bluuebunny/crossref_metadata_2025 huggingface dataset:
Normobaric Hypoxia Induces Tolerance to Focal Permanent Cerebral Ischemia in Association with an Increased Expression of Hypoxia-Inducible Factor-1 and its Target Genes, Erythropoietin and VEGF, in the Adult Mouse Brain
Authors: Bernaudin Myriam , Nedelec Anne-Sophie , Divoux Didier , MacKenzie Eric T. , Petit Edwige , Schumann-Bard Pascale
Published: November 2003

Tolerance to cerebral ischemia is achieved by preconditioning sublethal stresses, such as ischemia or hypoxia, paradigms in which the decrease of O2 availability may constitute an early signal inducing tolerance. In accordance with this concept, this study shows that hypoxia induces tolerance against focal permanent ischemia in adult mice. Normobaric hypoxia (8% O2 of 1-hour, 3-hour, or 6-hour duration), performed 24 hours before ischemia, reduces infarct volume by approximately 30% when compared with controls. To elucidate the mechanisms underlying this neuroprotection, the authors investigated the effects of preconditioning on cerebral expression of hypoxia-inducible factor-1α (HIF-1α) and its target genes, erythropoietin and vascular endothelial growth factor (VEGF). Hypoxia, whatever its duration (1 hour, 3 hours, 6 hours), rapidly increases the nuclear content of HIF-1α as well as the mRNA levels of erythropoietin and VEGF. Furthermore, erythropoietin and VEGF are upregulated at the protein level 24 hours after 6 hours of hypoxia. The authors' findings show that (1) hypoxia elicits a delayed, short-lasting (<72 hours) tolerance to focal permanent ischemia in the adult mouse brain; (2) HIF-1 target genes could contribute to the establishment of tolerance; and (3) this model might be a useful paradigm to further study the mechanisms of ischemic tolerance, to identify new therapeutic targets for stroke.
Three Steps of Neural Stem Cells Development in Gerbil Dentate Gyrus after Transient Ischemia
Authors: Iwai Masanori , Sato Keiko , Omori Nobuhiko , Nagano Isao , Manabe Yasuhiro , Shoji Mikio , Abe Koji
Published: November 2003

The stage of neurogenesis can be divided into three steps: proliferation, migration, and differentiation. To elucidate detailed relations between these three steps after ischemia, the authors evaluated the three steps in the adult gerbil dentate gyrus (DG) after 5 minutes of transient global ischemia using bromodeoxyuridine (BrdU), highly polysialylated neural cell adhesion molecule (PSA-NCAM), and neuronal nuclear antigen (NeuN) and glial fibrillary acidic protein (GFAP) as markers for proliferation, migration, and differentiation, respectively. Bromodeoxyuridine-labeled cells increased approximately sevenfold, and PSA-NCAM–positive cells increased approximately threefold in the subgranular zone (SGZ) with a peak 10 days after ischemia. Bromodeoxyuridine-labeled cells with PSA-NCAM expression were first detected both in the SGZ and the granule cell layer (GCL) 20 days after ischemia and gradually decreased after that, whereas BrdU-labeled cells with NeuN gradually increased in the GCL until 60 days after ischemia. A few BrdU-labeled cells with GFAP expression were detected in DG after ischemia; no PSA-NCAM–positive cells with GFAP expression were detected, but the radial processes of glial cells were partly in contact with PSA-NCAM–positive cell bodies and dendrites. These results suggest that neural stem cell proliferation begins at the SGZ, and that the cells then migrate into the GCL and differentiate mainly into neuronal cells. The majority of these three steps finished in 2 months after transient global ischemia.
Mitogen-Activated Protein Kinase Inhibition in Traumatic Brain Injury: In Vitro and In Vivo Effects
Authors: Mori Tatsuro , Wang Xiaoying , Jung Jae-Chang , Sumii Toshihisa , Singhal Aneesh B. , Fini M. Elizabeth , Dixon C. Edward , Alessandrini Alessandro , Lo Eng H.
Published: November 2003

The authors provide the first in vitro and in vivo evidence that perturbations in mitogen-activated protein kinase (MAPK) signal-transduction pathways are involved in the pathophysiology of traumatic brain injury. In primary rat cortical cultures, mechanical trauma induced a rapid and selective phosphorylation of the extracellular signal-regulated kinase (ERK) and p38 kinase, whereas there was no detectable change in the c-jun N-terminal kinase (JNK) pathway. Treatment with PD98059, which inhibits MAPK/ERK 1/2, the upstream activator of ERK, significantly increased cell survival in vitro. The p38 kinase and JNK inhibitor SB203580 had no protective effect. Similar results were obtained in vivo using a controlled cortical impact model of traumatic injury in mouse brain. Rapid and selective upregulation occurred in ERK and p38 pathways with no detectable changes in JNK. Confocal immunohistochemistry showed that phospho-ERK colocalized with the neuronal nuclei marker but not the astrocytic marker glial fibrillary acidic protein. Inhibition of the ERK pathway with PD98059 resulted in a significant reduction of cortical lesion volumes 7 days after trauma. The p38 kinase and JNK inhibitor SB203580 had no detectable beneficial effect. These data indicate that critical perturbations in MAPK pathways mediate cerebral damage after acute injury, and further suggest that ERK is a novel therapeutic target in traumatic brain injury.
Oxidation of Bilirubin Produces Compounds that Cause Prolonged Vasospasm of Rat Cerebral Vessels: A Contributor to Subarachnoid Hemorrhage–Induced Vasospasm
Authors: Clark Joseph F. , Reilly Melinda , Sharp Frank R.
Published: November 2003

