Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice—glioma coculture model

2004 ◽  
Vol 100 (6) ◽  
pp. 1049-1059 ◽  
Author(s):  
Christopher D. Duntsch ◽  
Qihong Zhou ◽  
Himangi R. Jayakar ◽  
James D. Weimar ◽  
Jon H. Robertson ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Vesicular Stomatitis Virus ◽  
Glioma Cells ◽  
Tissue Slice ◽  
High Grade ◽  
Content Type ◽  
Coculture System ◽  
Vesicular Stomatitis ◽  
High Grade Gliomas ◽  
Fine Print

Object. The purpose of this study was to evaluate both replication-competent and replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as therapeutic agents for high-grade gliomas by using an organotypic brain tissue slice—glioma coculture system. Methods. The coculture system involved growing different brain structures together to allow neurons from these tissues to develop synaptic connections similar to those found in vivo. Rat C6 or human U87 glioma cells were then introduced into the culture to evaluate VSV as an oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt) rapidly eliminated C6 glioma cells from the coculture, but also caused significant damage to neurons, as measured by a loss of microtubule-associated protein 2 immunoreactivity and a failure in electrophysiological responses from neurons in the tissue slice. Nonetheless, pretreatment with interferon beta (IFNβ) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNβ pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pretreatment with IFNβ and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-ΔG) effectively destroyed rat C6 and human U87 glioma cells in the coculture, without causing detectable damage to the neuronal integrity and electrophysiological properties of the healthy tissue in the culture. Conclusions. Data in this study provide in vitro proof-of-principle that rVSV-ΔG is an effective oncolytic agent that has minimal toxic side effects to neurons compared with rVSV-wt and therefore should be considered for development as an adjuvant to surgery in the treatment of glioma.

Efficacy of neuroradiological imaging, neurological examination, and symptom status in follow-up assessment of patients with high-grade gliomas

2000 ◽  
Vol 93 (2) ◽  
pp. 201-207 ◽  
Author(s):  
Evanthia Galanis ◽  
Jan C. Buckner ◽  
Paul Novotny ◽  
Roscoe F. Morton ◽  
William L. McGinnis ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Neurological Examination ◽  
High Grade ◽  
Performance Score ◽  
Content Type ◽  
Asymptomatic Patients ◽  
Symptom Status ◽  
High Grade Gliomas ◽  
Fine Print

Object. It is standard practice for the oncological follow-up of patients with brain tumors (especially in the setting of clinical trials) to include neurological examination and neuroradiological studies such as computerized tomography (CT) or magnetic resonance (MR) imaging in addition to evaluation of the patients' symptomatology and performance score. The validity of this practice and its impact on the welfare of patients with high-grade gliomas has not been adequately assessed. The purpose of this study is to provide such an assessment.Methods. The authors studied 231 similarly treated patients who were participating in three prospective North Central Cancer Treatment Group or Mayo Clinic trials who developed progressive disease during follow up. According to the protocol, the symptom status, performance score, results of neurological examination, and CT or MR status were recorded prospectively in each patient at each evaluation (every 6–8 weeks).At progression, 177 (77%) of 231 patients experienced worsening of their baseline symptoms or they developed new ones. In the remaining 54 asymptomatic patients (23%), neuroradiological imaging revealed the progression. Asymptomatic progression was more likely to be detected on MR imaging compared with CT studies (p < 0.01). In no asymptomatic patient was progression detected on neurological examination alone. The median survival time after tumor recurrence was 13.3 weeks in symptomatic patients compared with 41.7 weeks in the asymptomatic group (p < 0.0001). Asymptomatic patients were more aggressively treated, with surgery (p < 0.0001) and second-line chemotherapy (p < 0.0002). Multivariate analysis of survival time following first progression by using both classification and regression trees and Cox models showed that treatment at recurrence was the most important prognostic variable.Conclusions. Symptoms are the most frequent indicators of progression in patients with high-grade gliomas (77%). All asymptomatic progressions were detected on neuroradiological studies; MR imaging was more likely than CT scanning to reveal asymptomatic recurrences. Survival after disease progression was significantly longer in asymptomatic patients and could be related both to treatment following progression and to other favorable prognostic factors such as performance score.

