bluuebunny/crossref_metadata_2025 huggingface dataset:
Seismic structure of 15 Ma oceanic crust formed at an ultrafast spreading East Pacific Rise: Evidence for kilometer‐scale fracturing from dipping reflectors
Authors: Hallenborg Eric , Harding Alistair J. , Kent Graham M. , Wilson Douglas S.
Published: November 2003

A grid of seismic reflection data from 15 Ma Cocos Plate offers an unprecedented view of the structure of mature oceanic crust formed at an ultrafast spreading (∼200 mm/yr, full rate) East Pacific Rise (EPR). The data contain an unexpected quantity of bright reflectors throughout the crust, generally <5 km in length. Significant reflection dip angles (∼10–30°) are seen only on the isochron profiles, and several reflectors have a confirmed isochron dip orientation. Certain upper crustal reflectors (UCRs) appear to form a single network with isochron dip. The most prominent example (apparent reflection coefficient ∼0.2) projects toward a ∼70 m disruption in the igneous seafloor, and waveform analysis demonstrates that the reflector is likely the product of a low‐velocity zone on the order of tens of meters thick. Our observations suggest that the isochron‐dipping UCRs represent small‐slip, kilometer‐scale faults/fractures, and none are primarily related to the seismic 2/3 boundary or to the sheeted dike/gabbro transition. Lower crustal reflectors (LCRs) have no preferred orientation or regular pattern on the 30 km scale of this survey. Certain LCRs may be similar to the UCRs in origin, while others may originate from near‐axis ductile flow, lithologic banding, off‐axis magmatism, or some combination thereof. Overall, reflectors in this area are abundant and complex, consistent with previous off‐axis studies, but at odds with observations of young crust (<5 Ma) near the EPR. This dichotomy may be resolved by a delay in reflector formation, through some combination of postaccretionary tectonics, magmatism and hydrothermal alteration.
gURL Scenes and Grrrl Zines: The Regulation and Resistance of Girls in Late Modernity
Authors: Harris Anita
Published: November 2003

This article explores the images of ‘girlpower’ and ‘girls as risk-takers’ as important sources for the analysis and management of young women's experiences and behaviours under late modernity. It then focuses on what is known as the grrrlzine culture as a site where these contemporary images of girlhood are challenged and deconstructed. It is argued that grrrlzines create a community for young women within which they can participate in debates about the meaning of girlhood under late modernity. Grrrlzines offer spaces for young women to discuss and organize among themselves, and in particular to wrestle with and parody contemporary images of girlhood. In doing so, they help to complicate and advance feminist youth studies approaches to the role of the public/private split in girls’ cultures, places for youth resistance and the ‘problem’ of girls’ silence and invisibility in the context of late modernity. The article examines the ways grrrlzines appear to be complicit in the silencing of young women by insisting on expression only within liminal spaces. However, it is suggested that this constitutes an important attempt on the part of some young women to evade new regulatory regimes that operate primarily by inciting them to speak.
Inpatient Depression in Persons with Burns
Authors: Ptacek J. T. , Patterson David R. , Heimbach David M.
Published: November 2003

In this investigation the authors collected data regarding trait anxiety, well-being, and depression from 209 men and women who had been screened for prior psychiatric diagnosis and treated in an acute-care setting for burn injuries. Well-being was measured in reference to the month before the burn injury, whereas level of depression was self-rated by patients within 2 days of hospitalization, 5 days later, and 5 days after that. Ratings of depression were also obtained 1 month after hospital discharge. Results indicated that few patients rated their depression as severe at any point in time. Depression scores decreased significantly across the hospitalization period and were correlated with burn size, trait anxiety, and well-being. Depression ratings after discharge were significantly related to depression scores obtained at the end of the inpatient phase of the study. Although most patients did not report experiencing severe levels of depression, the stability of scores across time suggests the usefulness of early screening procedures. Catching such problems early may head off longer-term difficulties.
A Survey of Risk Factors for Burns in the Elderly and Prevention Strategies
Authors: Redlick F. , Cooke A. , Gomez M. , Banfield J. , Cartotto R. C. , Fish J. S.
Published: November 2003

Elderly burn patients suffer from greater morbidity and mortality than younger patients with similar burn extents. The purpose of this study was to identify risk factors for burn injuries in the elderly to develop an effective preventive program. A cross-sectional survey was conducted among 20 elderly (≥65 years of age) burn survivors on the circumstances surrounding their burn injury and on burn prevention. A control group of 20 nonburned elderly completed a similar survey only on burn prevention. The majority of burned subjects believed that their injury was preventable (85%). The home was the commonest location for burn injury (70%), and scalds (50%) and flame burns (25%) were the most common etiologies. Most subjects felt that a burn prevention program would be useful (95%) and television, news, and posters were the preferred sources of prevention information. Compared with the burn group, the control group had more risk factors for burn injury. However, the control group also took more active preventive measures. Burn prevention campaigns for elderly should focus on reducing flame and scald burns that occur in the home, preferably using television, news, and poster media.
THE 2002 MOYER AWARD
Authors: Wray Curtis J. , Mayes Theresa , Khoury Jane , Warden Glenn D. , Gottschlich Michele
Published: November 2003