The authors have previously shown that bilirubin-oxidation products (BOXes) are present in CSF of subarachnoid hemorrhage patients with vasospasm, and that BOXes cause vasoconstriction in vitro. This study determined whether BOXes cause vasospasm in vivo. Identical volumes of either lysed blood or standardized amounts of BOXes were injected into the cisterna magna of adult rats. BOX injections caused 6 of 10 rats to die within 10 minutes, whereas 12 of 12 rats survived for 24 hours after blood injections. The mechanism for this significant ( P ⩽ 0.01) increase in mortality was unclear. To directly test whether BOXes produced vasospasm, a cranial window technique was used. Application of 20 μL of 10-μmol/L bilirubin had little effect on the vessels. However, application of BOXes produced marked, dose-dependent small artery and arteriole vasospasm that approached a 90% decrease in diameter by 40 minutes after application in some vessels, and persisted for at least 24 hours. To determine if BOX-mediated vasospasm led to cortical injury, histology and immunocytochemistry were performed on animals that survived for 24 hours. There was a BOX-related stress protein response for HSP25 and HSP32 (HO-1) without evidence of infarction. The finding that the BOXes produce vasospasm of cerebral vessels in vivo, in conjunction with BOXes being found in CSF of vasospasm patients, supports our hypothesis that BOXes contribute to or cause cerebral vasospasm after subarachnoid hemorrhage.
Desferrioxamine Induces Delayed Tolerance against Cerebral Ischemia in Vivo and in Vitro
Authors: Prass Konstantin , Ruscher Karsten , Karsch Maria , Isaev Nikolay , Megow Dirk , Priller Josef , Scharff Anna , Dirnagl Ulrich , Meisel Andreas
Published: November 2003

The widely prescribed drug desferrioxamine is a known activator of the hypoxia-inducible transcription factor 1 (HIF-1) and the subsequent transcription of erythropoietin. In the brain, HIF-1 is a master switch of the transcriptional response to hypoxia, whereas erythropoietin is a potent neuroprotectant. The authors show that desferrioxamine dose-dependently and time-dependently induces tolerance against focal cerebral ischemia in rats and mice, and against oxygen–glucose deprivation in purified cortical neurons. Desferrioxamine induced HIF-1 DNA binding and transcription of erythropoietin in vivo, the temporal kinetics of which were congruent with tolerance induction. Desferrioxamine is a promising drug for the induction of tolerance in humans when ischemia can be anticipated.
MCT2 is a Major Neuronal Monocarboxylate Transporter in the Adult Mouse Brain
Authors: Pierre Karin , Magistretti Pierre J. , Pellerin Luc
Published: November 2003

Although previous Northern blot and in situ hybridization studies suggested that neurons express the monocarboxylate transporter MCT2, subsequent immunohistochemical analyzes either failed to confirm the presence of this transporter or revealed only a low density of immunolabeled neuronal processes in vivo. The authors report that appropriate section pretreatment (brief warming episode or proteinase K exposure) leads to extensive labeling of the neuropil, which appears as tiny puncta throughout the whole mouse brain. In addition, intense MCT2 immunoreactivity was found in cerebellar Purkinje cell bodies and their processes, on mossy fibers in the cerebellum, and on sensory fibers in the brainstem. Double immunofluorescent labeling with appropriate markers and observation with epifluorescence and confocal microscopy did not show extensive colocalization of MCT2 immunoreactivity with presynaptic or postsynaptic elements, but colocalization could be observed occasionally in the cortex with the postsynaptic density protein PSD95. Observations made at the electron microscopic level in the cortex corroborated these results and showed that MCT2 immunoreactivity was associated with wide membrane segments of neuronal processes. These data provide convincing evidence that MCT2 represents a major neuronal monocarboxylate transporter in the adult mouse brain, and further suggest that mature neurons could use monocarboxylates such as lactate as additional energy substrates.
Comparison of Near-Infrared Spectroscopy and Tissue Po2 Time Series in Patients after Severe Head Injury and Aneurysmal Subarachnoid Hemorrhage
Authors: Brawanski Alexander , Faltermeier Rupert , Rothoerl Ralf D. , Woertgen Chris
Published: November 2003

Monitoring of local oxygen pressure in brain white matter (tipo2) and of local hemoglobin oxygen saturation (rSo2) with near-infrared spectroscopy (NIRS) are increasingly employed techniques in neurosurgical intensive care units. Using frequency-based mathematical methods, the authors sought to ascertain whether both techniques contained similar information. Twelve patients treated in the intensive care unit were included (subarachnoid hemorrhage, n = 3; traumatic brain injury, n = 9). A tipo2 probe and an NIRS sensor were positioned over the frontal lobe with the most pathologic changes on initial computed tomography scan. The authors calculated coherence of tipo2 and rSo2, its overall density distribution, its distribution per data set, and its time evolution. The authors identified a band of significantly correlated frequencies (from 0 to 1.3 × 103 Hz) in more than 90% of the data sets for coherence and overall density distribution. Time evolution showed slow but marked changes of significant coherence. By means of spectral analysis the authors show that tipo2 and rSo2 signals contain similar information, albeit using completely different registration methodologies.
Tissue-Type Plasminogen Activator has Paradoxical Roles in Focal Cerebral Ischemic Injury by Thrombotic Middle Cerebral Artery Occlusion with Mild or Severe Photochemical Damage in Mice
Authors: Nagai Nobuo , Zhao Bing-Qiao , Suzuki Yasuhiro , Ihara Hayato , Urano Tetsumei , Umemura Kazuo
Published: November 2003