Long survival and therapeutic responses in patient histologically disparate high-grade gliomas demonstrating chromosome 1p loss

2000 ◽  
Vol 92 (6) ◽  
pp. 983-990 ◽  
Author(s):  
Yasushi Ino ◽  
Magdalena C. Zlatescu ◽  
Hikaru Sasaki ◽  
David R. Macdonald ◽  
Anat O. Stemmer-Rachamimov ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Genetic Alterations ◽  
Allelic Loss ◽  
High Grade ◽  
Prognostic Information ◽  
Content Type ◽  
Chromosome 1P ◽  
Oligodendroglial Tumors ◽  
High Grade Gliomas ◽  
Fine Print

Object. Allelic loss of chromosome 1p is a powerful predictor of tumor chemosensitivity and prolonged survival in patients with anaplastic oligodendrogliomas. Chromosome 1p loss also occurs in astrocytic and oligoastrocytic gliomas, although less commonly than in pure oligodendroglial tumors. This observation raises the possibility investigated in this study that chromosome 1p loss might also provide prognostic information for patients with high-grade gliomas with astrocytic components.Methods. The authors report on seven patients with high-grade gliomas composed of either pure astrocytic or mixed astrocytic-oligodendroglial phenotypes, who had remarkable neuroradiological responses to therapy or unexpectedly long survivals. All of the tumors from these seven patients demonstrated chromosome 1p loss, whereas other genetic alterations characteristic of high-grade gliomas (p53 gene mutations, EGFR gene amplification, chromosome 10 loss, chromosome 19q loss, or CDKN2A/p16 deletions) were only found in occasional cases. The authors also assessed the frequency of chromosome 1p loss in a series of anonymous high-grade astrocytoma samples obtained from a tumor bank and demonstrate that this genetic change is uncommon, occurring in only 10% of cases.Conclusions. Although any prognostic importance of chromosome 1p loss in astrocytic or mixed astrocytic—oligodendroglial gliomas can only be determined in larger and prospective series, these findings raise the possibility that some high-grade gliomas with chromosome 1p loss, in addition to pure anaplastic oligodendrogliomas, may follow a more favorable clinical course.

Functional outcomes and survival in patients with high-grade gliomas in dominant and nondominant hemispheres

2005 ◽  
Vol 102 (2) ◽  
pp. 276-283 ◽  
Author(s):  
Richard S. Polin ◽  
Nicholas F. Marko ◽  
Matthew D. Ammerman ◽  
Mark E. Shaffrey ◽  
Wei Huang ◽  
...  
Keyword(s):  
Functional Outcome ◽  
Functional Outcomes ◽  
Outcome Data ◽  
Karnofsky Performance Scale ◽  
Sample Population ◽  
High Grade ◽  
Content Type ◽  
Significant Difference ◽  
High Grade Gliomas ◽  
Fine Print

Object. The goal of this study was to investigate survival and functional outcomes in patients with high-grade intracranial astrocytomas as a function of the location of the lesion in the dominant or nondominant hemisphere (DH and NDH, respectively), and to suggest management strategies for such patients based on these data. Methods. Data were collected from the Glioma Outcomes Project database, a longitudinal database of demographic, clinical, and outcome data for patients with high-grade intracranial gliomas. From the entire database of 788 patients, a subset of all 280 right-handed patients with newly diagnosed, unilateral gliomas involving potentially eloquent cortex was selected as the sample population. Two cohorts were defined based on the location of the tumor in the right or left cerebral hemisphere. All other relevant demographic and clinical data were nearly identical between the cohorts. A Kaplan—Meier analysis was conducted to assess survival, and Karnofsky Performance Scale scores assigned at 6 and 12 months postoperatively were compared as a measure of functional outcome. The analysis demonstrated no difference in survival between patients with lesions in the DH and those with tumors in the NDH. Additionally, no statistically significant difference in functional outcomes was observed between the two groups. Conclusions. Laterality of high-grade gliomas is not an independent prognostic factor for predicting survival or functional outcome. The findings in this study demonstrate that fears of increased postoperative morbidity or mortality in otherwise resectable tumors of the DH are unfounded, and the authors therefore advocate that the surgeon's decision to operate be guided by validated outcome predictors and not biased by tumor lateralization.