Severe burn injury results in profound metabolic derangements. Recently, we have shown that vitamin D metabolism is disturbed after burn injury. Vitamin D is essential for calcium and phosphorus homeostasis and skeletal bone integrity. The role of vitamin D on magnesium homeostasis is not well understood. The purpose of this study was to assess the effects of vitamin D deficiency on serum electrolytes. Forty-one pediatric burn patients with a mean (± SEM) total body surface area burn of 53.1 ± 2.9% and full-thickness injury of 44.2 ± 4.1% were studied from July 1996 to December 2000. The mean age of the patients was 6.5 ± 0.8 years. Patients were studied for 6 weeks after admission to the hospital. Blood samples were obtained weekly for serum 25-hydroxycholecalciferol (25D), 1,25-dihydroxycholecalciferol (1,25D), and daily for calcium, magnesium, and phosphorus. Total intravenous (IV) replacement of calcium, magnesium, and phosphorus was also quantitated retrospectively. Bivariate and multivariate correlational analysis was used for statistical comparison. For the study duration, multivariate analysis demonstrated a positive correlation between 25D and serum calcium (r = .47, P < .05) and 1,25D and calcium (r = .27, P < .05). Overall, calcium had a positive correlation with phosphorus and a negative correlation with IV calcium replacement (ie, patients with lower calcium received more IV replacement). During the initial week of hospitalization (week 0), decreased 25D (mean 11.6 ng/ml; normal range 15–57 ng/ml) and 1,25D (mean 13.9 pg/ml; normal range 15–75 pg/ml) did not correlate with any other measured variable. In week 1, 1,25D (mean 15.2 ng/ml) had a positive correlation (r = .410, P < .05) with calcium (mean 7.70 mg/dl). Hypovitaminosis D observed in burn injury correlates with serum calcium and phosphorus abnormalities. Early after injury (<1 week) there was no observed correlation between vitamin D and other variables possibly because of the effects of burn shock. After 1 week, vitamin D appears to significantly effect phosphorus homeostasis. The relationship between vitamin D and magnesium is not well established. These results may indicate a role for vitamin D replacement therapy during the initial phase of burn resuscitation.
Comparison of Methods for Analysis of Clinical [11C]Raclopride Studies
Authors: Lammertsma A. A. , Bench C. J. , Hume S. P. , Osman S. , Gunn K. , Brooks D. J. , Frackowiak R. S. J.
Published: November 2003

Five different methods for the estimation of the binding potential, a measure of Bmax/Kd, of [11C]raclopride in human striatum were compared using data from a dose ranging study of the neuroleptic CP-88,059-01. Binding potential was estimated indirectly, from distribution volumes in striatum and cerebellum, using both single- and two-tissue compartment models with a metabolite-corrected plasma curve as input function. The two-tissue compartment model was also used for a direct estimate of the binding potential. In addition, a direct estimate was obtained from the reference tissue compartment model using the cerebellum as indirect input function. Finally, an estimate of binding potential was calculated from the ratio of striatum over cerebellum counts at late times after injection. The estimates of striatum binding potential from all methods, except the direct determination using a two-tissue compartment model with metabolite-corrected plasma input function, correlated with each other. Use of an average metabolite correction resulted in only a small reduction in accuracy in this series of normal subjects. The reference tissue model provided estimates of the binding potential with the same sensitivity for detecting changes as those methods that required a metabolite-corrected plasma input function. This indicates that for routine analysis of clinical [11C]raclopride studies, no arterial cannulation is required. The range of normal values was significantly less variable with the reference tissue method than when simple striatum-to-cerebellum ratios were used.
Clinical Outcome in Ischemic Stroke Predicted by Early Diffusion-Weighted and Perfusion Magnetic Resonance Imaging: A Preliminary Analysis
Authors: Warach Steven , Dashe John F. , Edelman Robert R.
Published: November 2003

Perfusion and diffusion-weighted magnetic resonance imaging (MRI) can demonstrate, respectively, cerebral ischemia and ischemic brain injury in the first several hours after onset of symptoms, when proton density and T2-weighted MRI may appear normal. It is hypothesized that these techniques could distinguish regions destined for infarction from those that will not progress to infarction. We provide preliminary evidence from an analysis of 19 patients with severely disabling clinical deficits attributable to ischemia in at least an entire division of the middle cerebral artery, that initial perfusion and diffusion MRI were more accurate than conventional MRI in predicting no, partial or complete improvement—17 of 19 cases ( p < 0.0001) versus 10 of 19 cases, respectively. In the subset of patients studied within 6 h of onset, diffusion/perfusion MRI was an even better predictor than conventional MRI—11 of 12 versus four of 12, respectively. In this small sample of patients with severe clinical deficits, perfusion and diffusion MRI were highly accurate in distinguishing those who would improve from those who would not. These results need to be confirmed in a larger prospective study, which may support a future role in the initial screening, selection, and evaluation of patients with stroke for acute pharmacologic interventions.
Short Therapeutic Window for MK-801 in Transient Focal Cerebral Ischemia in Normotensive Rats
Authors: Margaill I. , Parmentier S. , Callebert J. , Allix M. , Boulu R. G. , Plotkine M.
Published: November 2003

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg−1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.
Bioenergetic Recovery following Ischemia in Brain Slices Studied by 31P-NMR Spectroscopy: Differential Age Effect of Depolarization Mediated by Endogenous Nitric Oxide
Authors: Tasker Robert C. , Sahota Sati K. , Williams Stephen R.
Published: November 2003