The role of endogenous tissue-type plasminogen activator (tPA) in focal cerebral ischemic injury (FCII) after middle cerebral artery occlusion was studied using tPA gene-deficient (KO) mice and their wild-type (WT) littermates. The middle cerebral artery was occluded by thrombi induced by three different intensities of photochemical damage, a method that was newly introduced in mice. In both WT and KO mice, the intensity-dependent increase of FCII size was observed. The FCII size in tPA WT mice was smaller than in KO mice in cases of mild damage, whereas the FCII size was larger in WT mice than in KO mice in cases of severe damage. There was no difference in FCII size between WT and KO mice in cases of moderate damage. The number of microthrombi also increased with damage intensity in both WT and KO mice, but was less in WT mice at all intensities of damage. The results support the validity of the model of thrombotic occlusion by photochemical damage in mice, and suggest that endogenous tPA protects FCII through thrombolytic action on transient occlusion of middle cerebral artery with mild damage, but deteriorates on persistent occlusion with severe damage.
Modeling [18F]MPPF Positron Emission Tomography Kinetics for the Determination of 5-Hydroxytryptamine(1A) Receptor Concentration with Multiinjection
Authors: Costes Nicolas , Merlet Isabelle , Zimmer Luc , Lavenne Franck , Cinotti Luc , Delforge Jacques , Luxen André , Pujol Jean-François , Bars Didier Le
Published: November 2003

The selectivity of [18F]MPPF (fluorine-18-labeled 4-(2' -methoxyphenyl)-1-[2' -(N-2“-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: Fv (vascular fraction), K1, k2 (plasma/free compartment exchange rate), koff, kon/Vr (association and dissociation rate), Bmax (receptor concentration), and to deduce Kd (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential were compared with indices generated by Logan-Patlak graphical analysis. The 5HT1A specificity for MPPF was evidenced. A Bmax of 2.9 pmol/mL and a Kd of 2.8 nmol/L were found in hippocampal regions, Kd and distribution volume in the free compartment were regionally stable, and the Logan binding potential was linearly correlated to Bmax. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols.
Temporal and Spatial Profile of Bid Cleavage after Experimental Traumatic Brain Injury
Authors: Franz Gerhard , Beer Ronny , Intemann Denis , Krajewski Stanislaw , Reed John C. , Engelhardt Klaus , Pike Brian R. , Hayes Ronald L. , Wang Kevin K. , Schmutzhard Erich , Kampfl Andreas
Published: November 2003

Apoptosis plays an essential role in the cascade of CNS cell degeneration after traumatic brain injury. However, the underlying mechanisms are poorly understood. The authors examined the temporal profile and cell subtype distribution of the proapoptotic protein Bid from 6 hours to 7 days after cortical impact injury in the rat. Increased protein levels of tBid were seen in the cortex ipsilateral to the injury site from 6 hours to 3 days after trauma. Immunohistologic examinations revealed expression of tBid in neurons, astrocytes, and oligodendrocytes from 6 hours to 3 days after impact injury, and concurrent assessment of DNA damage using TUNEL identified tBid-immunopositive cells with apoptoticlike morphology in the traumatized cortex. Moreover, Bid cleavage and activation of caspase-8 and caspase-9 occurred at similar time points and in similar brain regions (i.e., cortical layers 2 to 5) after impact injury. In contrast, there was no evidence of caspase-8 or caspase-9 processing or Bid cleavage in the ipsilateral hippocampus, contralateral cortex, and hippocampus up to 7 days after the injury. The results provide the first evidence of Bid cleavage in the traumatized cortex after experimental traumatic brain injury in vivo, and demonstrate that tBid is expressed in neurons and glial cells. Further, findings indicate that cleavage of Bid may be associated with the activation of the initiator caspase-8 and caspase-9. Finally, these data support the hypothesis that cleavage of Bid contributes to the apoptotic degeneration of different CNS cells in the injured cortex.
Reduced Inflammatory Reactions to the Inoculation of Helper-Dependent Adenoviral Vectors in Traumatically Injured Rat Brain
Authors: Zou Linglong , Yotnda Patricia , Zhao Tiejun , Yuan Xiaoqing , Long Yan , Zhou Heshan , Yang Keyi
Published: November 2003

