bluuebunny/crossref_metadata_2025 huggingface dataset:
India and Russia
Authors: Menon Rajan
Published: December 2015

Pragmatism defined the partnership between India and the Soviet Union. What sustained it was the overlap between India’s non-alignment strategy and the USSR’s objective of countering the American policy of containment. The Soviet leadership sold India substantial amounts of arms and helped build its state-run industrial sector; India’s leaders saw the Soviet connection as a counterbalance against Pakistan, China, and the United States. Pragmatism also defines the India–Russia relationship. Russia remains India’s largest arms supplier. Their views on sovereignty, the dangers of unilateral military intervention, and the threats posed by terrorism converge. But Russia’s salience for India’s trade and investment has been surpassed by the West, even China. India is diversifying its arms purchases; the West and Israel are eager to oblige. Russia’s relative power is declining as China’s is rising; in response, India has forged new security ties with East Asia and the United States.
India and South Africa
Authors: Virk Kudrat
Published: December 2015

India and South Africa are democratic emerging powers that share a history of solidarity against colonialism, with India having played a leadership role and provided vital support to the anti-apartheid struggle. Since South Africa’s re-entry into international society, however, hard-headed economic and strategic imperatives have permeated relations between the two countries. Bilateral economic ties have grown rapidly, but rest on fragile foundations. Although security cooperation has been limited, it offers scope for deepening the India–South Africa ‘strategic partnership’, particularly in the Indian Ocean and in the field of peacekeeping. Both countries have sought closer engagement in multilateral forums across issues, including global governance reform, intervention, trade, and climate change, though differences persist. A key challenge relates to the place that Africa occupies in their respective perspectives. Although the depth India–South Africa relations can achieve remains in question, considerable potentiality exists.
Nehru’s Foreign Policy
Authors: Kennedy Andrew
Published: December 2015

India’s first Prime Minister towered over India’s international relations for nearly two critical decades. More than half a century after his death, however, scholars continue to debate the meaning and significance of Nehru’s most important initiatives in foreign policy. Some argue that he was a bold idealist crusader, one who frequently ignored important Indian interests. Others have described him as a subtle practitioner of realpolitik statecraft. This chapter argues that Nehru must be remembered as both an idealist and a realist. To make its case, the chapter delves into three of Nehru’s most important ‘idealistic’ preoccupations in foreign policy: his drive to build up the United Nations, his campaign for non-alignment, and his crusade for nuclear disarmament. In each case, the analysis reveals that Nehru was both sincerely committed to what he saw as a moral cause, but also convinced that advancing it would suit narrower Indian interests as well.
At the Cusp of Transformation
Authors: Raghavan Srinath
Published: December 2015

This chapter examines Indian foreign policy under Prime Minister Rajiv Gandhi (1984–89). It argues that during these years, Indian foreign policy was significantly reoriented. Gandhi made important moves to recast India’s relations with the United States and China. Although no major breakthroughs were achieved, his engagement with them set the tone and pattern for the approach and policy of all subsequent governments. In India’s own neighbourhood, his policies had a more activist edge. But the outcomes were mixed. Perhaps the most fundamental shift in foreign policy was Gandhi’s recognition that India’s modernization and economic development required greater and more adroit engagement with the world and that foreign policy had to be geared towards securing these objectives.
Complexity and Austrian Economics
Authors: Rosser J. Barkley
Published: December 2015

There is a deep link between complexity economics and Austrian economics. Ideas of complexity were foundational in the work of Austrian economics from its generally recognized beginnings in the work of Carl Menger to the modern day, with Friedrich Hayek being probably the most important carrier of this theme in the school. Although interest in complexity economics among Austrians has waxed and waned over time, today such ideas are quite influential in the work of many Austrian economists. This chapter discusses the varieties of economic complexity and the connection with the Austrian school of economics from Menger to Hayek, as well as more recent developments of Austrian views on complexity.
Assessment in Choral Music Instruction
Authors: Henry Michele L.
Published: December 2015

This article discusses the current state of assessment of student learning in the choral classroom. Assessing in the choral classroom presents many curricular and logistical challenges, the group instructional format and the large number of students enrolled being chief among them. A lack of preparation for and tradition in assessment further serves to discourage choral educators from assessing appropriately. Most of the available information about choral assessment comes from anecdotal evidence and advocacy pieces; however, researchers are making significant strides, particularly in the development of performance rating scales and sight-reading assessment. Very little assessment of knowledge-based content or written expressions is occurring, either in the classroom or by researchers. University choral education faculty must make instruction in assessment techniques a priority within the undergraduate curriculum rather than part of graduate study, as new teachers are expected to assess their students almost immediately upon entering the classroom.
Musical and Culinary Itineraries around the Mediterranean
Authors: Shannon Jonathan H.
Published: December 2015

This article explores the circulation of music and food in the Mediterranean in order to advance a novel theory of culture and cultural analysis. Borrowing from recent scholarship in ethnography, ethnomusicology, food studies, and critical theory, it proposes that the Mediterranean be understood as a space of cultural contradictions and indeterminacies that is best analyzed as a rhizome. Moreover, moving theory and ethnography offshore allows for a more nuanced engagement with culture in circulation. It demonstrates the advantages of such an “aquacentric” approach through analysis of the circulation of a song and a recipe from Egypt to France and beyond.
Bantu Phonology
Authors: Odden David
Published: December 2015

