bluuebunny/crossref_metadata_2025 huggingface dataset:
Triptans Reduce the Inflammatory Response in Bacterial Meningitis
Authors: Hoffmann Olaf , Keilwerth Nikolas , Bille Margarethe Bastholm , Reuter Uwe , Angstwurm Klemens , Schumann Ralf R. , Dirnagl Ulrich , Weber Joerg R.
Published: November 2003

Severe headache and meningism provide clear evidence for the activation of trigeminal neurotransmission in meningitis. The authors assessed the antiinflammatory potential of 5HT1B/D/F receptor agonists (triptans), which inhibit the release of proinflammatory neuropeptides from perivascular nerve fibers. In a 6-hour rat model of pneumococcal meningitis, zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, and attenuated the increase of regional cerebral blood flow. Elevated intracranial pressure as well as the brain water content at 6 hours was reduced by triptans. These effects were partially reversed by a specific 5HT1D as well as by a specific 5HT1B receptor antagonist. Meningitis caused a depletion of calcitonin gene-related peptide (CGRP) and substance P from meningeal nerve fibers, which was prevented by zolmitriptan and naratriptan. In line with these findings, patients with bacterial meningitis had significantly elevated CGRP levels in the cerebrospinal fluid. In a mouse model of pneumococcal meningitis, survival and clinical score at 24 hours were significantly improved by triptan treatment. The findings suggest that, besides mediating meningeal nociception, meningeal nerve fibers contribute to the inflammatory cascade in the early phase of bacterial meningitis. Adjunctive treatment with triptans may open a new therapeutic approach in the acute phase of bacterial meningitis.
Physiologically Based Model of Acute Ischemic Stroke
Authors: Duval Vincent , Chabaud Sylvie , Girard Pascal , Cucherat Michel , Hommel Marc , Boissel Jean Pierre
Published: November 2003

In the treatment of acute ischemic stroke most of the clinical trials have failed, contrasting with promising results in the preclinical stages. This continuing discrepancy suggests some misconceptions in the understanding of acute ischemic stroke. One possible method for identifying the shortcomings of present-day approaches is to integrate all the available knowledge into a single mathematical model and to subject that model to challenges via simulations with available experimental data. As a first stage, then, the authors developed a simplified model, defining the structure and the different parameters that represent the phenomena that occur during the hyperacute phase of ischemic stroke. First, the different critical points of the evolution of ischemic stroke, based on the available evidence on the pathophysiology of stroke, were identified. Those key steps were then related to the quantitative data obtained by magnetic resonance imaging and positron emission tomography scan. These two techniques allow the measurement of diverse key markers of cerebral metabolism: cerebral blood flow (CBF), oxygen extraction factor, cerebral metabolism rate of oxygen, and the apparent diffusion coefficient of water, among others. Those markers were organized together through mathematical equations, and changed over time in order to describe the evolution of an acute ischemic stroke. At each time during the evolution of stroke those parameters are summarized in a parameter called survival delay. This parameter made possible the definition of three different states for tissues—functional, infarcted, salvageable—as end point. Once the model was designed, simulations were performed to explore its internal validity. Simulation results were consistent with the reality of acute ischemic stroke and did not reveal any major drawbacks in the use of the model. The more rapid the decrease in CBF, the larger is the final infarcted area. The model also allowed for the characterization of two types of tissue in the penumbra: tissues with an initial metabolic impairment and tissues altered owing to the closeness of the ischemic area. The results of this experiment were consistent with what is known of acute ischemic stroke. The model integrated different markers of acute ischemic stroke into a single entity in order to mimic acute ischemic stroke, and has been shown to have a reasonable degree of internal validity.
Positron Emission Tomography Partial Volume Correction: Estimation and Algorithms
Authors: Aston John A. D. , Cunningham Vincent J. , Asselin Marie-Claude , Hammers Alexander , Evans Alan C. , Gunn Roger N.
Published: November 2003

Partial volume effects in positron emission tomography (PET) lead to quantitative under- and over-estimations of the regional concentrations of radioactivity in reconstructed images and corresponding errors in derived functional or parametric images. The limited resolution of PET leads to “tissue-fraction” effects, reflecting underlying tissue heterogeneity, and “spillover” effects between regions. Addressing the former problem in general requires supplementary data, for example, coregistered high-resolution magnetic resonance images, whereas the latter effect can be corrected for with PET data alone if the point-spread function of the tomograph has been characterized. Analysis of otherwise homogeneous region-of-interest data ideally requires a combination of tissue classification and correction for the point-spread function. The formulation of appropriate algorithms for partial volume correction (PVC) is dependent on both the distribution of the signal and the distribution of the underlying noise. A mathematical framework has therefore been developed to accommodate both of these factors and to facilitate the development of new PVC algorithms based on the description of the problem. Several methodologies and algorithms have been proposed and implemented in the literature in order to address these problems. These methods do not, however, explicitly consider the noise model while differing in their underlying assumptions. The general theory for estimation of regional concentrations, associated error estimation, and inhomogeneity tests are presented in a weighted least squares framework. The analysis has been validated using both simulated and real PET data sets. The relations between the current algorithms and those published previously are formulated and compared. The incorporation of tensors into the formulation of the problem has led to the construction of computationally rapid algorithms taking into account both tissue-fraction and spillover effects. The suitability of their application to dynamic and static images is discussed.
Effect of Basal Conditions on the Magnitude and Dynamics of the Blood Oxygenation Level-Dependent fMRI Response
Authors: Cohen Eric R. , Ugurbil Kamil , Kim Seong-Gi
Published: November 2003