Traumatic brain injury (TBI) causes delayed neuronal deficits that in principle could be prevented by timely intervention with therapeutic genes. However, appropriate vectors for gene transfer to the brain with TBI remain to be developed. First-generation adenoviruses (fgAd) are usually associated with inflammatory and toxic effects when inoculated into brains, despite their high efficiency of gene transfer to these tissues. In this study the authors attempted to determine whether a less immunogenic gene-transfer protocol can be established in the traumatically injured rat brain using helper-dependent adenoviruses (hdAd), a novel adenoviral construct with full deletion of viral coding sequences. Their results show that transgene expression from intrahippocampally inoculated hdAd is maintained for at least 2 months after TBI, in contrast to the much shorter duration of fgAd-mediated gene expression. There was only minimal secretion of proinflammatory IL-1β and TNF-α after inoculation of hdAd. Furthermore, the hdAd-mediated gene expression was associated with less microglial proliferation, astrocytic activation, and macrophage infiltration than observed in fgAd-inoculated brains. There was no additional tissue loss after hdAd inoculation compared with PBS injection. Although both anti-adenoviral and neutralizing antibodies were found in serum after brain inoculation of hdAd, they did not appear to affect transgene expression. The results suggest that hdAd are less immunogenic vectors than conventional adenoviral vectors, and offer improved vehicles for long-term therapeutic transgene transfer to traumatically injured brains.
Effect of Aging on Cerebral Vascular Response to Paco2 Changes in Humans as Measured by Positron Emission Tomography
Authors: Ito Hiroshi , Kanno Iwao , Ibaraki Masanobu , Hatazawa Jun
Published: November 2003

Vascular responses to changes in Paco2 are used widely to estimate cerebral perfusion reserve, and they can also be used to assess the degree of arteriosclerosis. In the present study, the effect of aging on cerebral vascular responses to both hypercapnia and hypocapnia was investigated. Cerebral blood flow was measured with positron emission tomography at rest, during hypercapnia, and during hypocapnia in 11 young men and 12 older men. The vascular response to change in Paco2 was calculated as the percent change in cerebral blood flow per absolute change in Paco2 in response to hypercapnia and hypocapnia. The total vascular response to change in Paco2 from hypocapnia to hypercapnia was also calculated. To evaluate age-related changes in regional cerebral vascular responses on a pixel-by-pixel basis, an anatomic standardization technique was also used. Although no significant differences between young and old subjects was observed for vascular responses to both hypercapnia and hypocapnia, a significant decrease in total vascular response was observed with aging, indicating progression of sclerotic changes in the cerebral perforating and medullary arteries with normal aging. According to anatomic standardization analysis, relative capacities for vasodilatation in the cerebellum and insular cortex, and relative capacity for vasoconstriction in the frontal cortex were greater in the younger subjects. Such aging effects should be considered when estimating cerebral perfusion reserve.
Imaging Amyloid-β Deposits In Vivo
Authors: Bacskai Brian J. , Klunk William E. , Mathis Chester A. , Hyman Bradley T.
Published: November 2003

Alzheimer disease (AD) is an illness that can only be diagnosed with certainty with postmortem examination of brain tissue. Tissue samples from afflicted patients show neuronal loss, neurofibrillary tangles (NFTs), and amyloid-β plaques. An imaging technique that permitted in vivo detection of NFTs or amyloid-β plaques would be extremely valuable. For example, chronic imaging of senile plaques would provide a readout of the efficacy of experimental therapeutics aimed at removing these neuropathologic lesions. This review discusses the available techniques for imaging amyloid-β deposits in the intact brain, including magnetic resonance imaging, positron emission tomography, single photon emission computed tomography, and multiphoton microscopy. A variety of agents that target amyloid-β deposits specifically have been developed using one or several of these imaging modalities. The difficulty in developing these tools lies in the need for the agents to cross the blood-brain barrier while recognizing amyloid-β with high sensitivity and specificity. This review describes the progress in developing reagents suitable for in vivo imaging of senile plaques.
Quantitative Real-Time RT—PCR Analysis of Inflammatory Gene Expression Associated with Ischemia—Reperfusion Brain Injury
Authors: Berti Rossana , Williams Anthony J. , Moffett John R. , Hale Sarah L. , Velarde Luisa C. , Elliott Peter J. , Yao Changping , Dave Jitendra R. , Tortella Frank C.
Published: November 2003

Ischemia-reperfusion brain injury initiates an inflammatory response involving the expression of adhesion molecules and cytokines, some of which are regulated by the nuclear transcription factor NF-κB. In this study the authors examined mRNA expression levels for several important genes associated with inflammation at five time points (3, 6, 12, 24, and 72 hours) after transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. A sensitive and quantitative technique (TaqMan real-time QRT-PCR) was used to simultaneously measure mRNA levels for key cell adhesion molecules and inflammatory cytokines. Gene expression increased significantly in the injured hemisphere for interleukin (IL)-1β (12-fold increase at 24 hours), IL-6 (25-fold increase at 6 hours) and ICAM-1 (4-fold increase at 24 hours), and the in-terhemispheric differences for these genes were significant for every time point examined ( P < 0.05 for all values). Tumor necrosis factor-α mRNA was upregulated in the injured versus uninjured hemisphere from 3 to 24 hours (5-fold increase at 6 hours), while E-selectin showed a significant increase in mRNA levels from 6 to 24 hours after MCAO (10-fold increase at 6 hours) ( P < 0.05 for all values). VCAM-1 mRNA levels did not respond differentially to injury at any time point between the two brain hemispheres. At all time points examined, activated NF-κB immunoreactivity was observed in cells throughout the infarct-damaged tissue. These results are consistent with the proinflammatory properties of the induced molecules, which are involved in the initiation of the inflammatory cascade, and may thus contribute to secondary cellular responses that lead to further brain damage.
In Vivo Receptor Assay with Multiple Ligand Concentrations: An Equilibrium Approach
Authors: Holden James E. , Jivan Salma , Ruth Thomas J. , Doudet Doris J.
Published: November 2003