This chapter surveys the main phonological phenomena found in Bantu languages. One such phenomenon is vowel harmony, where suffixes typically alternate in height depending on the preceding vowel. Combinations of nasal plus consonant are also frequently subject to various modifications; such clusters play an important role in debates over syllable structure, since Bantu languages seem to exhibit the peculiarity that the only onset clusters of consonantals are composed of a nasal followed by an obstruent, reversing the more general linguistic tendency for sonority to rise in the syllable onset. The tone systems of Bantu languages are especially well known for their complex systems of alternations in the form of spreading, dissimilation, and grammatically conditioned melodic alternation. A key feature of interest in the study of Bantu phonology is the considerable variability in the exact details of operation of a highly similar set of rules.
Shape Perception
Authors: Sawada Tadamasa , Li Yunfeng , Pizlo Zygmunt
Published: December 2015

This chapter provides a review of topics and concepts that are necessary to study and understand 3D shape perception. This includes group theory and their invariants; model-based invariants; Euclidean, affine, and projective geometry; symmetry; inverse problems; simplicity principle; Fechnerian psychophysics; regularization theory; Bayesian inference; shape constancy and shape veridicality; shape recovery; perspective and orthographic projections; camera models; as well as definitions of shape. All concepts are defined and illustrated, and the reader is provided with references providing mathematical and computational details. Material presented here will be a good starting point for students and researchers who plan to study shape, as well as for those who simply want to get prepared for reading the contemporary literature on the subject.
Neurocognitive Modeling of Perceptual Decision Making
Authors: Palmeri Thomas J. , Schall Jeffrey D. , Logan Gordon D.
Published: December 2015

Mathematical psychology and systems neuroscience have converged on stochastic accumulator models to explain decision making. We examined saccade decisions in monkeys while neurophysiological recordings were made within their frontal eye field. Accumulator models were tested on how well they fit response probabilities and distributions of response times to make saccades. We connected these models with neurophysiology. To test the hypothesis that visually responsive neurons represented perceptual evidence driving accumulation, we replaced perceptual processing time and drift rate parameters with recorded neurophysiology from those neurons. To test the hypothesis that movement related neurons instantiated the accumulator, we compared measures of neural dynamics with predicted measures of accumulator dynamics. Thus, neurophysiology both provides a constraint on model assumptions and data for model selection. We highlight a gated accumulator model that accounts for saccade behavior during visual search, predicts neurophysiology during search, and provides insights into the locus of cognitive control over decisions.
An Exemplar-Based Random-Walk Model of Categorization and Recognition
Authors: Nosofsky Robert M. , Palmeri Thomas J.
Published: December 2015

In this chapter, we provide a review of a process-oriented mathematical model of categorization known as the exemplar-based random-walk (EBRW) model (Nosofsky & Palmeri, 1997a). The EBRW model is a member of the class of exemplar models. According to such models, people represent categories by storing individual exemplars of the categories in memory, and classify objects on the basis of their similarity to the stored exemplars. The EBRW model combines ideas ranging from the fields of choice and similarity, to the development of automaticity, to response-time models of evidence accumulation and decision-making. This integrated model explains relations between categorization and other fundamental cognitive processes, including individual-object identification, the development of expertise in tasks of skilled performance, and old-new recognition memory. Furthermore, it provides an account of how categorization and recognition decision-making unfold through time. We also provide comparisons with some other process models of categorization.
Apolipoprotein E Polymorphism and Acute Ischemic Stroke: A Diffusion- and Perfusion-Weighted Magnetic Resonance Imaging Study
Authors: Liu Yawu , Laakso Mikko P. , Karonen Jari O. , Vanninen Ritva L. , Nuutinen Juho , Soimakallio Seppo , Aronen Hannu J.
Published: December 2015

Diffusion- and perfusion-weighted magnetic resonance imaging (MRI) was used to study the putative effects of apolipoprotein E (ApoE) polymorphism in stroke. Thirty-one patients with acute stroke, comparative for age and gender were scanned, nine of whom were ApoE allele ***ε4 carriers. Initially, less than 24 hours from the onset of stroke, the ε4 carriers had significantly smaller volumes of hypoperfusion on relative cerebral blood volume map ( P = 0.001), and smaller infarct volumes ( P = 0.008) compared with the noncarriers. By day 8, this difference in the infarct volumes had disappeared, suggesting relatively enhanced infarct growth. On average, the total infarct volume increased 145% of the initial infarct volume in the ε4 carriers, and 84% in the noncarriers. There were strong correlations between the imaging findings and clinical status initially and with the outcome 3 months after the stroke in the ε4 noncarriers, but, with a single exception at acute phase, a lack thereof in the ε4 carriers. These patterns were virtually similar in a subgroup of patients with middle cerebral artery stroke. These data support the hypothesis of increased general vulnerability of the brain in the e4 carriers. Thus, the effects of ApoE polymorphism should be accounted for when interpreting diffusion- and perfusion-weighted MRI studies, particularly if predicting lesion growth.
Upregulation of TACE/ADAM17 after Ischemic Preconditioning is Involved in Brain Tolerance
Authors: Cárdenas Antonio , Moro María A. , Leza Juan C. , O'Shea Esther , Dávalos Antoni , Castillo José , Lorenzo Pedro , Lizasoain Ignacio
Published: December 2015