Proximate neurotoxic mechanisms during postischemic recovery may be influenced by stage of development and complicating factors such as cortical spreading depression or secondary brain insult. Using 31P nuclear magnetic resonance spectroscopy, we have monitored pH and cellular energy metabolites phosphocreatine (PCr) and ATP in the ex vivo rat cerebral cortex before, during, and after substrate and oxygen deprivation, which represents “in vitro ischemia.” There were important developmental differences in resistance and response to an ischemic insult. Twenty-one-day-old (P21) rat cortical slices had no detectable β-ATP or PCr at the end of a 20-min insult, while γ-day-old (P7) slices had 50 ± 13.7% (mean ± SD, n = 12) and 17 ± 14.8% relative to preischemia levels, respectively. Postischemic depolarization resulted in age-dependent effects on PCr (p < 0.05): In the older tissue, depolarization significantly worsened the recovery of PCr, whereas in young tissue it ameliorated recovery. This amelioration could be prevented by inhibiting nitric oxide production with methylene blue (depolarization-methylene blue interaction, p < 0.05) and enhanced by administration of the nitric oxide donor glyceryl trinitrate (GTN; p < 0.01). However, in P21 tissue, GTN further exacerbated injury (age-GTN interaction, p < 0.01). Therefore, in this vascular-independent preparation, a neuronal or glial nitric oxide-dependent mechanism appears to confer improved postischemic bioenergetic recovery in the developing brain compared with the mature brain.
Coordinate IGF-I and IGFBP5 Gene Expression in Perinatal Rat Brain after Hypoxia-Ischemia
Authors: Lee W.-H. , Wang G.-M. , Seaman L. B. , Vannucci S. J.
Published: November 2003

Insulin-like growth factor I (IGF-I) is an anabolic pleiotrophic factor essential for postnatal rat brain development, especially during the first 21 days, the “critical growth period.” Cerebral hypoxic–ischemic insults occurring during the perinatal period can result in neuronal necrosis and permanent brain damage. To understand the regulation of the action of IGF-I in response to such a metabolic insult, we investigated the gene expression of IGF-I, type I IGF receptor, IGF binding protein (IGFBP) 2, and IGFBP5 during the first 72 h after hypoxia–ischemiain the immature rat. At 1 h of recovery, messenger RNA (mRNA) levels of all IGF system components were decreased throughout the hemisphere ipsilateral to the carotid artery ligation. This decrease is more pronounced at 24 h of recovery, especially in areas vulnerable to hypoxic–ischemic injury, such as the thalamus and hippocampus. At 72 h of recovery, although IGFBP2 and type 1 IGF receptor mRNA levels remain suppressed, gene expression of both IGF-I and IGFBP5 was activated in reactive astrocytes. Therefore, during the critical growth period in rats, the transcriptional levels of all IGF system components are extremely sensitive to metabolic perturbations associated with cerebral hypoxia–ischemia. The immediate decrease in IGF-I gene expression may be partially responsible for the impending neuronal death and selective vulnerability of myelinogenesis during the perinatal period.
Effects of Hypothermia on Traumatic Brain Injury in Immature Rats
Authors: Mansfield Robert T. , Schiding Joanne K. , Hamilton Ronald L. , Kochanek Patrick M.
Published: November 2003

Hypothermia is beneficial in adult models of traumatic brain injury (TBI), but it has not been evaluated in an immature animal model. We hypothesized that brief hypothermia applied after TBI would reduce cerebral edema and lesion volume in immature rats. Male Wistar rats (3–4 weeks of age, 90–140 g) were anesthetized, intubated, mechanically ventilated, and subjected to TBI by a weight drop onto the exposed right parietal cortex. Hypothermic rats were then cooled to a brain temperature of 32.0 ± 0.5°C for 4 h, and control rats were maintained at a brain temperature of 37.0 ± 0.5°C. Cerebral edema (wet — dry weight method) was assessed at 4 and 24 h, and lesion volume was assessed at 5 days. At 4 h, a reduction of percent brain water in the traumatized hemisphere was observed in hypothermic versus normothermic rats (81.75 ± 0.60 vs. 82.53 ± 0.67%; p < 0.05), but by 24 h posttrauma, the groups were similar (p = 0.82). Total lesion volume (47.2 ± 8.5 vs. 44.4 ± 10.0 mm3; p = 0.51) and necrotic volume (20.2 ± 6.3 vs. 20.0 ± 7.9 mm3; p = 0.95) were similar in the hypothermic and normothermic groups. We conclude that in this model, a transient (4-h) application of moderate (32°C) hypothermia reduces the cerebral edema characteristically seen in immature rats at 4 h, but this reduction is not sustained at 24 h. Attenuating or delaying the development of cerebral edema could have important therapeutic relevance after TBI. Transient hypothermia, however, did not reduce lesion volume at 5 days posttrauma.
Prolonged Transient Ischemia Results in Impaired CBF Recovery and Secondary Glutamate Accumulation in Cats
Authors: Taguchi J. , Graf R. , Rosner G. , Heiss W.-D.
Published: November 2003

Effects of prolonged focal ischemia [middle cerebral artery occlusion (MCAO)] of 1, 2, and 4 h followed by 15-h reperfusion on CBF, extracellular amino acids, purine catabolites, evoked potentials, and infarction were studied in core (A: auditory cortex) and border zone (SF: somatosensory cortex) areas of halothane-anesthetized cats. Following MCAO, CBF reduction was severe in A(<15 ml 100 g−1 min−1) and mild to moderate in SF. Prominent elevation of glutamate and abolition of evoked potentials in A contrasted with milder and more variable disturbances in SF. After reperfusion, recovery of CBF, glutamate, and evoked potentials was fast and persistent in the 1- and 2-h groups. In the 4-h group, immediate recovery of CBF, glutamate, and evoked potentials was incomplete, and secondary deterioration of all parameters was obtained at the end of the experiments. Infarction in the 4-h group was significantly larger than in the 1- and 2-h groups. Persistent recovery of extracellular glutamate concentration and electrical function and salvage of neuronal tissue from infarction therefore seem to depend on successful restoration of CBF, which in turn depends on the magnitude and the duration of CBF reduction and of exposure to potentially harmful substances such as glutamate during the ischemic attack.
Isovolemic Hemodilution Normalizes the Prolonged Passage of Red Cells and Plasma through Cerebral Microvessels in the Partially Ischemic Forebrain of Rats
Authors: Lin Shinn-Zong , Chiou Tsorng-Laang , Song Wen-Shen , Chiang Yung-Hsiao
Published: November 2003