The effect of the basal cerebral blood flow (CBF) on both the magnitude and dynamics of the functional hemodynamic response in humans has not been fully investigated. Thus, the hemodynamic response to visual stimulation was measured using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in human subjects in a 7-T magnetic field under different basal conditions: hypocapnia, normocapnia, and hypercapnia. Hypercapnia was induced by inhalation of a 5% carbon dioxide gas mixture and hypocapnia was produced by hyperventilation. As the fMRI baseline signal increased linearly with expired CO2 from hypocapnic to hypercapnic levels, the magnitude of the BOLD response to visual stimulation decreased linearly. Measures of the dynamics of the visually evoked BOLD response (onset time, full-width-at-half-maximum, and time-to-peak) increased linearly with the basal fMRI signal and the end-tidal CO2 level. The basal CBF level, modulated by the arterial partial pressure of CO2, significantly affects both the magnitude and dynamics of the BOLD response induced by neural activity. These results suggest that caution should be exercised when comparing stimulus-induced fMRI responses under different physiologic or pharmacologic states.
New Method for the Quantitative Assessment of Axonal Damage in Focal Cerebral Ischemia
Authors: Imai Hideaki , McCulloch James , Graham David I. , Masayasu Hiroyuki , Macrae I. Mhairi
Published: November 2003

Quantification of damage in both grey and white matter is required for comprehensive assessment of neuroprotective drug efficacy. Although methods for quantification of neuronal perikaryal damage after ischemia are well established, assessment of axonal damage has been limited. This article describes a new method for quantitation of axonal injury after middle cerebral artery (MCA) occlusion in rats and its application to the study of the antioxidant ebselen. The methodology is based on immunohistochemical detection of amyloid precursor protein (APP) accumulation in deformed, swollen axons in zones of ischemia. Sixty-five axon-rich sites throughout the MCA territory are assessed for the presence (scored 1) or absence (scored 0) of accumulated APP in axonal swellings. Scores for individual sites are summated in predefined neuroanatomic regions (e.g. corpus callosum), stereotaxic levels, or for a total hemisphere APP score. Both intra-rater and inter-rater reproducibility were high ( r = 0.87 and 0.80, respectively). Ebselen (1 mg kg−1 hr−1, intravenously) significantly reduced the volume of neuronal perikaryal damage (24%, P < 0.01) and axonal damage (total APP score reduced from 27 [23.9 to 35.1, 95% CI] to 21.5 [18.2 to 23.3], P = 0.002 with ebselen treatment). In conclusion, a robust and generally applicable method is described for assessing pathologic features in myelinated fiber tracts that is sensitive for detection of drug effects on axonal damage.
Grey Matter and White Matter Ischemic Damage is Reduced by the Competitive AMPA Receptor Antagonist, SPD 502
Authors: McCracken Eileen , Fowler Jill H. , Dewar Deborah , Morrison Steve , McCulloch James
Published: November 2003

Protection of both grey and white matter is important for improvement in stroke outcome. In the present study the ability of a competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist to protect axons, oligodendrocytes, and neuronal perikarya, was examined in a rodent model of transient focal cerebral ischemia. SPD 502 (8-methyl-5-(4-( N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-o(4-hydroxybutyricacid-2-yl)oxime) was administered as an intravenous bolus (16 mg/kg) 15 minutes before transient (3-hour) middle cerebral artery (MCA) occlusion, followed by an intravenous infusion (16 mg kg−1 hr−1) of the drug for 4 hours. Twenty-one hours after ischemia, axonal damage was reduced by 45% ( P = 0.006) in the SPD 502–treated group compared with the vehicle. The anatomic extent of ischemically damaged oligodendrocytes, determined by Tau1 immunoreactivity, was reduced in the cerebral cortex by 53% ( P = 0.024) in SPD 502–treated rats compared with vehicle-treated rats, but there was minimal effect in the subcortex. The volume of neuronal perikaryal damage after MCA occlusion was significantly reduced by SPD 502 in the cerebral cortex (by 68%; P = 0.005), but there was minimal change in the subcortex with drug treatment. The AMPA receptor antagonist significantly reduced the anatomic extent of lipid peroxidation (assessed as the volume of 4-hydroxynonenol immunoreactivity), and this may have contributed to its ability to protect multiple cell types in ischemia. The data demonstrate that AMPA blockade protects both grey and white matter from damage induced by transient focal ischemia.
Phosphorylation of Neuronal Nitric Oxide Synthase at Ser847 by CaM-KII in the Hippocampus of Rat Brain after Transient Forebrain Ischemia
Authors: Osuka Koji , Watanabe Yasuo , Usuda Nobuteru , Nakazawa Ayami , Fukunaga Kohji , Miyamoto Eishichi , Takayasu Masakazu , Tokuda Masaaki , Yoshida Jun
Published: November 2003