A short ischemic event (ischemic preconditioning [IPC]) can result in a subsequent resistance to severe ischemic injury (ischemic tolerance [IT]). Although tumor necrosis factor-α (TNF-α) contributes to the brain damage, its expression and neuroprotective role in models of IPC have also been described. However, the role of TNF-α convertase (TACE) in IPC and IT is not known. Using in vitro models, the authors previously demonstrated that TACE is upregulated after ischemic brain damage. In the present study, the authors used a rat model of transient middle cerebral artery occlusion as IPC to investigate TACE expression, its involvement in TNF-α release, and its role in IT. Western blot analysis showed that TACE expression is increased after IPC. Ischemic preconditioning caused TNF-α release, an effect that was blocked by the selective TACE inhibitor BB-1101 (10 mg · kg−1 · day−1; SHAM, 1,050 ± 180; IPC, 1,870 ± 290; IPC + BB, 1,320 ± 260 ng/mg; n = 4, P < 0.05). Finally, IPC produced a reduction in infarct volume, which was inhibited by treatment with BB-1101 and with anti–TNF-α (10 μg/5 doses; SHAM + permanent middle cerebral artery occlusion [pMCAO], 335 ± 20; IPC + pMCAO, 244 ± 14; IPC + BB + pMCAO, 300 ± 6; IPC + anti-TNF + pMCAO, 348 ± 22 mm3; n = 6–10, P < 0.05). Taken together, these data demonstrate that TACE is upregulated after IPC, plays a major role in TNF-α shedding in IPC, and has a neuroprotective role in IT.
Cortical Spreading Depression Causes a Long-Lasting Decrease in Cerebral Blood Flow and Induces Tolerance to Permanent Focal Ischemia in Rat Brain
Authors: Otori Tatsuo , Greenberg Joel H. , Welsh Frank A.
Published: December 2015

Cortical spreading depression (CSD) has previously been shown to induce tolerance to a subsequent episode of transient cerebral ischemia. The objective of the present study was to determine whether CSD also induces tolerance to permanent focal ischemia and, if so, whether tolerance may be mediated by alterations in cerebral blood flow (CBF). Sprague-Dawley rats were preconditioned by applying potassium chloride to one hemisphere for 2 hours, evoking 19 ± 5 episodes of CSD (mean ± SD, n = 19). Three days later, the middle cerebral artery (MCA) was permanently occluded using an intraluminal suture. In a subset of animals, laser Doppler blood flow (LDF) was monitored over the parietal cortex before and during the first 2 hours of MCA occlusion. Preconditioning with CSD reduced the hemispheric volume of infarction from 248 ± 115 mm3 (n = 18) in sham-conditioned animals to 161 ± 81 mm3 (n = 19, P < 0.02). Similarly, CSD reduced the neocortical volume of infarction from 126 ± 82 mm3 to 60 ± 61 mm3 ( P < 0.01). Moreover, preconditioning with CSD significantly improved LDF during MCA occlusion from 21% ± 7% (n = 9) of preischemic baseline in sham-conditioned animals to 29% ± 9% (n = 7, P < 0.02). Preconditioning with CSD therefore preserved relative levels of CBF during focal ischemia and reduced the extent of infarction resulting from permanent MCA occlusion. To determine whether CSD may have altered preischemic baseline CBF, [14C]iodoantipyrine was used in additional animals to measure CBF 3 days after CSD conditioning or sham conditioning. CSD, but not sham conditioning, significantly reduced baseline CBF in the ipsilateral neocortex to values 67% to 75% of those in the contralateral cortex. Therefore, CSD causes a long-lasting decrease in baseline CBF that is most likely related to a reduction in metabolic rate. A reduction in the rate of metabolism may contribute to the induction of tolerance to ischemia after preconditioning with CSD.
Prevention of Impairment of Cerebral Blood Flow Autoregulation during Acute Stage of Subarachnoid Hemorrhage by Gene Transfer of Cu/Zn SOD-1 to Cerebral Vessels
Authors: Shin Hwa Kyoung , Lee Jeong Hyun , Dae Kim Chi , Kim Yong Ki , Hong Jae Yong , Hong Ki Whan
Published: December 2015

The present study determined whether gene transfer of human copper/zinc superoxide dismutase-1 (Cu/Zn SOD-1) prevented the autoregulatory impairment of CBF induced by subarachnoid hemorrhage (SAH). After application of recombinant adenovirus (100 μL of 1 × 1010 pfu/mL, intracisternally) encoding human Cu/Zn SOD-1 3 days before experiments, Cu/Zn SOD-1 activity significantly increased in association with increase in Cu/Zn SOD-1 mRNA and protein expression in the cerebral vasculature of both sham-operated and SAH rats as determined by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry, and SAH-induced increase in superoxide anion was markedly reduced in accordance with increased nitric oxide production. In line with these findings, rats that received human Cu/Zn SOD-1 therapy showed the prominent restoration of blunted vasodilation of the pial artery in response to calcitonin gene-related peptide and levcromakalim, and the recovery of impaired autoregulatory vasodilation in response to acute hypotension, thereby leading to significant restoration of CBF autoregulation. These results provide a rational basis for application of Cu/Zn SOD-1 gene therapy for protection of the impairment of autoregulatory CBF during the acute stage of SAH.
Implications of Vascular Endothelial Growth Factor, sFlt-1, and sTie-2 in Plasma, Serum and Cerebrospinal Fluid during Cerebral Ischemia in Man
Authors: Scheufler Kai-Michael , Drevs Joachim , van Velthoven Vera , Reusch Petra , Klisch Joachim , Augustin Helmut G. , Zentner Josef , Marme Dieter
Published: December 2015