The objective of this study was to determine whether hemodilution could normalize the mean transit times of red blood cells (Tr) and plasma (Tp) through cerebral microvessels in a partially ischemic brain. Wistar-Kyoto (WKY) rats, aged 30–40 weeks, were divided randomly into three groups. The first group was the nonocclusion, nonhemodilution (NN) normal control group. The second group was the occlusion, nonhemodilution (ON) group, in which animals were treated with bilateral carotid artery ligation. The third group was the occlusion–hemodilution (OH) group, in which animals were treated with bilateral common carotid artery ligation and, then, isovolemic hemodilution by replacing blood with the same volume of 3% modified fluid gelatin. Local cerebral blood flow (lCBF) and microvascular volumes of red blood cells (Vr) and plasma (Vp) in 14 brain structures were measured using 14C-iodoantipyrine, iron-55-labeled red blood cells, and 14C-inulin, respectively. The amount of oxygen delivered to local brain structures (OD), cerebral microvascular blood volume (Vb), mean transit time of blood (Tb), Tr, and Tp through cerebral microvessels were calculated from the data. Two hours after carotid artery ligation, lCBF decreased by ∼38% in forebrain structures, 22% in rostral hindbrain areas, and 8% in the caudal hindbrain (29% for all 14 structures). The decreases in ODs were parallel with those of lCBFs, at 33, 17, and 2% in the three regions, respectively (24% for all structures). In contrast, Vb increased by 68, 37, and 16% in the three regions, respectively (48% for all structures). Tr and Tp were markedly prolonged (180% for Tr and 154% for Tp) in the forebrain regions, moderately (91% for Tr and 73% for Tp) in the rostral hindbrain, and mildly (60% for Tr and 13% for Tp) in the caudal hindbrain, with a mean increase of 136% for Tr and 111% for Tp in all structures. When data in the OH and NN groups were compared, lCBF values tended to be slightly higher and Vb values were significantly higher ( p < 0.05) in the OH group. ODs in the eight forebrain structures were all significantly less ( p < 0.05) in the OH group than the NN group. Tr and Tp values in the forebrain were similar between the OH and the NN groups. In conclusion, occlusion of the bilateral common carotid arteries in WKY rats causes partial forebrain ischemia, in which both Tr and Tp are prolonged. These prolongations of Tr and Tp can be normalized by isovolemic hemodilution. However, the ischemic forebrain remains hypoxic after hemodilution.
Widespread Hemodynamic Depression and Focal Platelet Accumulation after Fluid Percussion Brain Injury: A Double-Label Autoradiographic Study in Rats
Authors: Dietrich W. Dalton , Alonso Ofelia , Busto Raul , Prado Ricardo , Dewanjee Sumit , Dewanjee Mrinal K. , Ginsberg Myron D.
Published: November 2003

Cerebrovascular damage leading to subsequent reductions in local cerebral blood flow (lCBF) may represent an important secondary injury mechanism following traumatic brain injury (TBI). We determined whether patterns of 111indium-labeled platelet accumulation were spatially related to alterations in lCBF determined autoradiographically 30 min after TBI. Sprague–Dawley rats (n = 8), anesthetized with halothane and maintained on a 70:30 (vol/vol) mixture of nitrous oxide/oxygen and 0.5% halothane, underwent parasagittal fluid percussion brain injury (1.7–2.2 atm). 111Indiumtropolone–labeled platelets were injected 30 min prior to TBI while [l4C]-iodoantipyrine was infused 30 min after trauma. Sham-operated animals (n = 7) underwent similar surgical procedures but were not injured. In autoradiographic images of the indium-labeled platelets, focal sites of platelet accumulation within the traumatized hemisphere were restricted to the pial surface (five of eight rats), the external capsule underlying the lateral parietal cortex (five of eight rats), and within cerebrospinal fluid (CSF) compartments (six of eight rats). In contrast, mild-to-moderate reductions in lCBF, not restricted to sites of platelet accumulation, were seen throughout the traumatized hemisphere. Flow reductions were most severe in coronal sections underlying the impact site. For example, within the lateral parietal cortex and hippocampus, lCBF was significantly reduced [ p < 0.01; analysis of variance (ANOVA)] from 1.71 ± 0.34 (mean ± SD) and 0.78 ± 0.12 ml/g/min, respectively, versus 0.72 ± 0.17 and 0.41 ± 0.06 ml/g/min within the traumatized hemisphere. Significant flow reductions were also seen in remote cortical and subcortical areas, including the right frontal cortex and striatum. These results indicate that focal platelet accumulation and widespread hemodynamic depression are both early consequences of TBI. Therapeutic strategies directed at these early microvascular consequences of TBI may be neuroprotective by attenuating secondary ischemic processes.
NADPH-Diaphorase Neurons Contacting the Cerebrospinal Fluid in the Ventricles of Rat Brain
Authors: Sancesario Giuseppe , Morello Maria , Massa Roberto , Fusco Francesca R. , D'Angelo Vincenza , Bernardi Giorgio
Published: November 2003

