and histology up to 2 weeks later. Localized one- and two-dimensional 1H-magnetic resonance spectroscopy (MRS) demonstrated that the early excitotoxic diffusion changes were not accompanied by an overall metabolic disturbance. Furthermore, 31P-MRS demonstrated that energy depletion is not a prerequisite for ADC decrease or excitotoxic cell death. Treatment with the NMDA-antagonist MK-80 (1 mg/kg) attenuated the volume of tissue exhibiting a decreased ADC ( P < 0.005), demonstrating that the ouabain-induced injury is indeed excitotoxic in nature. The authors argue that, compared with NMDA-injection, ouabain-induced excitotoxicity elicits more appropriate glutamate-receptor overstimulation and is better suited to detect relevant neuroprotection in that it is more sensitive to attenuation of synaptic glutamate levels.
Increased S-Nitrosothiols and S-Nitrosoalbumin in Cerebrospinal Fluid after Severe Traumatic Brain Injury in Infants and Children: Indirect Association with Intracranial Pressure
Authors: Bayir Hülya , Kochanek Patrick M. , Liu Shang-Xi , Arroyo Antonio , Osipov Anatoly , Jiang Jianfei , Wisniewski Stephan , Adelson P. David , Graham Steven H. , Kagan Valerian E.
Published: December 2015

Nitric oxide (NO) is implicated in both secondary damage and recovery after traumatic brain injury (TBI). Transfer of NO groups to cysteine sulfhydryls on proteins produces S-nitrosothiols (RSNO). S-nitrosothiols may be neuroprotective after TBI by nitrosylation of N-methyl-D-aspartate receptor and caspases. S-nitrosothiols release NO on decomposition for which endogenous reductants (i.e., ascorbate) are essential, and ascorbate is depleted in cerebrospinal fluid (CSF) after pediatric TBI. This study examined the presence and decomposition of RSNO in CSF and the association between CSF RSNO level and physiologic parameters after severe TBI. Cerebrospinal fluid samples (n = 72) were obtained from 18 infants and children on days 1 to 3 after severe TBI (Glasgow Coma Scale score < 8) and 18 controls. Cerebrospinal fluid RSNO levels assessed by fluorometric assay peaked on day 3 versus control (1.42 ± 0.11 μmol/L vs. 0.86 ± 0.04, P < 0.05). S-nitrosoalbumin levels were also higher after TBI (n = 8, 0.99 ± 0.09 μmol/L on day 3 vs. n = 6, 0.42 ± 0.02 in controls, P < 0.05). S-nitrosoalbumin decomposition was decreased after TBI. Multivariate analysis showed an inverse relation between CSF RSNO and intracranial pressure and a direct relation with barbiturate treatment. Using a novel assay, the presence of RSNO and S-nitrosoalbumin in human CSF, an ∼1.7-fold increase after TBI, and an association with low intracranial pressure are reported, supporting a possible neuroprotective role for RSNO. The increase in RSNO may result from increased NO production and/or decreased RSNO decomposition.
Anti—Nogo-A Antibody Infusion 24 Hours after Experimental Stroke Improved Behavioral Outcome and Corticospinal Plasticity in Normotensive and Spontaneously Hypertensive Rats
Authors: Wiessner Christoph , Bareyre Florence M. , Allegrini Peter R. , Mir Anis K. , Frentzel Stefan , Zurini Mauro , Schnell Lisa , Oertle Thomas , Schwab Martin E.
Published: December 2015