The ligand-receptor binding potential determined by in vivo PET studies at high ligand-specific radioactivity reflects both the receptor density and ligand-receptor affinity. This ambiguity has been resolved by various methods based on the administration of multiple unlabeled ligand concentrations. The authors aimed to implement and refine an approach to multiple ligand concentration receptor assay that combined maximum simplicity and a minimum of assumptions and model dependence that would nonetheless reliably distinguish density from affinity effects. The approach uses administration by bolus followed by infusion to obtain a true equilibrium between bound ligand and the other components of the ligand concentration, and does not require measurements of ligand in blood plasma. Four approaches to the optimization of the desired density and affinity parameters from the measured equilibrium data were implemented and compared in the analysis of raclopride studies performed in both normal control and MPTP-lesioned nonhuman primates. The authors conclude that the method is simple enough for routine use and yet reliable enough to apply in ongoing studies of both chronic and acute drug effects in the dopamine system.
Absolute Quantification of Cerebral Blood Flow with Magnetic Resonance, Reproducibility of the Method, and Comparison with H215O Positron Emission Tomography
Authors: Carroll Timothy J. , Teneggi Vincenzo , Jobin Mathieu , Squassante Lisa , Treyer Valerie , Hany Thomas F. , Burger Cyrill , Wang Liqun , Bye Alan , von Schulthess Gustav K. , Buck Alfred
Published: November 2003

While H215O positron emission tomography (PET) is still the gold standard in the quantitative assessment of cerebral perfusion (rCBF), its technical challenge, limited availability, and radiation exposure are disadvantages of the method. Recent work demonstrated the feasibility of magnetic resonance (MR) for quantitative cerebral perfusion imaging. There remain open questions, however, especially regarding reproducibility. The main purpose of this study was to assess the accuracy and reproducibility of MR-derived flow values to those derived from H215O PET. Positron emission tomography and MR perfusion imaging was performed in 20 healthy male volunteers, who were chronic smokers, on day 1 and day 3 of a 4-day hospitalization. Subjects were randomly assigned to one of two groups, each with 10 subjects. One group was allowed to smoke as usual during the hospitalization, while the other group stopped smoking from day 2. Positron emission tomography and MR images were coregistered and rCBF was determined in two regions of interest, defined over gray matter (gm) and white matter (wm), yielding rCBFPETgm, rCBFMRgm, rCBFPETwm, and rCBFMRwm. Bland-Altman analysis was used to investigate reproducibility by assessing the difference rCBFday3 - rCBFday1 in eight continual-smoker volunteers. The analysis showed a good reproducibility for PET, but not for MR. Mean ± SD of the difference rCBFday3 - rCBFday1 in gray matter was 6.35 ± 21.06 and 0.49 ± 5.27 mL · min−1 · 100 g−1 for MR and PET, respectively; the corresponding values in white matter were 2.60 ± 15.64 and −1.14 ± 4.16 mL · min−1 · 100 g−1. The Bland-Altman analysis was also used to assess MRI and PET agreement comparing rCBF measured on day 1. The analysis demonstrated a reasonably good agreement of MR and PET in white matter (rCBFPETwm - rCBFMRwm; −0.09 ± 7.23 mL · min−1 · 100 g−1), while in gray matter a reasonable agreement was only achieved after removing vascular artifacts in the MR perfusion maps (rCBFPETgm - rCBFMRgm; −11.73 ± 14.52 mL · min−1 · 100 g−1). In line with prior work, these results demonstrate that reproducibility was overall considerably better for PET than for MR. Until reproducibility is improved and vascular artifacts are efficiently removed, MR is not suitable for reliable quantitative perfusion measurements.
Cholesterol and Interkeukin-6 Concentrations Relate to Outcomes in Burn-Injured Patients
Authors: Vanni Holly E. Colwell , Gordon Bruce R. , Levine Daniel M. , Sloan Betty-Jane , Stein David R. , Yurt Roger W. , Saal Stuart D. , Parker Thomas S.
Published: November 2003

The goal of this study was to determine the relationship among lipid concentrations, cytokine concentrations, and clinical outcomes of burn patients. Twenty-eight patients admitted within 24 hours of burn injury, segregated based on burn size, had blood samples drawn 24 and 48 hours after burn injury and then weekly for 3 weeks. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, interleukin (IL)-6, soluble IL-2 receptor, and soluble necrosis factor p55 and p75 receptors. Infection, length of stay (LOS), and survival were monitored. Cholesterol and lipoprotein concentrations decreased by at least 40% in patients with burns >20% total body surface area and inversely correlated with IL-6. Lower cholesterol and higher IL-6 values correlated with higher infection rates and longer LOS. IL-6 was the strongest predictor for LOS. In conclusion, outcomes after burn injury are related to low cholesterol and elevated IL-6 levels.
Successful Placement of an Adult Sternal Intraosseous Line Through Burned Skin
Authors: Frascone Ralph , Kaye Koren , Dries David , Solem Lynn
Published: November 2003

