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R. Bryan Mason, Ryszard M. Pluta, Stuart Walbridge, David A. Wink, Edward H. Oldfield and Robert J. Boock

cytotoxic 2, 10 and cytoprotective 18, 27, 50, 56 in ischemic injury. We hypothesized that NOS activity is upregulated in response to decreased oxygen tension during the ischemic insult and that, in the period of reperfusion following oxygen deprivation, NO is overproduced, potentially providing cytoprotection by reacting with ROS as well as providing vasodilatory benefits to the ischemic tissue. In a series of in vitro and in vivo models of reperfusion injury, we examined the levels of NO and free radicals in response to anoxia and ischemia followed by reoxygenation

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W. M. Lougheed and D. S. Kahn

C omparison of Shunts and of Local and Systemic Hypothermia. Effect of Hypothermia on Cerebral Metabolic Rate and Cerebral Tolerance to Anoxia . Vascular lesions of the brain could be treated more adequately if the blood supply to the affected area were occluded or at least diminished. This necessitates supplying the brain distal to the lesion with arterial blood or protecting it from anoxia. In searching for a method to facilitate the neurosurgical approach to these lesions of the brain, we first tried in dogs various kinds of polyethylene shunts and perfusion

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Robert A. Feldman, David Yashon, George E. Locke and William E. Hunt

L actate is known to accumulate in animal tissues as a result of anoxia. Lactate elevation has been quantitated in cerebral tissue following circulatory arrest and has been shown to increase in cerebral tissue after death, 5, 9 but such determinations have not been made on spinal cord tissue. This study explores the biochemical background for the chemical observation that, following profound central nervous system anoxia, the spinal cord tolerates anoxia better than the brain. Methods and Materials Eight rhesus monkeys weighing 3 to 5 kg were

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Brain energetics and neurosurgery

A review of recent studies done at Duke University

Barnes Woodhall, Richard S. Kramer, William D. Currie and Aaron P. Sanders

substrates? Preliminary Study of Cerebral Hypoxia and Autolysis in Situ Haldane's famous statement that anoxia “not only stops the machine but wrecks the machinery” 6 is certainly true in the long run. Until recently, however, little information was available concerning the nature of the “wrecking” process, or the rate of development of injury in different tissues. Early in 1965, two related papers described studies illustrating the effects of autolysis in situ and hypoxia on respiratory metabolism in brain, liver, and kidney; the findings proved sufficient to

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Isadore M. Tarlov

likelihood of recovery in some patients. This report summarizes these data. Summary of Experimental Evidence on Mechanism of Spinal Compression Paralysis Whether the paralysis caused by spinal compression is due to mechanical deformation of tissue or to anoxia has long been controversial. In evaluating their respective roles, a comparison of the electrophysiological effects produced by compressing the spinal cord with those caused by ischemia and anoxia was made. 5, 6 Figure 1 shows a comparison of the action potentials taken from the dorsum of the dog

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Tetsuaki Teraura, John Stirling Meyer, Keizo Sakamoto, Kazuo Hashi, Peter Marx, Cornelia Sterman-Marinchesu and Seiji Shinmaru

by numerous experimental means. 2, 10, 14, 20 45 Opinions concerning the etiology of cerebral edema due to hypoxia are conflicting, however, and the terminology is often vague. 40 White, et al., 44 and Zaren, et al., 45 reported that systemic hypoxia caused striking increases in brain volume that persisted for as long as 2 hours. Edstrom and Essex, 7 however, were unable to provoke brain swelling by systemic anoxia, hypercarbia, hypotension, or cardiac arrest for 2 minutes’ duration. Other investigators also failed to produce cerebral edema following

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Albert Hijdra and Jan van Gijn

from acutely raised intracranial pressure and a fall in perfusion pressure, 11 the ensuing systemic anoxia may have contributed to the death of these patients. This secondary brain damage in patients with purely subarachnoid bleeding and apnea might be prevented by mechanical ventilation at an early stage. This is only partially confirmed by analysis of all patients in the original group of 142 who had apnea after aneurysm rupture and who could be resuscitated immediately — which in fact means that they had a rebleed in the hospital. Of 14 such cases, six survived

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Frederick A. Simeone, John P. Laurent, Peter J. Trepper, Daniel J. Brown and John Cotter

the intracranial pressure rise to dangerous levels. This was in a dog who early in the experiment underwent a significant period of anoxia and whose brain had apparently lost the capacity to autoregulate. This animal succumbed after developing an extremely high intracranial pressure. Effect on Kidney Function Urinary output was measured continuously, and periodic phenolsulfonphthalein clearance tests were performed in a series of animals. Urinary output was noted to decrease somewhat during prolonged aortic occlusion. This decrement, however, was never

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Edgar A. Bering Jr.

T his is a study of cerebrospinal fluid (CSF) electrolyte changes during circulatory arrest at brain temperatures ranging from 37° to 10° C and their relationship to cerebral oxygen metabolism. The maintenance of the intracellular sodium and potassium content is dependent on the metabolic processes which excludes or removes sodium from cells (the “sodium pump”). As the cerebral metabolism is, under normal conditions, almost entirely aerobic, the cerebral sodium pump is dependent directly on the availability of oxygen to the brain. Anoxia generated by

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Hangjun Ruan, Lily Hu, Jingli Wang, Tomoko Ozawa, Nader Sanai, Michael Zhang, Kathleen R. Lamborn and Dennis F. Deen

Object

The presence of hypoxic cells in human brain tumors contributes to the resistance of these tumors to radiation therapy. However, because normal tissues are not hypoxic, the presence of hypoxic cells also provides the potential for designing cancer-specific gene therapy. Suicide genes can be expressed specifically in hypoxic conditions by hypoxia-responsive elements (HREs), which are activated through the transcriptional complex hypoxia-inducible factor–1 (HIF-1).

Methods

The authors have transfected the murine BAX–green fluorescent protein (GFP) fusion gene under the regulation of three copies of HRE into U-87 MG and U-251 MG cells and selected stably transfected clones. Even though BAX was expressed under both oxic and anoxic conditions in these clones, cell survival assays demonstrated increased cell killing under anoxic as compared with oxic conditions. Cells obtained from most of these clones did not grow in vivo, or the tumors exhibited highly variable growth rates. However, cells obtained from the U-251 MG clone A produced tumors that grew as well as tumors derived from parental cells, and examination of the tumor sections under fluorescent microscopy revealed GFP expression in localized regions. Western blot analyses confirmed an increased BAX expression in these tumors. Analysis of the results suggests that HRE-regulated BAX can be a promising tool to target hypoxic brain tumor cells. However, there are measurable levels of BAX-GFP expression in this three-copy HRE–mediated expression system under oxia, suggesting promoter leakage. In addition, most clones did not show significant induction of BAX-GFP under anoxia. Therefore, the parameters of this HRE-mediated expression system, including HRE copy number and the basal promoter, need to be optimized to produce preferential and predictable gene expression in hypoxic cells.