Nogo-A is a myelin-associated neurite outgrowth inhibitory protein limiting recovery and plasticity after central nervous system injury. In this study, a purified monoclonal anti—Nogo-A antibody (7B12) was evaluated in two rat stroke models with a time-to-treatment of 24 hours after injury. After photothrombotic cortical injury (PCI) and intraventricular infusion of a control mouse immunoglobulin G for 2 weeks, long-term contralateral forepaw function was reduced to about 55% of prelesion performance until the latest time point investigated (9 weeks). Forepaw function was significantly better in the 7B12-treated group 6 to 9 weeks after PCI, and reached about 70% of prelesion levels. Cortical infarcts were also produced in spontaneously hypertensive rats (SHR) by permanent middle cerebral artery occlusion (MCAO). In the control group, forepaw function remained between 40% and 50% of prelesion levels 4 to 12 weeks after MCAO. In contrast, 7B12-treated groups showed significant improvement between 4 and 7 weeks after MCAO from around 40% of prelesion levels at week 4 to about 60% to 70% at 7 to 12 weeks after MCAO. Treatment in both models was efficacious without influencing infarct volume or brain atrophy. Neuroanatomically in the spinal cord, a significant increase of midline crossing corticospinal fibers originating in the unlesioned sensorimotor cortex was found in 7B12-treated groups, reaching 2.3 ± 1.5% after PCI (control group: 1.1 ± 0.5%) and 4.5 ± 2.2% after MCAO in SHR rats (control group: 1.8 ± 0.8%). Behavioral outcome and the presence of midline crossing fibers in the cervical spinal cord correlated significantly, suggesting a possible contribution of the crossing fibers for forepaw function after PCI and MCAO. The results suggest that specific anti—Nogo-A antibodies bear potential as a new rehabilitative treatment approach for ischemic stroke with a prolonged time-to-treatment window.
Ischemic Tolerance
Authors: Kirino Takaaki
Published: December 2015

A brief period of cerebral ischemia confers transient tolerance to a subsequent ischemic challenge in the brain. This phenomenon of ischemic tolerance has been confirmed in various animal models of forebrain ischemia and focal cerebral ischemia. Since the ischemic tolerance afforded by preceding ischemia can bring about robust protection of the brain, the mechanism of tolerance induction has been extensively studied. It has been elucidated that ischemic tolerance protects neurons, and at the same time, it preserves brain function. Further experiments have shown that metabolic and physical stresses can also induce cross-tolerance to cerebral ischemia, but the protection by cross-tolerance is relatively modest. The underlying mechanism of ischemic tolerance still is not fully understood. Potential mechanisms may be divided into two categories: (1) A cellular defense function against ischemia may be enhanced by the mechanisms inherent to neurons. They may arise by posttranslational modification of proteins or by expression of new proteins via a signal transduction system to the nucleus. These cascades of events may strengthen the influence of survival factors or may inhibit apoptosis. (2) A cellular stress response and synthesis of stress proteins may lead to an increased capacity for health maintenance inside the cell. These proteins work as cellular “chaperones” by unfolding misfolded cellular proteins and helping the cell to dispose of unneeded denatured proteins. Recent experimental data have demonstrated the importance of the processing of unfolded proteins for cell survival and cell death. The brain may be protected from ischemia by using multiple mechanisms that are available for cellular survival. If tolerance induction can be manipulated and accelerated by a drug treatment that is safe and effective enough, it could greatly improve the treatment of stroke.
Tissue Inhibitor of Metalloproteinase-3 is Associated with Neuronal Death in Reperfusion Injury
Authors: Wallace James A. , Alexander Susan , Estrada Eduardo Y. , Hines Curt , Cunningham Lee Anna , Rosenberg Gary A.
Published: December 2015