Obtaining vascular access can be difficult in the critical adult patient. This can be especially true in a severely burned patient, where the usual insertion site may be involved in the burn injury. We present a case in which a sternal intraosseous line was placed through a full-thickness injury, in a patient in full arrest, who subsequently underwent a succesful cardiac resuscitation.
Car Seat Heaters: A Potential Hazard for Burns
Authors: Maguiña Pirko , Palmieri Tina L. , Greenhalgh David G.
Published: November 2003

Car seat heaters have gained popularity in America and worldwide. They offer comfort by heating the sitting surface to a soothing temperature. Several cases of heating-element malfunction resulted in burn injuries and have triggered recalls of thousands of cars by the manufacturers. We present a case of a 48-year-old patient with long-standing paraplegia who sustained third-degree burns on his buttock during the initial drive of a new car with seat heaters. Car seat heaters can cause severe burns. Patients with decreased sensation or immobility are at increased risk and should not use car seat heaters. This case illustrates the need for design modifications and consumer education regarding the risks associated with car seat heaters.
Premorbid Mental Health Status of Adult Burn Patients: Comparison with a Normative Sample
Authors: Patterson David R. , Finch Carmel P. , Wiechman Shelley A. , Bonsack Rhonda , Gibran Nicole , Heimbach David
Published: November 2003

The presence of psychiatric problems in burn patients has been found to have an impact on their burn care and long-term adjustment. This study investigated rates of previous mental health symptoms in a sample of 199 hospitalized burn patients screened for previous psychiatric diagnoses. Patients were instructed to fill out a questionnaire about their mental health functioning on the Rand Inventory for the month preceding their burn injury. Scores compared with a national normative sample on the Rand Mental Health Inventory revealed that burn patients scored higher on psychological distress, anxiety, depression, and loss of behavioral and emotional control. These results reflect other studies in the literature, indicating that burn patients are premorbidly more psychologically vulnerable than the general population, a factor that likely contributes to many of them sustaining their injuries.
Management of An Unusual Extreme Extension Contracture of the Wrist
Authors: Saraiya Hemant
Published: November 2003

An extreme extension contracture of wrist with dorsal contracture of fingers 15 years after burn injury is described. Shortening of extensor tendons, secondary lengthening of flexor tendons, contracted wrist joint capsule, unusual dislocation of carpals, dorsal dislocation of metacarpophalangeal joints of fingers, and provision of sufficient amount of good-quality skin were some of the issues that had to be addressed in treatment. The contracture was released, the carpals and metacarpophalangeal joint dislocations were corrected and fixed with K wires, and the resulting defect was covered with a sheet split-thickness skin graft. An exercise program was designed that consisted of isotonic, isokinetic, and isometric resistance exercises and passive, active, and active-assistive range of motion exercises. These exercises were pursued with the intention of increasing dynamic strength, endurance, and overall functional recovery of the flexor muscles by exploiting the immature nature of early scar tissue. The resultant enhanced flexor muscle power from exercises along with the dynamic splint helped in lengthening of extensor tendons, wrist joint capsule, and split-thickness skin graft. It also helped in resisting the recontracting tendency, with further recovery of good range of wrist and fingers movements, obviating the need of tendon-lengthening surgery and flap coverage. One and half years of follow up didn't show any sign of recontracture, and the patient was able to perform his routine activities. Postburn wrist contractures of such magnitude have been seldom described. Emphasis is put on simple contracture release and a postoperative exercise program.
Cerebral Hemodynamics and White Matter Hyperintensities in CADASIL
Authors: van den Boom Rivka , Oberstein Saskia A. Lesnik , Spilt Aart , Behloul Faiza , Ferrari Michel D. , Haan Joost , Westendorp Rudi G. , van Buchem Mark A.
Published: November 2003

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. On magnetic resonance imaging (MRI), subcortical white matter hyperintensities and lacunar infarcts are visualized. It is unknown whether a decrease in cerebral blood flow or cerebrovascular reactivity is primarily responsible for the development of white matter hyperintensities and lacunar infarcts. The authors used phase-contrast MRI in 40 NOTCH3 mutation carriers (mean age 45 ± 10 years) and 22 nonmutated family members (mean age 39 ± 12 years), to assess baseline total cerebral blood flow (TCBF) and cerebrovascular reactivity after acetazolamide. Mean baseline TCBF was significantly decreased in NOTCH3 mutation carriers. In young subjects, baseline TCBF was significantly lower than in nonmutation carriers (mean difference 124 mL/min). Furthermore, baseline TCBF did not differ significantly between mutation carriers with minimal and mutation carriers with moderate or severe white matter hyperintensities. No significant difference in mean cerebrovascular reactivity was found between mutation carriers and nonmutation carriers. This study suggests that a decrease in baseline TCBF in NOTCH3 mutation carriers precedes the development of white matter hyperintensities.
Dynamic Observation of Oxygenation-Induced Contraction of and Transient Fiber-Network Formation–Disassembly in Cultured Human Brain Microvascular Endothelial Cells
Authors: Inoue Kouji , Tomita Minoru , Fukuuchi Yasuo , Tanahashi Norio , Kobari Masahiro , Takao Masaki , Takeda Hidetaka , Yokoyama Masako
Published: November 2003