The authors previously demonstrated that Ca 2+/calmodulin (CaM)-dependent protein kinase IIα (CaM-KIIα) can phosphorylate neuronal nitric oxide synthase (nNOS) at Ser847 and attenuate NOS activity in neuronal cells. In the present study, they established that forebrain ischemia causes an increase in the phosphorylation of nNOS at Ser847 in the hippocampus. This nNOS phosphorylation appeared to be catalyzed by CaM-KII: (1) it correlated with the autophosphorylation of CaM-KIIα; (2) it was blocked by the CaM-KII inhibitor, KN-93; and (3) nNOS and CaM-KIIα were found to coexist in the hippocampus. Examination of the spatial relation between nNOS and CaM-KIIα in the brain revealed coexistence in the hippocampus but not in the cortex during reperfusion, with a concomitant increase in autophosphorylation of CaM-KIIα. The phosphorylation of nNOS at Ser847 probably takes place in nonpyramidal hippocampal neurons, which increased after 30 minutes of reperfusion in the hippocampus, whereas no significant increase was detected in the cortex. An intraventricular injection of KN-93 significantly decreased the phosphorylation of nNOS in the hippocampus. These results point to CaM-KII as a protein kinase, which by its colocalization may attenuate the activity of nNOS through its Ser847 phosphorylation, and may thus contribute to promotion of tolerance to postischemic damage in hippocampal neurons.
The Phosphodiesterase 5 Inhibitor Sildenafil Has No Effect on Cerebral Blood Flow or Blood Velocity, but Nevertheless Induces Headache in Healthy Subjects
Authors: Kruuse Christina , Thomsen Lars Lykke , Jacobsen Torsten Bjørn , Olesen Jes
Published: November 2003

Cyclic nucleotides are important hemodynamic regulators in many tissues. Glyceryl trinitrate markedly dilates large cerebral arteries and increases cGMP. Here, the authors study the effect of sildenafil, a selective inhibitor of cGMP-hydrolyzing phosphodiesterase 5 on cerebral hemodynamics and headache induction. Ten healthy subjects were included in a double-blind, placebo-controlled crossover study where placebo or sildenafil 100 mg (highest therapeutic dose) were administered on two separate days. Blood velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler, and regional cerebral blood flow in the perfusion area of the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133xenon inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasound. Blood pressure and heart rate were recorded repeatedly. Headache responses and tenderness of pericranial muscles were scored verbally. Sildenafil caused no significant changes in rCBFmca, Vmca, or in temporal or radial artery diameter, but heart rate increased and diastolic blood pressure decreased significantly compared to placebo. Despite the lack of cerebral arterial dilatation, sildenafil caused significantly more headache than placebo. The present results show that sildenafil 100 mg does not dilate cerebral or extracerebral arteries but nevertheless causes headache, which may be attributed to nonvascular mechanisms.
Use of Cerebrovascular Reactivity in Patients with Symptomatic Major Cerebral Artery Occlusion to Predict 5-Year Outcome: Comparison of Xenon-133 and Iodine-123-IMP Single-Photon Emission Computed Tomography
Authors: Ogasawara Kuniaki , Ogawa Akira , Terasaki Kazunori , Shimizu Hiroaki , Tominaga Teiji , Yoshimoto Takashi
Published: November 2003

The aim of this prospective study was to investigate whether decreased cerebrovascular reactivity to acetazolamide, as determined by single-photon emission computed tomography (SPECT), is an independent predictor of the 5-year risk of subsequent stroke in patients with symptomatic major cerebral artery occlusion. Cerebrovascular reactivity to acetazolamide in the middle cerebral artery (MCA) territory ipsilateral to the occluded artery was determined on the basis of two different methodologies: cerebral blood flow (CBF) percent change obtained quantitatively from xenon-133 (133Xe) SPECT, and asymmetry index (AI) percent change obtained qualitatively from N-isopropyl- p-[123I]-iodoamphetamine (IMP) SPECT. Seventy patients with unilateral internal carotid artery or MCA occlusion were divided into two groups within each SPECT methodology (normal or decreased CBF percent change and AI percent change) and followed up for 5 years. Cumulative recurrence-free survival rates for patients with decreased CBF percent change were significantly lower than for those with normal CBF percent change ( P = 0.0205). There was no significant difference in cumulative recurrence-free survival rates between patients with decreased AI percent change and those with normal AI percent change. Only decreased CBF percent change was a significant independent predictor of stroke recurrence ( P = 0.0051). The present study demonstrated that decreased cerebrovascular reactivity to acetazolamide determined quantitatively by Xe SPECT is an independent predictor of the 5-year risk of subsequent stroke in patients with symptomatic major cerebral artery occlusion, and that the qualitative method using I-IMP SPECT is a poor predictor of the risk of subsequent stroke in this type of patient.
Silver-Sulfadiazine Eschar Pigmentation Mimics Invasive Wound Infection
Authors: Eldad A. , Icekson M. , Zur T. , Slosser D. , Maly A. , Arielli D. , Burvin R. , Ad-El D. , Neuman A.
Published: November 2003

A 3-year-old girl with 52% TBSA scalds, mostly partial thickness, was treated topically with 5% mafenide acetate solution and 1% silver sulfadiazine cream. All blood cultures and wound swabs were negative for the first 5 days. On day 6 gram-negative bacteria and yeast forms were isolated from her wounds. High fever and leukocytosis were present and the child was treated with intravenous ampicillin and gentamicin according to sensitivity bacteriogram. The bacteria were identified as Pseudomonas aeruginosa and the yeast was Candida tropicalis. On day 7, Escherichia coli was identified in blood cultures and intravenous cefixime was added. Amphotericin B was added on day 9 when blood cultures grew Candida tropicalis and Burkholderia cepacia. On day 13 dark pigmentation foci developed on some areas of partial-thickness burns in the back, resembling invasive wound infection. White blood cell count was 14,300 cells/mm3, and her body temperature reached 39.7°C. Cultures from the pigmented areas were negative, and biopsies revealed deposits of silver. Most of the areas healed uneventfully, and only about 8% TBSA needed grafting, including some of the pigmented areas. No residual pigmentation remained on discharge.
What Are the Acute Cardiovascular Effects of Subcutaneous and Topical Epinephrine for Hemostasis During Burn Surgery?
Authors: Cartotto Robert , Kadikar Nisha , Musgrave Melinda A. , Gomez Manuel , Cooper Andrew B.
Published: November 2003