The relation between cerebral ischemia and local release of angiogenic factors was investigated after subarachnoid hemorrhage (SAH) in humans. Time-dependent concentration-changes of vascular endothelial growth factor (VEGF), sFlt-1 and sTie-2 extracted from plasma, serum, and cerebrospinal fluid (ventricular, cisternal, and lumbar) were analyzed in 15 patients surgically treated for ruptured aneurysms of the anterior circulation (Hunt and Hess grades I-V). Data were related to brain Po2 (Pbro2) and cerebral energy metabolites (extracellular lactate, pyruvate, glutamate, and glycerin concentrations) as well as clinical and radiologic reference data. Delayed impairment of cerebral perfusion secondary to progressive microcirculatory alterations was associated with reduced local Pbro2 and energy metabolism (increased lactate-pyruvate ratio, glutamate and glycerine levels). Elevated serum/plasma and CSF concentrations of VEGF, sFlt-1, and sTie-2 matched the scale of ischemic tissue hypoxia. Excessive VEGF/sFlt-1 and sTie-2 levels were related to Pbro2 values consistently less than 5 mm Hg, glutamate concentrations greater than 300 μmol/L, lactate-pyruvate ratio greater than 300, cerebral infarction, and reduced outcome ( P < 0.01). Delayed microcirculatory impairment was mirrored by distinct elevation of cisternal and arterial VEGF and sFlt-1 concentrations, suggesting local induction of angiogenesis. Arterial levels of VEGF, sFlt-1, and sTie-2 reflect both extent and time course of compensatory, yet clinically inefficient, angiogenesis in the absence of general hypoxia.
Inflammation and Infection in Clinical Stroke
Authors: Emsley Hedley C. A. , Tyrrell Pippa J.
Published: December 2015

Stroke has enormous clinical, social, and economic implications, and demands a significant effort from both basic and clinical science in the search for successful therapies. Atherosclerosis, the pathologic process underlying most coronary artery disease and the majority of ischemic stroke in humans, is an inflammatory process. Complex interactions occur between the classic risk factors for atherosclerosis and its clinical consequences. These interactions appear to involve inflammatory mechanisms both in the periphery and in the CNS. Central nervous system inflammation is important in the pathophysiologic processes occurring after the onset of cerebral ischemia in ischemic stroke, subarachnoid hemorrhage, and head injury. In addition, inflammation in the CNS or in the periphery may be a risk factor for the initial development of cerebral ischemia. Peripheral infection and inflammatory processes are likely to be important in this respect. Thus, it appears that inflammation may be important both before, in predisposing to a stroke, and afterwards, where it is important in the mechanisms of cerebral injury and repair. Inflammation is mediated by both molecular components, including cytokines, and cellular components, such as leukocytes and microglia, many of which possess pro- and/or antiinflammatory properties, with harmful or beneficial effects. Classic acute-phase reactants and body temperature are also modified in stroke, and may be useful in the prediction of events, outcome, and as therapeutic targets. New imaging techniques are important clinically because they facilitate in vivo dynamic evaluation of tissue damage in relation to outcome. Inflammatory conditions such as giant cell arteritis and systemic lupus erythematosus predispose to stroke, as do a range of acute and chronic infections, principally respiratory. Diverse mechanisms have been proposed to account for inflammation and infection-associated stroke, ranging from classic risk factors to disturbances of the immune and coagulation systems. Considerable opportunities therefore exist for the development of novel therapies. It seems likely that drugs currently used in the treatment of stroke, such as aspirin, statins, and modulators of the renin–angiotensin–aldosterone system, act at least partly via antiinflammatory mechanisms. Newer approaches have included antimicrobial and antileukocyte strategies. One of the most promising avenues may be the use of cytokine antagonism, for example, interleukin-1 receptor antagonist.
Vascular Endothelial Growth Factor Protects Cultured Rat Hippocampal Neurons against Hypoxic Injury via an Antiexcitotoxic, Caspase-Independent Mechanism
Authors: Svensson Birte , Peters Marion , König Hans-Georg , Poppe Monika , Levkau Bodo , Rothermundt Matthias , Arolt Volker , Kögel Donat , Prehn Jochen H. M.
Published: December 2015

The authors investigated the effect of vascular endothelial growth factor (VEGF) on hypoxic injury of cultured rat hippocampal neurons. Treatment with glutamate receptor antagonists prevented hypoxic neuron death. The same magnitude of protection was observed in cultures treated with VEGF, which also reduced excitotoxic neuron death induced directly by an exposure to N-methyl-d-aspartate. Vascular endothelial growth factor did not alter the activation of the transcription factor nuclear factor-κB during hypoxia and protected cells in a PI-3-kinase-independent manner. Vascular endothelial growth factor failed to protect against staurosporine-induced, caspase-dependent apoptosis. These data suggest that VEGF-induced protection against hypoxic injury primarily involves the inhibition of excitotoxic processes.
Estrogen is Neuroprotective via an Apolipoprotein E—Dependent Mechanism in a Mouse Model of Global Ischemia
Authors: Horsburgh Karen , Macrae I. Mhairi , Carswell Hilary
Published: December 2015