Oxygenation-induced contraction of nonconfluent cultured human brain microvascular endothelial cells (HBECs, n = 30) was examined by video-enhanced contrast-differential interferential contrast microscopy. After administering a continuous gentle blow of pure oxygen gas to the surface of the medium just above the flattened HBEC, the plasma membrane exhibited tensioning and wrinkling, resulting in a strong contraction of the cell body by 14 ± 7% ( P < 0.001). When the cell stopped contracting, transient formation of a fiber network starting from certain spots (possibly adhesion plaques, though these were not visible in the majority of cases) and expanding to the whole cell was observed. The occurrence of fiber network formation was statistically significant (26 of 30 separate cells, P < 0.05). After cessation of oxygen delivery, the observed network of fibers broke up rapidly (in a period of 3.3 ± 1.2 seconds) into small particles of <0.5 μm in diameter, which subsequently fused into the cellular structure. The HBEC completely recovered the control appearance. The sequential process was completed within 30 seconds and was reproduced in individual cells each time that oxygen gas was supplied. The authors conclude that the HBEC strongly contracts in response to a transient oxygenation stimulus, followed by rapid formation/disassembly of a network structure.
Accelerated Glial Reactivity to Stroke in Aged Rats Correlates with Reduced Functional Recovery
Authors: Badan I. , Buchhold B. , Hamm A. , Gratz M. , Walker L. C. , Platt D. , Kessler Ch. , Popa-Wagner A.
Published: November 2003

Following cerebral ischemia, perilesional astrocytes and activated microglia form a glial scar that hinders the genesis of new axons and blood vessels in the infarcted region. Since glial reactivity is chronically augmented in the normal aging brain, the authors hypothesized that postischemic gliosis would be temporally abnormal in aged rats compared to young rats. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14, and 28 days after surgery. Brain tissue was immunostained for microglia, astrocytes, oligodendrocytes, and endothelial cells. Behaviorally, aged rats were more severely impaired by stroke and showed diminished functional recovery compared with young rats. Histologically, a gradual activation of both microglia and astrocytes that peaked by days 14 to 28 with the formation of a glial scar was observed in young rats, whereas aged rats showed an accelerated astrocytic and microglial reaction that peaked during the first week after stroke. Oligodendrocytes were strongly activated at early stages of infarct development in all rats, but this activation persisted in aged rats. Therefore, the development of the glial scar was abnormally accelerated in aged rats and coincided with the stagnation of recovery in these animals. These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats leads to the premature formation of scar tissue that impedes functional recovery after stroke.
N-Acetylaspartate to Total Creatine Ratio in the Hippocampal CA1 Sector after Transient Cerebral Ischemia in Gerbils: Influence of Neuronal Elements, Reactive Gliosis, and Tissue Atrophy
Authors: Konaka Kuni , Ueda Hirokazu , Li Ji-Yao , Matsumoto Masayasu , Sakoda Saburo , Yanagihara Takehiko
Published: November 2003

The authors compared temporal profiles of Nacetylaspartate (NAA) and the NAA/total creatine ratio with neuronal and astrocytic densities and with tissue atrophy in the hippocampal CA1 sector of gerbils after 5-minute bilateral forebrain ischemia and subsequent reperfusion for up to 6 months. The CA1 sector was dissected from 20-μm lyophilized sections (n = 5) for NAA, phosphocreatine, and creatine assays using high-performance liquid chromatography. Adjacent 10-μm sections were used for immunohistochemical analysis to follow neuronal and astrocytic responses. The NAA concentration was significantly ( P<0.01) decreased after 7 days but leveled off thereafter. The NAA/total creatine (phosphocreatine + creatine) ratio was significantly decreased after 7 days and further decreased ( P<0.05) after 6 months. Extensive neuronal damage developed beyond 7 days, while reactive astrogliosis progressed throughout the observation period. There was a good linear correlation ( P<0.01) between astroglial density and the NAA/total creatine ratio beyond 7 days. The thickness of the CA1 sector was significantly reduced after 1 month and further reduced after 6 months. Although both NAA level and the NAA/total creatine ratio seemed to be indicators of neuronal damage, the latter could be influenced by reactive astrogliosis with progression of tissue atrophy.
Heme and Iron Metabolism: Role in Cerebral Hemorrhage
Authors: Wagner Kenneth R. , Sharp Frank R. , Ardizzone Timothy D. , Lu Aigang , Clark Joseph F.
Published: November 2003

Heme and iron metabolism are of considerable interest and importance in normal brain function as well as in neurodegeneration and neuropathologically following traumatic injury and hemorrhagic stroke. After a cerebral hemorrhage, large numbers of hemoglobin-containing red blood cells are released into the brain's parenchyma and/or subarachnoid space. After hemolysis and the subsequent release of heme from hemoglobin, several pathways are employed to transport and metabolize this heme and its iron moiety to protect the brain from potential oxidative stress. Required for these processes are various extracellular and intracellular transporters and storage proteins, the heme oxygenase isozymes and metabolic proteins with differing localizations in the various braincell types. In the past several years, additional new genes and proteins have been discovered that are involved in the transport and metabolism of heme and iron in brain and other tissues. These discoveries may provide new insights into neurodegenerative diseases like Alzheimer's, Parkinson's, and Friedrich's ataxia that are associated with accumulation of iron in specific brain regions or in specific organelles. The present review will examine the uptake and metabolism of heme and iron in the brain and will relate these processes to blood removal and to the potential mechanisms underlying brain injury following cerebral hemorrhage.
Interferon-Beta Blocks Infiltration of Inflammatory Cells and Reduces Infarct Volume after Ischemic Stroke in the Rat
Authors: Veldhuis Wouter B. , Derksen Joris W. , Floris Sarah , van der Meide Peter H. , de Vries Helga E. , Schepers Janneke , Vos Ine M. P. , Dijkstra Christien D. , Kappelle L. Jaap , Nicolay Klaas , Bär Peter R.
Published: November 2003