Although subcutaneous and topical epinephrine are widely used for hemostasis during burn surgery, the acute systemic cardiovascular effects of the epinephrine are neither well documented nor completely understood. The purpose of this work was to prospectively study the acute cardiovascular responses to epinephrine (epi) administered subcutaneously and topically during burn surgery. Consecutive patients who received subcutaneous and topical epi during burn surgery were monitored prior to the administration of epi, at 2-minute intervals during subcutaneous epi infiltration, and then after epi infiltration (during which time, topical epi was applied). This period of monitoring lasted up to 20 minutes and was referred to as an epinephrine event (EE). A total of 100 EEs from 38 operations in 24 patients (mean ± SD: age 43 ± 16 years, mean % TBSA burn 23 ± 17%) were studied. The mean dose of subcutaneous epi was 30 ± 30 μg/kg. Although all patients received topical epi, it was impossible to document the topical dose. There was no significant increase in heart rate from baseline, and no arrhythmias occurred. Mean arterial pressure (MAP) did acutely increase significantly by 17.0 ± 14.1% from baseline (P = .009) and increased more than 10% from baseline in 64/100 EEs. However, the increase in MAP was independent of the dose of epi (r = .053). The increase in MAP was not clinically significant, did not require intervention, and did not appear to be related to the type of wound that received epi (donor site vs burn wound), or the depth of anesthesia, analgesia, or sedation. On the basis of these findings, the use of subcutaneous and topical epi appears to be safe and produces minimal acute cardiovascular effects.
Alternative Splinting Methods for the Prevention and Correction of Burn Scar Torticollis
Authors: Serghiou Michael A. , McLaughlin Alex , Herndon David N.
Published: November 2003

Significant neck burns may lead to deforming lateral flexion and rotation contractures. A two-device splinting regimen has been designed to prevent such contractures. In the acute phase, the Dynamic Antitorticollis Strap is applied while the patient is in bed to gently rotate the head and neck toward the neutral position. This dynamic strap includes a Velfoam® headband attached to Thera-Band® secured to the patient's bed. The antitorticollis neck splint is used in the rehabilitation phase and can be serially adjusted to correct lateral flexion contractures of the neck. Thermoplastic material is cut from a modified neck splint pattern and draped over the temporaloccipital region and anterior/posterior shoulder ipsilateral to the contracture and the anterior and contralateral aspect of the neck. The combined use of these devices during the scar maturation phase provides therapists with alternatives in preventing burn scar torticollis.
Noncontact Electrosurgical Grounding Is Useful in Burn Surgery
Authors: Sheridan Robert L. , Wilson Norman C. , O'Connell Mark F. , Fabri Judith A.
Published: November 2003

Grounding patients with large burns to facilitate the use of electrocautery devices during surgery is commonly difficult because of the paucity of available grounding sites. The Mega 2000 Patient Return Electrode System (Megadyne Medical Products, Draper, UT) is an electrode designed to provide electrical return to facilitate function of electrocautery devices without direct patient contact. It accomplishes this by having a very large surface area (720 square inches) in the form of a reusable pad placed on the operating table that is covered by an impermeable drape and clean sheet beneath the patient. We used this noncontact device in 25 operations of 17 children with large burns and limited availability of traditional grounding sites. The patients had an average age of 8.8 + 4.6 years (range, 14 months–14 years), average burn size of 55 + 33% of the body surface (range, 10–95%), and average weight of 33.0 + 17.9 kg (range, 9–75 kg). Operations included 22 excision and grafting operations, an axillary release, a neck release, and bilateral groin releases. The device functioned well in all cases. There were no cutaneous burns observed. No additional traditional devices required placement. We found the device useful in burn surgery in those cases where there is a paucity of traditional grounding sites available.
Overexpression of Rat Heat Shock Protein 70 is Associated with Reduction of Early Mitochondrial Cytochrome c Release and Subsequent DNA Fragmentation after Permanent Focal Ischemia
Authors: Tsuchiya Daisuke , Hong Shwuhuey , Matsumori Yasuhiko , Shiina Hiroaki , Kayama Takamasa , Swanson Raymond A. , Dillman Wolfgang H. , Liu Jialing , Panter S. Scott , Weinstein Philip R.
Published: November 2003

Although protective effects of heat shock protein 70 (HSP70) overproduction after ischemic injury have been shown both in vitro and in vivo in neurons, the mechanisms are not fully understood. The hypothesis of this study is that transgenic mice overexpressing HSP70 (HSP70 Tg) show reduced mitochondrial cytochrome c release into cytosol and diminished apoptotic cell death after permanent focal ischemia in comparison to wild-type (Wt) mice.