Programmed cell death occurs in ischemia when cell surface death receptors (DRs) are stimulated by death-inducing ligands (DILs). Matrix metalloproteinases are extracellular matrix-degrading enzymes involved in the shedding of DRs and DILs from the cell surface. Tissue inhibitor of metalloproteinase-3 (TIMP-3), which is bound to the extracellular matrix, has been shown to promote apoptosis in cancer cell lines by inhibiting cell surface sheddases. Since apoptosis is an important mechanism of cell death in ischemia, the authors hypothesized that TIMP-3 would be expressed in ischemic neurons that are undergoing programmed cell death. Spontaneously hypertensive rats had a 90-minute middle cerebral artery occlusion with reperfusion. Transcription of TIMP-3 mRNA was measured by quantitative reverse transcription–polymerase chain reaction at 2, 6, 24 and 48 hours after reperfusion. Western blots were used to measure TIMP-3 protein expression. Spatial distribution and production of TIMP-3 was studied by immunohistochemistry at 3, 24, and 48 hours, 5 days, and 3 weeks. DNA fragmentation in cells dying by necrosis and apoptosis was identified with terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling (TUNEL). After 2 hours of reperfusion, TIMP-3 mRNA increased significantly in both ischemic and nonischemic hemispheres. Western blot analysis confirmed the identity of the TIMP-3, which appeared to be increased on the ischemic side. After 3 hours of reperfusion, TIMP-3 immunostaining was increased in neurons on the ischemic side, and by 24 hours the majority of the ischemic neurons were TIMP-3–positive. Dual-fluorescence staining for TUNEL and TIMP-3 showed that they were coexpressed in many neurons. The results suggest that ischemic neurons express TIMP-3, which may be inhibiting sheddases. The authors propose that TIMP-3 facilitates cell death in ischemic neurons. Further studies are needed to identify the sheddases inhibited by the TIMP-3, and on the effect of inhibition of matrix metalloproteinases on cell death mechanisms.
Rat Blood–Brain Barrier Genomics. II
Authors: Li Jian Yi , Boado Ruben J. , Pardridge William M.
Published: December 2015

The tissue-specific gene expression at the brain microvasculature, which forms the blood–brain barrier (BBB) in vivo, can be elucidated with a brain vascular genomics program, which starts with the isolation of gene products derived from purified brain microvessels. Genes commonly expressed in peripheral organs are subtracted with the suppression subtractive hybridization method using driver cDNA produced from a pool of rat liver/kidney–derived poly A+RNA. From a screen of 480 clones in the subtracted tester cDNA library, 156 clones were sequenced. The clones fell into 3 groups: known genes (51%), rat expressed sequence tags (31%), and novel rat genes not found in databases (18%). The known genes could be categorized into families of common function including vascular remodeling, signal transduction, transcription factors, biologic transport, vascular amyloid, hemostasis, myelin, lipids, secretion, cytoskeleton, and junctional complexes. Brain vascular genomics, or BBB genomics, allows for an accelerated discovery of the gene families that are differentially expressed at the microvasculature in brain.
Strategy for the Formation of Parametric Images under Conditions of Low Injected Radioactivity Applied to PET Studies with the Irreversible Monoamine Oxidase a Tracers [11C]Clorgyline and Deuterium-Substituted [11C]Clorgyline
Authors: Logan Jean , Fowler Joanna S. , Ding Yu-Shin , Franceschi Dinko , Wang Gene-Jack , Volkow Nora D. , Felder Christoph , Alexoff David
Published: December 2015

The construction of parametric positron emission tomography images of enzyme or receptor concentration obtained using irreversibly binding radiotracers presents problems not usually encountered with reversibly binding radiotracers. Difficulties are most apparent in brain regions having low blood flow and/or high enzyme or receptor concentration and are exacerbated with noisy data. This is especially true when minimal doses of radiotracer are administered. A comparison was recently reported of the irreversible monoamine oxidase A (MAO A) radiotracers [11C]clorgyline (CLG) and deuterium-substituted [11C]clorgyline (CLG-D) in the human brain using region of interest (ROI) analysis in which the authors observed an unexpected loss of image contrast with CLG-D compared with CLG. In order to more fully investigate patterns of binding of these irreversibly binding radiotracers, a strategy was devised to reduce noise in the generation of parametric images of the model term related to enzyme or receptor concentration. The generalized linear least squares (GLLS) method of Feng et al. (1995) , a rapid linear method that is unbiased, was used for image-wide parameter estimation. Since GLLS can fail in the presence of large amounts of noise, local voxels were grouped within the image to increase the signal, and the GLLS method was combined with the standard nonlinear estimation methods when necessary. Voxels were grouped together depending on their proximity and whether they fell within a specified range of the time-integrated image. It was assumed that voxels meeting both criteria are functionally related. Simulations reflecting varying enzyme concentrations were performed to assess precision and accuracy of parameter estimates in the presence of varying amounts of noise. Using this approach, images were generated of the combination parameter λ k3 (λ = K1/ k2, where K1 and k2 are plasma-to-tissue and tissue-to-plasma transport constants, respectively) that is related to enzyme concentration as well as images of the transport constant K1 for individual subjects. Reasonably high-quality images of both K1 and λ k3 were obtained for CLG and CLG-D for individual subjects even with low injected doses averaging 6 mCi. While there were no differences in the K1 images, the λ k3 images revealed the loss of contrast previously reported for CLG-D using the ROI analysis. This method should be generalizable to other tracers and should facilitate the analysis of group differences.
Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM
Authors: Huang Yiyun , Hwang Dah-Ren , Narendran Raj , Sudo Yasuhiko , Chatterjee Rano , Bae Sung-A , Mawlawi Osama , Kegeles Lawrence S. , Wilson Alan A. , Kung Hank F. , Laruelle Marc
Published: December 2015