Estrogen can ameliorate brain damage in experimental models of focal cerebral ischemia. In vitro, estrogen increases levels of apolipoprotein E (apoE), which also has neuroprotective effects in brain injury. The authors tested the hypotheses that physiologically relevant levels of 17β-estradiol are neuroprotective in global cerebral ischemia and that neuroprotection is mediated via apoE. In the first study, subcutaneous implants of 17β-estradiol were tested in female C57Bl/6J mice (ovariectomized and nonovariectomized) and plasma levels measured by radioimmunoassay to validate that physiologically relevant levels could be achieved. In the second study, female C57Bl/6J and apoE-deficient mice were ovariectomized and implanted with 17β-estradiol or placebo pellet. Two weeks later, transient global ischemia was induced by bilateral carotid artery occlusion and the mice killed after 72 hours. Ischemic and normal neurons were counted in the caudate nucleus and CA1 pyramidal cell layer and the percentage of neuronal damage was compared between the treated groups. In C57Bl/6J mice, there was less neuronal damage in the 17β-estradiol-treated group compared with placebo group in the caudate nucleus (15 ± 20% versus 39 ± 27%, P = 0.02) and in the CA1 pyramidal cell layer (1.8 ± 2% versus 10 ± 14%, P = 0.08). In contrast, neuronal damage was not significantly different between the 17β-estradiol and placebo groups in apoE-deficient mice in the caudate nucleus (47 ± 35% versus 53 ± 29%, P = 0.7) or in the CA1 pyramidal cell layer (24 ± 19% versus 24 ± 19%, P = 1.0). The data indicate a neuroprotective role for estrogen in global ischemia, the mechanism of which is apoE-dependent.
A Combined Treatment with Tacrolimus (FK506) and Recombinant Tissue Plasminogen Activator for Thrombotic Focal Cerebral Ischemia in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window
Authors: Maeda Masashi , Furuichi Yasuhisa , Ueyama Noriko , Moriguchi Akira , Satoh Natsuki , Matsuoka Nobuya , Goto Toshio , Yanagihara Takehiko
Published: December 2015

The authors evaluated the therapeutic efficacy of tacrolimus (FK506), administered alone or in combination with recombinant tissue plasminogen activator (t-PA), on brain infarction following thrombotic middle cerebral artery (MCA) occlusion. Thrombotic occlusion of the MCA was induced by a photochemical reaction between rose bengal and green light in Sprague-Dawley rats, and the volume of ischemic brain damage was determined 24 hours later. Intravenous administration of tacrolimus or t-PA dose-dependently reduced the volume of ischemic brain infarction, whether administered immediately or 1 hour after MCA occlusion. When tacrolimus or t-PA was administered 2 hours after MCA occlusion, each drug showed a tendency to reduce ischemic brain damage. However, combined treatment with both drugs resulted in a significant reduction in ischemic brain damage. On administration 3 hours after MCA occlusion, tacrolimus alone showed no effect, and t-PA tended to worsen ischemic brain damage. However, the combined treatment with both drugs not only ameliorated the worsening trend seen with t-PA alone, but also tended to reduce ischemic brain damage. In conclusion, tacrolimus, used in combination with t-PA, augmented therapeutic efficacy on brain damage associated with focal ischemia and extended the therapeutic time window compared to single-drug treatments.
Brain Glucose Hypometabolism after Perirhinal Lesions in Baboons: Implications for Alzheimer Disease and Aging
Authors: Millien Isabelle , Blaizot Xavier , Giffard Cyrille , Mézenge Florence , Insausti Ricardo , Baron Jean-Claude , Chavoix Chantal
Published: December 2015

The authors previously reported that excitotoxic lesions of both the perirhinal and entorhinal cortices in baboons induce remote neocortical and hippocampal hypometabolism reminiscent of that observed in Alzheimer disease (AD), suggesting that disconnection may play a role in AD. Because the cerebral metabolic rate of glucose (CMRglc) was preferentially correlated with perirhinal damage, the area first affected by neurofibrillary tangles in both AD and normal aging, the present series of experiments aimed at assessing the specific metabolic effects of perirhinal lesions. Using PET, CMRglc was measured before surgery and sequentially over the ensuing 10 months. Compared with sham-operated baboons, perirhinal lesions induced significant—albeit late and transient—CMRglc decreases in several brain regions, which significantly correlated with histologic damage for some of these regions. Among them, the temporal and hippocampal regions are metabolically affected after extensive rhinal lesions, in early AD, and aging, while the prefrontal region is affected in aging only. Furthermore, in contrast to AD and rhinal lesions, the posterior cingulate cortex was spared. Both the progressive but significant metabolic effects and specific hypometabolic pattern after perirhinal lesions were confirmed by direct comparisons with previous data obtained after combined lesions of both rhinal areas. Thus, although perirhinal damage appears in itself insufficient to induce sustained CMRglc decreases, it may contribute to the hypometabolic profile of both AD and normal aging, most likely with a stronger contribution in the latter.
Strategies to Improve Neuroreceptor Parameter Estimation by Linear Regression Analysis
Authors: Ichise Masanori , Toyama Hiroshi , Innis Robert B. , Carson Richard E.
Published: December 2015