Permanent middle cerebral artery occlusion (pMCAO) was produced by intraluminal suture cannulation in HSP70 Tg and Wt mice. DNA fragmentation was evaluated with DNA gel electrophoresis and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) 24 h after pMCAO. Mitochondrial cytochrome c release into cytosol was assessed with Western blotting and immunohistochemistry 4 h after pMCAO. Cytochrome c levels in the cytosolic fraction were significantly reduced and immunoreactivity of cytochrome c in both cortex and striatum was significantly less in HSP70 Tg mice compared with Wt mice after 4-h pMCAO. DNA laddering, which was clearly observed in Wt mice, was markedly attenuated in HSP70 Tg mice 24 h after pMCAO. The number of TUNEL-positive cells was significantly reduced in HSP70 Tg mice compared with Wt mice. Results are consistent with an association between overexpression of HSP70 and reduction of cytochrome c release with subsequent DNA fragmentation. This may contribute to the HSP70-mediated neuroprotective effect observed after cerebral ischemia.
Energy Metabolism in Astrocytes and Neurons Treated with Manganese: Relation among Cell-Specific Energy Failure, Glucose Metabolism, and Intercellular Trafficking Using Multinuclear NMR-Spectroscopic Analysis
Authors: Zwingmann Claudia , Leibfritz Dieter , Hazell Alan S.
Published: November 2003

A central question in manganese neurotoxicity concerns mitochondrial dysfunction leading to cerebral energy failure. To obtain insight into the underlying mechanism(s), the authors investigated cell-specific pathways of [1–13C]glucose metabolism by high-resolution multinuclear NMR-spectroscopy. Five-day treatment of neurons with 100-μmol/L MnCl2 led to 50% and 70% decreases of ATP/ADP and phosphocreatine–creatine ratios, respectively. An impaired flux of [1-13C]glucose through pyruvate dehydrogenase, which was associated with Krebs cycle inhibition and hence depletion of [4–13C]glutamate, [2–13C]GABA, and [13C]glutathione, hindered the ability of neurons to compensate for mitochondrial dysfunction by oxidative glucose metabolism and further aggravated neuronal energy failure. Stimulated glycolysis and oxidative glucose metabolism protected astrocytes against energy failure and oxidative stress, leading to twofold increased de novo synthesis of [3–13C]lactate and fourfold elevated [4–13C]glutamate and [13C]glutathione levels. Manganese, however, inhibited the synthesis and release of glutamine. Comparative NMR data obtained from cocultures showed disturbed astrocytic function and a failure of astrocytes to provide neurons with substrates for energy and neurotransmitter metabolism, leading to deterioration of neuronal antioxidant capacity (decreased glutathione levels) and energy metabolism. The results suggest that, concomitant to impaired neuronal glucose oxidation, changes in astrocytic metabolism may cause a loss of intercellular homeostatic equilibrium, contributing to neuronal dysfunction in manganese neurotoxicity.
No Role for Interleukin-18 in Acute Murine Stroke-Induced Brain Injury
Authors: Wheeler Rachel D. , Boutin Herve , Touzani Omar , Luheshi Giamal N. , Takeda Kiyoshi , Rothwell Nancy J.
Published: November 2003

There is now extensive evidence to show that the cytokine interleukin-1 (IL-1) contributes directly to reversible and permanent ischemic brain damage in rodents. Because interleukin-18 (IL-18) shares many structural and functional similarities with IL-1, the authors tested the hypothesis that IL-18 contributes directly to ischemic brain damage in mice exposed to focal, reversible (15-minute or 30-minute) middle cerebral artery occlusion. IL-18 expression was not induced acutely by middle cerebral artery occlusion, and deletion of the IL-18 gene (IL-18 knockout mice) did not affect infarct volume. The present results suggest that IL-18 does not contribute to acute ischemic brain damage.
Participation of Bone Marrow-Derived Cells in Long-Term Repair Processes after Experimental Stroke
Authors: Beck Heike , Voswinckel Robert , Wagner Shawn , Ziegelhoeffer Tibor , Heil Matthias , Helisch Armin , Schaper Wolfgang , Acker Till , Hatzopoulos Antonis K. , Plate Karl H.
Published: November 2003

Bone marrow-derived cells participate in remodeling processes of many ischemia-associated diseases, which has raised hopes for the use of bone marrow as a source for cell-based therapeutic approaches. To study the participation of bone marrow-derived cells in a stroke model, bone marrow from C57BL/6-TgN(ACTbEGFP)1Osb mice that express green fluorescent protein (GFP) in all cells was transplanted into C57BL/6J mice. The recipient mice underwent permanent occlusion of the middle cerebral artery, and bone marrow-derived cells were tracked by fluorescence. The authors investigated the involvement of bone marrow-derived cells in repair processes 6 weeks and 6 months after infarction. Six weeks after occlusion of the artery, more than 90% of the GFP-positive cells in the infarct border zone were microglial cells. Very few GFP-positive cells expressed endothelial markers in the infarct/infarct border zone, and no bone marrow-derived cells transdifferentiated into astrocytes, neurons, or oligodendroglial cells at all time points investigated. The results indicate the need for additional experimental studies to determine whether therapeutic application of nonselected bone marrow will replenish brain cells beyond an increase in microglial engraftment.
Effects of Hypothermia on Energy Metabolism in Mammalian Central Nervous System
Authors: Erecinska Maria , Thoresen Marianne , Silver Ian A.
Published: November 2003