The recent introduction of a number of new radiotracers suitable for imaging the serotonin transporters (SERT) has radically changed the field of SERT imaging. Whereas, until recently, only one selective SERT radiotracer was available ([11C]McN 5652) for SERT imaging with positron emission tomography (PET), several new C-11-labeled radiotracers of the N,N-dimethyl-2-(arylthio)benzylamine class have been described as appropriate imaging agents for the SERT. The aim of this study was to conduct a comparative evaluation of four of the most promising agents in this class ([11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM) with the reference tracer [11C]McN 5652 under standardized experimental conditions. This evaluation included in vitro measurements of affinity and lipophilicity, and in vivo PET imaging experiments in baboons. In vitro, DASB displayed significantly lower affinity for SERT than the other four tracers. In the blood, [11C]DASB and [11C]AFM display faster clearance and higher free fractions. Brain uptake was analyzed with kinetic modeling using a one-tissue compartment model and the metabolite-corrected arterial input function. The kinetic uptake of [11C]DASB was significantly faster compared with the other compounds, and the scan duration required to derive time-independent estimates of regional distribution volumes was shorter. [11C]DAPA exhibited the slowest brain kinetic. Regional-specific-to-nonspecific equilibrium partition coefficient (V3“) was the highest for [11C]AFM, followed by [11C]DASB and [11C]DAPA, which in turn provided higher V3” values than [11C]ADAM and [11C]McN 5652. From these experiments, two ligands emerged as superior radiotracers that provide a significant improvement over [11C]McN 5652 for PET imaging of SERT: [11C]DASB, because it enables the measurement of SERT availability in a shorter scanning time, and [11C]AFM, because its higher signal-to-noise ratios provide a more reliable measurement of SERT availability in brain regions with relatively low density of SERT, such as in the limbic system.
Cholecystokinin Induces Cerebral Vasodilatation via Presynaptic CCK2 Receptors: New Implications for the Pathophysiology of Panic
Authors: Sánchez–Fernández Cristina , González Carmen , Mercer Linda D. , Beart Philip M. , Ruiz–Gayo Mariano , Fernández-Alfonso María S.
Published: December 2015

The authors report that cholecystokinin (CCK), via its subtype 2 receptor (CCK2R) located presynaptically on cerebral arteries, mediates the release of nitric oxide (NO), which induces vasodilatation. Whereas CCK octapeptide and its fragment CCK tetrapeptide (CCK-4) lack a direct effect on the smooth muscle of pial vessels, the authors showed that both CCK peptides modulate the neurogenic responses in bovine cerebral arteries. The neurogenic vasodilatation induced by CCK-4 was blocked by the CCK2R antagonist, L-365,260, and antagonized by neuronal NO synthase (nNOS) inhibitors, but was independent of the endothelium. In whole-mount arteries, CCK2Rs were detected in nerve fibers and colocalized with nNOS and synaptophysin. The findings provide, for the first time, a neural mechanism by which CCK may increase cerebral blood flow.
Novel Diketopiperazine Enhances Motor and Cognitive Recovery after Traumatic Brain Injury in Rats and Shows Neuroprotection In Vitro and In Vivo
Authors: Faden Alan I. , Knoblach Susan M. , Cernak Ibolja , Fan Lei , Vink Robert , Araldi Gian Luca , Fricke Stanley T. , Roth Bryan L. , Kozikowski Alan P.
Published: December 2015