The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-β), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-β treatment reduced lesion volume on diffusion-weighted MRI by 70% ( P < 0.01) at 1 day after stroke. IFN-β attenuated the leakage of contrast agent through the blood–brain barrier ( P < 0.005), indicating a better-preserved blood–brain barrier integrity. Both control and IFN-β-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-β was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-β treatment resulted in an 85% reduction ( P < 0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN-β almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN-β affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-β has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.
Nitric Oxide Synthase Inhibition Depresses the Height of the Cerebral Blood Flow–Pressure Autoregulation Curve during Moderate Hypotension
Authors: Jones Stephen C. , Easley Kirk A. , Radinsky Carol R. , Chyatte Douglas , Furlan Anthony J. , Perez-Trepichio Alejandro D.
Published: November 2003

Variations in the height of the CBF response to hypotension have been described recently in normal animals. The authors evaluated the effects of nitric oxide synthase (NOS) inhibition on these variations in height using laser Doppler flowmetry in 42 anesthetized (halothane and N2O) male Sprague-Dawley rats prepared with a superfused closed cranial window. In four groups (time control, enantiomer control, NOS inhibition, and reinfusion control) exsanguination to MABPs from 100 to 40 mm Hg was used to produce autoregulatory curves. For each curve the lower limit of autoregulation (the MABP at the first decrease in CBF) was identified; the pattern of autoregulation was classified as “peak” (15% increase in %CBF), “classic” (plateau with a decrease at the lower limit of autoregulation), or “none” (15% decrease in %CBF); and the autoregulatory height as the %CBF at 70 mm Hg (%CBF70) was determined. NOS inhibition decreased %CBF70 in the NOS inhibition group (P = 0.014), in the control (combined time and enantiomer control) group (P = 0.015), and in the reinfusion control group (P = 0.025). NOS inhibition via superfusion depressed the autoregulatory pattern (P = 0.02, McNemar test on changes in autoregulatory pattern) compared with control (P = 0.375). Analysis of covariance showed that changes induced by NOS inhibition in the parameters of autoregulatory height are not related to changes in the lower limit, but are strongly (P < 0.001) related to each other. NOS inhibition depressed the autoregulatory pattern, decreasing the seemingly paradoxical increase in CBF as blood pressure decreases. These results suggest that nitric oxide increases CBF near the lower limit and augments the hypotensive portion of the autoregulatory curve.
Activation of p38 Kinase in the Gerbil Hippocampus Showing Ischemic Tolerance
Authors: Nishimura Masaki , Sugino Toshiyuki , Nozaki Kazuhiko , Takagi Yasushi , Hattori Itaro , Hayashi Junya , Hashimoto Nobuo , Moriguchi Tetsuo , Nishida Eisuke
Published: November 2003

Ischemic tolerance is a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia. The authors investigated the activation of p38 mitogen-activated protein kinase (p38) in the gerbil hippocampus by Western blotting and immunohistochemistry to clarify the role of p38 kinase in ischemic tolerance. After the 2-minute global ischemia, immunoreactivity indicating active p38 was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 and CA3 neurons. Pretreatment with SB203580, an inhibitor of active p38 (0–30 μmol/L), 30 minutes before the 2-minute ischemia reduced the ischemic tolerance effect in a dose-dependent manner. Immunoblot analysis indicated that alteration of the phosphorylation pattern of p38 kinase in the hippocampus after subsequent lethal ischemia was induced by the preconditioning. These findings suggest that lasting activation of p38 may contribute to ischemic tolerance in CA1 neurons of the hippocampus and that components of the p38 cascade can be target molecules to modify neuronal survival after ischemia.
Tissue Microenvironments within Functional Cortical Subdivisions Adjacent to Focal Stroke
Authors: Katsman Diana , Zheng Jian , Spinelli Kateri , Carmichael S. Thomas
Published: November 2003

Stroke produces a region of complete cell death and areas of partial damage, injury, and gliosis. The spatial relationship of these regions of damage to the infarct core and within spared neuronal circuits has not been identified. A model of cortical stroke was developed within functional subsets of the somatosensory cortex. Infarct size, regions of apoptosis, oxidative DNA damage, heat shock protein induction, and subtypes of reactive gliosis were precisely mapped with the somatosensory body map, quantified, and interrelated. Three tissue microenvironments were recognized: zones of partial ischemic damage, heat shock protein induction, and distributed gliosis. These three zones involved progressively more distant cortical regions, each larger than the infarct core. The zone of partial ischemic damage represents an overlap region of apoptotic cell death, oxidative DNA damage, loss of synaptic connections, and local reactive gliosis. The zone of distributed gliosis occupies distinct functional areas of the somatosensory cortex. The tissue reorganization induced by stroke is much larger than the stroke site itself. Adjacent tissue microenvironments are sites of distinct reactive cellular signaling and may serve as a link between the processes of acute cell death and delayed neuronal plasticity after focal stroke.