This review analyzes, in some depth, results of studies on the effect of lowered temperatures on cerebral energy metabolism in animals under normal conditions and in some selected pathologic situations. In sedated and paralyzed mammals, acute uncomplicated 0.5- to 3-h hypothermia decreases the global cerebral metabolic rate for glucose (CMRglc) and oxygen (CMRO2) but maintains a slightly better energy level, which indicates that ATP breakdown is reduced more than its synthesis. Intracellular alkalinization stimulates glycolysis and independently enhances energy generation. Lowering of temperature during hypoxia–ischemia slows the rate of glucose, phosphocreatine, and ATP breakdown and lactate and inorganic phosphate formation, and improves recovery of energetic parameters during reperfusion. Mild hypothermia of 12 to 24-h duration after normothermic hypoxic–ischemic insults seems to prevent or ameliorate secondary failures in energy parameters. The authors conclude that lowered head temperatures help to protect and maintain normal CNS function by preserving brain ATP supply and level. Hypothermia may thus prove a promising avenue in the treatment of stroke and trauma and, in particular, of perinatal brain injury.
Development of Injectable O-15 Oxygen and Estimation of Rat OEF
Authors: Magata Yasuhiro , Temma Takashi , Iida Hidehiro , Ogawa Mikako , Mukai Takahiro , Iida Yasuhiko , Morimoto Takayuki , Konishi Junji , Saji Hideo
Published: November 2003

Cerebral metabolic rate for oxygen (CMRO2) and cerebral oxygen extraction fraction (OEF) are some of the most fundamental parameters to characterize the pathophysiologic status of cerebral tissue. Although O-15-labeled gases inhalation method is performed in clinical studies, application of the inhalation method on small animals requires too many intensive procedures. On this basis, the development of a new method to measure CMRO2 and OEF in small animals is of interest. This study was aimed at developing a method to assess CMRO2 and OEF using intravenously injectable oxygen (injectable 15O–O2) for small animals such as rats. Injectable 15O–O2, 72 MBq/mL of radioactivity, was obtained after 15O–O2 gas circulation into the artificial lung. OEF after injection of injectable 15O–O2 was calculated using the same equation as that applied to the bolus inhalation of 15O–O2 gas method. Values of 44 ± 4.5 mL · min−1 · 100 g−1 of CBF and 0.54 ± 0.11 of OEF were obtained (n = 13). This OEF value was well accordance with OEF evaluated by arterial-venous difference of oxygen concentration (0.57 ± 0.13). This method is useful to study the CMRO2 and OEF in small animals using an animal positron emission tomography system. It may accelerate the basic research of several cerebral perfusion diseases.
The Ras Inhibitor S-Trans, Trans-Farnesylthiosalicylic Acid Exerts Long-Lasting Neuroprotection in a Mouse Closed Head Injury Model
Authors: Shohami Esther , Yatsiv Ido , Alexandrovich Alexander , Haklai Roni , Elad-Sfadia Galit , Grossman Rachel , Biegon Anat , Kloog Yoel
Published: November 2003

Traumatic brain injury activates N-methyl-D-aspartate receptors (NMDAR) inducing activation of the Ras protein (a key regulator of cell growth, survival, and death) and its effectors. Thus, trauma-induced increase in active Ras-GTP might contribute to traumatic brain injury pathology. Based on this hypothesis, a new concept of neuroprotection is proposed, examined here by investigating the effect of the Ras inhibitor S- trans, trans-farnesylthiosalicylic acid (FTS) in a mouse model of closed head injury (CHI). Mice subjected to CHI were treated systemically 1 h later with FTS (5 mg/kg) or vehicle. After 1 h, Ras-GTP in the contused hemisphere showed a significant (3.8-fold) increase, which was strongly inhibited by FTS (82% inhibition) or by the NMDA-receptor antagonist MK-801 (53%). Both drugs also decreased active (phosphorylated) extracellular signal-regulated kinase. FTS prevented the CHI-induced reduction in NMDAR binding in cortical, striatal, and hippocampal regions, measured by [3H]-MK-801 autoradiography, and decreased lesion size by 50%. It also reduced CHI-induced neurologic deficits, indicated by the highly significant ( P < 0.0001) 60% increase in extent of recovery. Thus, FTS provided long-term neuroprotection after CHI, rescuing NMDAR binding in the contused hemisphere and profoundly reducing neurologic deficits. These findings suggest that nontoxic Ras inhibitors such as FTS may qualify as neuroprotective drugs.
Host-Dependent Tumorigenesis of Embryonic Stem Cell Transplantation in Experimental Stroke
Authors: Erdö Franciska , Bührle Christian , Blunk James , Hoehn Mathias , Xia Ying , Fleischmann Bernd , Föcking Melanie , Küstermann Ekkehardt , Kolossov Eugen , Hescheler Jürgen , Hossmann Konstantin-A. , Trapp Thorsten
Published: November 2003

The therapeutical potential of transplantation of undifferentiated and predifferentiated murine embryonic stem cells for the regeneration of the injured brain was investigated in two rodent stroke models. Undifferentiated embryonic stem cells xenotransplanted into the rat brain at the hemisphere opposite to the ischemic injury migrated along the corpus callosum towards the damaged tissue and differentiated into neurons in the border zone of the lesion. In the homologous mouse brain, the same murine embryonic stem cells did not migrate, but produced highly malignant teratocarcinomas at the site of implantation, independent of whether they were predifferentiated in vitro to neural progenitor cells. The authors demonstrated a hitherto unrecognized inverse outcome after xenotransplantation and homologous transplantation of embryonic stem cells, which raises concerns about safety provisions when the therapeutical potential of human embryonic stem cells is tested in preclinical animal models.
BOLD and Perfusion Response to Finger-Thumb Apposition after Acetazolamide Administration: Differential Relationship to Global Perfusion
Authors: Brown Gregory G. , Zorrilla Lisa T. Eyler , Georgy Bassem , Kindermann Sandra S. , Wong Eric C. , Buxton Richard B.
Published: November 2003