Two populations of scattered neurons containing nitric oxide synthase activity were detected in the wall of the third and lateral cerebral ventricles of rat brain, using histochemistry for NADPH-diaphorase activity. One type was multipolar and lay supraependymally, with dendrites oriented in the plane of the ependymal layer. The second type was bipolar and was situated subependymally, with dendrites extending in opposite directions, either into the surrounding brain tissue or to the ventricular surface. Moreover, multipolar neurons, situated in the corpus callosum and in the subcortical white matter, had long varicose dendrites extending toward the roof of the lateral ventricles. As a result, numerous NADPH-diaphorase neurites spread out on the free surface of the ependymal layer in contact with the CSF. These observations raise the possibility that periventricular nitrergic neurons play an essential role in registering the composition of the CSF and in modulating subcortical cerebral blood flow. A further possibility is that supraependymal nitrergic neuronal processes are effectors regulating activity of ependymal cells.
A Feedback-Controlled Pump Produces Stable Hypotension in Anaesthetised Rabbits
Authors: Smielewski Peter , Kirkpatrick Peter J. , Richards Hugh , Pickard John D. , Czosnyka Marek
Published: November 2003

A method is described for the reliable production of controlled hypotension in experimental animals. Reduction in arterial blood pressure was obtained in rabbits by withdrawing arterial blood using a computer-driven pump operating within a feedback control system. Arterial blood pressure, blood flow velocity in the basilar artery (measured using transcranial Doppler), and anterior cortical microcirculation (measured using laser Doppler) were monitored. The aim of the experiments was to compare stability of hypotension produced using arterial blood pressure or basilar flow velocity as feedback control variables. Basilar artery flow velocity provided the most stable profound hypotension and during reinfusion when animals were not autoregulating. However, arterial blood pressure provided the most accurate stepwise control in autoregulating animals.
Influence of Endothelial Nitric Oxide on Adrenergic Contractile Responses of Human Cerebral Arteries
Authors: Aldasoro Martín , Martínez Carmen , Vila José M. , Medina Pascual , Lluch Salvador
Published: November 2003

The present study was designed to investigate the influence of the endothelium and that of the L-arginine pathway on the contractile responses of isolated human cerebral arteries to electrical field stimulation (EFS) and norepinephrine. Rings of human middle cerebral artery were obtained during autopsy of 19 patients who had died 3–8 h before. EFS (1–8 Hz) induced frequency-dependent contractions that were abolished by tetrodotoxin, prazosin, and guanethidine (all at 10-6 M). The increases in tension were of greater magnitude in arteries denuded of endothelium. NG-monomethyl L-arginine (L-NMMA 10-4 M) potentiated the contractile response to EFS in artery rings with endothelium but did not influence responses of endothelium-denuded arteries. L-arginine (10-4 M) reversed the potentiating effects of L-NMMA on EFS-induced contractions. Norepinephrine induced concentration-dependent contractions, which were similar in arteries with and without endothelium or in arteries treated with L-NMMA. Indomethacin (3 × 10−6 M) had no significant effect on the contractile response to EFS or on the inhibition by L-NMMA of acetylcholine-induced relaxation. These results suggest that the contractile response of human cerebral arteries to EFS is modulated by nitric oxide mainly derived from endothelial cells; although adrenergic nerves appear to be responsible for the contraction, the transmitter involved in the release of nitric oxide does not appear to be norepinephrine. The effects of L-NMMA in this preparation appear to be due to inhibition of nitric oxide formation rather than caused by cyclooxygenase activation.
Characterization of Endothelin Receptors in the Cerebral Vasculature and Their Lack of Effect on Spreading Depression
Authors: Goadsby Peter J. , Adner Mikael , Edvinsson Lars
Published: November 2003

The changes in cerebral blood flow that accompany spreading depression are well-described, as are parallel changes in cellular activity, with a wave of hyperemia followed by a prolonged oligemic phase. In this study, a cat model of the CBF changes associated with spreading depression and in vitro pharmacology were used to determine if there is a role for the powerful peptide vasoconstrictor endothelin in this response. For the pharmacological studies, the middle cerebral artery was harvested from cats postmortem. For the physiological studies, cats were anesthetized with halothane induction and α-chloralose (60 mg/kg, intraperitoneal loading; 20 mg/kg i.v. 2-h maintenance). CBF was monitored continuously in the parietal cortex using laser Doppler flowmetry (CBFLDF) after exposure of the dura mater. The in vitro work demonstrated that endothelin-1 (ET-1) mediates a strong and potent contraction of cerebral vessels. Both the selective ETA receptor antagonist FR139317 and the combined ETA and ETB receptor antagonist Bosentan caused a rightward shift of the concentration-response curve without attenuation of the maximum effect. The calculated pA2 values were 6.28 and 6.90, respectively. The slope did not differ from unity, suggesting that the ET-1-mediated contraction is evoked by a single population of ETA receptors, which were effectively antagonized by these compounds. Spreading depression was induced with a needle stick injury to the cortex. Local administration of the endothelin antagonists FR139317 (10 μ M) and Bosentan (10 μ M) did not affect resting blood flow in the cortex. Induction of spreading depression following local administration of FR139317 and Bosentan resulted in responses no different from those in control cortex. These data demonstrate that endothelin does not play a significant role in the vasoconstrictor portion of the CBF change seen in spreading depression, nor does it affect resting flow. Since it is widely held that spreading depression, or a very similar mechanism, underlies the aura phase of migraine, it may be suggested from these studies that endothelin antagonists are unlikely to be useful in migraine.
Effect of Renin on Brain Arterioles and Cerebral Blood Flow in Rabbits
Authors: Haberl Roman L. , Decker-Hermann Pamla J. , Hermann Klaus
Published: November 2003