In an attempt to improve neuroreceptor distribution volume ( V) estimates, the authors evaluated three alternative linear methods to Logan graphical analysis (GA): GA using total least squares (TLS), and two multilinear analyses, MA1 and MA2, based on mathematical rearrangement of GA equation and two-tissue compartments, respectively, using simulated and actual PET data of two receptor tracers, [18F]FCWAY and [11C]MDL 100,907. For simulations, all three methods decreased the noise-induced GA bias (up to 30%) at the expense of increased variability. The bias reduction was most pronounced for MA1, moderate to large for MA2, and modest to moderate for TLS. In addition, GA, TLS, and MA1, methods that used only a portion of the data ( T > t*, chosen by an automatic process), showed a small V underestimation for [11C]MDL 100,907 with its slow kinetics, due to selection of t* before the true point of linearity. These noniterative methods are computationally simple, allowing efficient pixelwise parameter estimation. For tracers with kinetics that permit t* to be accurately identified within the study duration, MA1 appears to be the best. For tracers with slow kinetics and low to moderate noise, however, MA2 may provide the lowest bias while maintaining computational ease for pixelwise parameter estimation.
Delayed Treatment with MLN519 Reduces Infarction and Associated Neurologic Deficit Caused by Focal Ischemic Brain Injury in Rats via Antiinflammatory Mechanisms Involving Nuclear Factor-κB Activation, Gliosis, and Leukocyte Infiltration
Authors: Williams Anthony J. , Hale Sarah L. , Moffett John R. , Dave Jitendra R. , Elliott Peter J. , Adams Julian , Tortella Frank C.
Published: December 2015

Secondary brain injury due to ischemia includes the infiltration of leukocytes into the brain parenchyma mediated by activation of nuclear factor-κB (NF-κB), which is activated by proteasome degradation. Neuroprotection with the proteasome inhibitor MLN519 has previously been reported to decrease ischemic brain injury in rats. The authors used higher doses of MLN519 to evaluate the neuroprotection therapeutic window after 24 hours of brain injury in rats as correlated to proteasome levels, activated NF-κB immunoreactivity, and leukocyte infiltration. Male Sprague-Dawley rats were subjected to 2-hour middle cerebral artery occlusion (MCAO) and recovery. MLN519 or vehicle was administered after injury with a single injection given in delayed increments of 2 hours (i.e., 4, 6, or 8 hours after MCAO). Treatment with MLN519 up to 6 hours after MCAO (4 hours after reperfusion) effectively reduced neuronal and astrocytic degeneration, decreased cortical infarct volume, and increased neurologic recovery. These effects were related to >80% reductions in blood proteasome levels, reduced neutrophil infiltration, and a decrease in activated NF-κB immunoreactivity. This improved neuroprotection profile and antiinflammatory effect of MLN519 provides an exciting avenue for potential treatment of focal ischemic brain injury in humans.
Structural and Functional Damage Sustained by Mitochondria after Traumatic Brain Injury in the Rat: Evidence for Differentially Sensitive Populations in the Cortex and Hippocampus
Authors: Lifshitz Jonathan , Friberg Hans , Neumar Robert W. , Raghupathi Ramesh , Welsh Frank A. , Janmey Paul , Saatman Kathryn E. , Wieloch Tadeusz , Grady M. Sean , McIntosh Tracy K.
Published: December 2015

The cellular and molecular pathways initiated by traumatic brain injury (TBI) may compromise the function and structural integrity of mitochondria, thereby contributing to cerebral metabolic dysfunction and cell death. The extent to which TBI affects regional mitochondrial populations with respect to structure, function, and swelling was assessed 3 hours and 24 hours after lateral fluid—percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared with uninjured parietotemporal cortex, whereas comparable yields were obtained from the hippocampus. After injury, cortical and hippocampal tissue ATP concentrations declined significantly to 60% and 40% of control, respectively, in the absence of respiratory deficits in isolated mitochondria. Mitochondria with ultrastructural morphologic damage comprised a significantly greater percent of the population isolated from injured than uninjured brain. As determined by photon correlation spectroscopy, the mean mitochondrial radius decreased significantly in injured cortical populations (361 ± 40 nm at 24 hours) and increased significantly in injured hippocampal populations (442 ± 36 at 3 hours) compared with uninjured populations (Ctx: 418 ± 44; Hipp: 393 ± 24). Calcium-induced deenergized swelling rates of isolated mitochondrial populations were significantly slower in injured compared with uninjured samples, suggesting that injury alters the kinetics of mitochondrial permeability transition (MPT) pore activation. Cyclosporin A (CsA)-insensitive swelling was reduced in the cortex, and CsA-sensitive and CsA-insensitive swelling both were reduced in the hippocampus, demonstrating that regulated MPT pores remain in mitochondria isolated from injured brain. A proposed mitochondrial population model synthesizes these data and suggests that cortical mitochondria may be depleted after TBI, with a physically smaller, MPT-regulated population remaining. Hippocampal mitochondria may sustain damage associated with ballooned membranes and reduced MPT pore calcium sensitivity. The heterogeneous mitochondrial response to TBI may underlie posttraumatic metabolic dysfunction and contribute to the pathophysiology of TBI.
Effect of Deep Pentobarbital Anesthesia on Neurotransmitter Metabolism in Vivo: On the Correlation of Total Glucose Consumption with Glutamatergic Action
Authors: Choi In-Young , Lei Hongxia , Gruetter Rolf
Published: December 2015