The authors studied the effects of altering global cerebral blood flow on both blood oxygen level–dependent (BOLD) response and perfusion response to finger-thumb apposition. A PICORE/QUIPSS II protocol was used to collect interleaved BOLD-weighted and perfusion-weighted images on eight finger-thumb apposition trials. Subjects were studied on a drug-free day and on a day when acetazolamide was administered between the second and third trials. After acetazolamide administration, resting cortical perfusion increased an average of 20% from preadministration levels, whereas the BOLD response to finger-thumb apposition decreased by an average of 35% in the S1M1 hand area. Contrary to predictions from the exhausted cerebrovascular reserve hypothesis and the oxygen limitation model, an effect of acetazolamide on cerebral blood flow response in the S1M1 hand area was not observed. Across the acetazolamide trials, BOLD response was inversely correlated with resting cortical perfusion for individual subject data. These results suggest that resting perfusion affects the magnitude of the BOLD response and is thus an important confounding factor in fMRI studies, and that the physiologic systems that increase cerebral blood flow in response to acetazolamide administration and systems that increase cerebral blood flow in response to altered neural activity appear to have additive effects.
15O Radioactivity Clearance is Faster after Intracarotid Bolus Injection of 15O-Labeled Oxyhemoglobin than after 15O-Water Injection
Authors: Seki Chie , Kershaw Jeff , Toussaint Paule-Joanne , Kashikura Kenichi , Matsuura Tetsuya , Fujita Hideaki , Kanno Iwao
Published: November 2003

The authors tested the hypothesis that the oxygen content of brain tissue is negligible by injecting an intracarotid bolus of 15O-labeled tracer into rats. Under the hypothesis, the clearance rates of 15O radioactivity from the brain after injections of both 15O-labeled water (H215O) and 15O-labeled oxyhemoglobin (HbO15O) should be identical. However, the logarithmic slope of the 15O radioactivity curve after HbO15O injection (0.494 ± 0.071 min-1) was steeper than that after H215O injection (0.406 ± 0.038 min−1) ( P<0.001, n = 13), where the time range used in the comparison was between 60 and 120 seconds after the injection. A possible interpretation of this result is that nonmetabolized O15O may dwell in the brain tissue for a finite period of time before it is eventually metabolized or returned to the blood stream unaltered. These findings contradict assumptions made by models currently used to measure cerebral oxygen metabolism.
Antiactin-Targeted Immunoliposomes Ameliorate Tissue Plasminogen Activator-Induced Hemorrhage after Focal Embolic Stroke
Authors: Asahi Minoru , Rammohan Ram , Sumii Toshihisa , Wang Xiaoying , Pauw Robert Jan , Weissig Volkmar , Torchilin Vladimir P , Lo Eng H
Published: November 2003

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli. Delayed administration of tPA (10 mg/kg, 6 hours after ischemia) induced intracerebral hemorrhage at 24 hours. In control rats treated with tPA plus vehicle, hemorrhage volumes were 9.0 ± 2.4 uL (n = 7). In rats treated with tPA plus antiactin immunoliposomes, hemorrhage volumes were significantly reduced to 4.8 ± 2.7 uL (n = 8, P < 0.05). No significant effects were seen when rats were treated with tPA plus a nontargeted liposome (7.8 ± 2.1 uL, n = 9). Fluorescent immunohistochemistry showed that rhodamine-labeled targeted liposomes colocalized with vascular structures in ischemic brain that stained positive for endothelial barrier antigen, a marker of cerebral endothelial cells. These data suggest that immunoliposomes may ameliorate vascular membrane damage and reduce hemorrhagic transformation after thrombolytic therapy in cerebral ischemia.
Functional Brain Mapping in Freely Moving Rats during Treadmill Walking
Authors: Holschneider D P , Maarek J-M I , Yang J , Harimoto J , Scremin O U
Published: November 2003

A dilemma in functional neuroimaging is that immobilization of the subject, necessary to avoid movement artifact, extinguishes all but the simplest behaviors. Recently, we developed an implantable microbolus infusion pump (MIP) that allows bolus injection of radiotracers by remote activation in freely moving, nontethered animals. The MIP is examined as a tool for brain mapping in rats during a locomotor task. Cerebral blood flow–related tissue radioactivity (CBF-TR) was measured using [14C]-iodoantipyrine with an indicator-fractionation method, followed by autoradiography. Rats exposed to walking on a treadmill, compared to quiescent controls, showed increases in CBF-TR in motor circuits (primary motor cortex, dorsolateral striatum, ventrolateral thalamus, midline cerebellum, copula pyramis, paramedian lobule), in primary somatosensory cortex mapping the forelimbs, hindlimbs and trunk, as well as in secondary visual cortex. These results support the use of implantable pumps as adjunct tools for functional neuroimaging of behaviors that cannot be elicited in restrained or tethered animals.
Quantification of 5-HT2A Receptors in the Human Brain Using [18F]Altanserin-PET and the Bolus/Infusion Approach
Authors: Pinborg Lars H , Adams Karen H , Svarer Claus , Holm Søren , Hasselbalch Steen G , Haugbøl Steven , Madsen Jacob , Knudsen Gitte M
Published: November 2003