There is evidence of an intrinsic renin–angiotensin system in the brain. The goal of the study was to determine whether stimulation of endogenous angiotensin production by applying renin to the brain surface has an effect on pial arteriolar caliber and CBF. Pial vessel diameters were measured through a closed cranial window in anesthetized rabbits. Percent changes of blood flow in the cortical area under the cranial window were simultaneously measured by laser-Doppler flowmetry. Topical application of 0.01–0.1 U/ml renin induced maximum dilation of 18.9 ± 4% (mean ± SD) of pial arterioles within 2 min. Arteriolar calibers thereafter decreased slowly. Flow gradually increased to peak at 38 ± 15% 50 min after renin application. Angiotensin I levels in jugular blood, as measured by radioimmunoassay, increased to a peak 40 min after topical renin application. Angiotensin II levels in jugular blood and both angiotensin I and II levels in blood samples from the femoral artery did not change. Diameter and flow changes were inhibited by intravenous pretreatment with the converting enzyme blocker captopril (10 mg/kg body wt i.v.). Captopril did not affect the vasodilation and flow increase in response to hypercapnia. Topically applied Captopril (10−5 M) blocked renin-induced arteriolar dilation. We conclude that renin increases pial arteriolar diameters and cortical blood flow in the rabbit brain. Stimulation of angiotensin production is likely to be a mediator of this response.
A Multicenter Validation of Regional Cerebral Blood Flow Quantitation Using [123I]Iodoamphetamine and Single Photon Emission Computed Tomography
Authors: Iida Hidehiro , Akutsu Tooru , Endo Keigo , Fukuda Hiroshi , Inoue Takeshi , Ito Hiroshi , Koga Sukehiko , Komatani Akio , Kuwabara Yasuo , Momose Toshimitsu , Nishizawa Sadahiko , Odano Ikuo , Ohkubo Masaki , Sasaki Yasuhito , Suzuki Hideki , Tanada Shuuji , Toyama Hiroshi , Yonekura Yoshiharu , Yoshida Tsuyoshi , Uemura Kazuo
Published: November 2003

Recently, two methods have been proposed for regional cerebral blood flow (rCBF) quantitation using [123I]iodoamphetamine (IMP) and single-photon emission computed tomography (SPECT). The table look-up (TLU) method has been shown to provide both rCBF and volume of distribution, Vd, images from two SPECT scans, while a single-scan autoradiographic (ARG) technique provided rCBF using a fixed and assumed Vd. In both methods, a single blood sample was referred to calibrate the previously determined standard input function The present multicenter project was designed to evaluate the accuracy of both methods for use as clinical investigative tools. Ten independent institutions performed [123I]IMP-SPECT studies according to both methods in 76 subjects (10 normal volunteers, 32 patients with cerebrovascular disease, and 34 patients with other diseases). Calculated rCBF values were compared with those obtained by the following reference methods available in the participating institutions; [15O] H2O positron emission tomography (PET) (five institutions), [133Xe]SPECT (four institutions), and the [123I]IMP microsphere method (three institutions). Both ARG and TLU methods provided rCBF values that were significantly correlated with those measured by the [15O] H2O PET technique ( p < 0.001 for all subjects; overall regression equation, y = 15.14 + 0.54×) and those measured by the [123I]IMP-microsphere method ( p < 0.001 for all subjects; y = 2.0 + 0.80×). Significant correlation ( p < 0.05) was observed in 18 of 24 subjects studied with the [133Xe] SPECT reference technique (overall regression equation, y = 15.0 + 0.55×). Mean cortical gray matter rCBF in a group of normal subject was 43.9 ± 3.3 and 43.4 ± 2.0 ml/min/100 g for the ARG and TLU methods, respectively. Regional Vd of [123I]IMP estimated by the TLU method was 45 ml/ml ± 20% in the normal cortical region. Close agreement between ARG and TLU rCBF values was observed (y = −3.21 + 1.07×, r = 0.97), confirming the validity of assuming a fixed Vd in the ARG method. Results of this study demonstrate that both the ARG and TLU methods accurately and reliably estimate rCBF in a variety of clinical settings.
NMDA Receptor–Dependent Increase of Cerebral Glucose Utilization after Hypoxia–Ischemia in the Immature Rat
Authors: Gilland Eric , Hagberg Henrik
Published: November 2003

Post-treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 reduces hypoxic–ischemic brain injury in immature animals. To elucidate possible mechanisms, cerebral glucose utilization (CMRglc) and cerebral blood flow (CBF) were measured 1–5 h after hypoxia–ischemia and administration of MK-801 in 7-day-old rats. After 100 min of unilateral hypoxia–ischemia, half of the pups were injected with MK-801. CMRglc was assessed by the [14C]deoxyglucose (2-DG) method. The brains were analyzed either by autoradiography or for energy metabolites and chromatographic separation of 2-DG-6-phosphate and 2-DG. CBF was measured by the autoradiographic [14C]iodoantipyrine method. Mean CMRglc in the cerebral cortex was increased ipsilaterally after hypoxia–ischemia to 15 ± 3.3 μmol 100 g−1 min−1 ( p < 0.01) and areas with CMRglc >20 μmol 100 g−1 min−1 amounted to 8.0 ± 7.7 mm2 in the ipsilateral hemisphere compared with 1.2 ± 1.6 mm2 contralateral ( p < 0.001). Treatment with MK-801 decreased CMRglc bilaterally ( p < 0.05) and reduced ipsilateral areas with increased CMRglc by 64% ( p < 0.01). CBF was unaltered after hypoxia–ischemia and by MK-801 treatment. In conclusion, regional glucose hyper-utilization in the parietal cortex after hypoxia–ischemia was attenuated by MK-801; this may have relevance to the neuroprotective effect of NMDA-receptor antagonists in this model.
Carbon Monoxide, a Novel Neural Messenger, Does Not Modulate Extracellular Glutamate Concentration in Forebrain Ischemia
Authors: Takizawa Shunya , Fujita Hitoshi , Ogawa Saori , Shinohara Yukito
Published: November 2003