The effect of deep barbiturate anesthesia on brain glucose transport, TCA cycle flux, and aspartate, glutamate, and glutamine metabolism was assessed in the rat brain in vivo using 13C nuclear magnetic resonance spectroscopy at 9.4 T in conjunction with [1-13C] glucose infusions. Brain glucose concentrations were elevated, consistent with a twofold reduced cerebral metabolic rate for glucose (CMRglc) compared with light α-chloralose anesthesia. Using a mathematical model of neurotransmitter metabolism, several metabolic reaction rates were extracted from the rate of label incorporation. Total oxidative glucose metabolism, CMRglc(ox), was 0.33 ± 0.03 μmol·g−1 · min−1. The neuronal TCA cycle rate was similar to that in the glia, 0.35 ± 0.03 μmol · g−1 · min−1 and 0.26 ± 0.06 μmol · g−1 · min−1, respectively, suggesting that neuronal energy metabolism was mainly affected. The rate of pyruvate carboxylation was 0.03 ± 0.01 μmol·g−1 · min−1. The exchange rate between cytosolic glutamate and mitochondrial 2-oxoglutarate, Vx, was equal to the rate of neuronal pyruvate dehydrogenase flux. This indicates that Vx is coupled to CMRglc(ox), implying that the malate-aspartate shuttle is the major mechanism that facilitates label exchange across the inner mitochondrial membrane. The apparent rate of glutamatergic neurotransmission, VNT, was 0.04 ± 0.01 μmol·g−1 · min−1, consistent with strong reductions in electrical activity. However, the rates of cerebral oxidative glucose metabolism and glutamatergic neurotransmission, CMRglc(ox)/VNT, did not correlate with a 1:1 stoichiometry.
Kinetic Compartment Modeling of [11C]-5-Hydroxy-L-Tryptophan for Positron Emission Tomography Assessment of Serotonin Synthesis in Human Brain
Authors: Hagberg Gisela E. , Torstenson Richard , Marteinsdottir Ina , Fredrikson Mats , Långström Bengt , Blomqvist Gunnar
Published: December 2015

The substrate for the second enzymatic step in serotonin synthesis, 5-hydroxy-L-tryptophan, labeled in the β-position ([11C]-HTP), was used for positron emission tomography (PET) measurements in six healthy human participants, examined on two occasions. One- and two-tissue kinetic compartment modeling of time-radioactivity curves was performed, using arterial, metabolite-corrected [11C]-HTP values as input function. The availability of unchanged tracer in arterial blood plasma was ⩽ 80% up to 60 minutes after injection, while [11C]-hydroxyindole acetic acid and [11C]-serotonin accounted for the remaining radioactivity, amounting to ⩽16% and ⩽4%, respectively. Compartment modeling was performed for brain stem, putamen, caudate nucleus, anterior cingulate, white matter, and superior occipital, occipitotemporal, and temporal cortices. The average biologic half-life for plasma-to-tissue equilibrium was 7 to 12 minutes, and the volume of distribution was 0.2 to 0.5 μL·mL−1. In all regions except white matter, the kinetic compartment model that included irreversible [11C]-HTP trapping showed significantly improved model fits with respect to a one-tissue compartment model. The [11C]-HTP trapping rate constant depended on the estimated tissue availability of the serotonin precursor tryptophan, known to reflect serotonin synthesis in healthy individuals, and correlated with serotonin tissue concentration and synthesis rates reported previously in literature. These findings suggest the use of [11C]-HTP PET measurements to investigate serotonin synthesis.
Temporal Profile of Angiogenesis and Expression of Related Genes in the Brain after Ischemia
Authors: Hayashi Takeshi , Noshita Nobuo , Sugawara Taku , Chan Pak H.
Published: December 2015

Angiogenesis is an intricately regulated phenomenon. Its mechanisms in the ischemic brain have not been clearly elucidated. The authors investigated expression of angiogenesis-related genes using a complementary DNA (cDNA) array method as well as Western blotting and immunohistochemistry, and compared these studies with a temporal profile of angiogenesis in mouse brains after ischemia. The number of vessels significantly increased 3 days after injury, and proliferating endothelial cells increased as early as 1 day. This means that angiogenesis occurs immediately after the injury. Ninety-six genes implicated in angiogenesis were investigated with a cDNA array study. It was found that 42, 29, and 13 genes were increased at 1 hour, 1 day, and 21 days, respectively. Most of the well-known angiogenic factors increased as early as 1 hour. Vessel-stabilizing factors such as thrombospondins also increased. At 1 day, however, thrombospondins decreased to lower levels than in the control, indicating a shift from vascular protection to angiogenesis. At 21 days, many genes were decreased, but some involved in tissue repair were newly increased. Western blotting and immunohistochemistry showed findings compatible with the cDNA array study. Many molecules act in an orchestrated fashion in the brain after ischemia and should be taken into account for therapeutic angiogenesis for stroke.
Early Magnetic Resonance Imaging Prediction of Arterial Recanalization and Late Infarct Volume in Acute Carotid Artery Stroke
Authors: Hermier Marc , Nighoghossian Norbert , Adeleine Patrice , Berthezène Yves , Derex Laurent , Yilmaz Hasan , Dugor Jean-François , Dardel Pascal , Cotton Francois , Philippeau Frédéric , Trouillas Paul , Froment Jean-Claude
Published: December 2015