The aim of the present study is to describe and validate a method for accurate quantification of 5-hydroxytryptamine (5-HT)2A receptors using [18F]altanserin-positron emission tomography (PET) and the bolus/infusion approach. A bolus/infusion ratio of 1.75 h aimed at attaining rapid steady state in blood and brain was predicted from previous bolus studies performed in our laboratory. The infusion schedule was tested in normal subjects (n = 10) using dynamic PET and frequent plasma sampling for 6 h. Steady state was attained in brain and plasma within 2 h, and time–activity curves remained constant for another 3 h. To represent free and nonspecifically bound [18F]altanserin and its radiolabeled metabolites only, cerebellum must show no displacement in 5-HT2A displacement studies. To validate this, saturating doses of cold ketanserin were administered and it was found that specific binding of [18F]altanserin decreased uniformly to the level of the cerebellum and no change in the cerebellar time–activity curve was found after ketanserin administration. A shorter experimental setup was tested in a second group (n = 20) including patients with neuropsychiatric disorders. Dynamic PET (five frames of 8 minutes each) and venous blood sampling at midscan time started 2 h after [18F]altanserin administration. The mean percentage rate of change per hour in the outcome parameter, DV3′, was low (mean −0.3% h−1; range −7.3–7.2% h−1) and no correlation of DV3′ versus time was demonstrated. It is concluded that 5-HT2A receptor studies can be conducted within 2 h of [18F]altanserin infusion, yielding reliable results.
Shutdown of Translation: Lethal or Protective? Unfolded Protein Response versus Apoptosis
Authors: Paschen Wulf
Published: November 2003

Shutdown of translation is a highly conserved response of cells to a severe form of metabolic, thermal, or physical stress. After the metabolic stress induced by transient cerebral ischemia, translational recovery is observed only in cells that withstand the transient interruption of blood supply, implying that restoration of translation critically determines the final outcome. On the other hand, apoptosis is believed to play a role in ischemia-induced cell death. Apoptosis is an active process that is blocked by agents known to suppress protein synthesis. Thus, the question arises whether stress-induced suppression of protein synthesis is protective or toxic for the affected cells. Accepting the notion that endoplasmic reticulum (ER) dysfunction is the mechanism underlying shutdown of translation after transient cerebral ischemia, an attempt may be made to try to solve the protein synthesis paradox by understanding the role of protein synthesis suppression in conditions associated with ER dysfunction. Endoplasmic reticulum dysfunction-induced accumulation of unfolded proteins in the ER lumen is the trigger of two signal transduction pathways: PKR-like ER kinase–induced shutdown of translation to suppress new synthesis of proteins that cannot be correctly folded, and IRE1-induced expression of ER stress genes, a protein synthesis–dependent pathway needed to restore ER functions. Together these comprise the unfolded protein response. They are also induced after transient ischemia, implying a dual effect of protein synthesis suppression, a protective and a pathologic effect during early and prolonged reperfusion.
Induction of GRP78 by Ischemic Preconditioning Reduces Endoplasmic Reticulum Stress and Prevents Delayed Neuronal Cell Death
Authors: Hayashi Takeshi , Saito Atsushi , Okuno Shuzo , Ferrand-Drake Michel , Chan Pak H
Published: November 2003

Although the endoplasmic reticulum (ER) is implicated in neuronal degeneration in some situations, its role in delayed neuronal cell death (DND) after ischemia remains uncertain. The authors speculated that ER stress is involved in DND, that it is reduced by ischemic preconditioning, and that ER stress reduction by preconditioning is due to ER molecular chaperone induction. The phosphorylation status of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase–like ER eIF2α kinase (PERK) was investigated in the rat hippocampus after ischemia with and without preconditioning. PERK is phosphorylated by ER stress, which phosphorylates eIF2α. To investigate the role of ER molecular chaperones in preconditioning, the authors examined GRP78 and GRP94 expression, both of which are ER chaperones that inhibit PERK phosphorylation, and compared their induction and ischemic tolerance time windows. Phosphorylation of eIF2α and PERK was confirmed after severe ischemia but was inhibited by preconditioning. After preconditioning, GRP78 was increased in the brain with a peak at 2 days, which corresponded with the ischemic tolerance time window. Immunoprecipitation and double staining demonstrated involvement of GRP78 in prevention of PERK phosphorylation. These results suggest that GRP78 induced by preconditioning may reduce ER stress and eventual DND after ischemia.
Cerebral Microvessel Responses to Focal Ischemia
Authors: del Zoppo Gregory J , Mabuchi Takuma
Published: November 2003

Cerebral microvessels have a unique ultrastructure form, which allows for the close relationship of the endothelium and blood elements to the neurons they serve, via intervening astrocytes. To focal ischemia, the cerebral microvasculature rapidly displays multiple dynamic responses. Immediate events include breakdown of the primary endothelial cell permeability barrier, with transudation of plasma, expression of endothelial cell-leukocyte adhesion receptors, loss of endothelial cell and astrocyte integrin receptors, loss of their matrix ligands, expression of members of several matrix-degrading protease families, and the appearance of receptors associated with angiogenesis and neovascularization. These events occur pari passu with neuron injury. Alterations in the microvessel matrix after the onset of ischemia also suggest links to changes in nonvascular cell viability. Microvascular obstruction within the ischemic territory occurs after occlusion and reperfusion of the feeding arteries (“focal no-reflow” phenomenon). This can result from extrinsic compression and intravascular events, including leukocyte(-platelet) adhesion, platelet-fibrin interactions, and activation of coagulation. All of these events occur in microvessels heterogeneously distributed within the ischemic core. The panorama of acute microvessel responses to focal cerebral ischemia provide opportunities to understand interrelationships between neurons and their microvascular supply and changes that underlie a number of central nervous system neurodegenerative disorders.