We investigated the role of carbon monoxide as a neural modulator of extracellular glutamate concentration in rat hippocampus CA1 in transient forebrain ischemia by using metalloporphyrins, which block the production of carbon monoxide through the inhibition of heme oxygenase (HO) activity. Infusion of 10 and 100 μ M zinc protoporphyrin IX, which inhibits nitric oxide synthase activity as well as HO activity, significantly increased glutamate concentration compared with that on the vehicle-treated side. However, infusion of 100 μ M tin mesoporphyrin IX, which inhibits only HO activity, did not affect glutamate concentration in ischemia. Our results therefore do not support the hypothesis that carbon monoxide acts as a neural messenger through the modulation of extracellular glutamate concentration in ischemia.
Role of Nitric Oxide Synthase Inhibition in Leukocyte-Endothelium Interaction in the Rat Pial Microvasculature
Authors: Lindauer Ute , Dreier Jens , Angstwurm Klemens , Rubin Inger , Villringer Arno , Einhäupl Karl-Max , Dirnagl Ulrich
Published: November 2003

We investigated the role of nitric oxide (NO) in leukocyte-endothelium interaction, blood-brain barrier (BBB) function and oxygen free-radical production in the rat pial microcirculation. In a closed cranial window preparation (dura removed) over the parietal cortex of pentobarbital-anesthetized Wistar rats, NO synthase (NOS) was inhibited by systemic and/or topical application of Nω-nitro-l-arginine (l-NNA) under physiological conditions and during leukotriene B4 (LTB4) activation. Circulating leukocytes were labeled by intravenous injection of rhodamine 6G. We used a confocal laser scanning microscope (CLSM) and studied leukocyte rolling and sticking in pial veins and arteries before and after NOS inhibition. At the end of the experiments, sodium-fluorescein was injected intravenously to test BBB integrity. Brain cortex oxygen free-radical production was investigated in the cranial window preparation using lucigenin-enhanced chemiluminescence (CL). l-NNA application did not lead to significant changes in leukocyte-endothelium interaction, BBB function, and oxygen free-radical production under physiological conditions [leukocyte-endothelium interaction: control (n = 5), l-NNA systemically (n = 5), l-NNA topically (n = 5): at baseline rollers/100 μm: 0.76 ± 0.55, 0.64 ± 0.94, 0.44 ± 0.55 and stickers/100 μm: 0.90 ± 0.28, 0.76 ± 0.24, 0.84 ± 0.42; at 60 min rollers/100 μm: 1.49 ± 0.66, 1.21 ± 0.99, 0.67 ± 0.66 and stickers/100 μm: 1.04 ± 0.20, 1.19 ± 0.23, 1.21 ± 0.54; oxygen free-radical production (n = 4): CL count before l-NNA application 35 ± 17 cps, after 1 h of topical superfusion of l-NNA 38 ± 14 cps; p < 0.05]. In contrast to the results achieved under physiological conditions, a significant further increase of rolling leukocytes and BBB permeability occurred due to NOS inhibition under LTB4-activated conditions [76 ± 47% significant ( p ≤ 0.01, n = 7) further increase of rollers/100 μm due to 60 min l-NNA application following the activation period of 120 min LTB4 superfusion]. Our results support a modulatory role for NO in leukocyte-endothelium interaction and BBB permeability in the pial microcirculation when this interaction is increased.
Apoptosis Repressor Genes Bcl-2 and Bcl-x-Long are Expressed in the Rat Brain following Global Ischemia
Authors: Chen Jun , Graham Steven H. , Nakayama Masaki , Zhu Raymond L. , Jin Kunlin , Stetler R. Anne , Simon Roger P.
Published: November 2003

The proto-oncogenes bcl-2 and bcl-x-long have been shown to suppress apoptotic cell death in a variety of in vitro systems and cell lines, including neurons. An alternatively spliced form of bcl-x, bcl-x-short, is a promoter of apoptotic death. Whether these genes are induced after ischemia or play any role in determining the fate of ischemic neurons is unknown. To begin to address this issue, we studied the expression of bcl-2, and bcl-x mRNA and protein after global ischemia in the rat. Ischemia was induced in isoflurane-anesthetized rats by the four-vessel occlusion method. mRNA expression was studied by Northern blot analysis at 24 h after ischemia and by in situ hybridization at 2, 4, 8, 24, and 72 h after 15 min of global ischemia. Protein expression was studied using both immunocytochemistry at 4, 8, 16, 24, and 72 h after ischemia and Western blot analysis from tissue harvested at 16, 24, and 72 h after ischemia. Western blots showed that bcl-x-long is the predominant form of bcl-x protein expressed in both normal and ischemic brain. Both bcl-2 and bcl-x-long mRNA were expressed in CA1, CA3, and the molecular layer of the dentate after ischemia. However, bcl-2 and bcl-x protein were expressed only in CA3 and dentate. Thus, while bcl-2 and bcl-x-long mRNA were expressed in both surviving and dying neurons, their proteins were expressed in neurons destined to survive. These results support potential roles for these two apoptosis suppressor proteins in promoting survival after cerebral ischemia.
Expression of Interleukin-1β Converting Enzyme Gene Family and bcl-2 Gene Family in the Rat Brain following Permanent Occlusion of the Middle Cerebral Artery
Authors: Asahi Minoru , Hoshimaru Minoru , Uemura Yoshihiko , Tokime Tomoo , Kojima Masahiro , Ohtsuka Toshiyuki , Matsuura Nobuki , Aoki Tomokazu , Shibahara Keiichi , Kikuchi Haruhiko
Published: November 2003