In patients with acute ischemic stroke, early recanalization may save tissue at risk for ischemic infarction, thus resulting in smaller infarcts and better clinical outcome. The hypothesis that clinical and diffusion- and perfusion-weighted imaging (DWI, PWI) parameters may have a predictive value for early recanalization and final infarct size was assessed. Twenty-nine patients were prospectively enrolled and underwent sequential magnetic resonance imaging (1) within 6 hours from hemispheric stroke onset, before thrombolytic therapy; (2) at day 1; and (3) at day 60. Late infarct volume was assessed by T2-weighted imaging. At each time, clinical status was assessed by the National Institutes of Health Stroke Scale (NIHSS). Twenty-eight patients had arterial occlusion at day 0 magnetic resonance angiography (MRA). They were classified into two groups according to day 1 MRA: recanalization (n = 18) versus persistent occlusion (n = 10). Any significant differences between these groups were assessed regarding (1) PWI and DWI abnormality volumes, (2) relative and absolute time-to-peak (TTP) and apparent diffusion coefficient within the lesion on DWI; and (3) day 60 lesion volume on T2-weighted imaging. Univariate and multivariate logistic regression analysis showed that the most powerful predictive factors for recanalization were lower baseline NIHSS score and lower baseline absolute TTP within the lesion on DWI. The best predictors of late infarct size were day 0 lesion volume on DWI and day 1 recanalization. Early PWI and DWI studies and day 1 MRA provide relevant predictive information on stroke outcome.
Estrogen Deprivation and Replacement Modulate Cerebral Capillary Density with Vascular Expression of Angiogenic Molecules in Middle-Aged Female Rats
Authors: Jesmin Subrina , Hattori Yuichi , Sakuma Ichiro , Liu Ming-Yue , Mowa Chishimba N. , Kitabatake Akira
Published: December 2015

The effect of postmenopausal estrogen replacement therapy (ERT) on the risk or severity of cerebrovascular disorders is as yet unclear, and the evidence for flow preservation being a mechanism of estrogen neuroprotection remains elusive. The authors examined whether estrogen-mediated flow-preserving neuroprotective mechanisms, if any, may involve its angiogenic action. This study was conducted using middle-aged (44 weeks) female rats because of the importance of aging in cerebrovascular disease in women. Middle-aged female rats were subjected to sham operation, ovariectomy, or ovariectomy with ERT. The anatomic cerebral capillary morphology showed a significant reduction in the total capillary density in the frontal cortex after ovariectomy. This was associated with marked decreases in protein and gene expression of vascular endothelial growth factor and its angiogenic receptors in cerebral vessels, as demonstrated by immunohistochemistry and in situ hybridization. The expression levels of both estrogen receptor (ER) subtypes, ERα and ERβ, in cerebral vessels were significantly reduced after ovariectomy, but ERβ was more dramatically downregulated as assessed by the ERβ/ERα ratio. These ovariectomy-induced changes were completely prevented by ERT. Vascular endothelial growth factor appears to be a critical regulatory molecule for physiologic cerebral angiogenesis in middle-aged female rats and may play an important role in the flow-preserving neuroprotective action of estrogen through its angiogenic and antiapoptotic properties.
Beyond the Visible—Imaging the Human Brain with Light
Authors: Obrig Hellmuth , Villringer Arno
Published: December 2015

Optical approaches to investigate cerebral function and metabolism have long been applied in invasive studies. From the neuron cultured in vitro to the exposed cortex in the human during neurosurgical procedures, high spatial resolution can be reached and several processes such as membrane potential, cell swelling, metabolism of mitochondrial chromophores, and vascular response can be monitored, depending on the respective preparation. The authors focus on an extension of optical methods to the noninvasive application in the human. Starting with the pioneering work of Jöbsis 25 years ago, near-infrared spectroscopy (NIRS) has been used to investigate functional activation of the human cerebral cortex. Recently, several groups have started to use imaging systems that allow the generation of images of a larger area of the subject's head and, thereby, the production of maps of cortical oxygenation changes. Such images have a much lower spatial resolution compared with the invasively obtained optical images. The noninvasive NIRS images, however, can be obtained in undemanding set-ups that can be easily combined with other functional methods, in particular EEG. Moreover, NIRS is applicable to bedside use. The authors briefly review some of the abundant literature on intrinsic optical signals and the NIRS imaging studies of the past few years. The weaknesses and strengths of the approach are critically discussed. The authors conclude that NIRS imaging has two major advantages: it can address issues concerning neurovascular coupling in the human adult and can extend functional imaging approaches to the investigation of the diseased brain.
Stroke Damage in Mice after Knocking the Neutrophin-4 Gene into the Brain-Derived Neurotrophic Factor Locus
Authors: Endres Matthias , Fan Guoping , Hirt Lorenz , Jaenisch Rudolf
Published: December 2015

Neurotrophins play a protective role during cerebral ischemia, and mice lacking both alleles for neurotrophin 4 (Nt4−/-) or deficient in a single allele for brain-derived neurotrophic factor (Bdnf−/-) have increased susceptibility to cerebral ischemia. This study directly compared the biologic activities of brain-derived neurotrophic factor (BDNF) and NT4 by replacing the Bdnf coding sequence with the Nt4 sequence (Bdnf+/nt4–ki). Mice expressing one Nt4 allele in place of Bdnf develop 61% bigger lesions after 1-hour middle cerebral artery occlusion compared with wild-type littermates. Physiologic parameters did not contribute to ischemia susceptibility. In conclusion, NT4 is less potent than BDNF in promoting brain survival after stroke.
Astrocytes and Brain Injury
Authors: Chen Yongmei , Swanson Raymond A.
Published: December 2015

Astrocytes are the most numerous cell type in the central nervous system. They provide structural, trophic, and metabolic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions during brain ischemia and other insults can critically influence neuron survival. Astrocyte functions that are known to influence neuronal survival include glutamate uptake, glutamate release, free radical scavenging, water transport, and the production of cytokines and nitric oxide. Long-term recovery after brain injury, through neurite outgrowth, synaptic plasticity, or neuron regeneration, is influenced by astrocyte surface molecule expression and trophic factor release. In addition, the death or survival of astrocytes themselves may affect the ultimate clinical outcome and rehabilitation through effects on neurogenesis and synaptic reorganization.