The authors developed a novel diketopiperazine that shows neuroprotective activity in a variety of in vitro models, as well as in a clinically relevant experimental model of traumatic brain injury (TBI) in rats. Treatment with 1-ARA-35b (35b), a cyclized dipeptide derived from a modified thyrotropin-releasing hormone (TRH) analog, significantly reduced cell death associated with necrosis (maitotoxin), apoptosis (staurosporine), or mechanical injury in neuronal–glial cocultures. Rats subjected to lateral fluid percussion–induced TBI and then treated with 1 mg/kg intravenous 35b thirty minutes after trauma showed significantly improved motor recovery and spatial learning compared with vehicle-treated controls. Treatment also significantly reduced lesion volumes as shown by magnetic resonance imaging, and decreased the number of TUNEL-positive neurons observed in ipsilateral hippocampus. Unlike TRH or traditional TRH analogs, 35b treatment did not change mean arterial pressure, body temperature, or thyroid-stimulating hormone release, and did not have analeptic activity. Moreover, in contrast to TRH or typical TRH analogs, 35b administration after TBI did not alter free-magnesium concentration or cellular bioenergetic state. Receptor-binding studies showed that 35b did not act with high affinity at 50 classical receptors, channels, or transporters. Thus, 35b shows none of the typical physiologic actions associated with TRH, but possesses neuroprotective actions in vivo and in vitro, and appears to attenuate both necrotic and apoptotic cell death.
Neuroprotective and Nootropic Actions of a Novel Cyclized Dipeptide after Controlled Cortical Impact Injury in Mice
Authors: Faden Alan I. , Fox Gerard B. , Di Xiao , Knoblach Susan M. , Cernak Ibolja , Mullins Paul , Nikolaeva Maria , Kozikowski Alan P.
Published: December 2015

1-ARA-35b (35b) is a cyclized dipeptide that shows considerable neuroprotective activity in vitro and improves neurologic recovery after fluid percussion–induced traumatic brain injury in rats. The authors evaluated the effects of treatment with 35b in mice subjected to controlled cortical impact brain injury. Animals treated with intravenous 35b after traumatic injury showed significantly enhanced recovery of beam walking and place learning functions compared with vehicle-treated controls, in addition to reduced lesion volumes. Beneficial effects were dose related and showed an inverted U-shaped dose–response curve between 0.1 and 10 mg/kg. Protective actions were found when the drug was administered initially at 30 minutes or 1, 4, or 8 hours, but not at 24 hours, after trauma. In separate experiments, rats treated with 35b on days 7 through 10 after injury showed remarkably improved place learning in comparison with injured controls. These studies confirm and extend the neuroprotective effects of this diketopiperazine in traumatic brain injury. In addition, they show that 35b has a relatively wide therapeutic window and improves cognitive function after both acute and chronic injury.
Neuroprotection by Complement (C1) Inhibitor in Mouse Transient Brain Ischemia
Authors: De Simoni M. G. , Storini C. , Barba M. , Catapano L. , Arabia A. M. , Rossi E. , Bergamaschini L.
Published: December 2015

The authors investigated the effect of the C1 inhibitor (C1-INH), the only known inhibitor of complement C1, in a murine model of transient focal ischemia. Ischemia was induced by intraluminal occlusion of the middle cerebral artery. After 2 hours, reperfusion was produced by removing the nylon monofilament occluding the artery. The effect of 15 U C1-INH (intravenously) was evaluated in terms of general and focal neurologic deficits, ischemic volume, neutral red staining (to identify the brain areas subject to ischemic damage), and glial fibrillary acidic protein immunoreactivity (to show astrocytic response). Forty-eight hours after ischemia, C1-INH significantly improved general and focal deficits by 36% and 54%, respectively, and significantly reduced infarct volume (CI-INH, 6.69% ± 2.93%; saline, 24.24% ± 8.24%) of total brain. Neutral red staining further showed the strong protective effect of C1-INH in cortex, hippocampus, and striatum. Astrocyte activation induced by ischemia was not affected by C1-INH. These findings show that C1-INH displayed a potent neuroprotective action by effectively reducing ischemia—reperfusion injury.