Recent investigations have been suggesting that some neuronal subpopulations may die via programmed cell death after focal ischemic injury. To clarify the possible roles of the genes involved in the cell-death program, this study examined the expression of three members of the interleukin-1β converting enzyme ( Ice) gene family ( Ice, Nedd2, and Yama/CPP32) and two members of the bcl-2 gene family ( bcl-2 and bcl-x) in the rat brain after permanent occlusion of the middle cerebral artery. Northern blot analysis revealed a transient induction of Nedd2 mRNA 8 h after the ischemic insult (3.8-fold) and an increase in Yama/CPP32 mRNA 16 to 24 h after the insult (5.8-fold at 24 h), whereas the expression of Ice remained constant. The expression of bcl-2 and bcl-x remained constant after the ischemic insult. Taking into account the key role of the Ice gene family in the execution of programmed cell death, the induction of Ice gene family might play a causative role in apoptotic cell death.
Intravenous Infusion of Adrenomedullin and Increase in Regional Cerebral Blood Flow and Prevention of Ischemic Brain Injury after Middle Cerebral Artery Occlusion in Rats
Authors: Dogan Aclan , Suzuki Yoshio , Koketsu Naoki , Osuka Koji , Saito Kiyoshi , Takayasu Masakazu , Shibuya Masato , Yoshida Jun
Published: November 2003

The intravenous infusion of rat adrenomedullin, at concentrations ranging from 0.1 to 1.0 μg/kg/min, for 60 min increased the regional cerebral blood flow (rCBF) in a dose-dependent manner in rats. rCBF was measured using a laser Doppler flowmetry device placed on the surface of the parietal cortex. The increase in rCBF induced by 1.0 μg/kg/min of adrenomedullin was up to 145 ± 10.8% of controls at 60 min (n = 5, p < 0.001). These concentrations of adrenomedullin did not affect systemic blood pressure or other physiologic parameters, including pH, PaCO2, PaO2, hemoglobin, and blood glucose. Repeated infusion of 1.0 μg/kg/min of adrenomedullin at 2-h intervals caused tachyphylaxis (n = 5, p < 0.01). Rat adrenomedullin (1.0 μg/kg/min) demonstrated a more potent effect than the same dose of human adrenomedullin. The C-terminal fragment of human adrenomedullin (0.5 and 5.0 μg/kg/min), adrenomedullin22–52, which did not affect rCBF alone, inhibited the effect of rat adrenomedullin (0.5 μg/kg/min) as a receptor antagonist in a dose-dependent manner. In a model of middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats, pre- and postinfusion of 1.0 μg/kg/min of adrenomedullin suppressed the reduction in rCBF following MCA occlusion (control, 29 ± 15.1%; adrenomedullin group, 45 ± 14.4%; not significant) and decreased the volume of ischemic brain injury (control, 288 ± 35 mm3; adrenomedullin group, 232 ± 35 mm3; p < 0.05). These results suggest that adrenomedullin increases rCBF and prevents ischemic brain injury, partly by increasing the collateral circulation.
Methionine Sulfoximine, a Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity during Acute Hyperammonemia
Authors: Sugimoto Hideyoshi , Koehler Raymond C. , Wilson David A. , Brusilow Saul W. , Traystman Richard J.
Published: November 2003

Hyperammonemia causes glutamine accumulation and astrocyte swelling. Inhibition of glutamine synthesis reduces ammonia-induced edema formation and watery swelling in astrocyte processes. Ordinarily, astrocytes tightly control extracellular K+ activity [K+]e. We tested the hypothesis that acute hyperammonemia interferes with this tight regulation such that [K+]e increases and that inhibition of glutamine synthetase reduces this increase in [K+]e. Ion-sensitive microelectrodes were used to measure [K+]e in parietal cortex continuously over a 6-h period in anesthetized rats. After i.v. sodium acetate infusion in eight control rats, plasma ammonia concentration was 33 ± 26 μmol/L (± SD) and [K+]e remained stable at 4.3 ± 1.6 mmol/L. During ammonium acetate infusion in nine rats, plasma ammonia increased to 594 ± 124 μmol/L at 2 h and to 628 ± 135 μmol/L at 6 h. There was a gradual increase in [K+]e from 3.9 ± 0.7 to 6.8 ± 2.7 mmol/L at 2 h and 11.8 ± 6.7 mmol/L at 6 h. In eight rats, L-methionine-D,L-sulfoximine (150 mg/kg) was infused 3 h before ammonium acetate infusion to inhibit glutamine synthetase. At 2 and 6 h of ammonium acetate infusion, plasma ammonia concentration was 727 ± 228 and 845 ± 326 μmol/L, and [K+]e was 4.5 ± 1.9 and 6.1 ± 3.8 mmol/L, respectively. The [K+]e value at 6 h was significantly less than that obtained with ammonium acetate infusion alone but was not different from that obtained with sodium acetate infusion. We conclude that acute hyperammonemia impairs astrocytic control of [K+]e and that this impairment is linked to glutamine accumulation rather than ammonium ions per se.
A Model for the Coupling between Cerebral Blood Flow and Oxygen Metabolism during Neural Stimulation
Authors: Buxton Richard B. , Frank Lawrence R.
Published: November 2003

A general mathematical model for the delivery of O2 to the brain is presented, based on the assumptions that all of the brain capillaries are perfused at rest and that all of the oxygen extracted from the capillaries is metabolized. The model predicts that disproportionately large changes in blood flow are required in order to support small changes in the O2 metabolic rate. Interpreted in terms of this model, previous positron emission tomography (PET) studies of the human brain during neural stimulation demonstrating that cerebral blood flow (CBF) increases much more than the oxygen metabolic rate are consistent with tight coupling of flow and oxidative metabolism. The model provides a basis for the quantitative interpretation of functional magnetic resonance imaging (fMRI) studies in terms of changes in local CBF.