Diffusion tensor analysis of peritumoral edema using lambda chart analysis indicative of the heterogeneity of the microstructure within edema

2005 ◽  
Vol 102 (2) ◽  
pp. 336-341 ◽  
Author(s):  
Ken-ichi Morita ◽  
Hitoshi Matsuzawa ◽  
Yukihiko Fujii ◽  
Ryuichi Tanaka ◽  
Ingrid L. Kwee ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Low Grade ◽  
High Grade ◽  
Peritumoral Edema ◽  
Resonance Imaging ◽  
Content Type ◽  
Water Diffusivity ◽  
High Grade Gliomas ◽  
Fine Print

Object. Histopathological studies indicate that cerebral edema associated with tumors (peritumoral edema) does not represent a single pathophysiological or clinical entity. In this study the authors investigated peritumoral edema by performing lambda chart analysis (LCA), a noninvasive technique that can be used to make visible and analyze apparent water diffusivity in tissues in vivo, and assessed the utility of LCA in differentiating high-grade gliomas from nonglial tumors. Methods. The water diffusivity characteristics of peritumoral edema associated with four tumor groups—12 high-grade gliomas, five low-grade gliomas, 11 metastatic tumors, and 15 meningiomas—were assessed in 43 patients by performing magnetic resonance imaging with the aid of a 3-tesla magnetic resonance imaging system. In all tumor groups, peritumoral edema exhibited greater trace values and reduced anisotropy compared with normal white matter. Edema associated with high-grade gliomas had significantly higher trace values than edema associated with the other three tumor groups, although the anisotropic angles of those groups were comparable. Conclusions. Lambda chart analysis identified two distinct types of peritumoral edema: edema associated with high-grade gliomas and edema associated with low-grade gliomas or nonglial tumors. The apparent water diffusivity was significantly greater in high-grade gliomas, whereas the anisotropy in these lesions was comparable to that of edema in other tumors. These findings indicated that water movement in areas of edema, predominantly in the extracellular spaces, was less restricted in high-grade gliomas, a phenomenon that likely reflected the destruction of the extracellular matrix ultrastructure by malignant cell infiltration and consequently greater water diffusion. Although preliminary, this study indicates that LCA could be used as a clinical tool for differentiating high-grade gliomas and for evaluating the extent of cellular infiltration.

Cell cycle arrest and astrocytic differentiation resulting from PTEN expression in glioma cells

1999 ◽  
Vol 91 (5) ◽  
pp. 822-830 ◽  
Author(s):  
Jun-ichi Adachi ◽  
Katsumi Ohbayashi ◽  
Tomonari Suzuki ◽  
Tomio Sasaki
Keyword(s):  
Expression System ◽  
Biological Significance ◽  
Glioma Cells ◽  
Genetic Alterations ◽  
Pten Expression ◽  
Human Glioma ◽  
Wild Type ◽  
Content Type ◽  
Astrocytic Differentiation ◽  
Fine Print

Object. Genetic alterations of the PTEN gene (also known as MMAC1 or TEP1) have frequently been identified in high-grade gliomas, indicating that inactivation of PTEN plays a crucial role in human glioma progression. The aim of this study was to assess the biological significance of PTEN inactivation in the development of glioma.Methods. The authors introduced wild-type PTEN complementary DNA into four human glioma cell lines (T98G, U-251MG, U-87MG, and A172) containing endogenous aberrant PTEN alleles. The number of colonies transfected with the wild-type PTEN was reduced to 15 to 32% of those found after transfection of a control vector, suggesting growth suppression by the exogenous PTEN. To analyze phenotypic alterations produced by PTEN expression, T98G-derived clones with inducible PTEN expression were further established using a tetracycline-regulated inducible gene expression system. Induction of PTEN expression suppressed the in vitro growth of T98G cells with accumulation of G1 phase cells. Furthermore, when cells were cultured in the presence of the extracellular matrix (ECM), PTEN expression caused distinct morphological changes, with multiple and elongated cytoplasmic processes similar to those of normal astrocytes. The level of glial fibrillary acidic protein, an intermediate protein specifically expressed in differentiated astrocytes, was upregulated concomitantly.Conclusions. These findings strongly indicate that exogenous PTEN expression inhibits the proliferation of glioma cells by inducing G1 arrest and elicits astrocytic differentiation in the presence of the ECM. Inactivation of PTEN would play an important role in the enhancement of unregulated growth of undifferentiated glioma cells.

Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

2002 ◽  
Vol 97 (5) ◽  
pp. 1184-1190 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
Junpei Honma ◽  
Ryuichi Tanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Antitumor Effects ◽  
Content Type ◽  
Immunogene Therapy ◽  
Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

Enhancement of radiosensitivity of wild-type p53 human glioma cells by adenovirus-mediated delivery of the p53 gene

1998 ◽  
Vol 89 (1) ◽  
pp. 125-132 ◽  
Author(s):  
Frederick F. Lang ◽  
W. K. Alfred Yung ◽  
Uma Raju ◽  
Floralyn Libunao ◽  
Nicholas H. A. Terry ◽  
...  
Keyword(s):  
Cell Line ◽  
Glioma Cell ◽  
Radiation Treatment ◽  
P53 Protein ◽  
Glioma Cells ◽  
Glioma Cell Line ◽  
Wild Type ◽  
Content Type ◽  
Infected Cells ◽  
Fine Print

Object. The authors sought to determine whether combining p53 gene transfer with radiation therapy would enhance the therapeutic killing of p53 wild-type glioma cells. It has been shown in several reports that adenovirus-mediated delivery of the p53 gene into p53 mutant gliomas results in dramatic apoptosis, but has little effect on gliomas containing wild-type p53 alleles. Therefore, p53 gene therapy alone may not be a clinically effective treatment for gliomas because most gliomas are composed of both p53 mutant and wild-type cell populations. One potential approach to overcome this problem is to exploit the role p53 plays as an important determinant in the cellular response to ionizing radiation. Methods. In vitro experiments were performed using the glioma cell line U87MG, which contains wild-type p53. Comparisons were made to the glioma cell line U251MG, which contains a mutant p53 allele. Monolayer cultures were infected with an adenovirus containing wild-type p53 (Ad5CMV-p53), a control vector (dl312), or Dulbecco's modified Eagle's medium (DMEM). Two days later, cultures were irradiated and colony-forming efficiency was determined. Transfection with p53 had only a minor effect on the plating efficiency of nonirradiated U87MG cells, reducing the plating efficiency from 0.23 ± 0.01 in DMEM to 0.22 ± 0.04 after addition of Ad5CMV-p53. However, p53 transfection significantly enhanced the radiosensitivity of these cells. The dose enhancement factor at a surviving fraction of 0.10 was 1.5, and the surviving fraction at 2 Gy was reduced from 0.61 in untransfected controls to 0.38 in p53-transfected cells. Transfection of the viral vector control (dl312) had no effect on U87MG radiosensitivity. In comparison, transfection of Ad5CMV-p53 into the p53 mutant cell line U251MG resulted in a significant decrease in the surviving fraction of these cells compared with controls, and no radiosensitization was detected. To determine whether Ad5CMV-p53—mediated radiosensitization of U87MG cells involved an increase in the propensity of these cells to undergo apoptosis, flow cytometric analysis of terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridinetriphosphate nick-end labeling—stained cells was performed. Whereas the amount of radiation-induced apoptosis in uninfected and dl312-infected control cells was relatively small (2.1 ± 0.05% and 3.7 ± 0.5%, respectively), the combination of Ad5CMV-p53 infection and radiation treatment significantly increased the apoptotic frequency (18.6 ± 1.4%). To determine whether infection with Ad5CMV-p53 resulted in increased expression of functional exogenous p53 protein, Western blot analysis of p53 was performed on U87MG cells that were exposed to 9 Gy of radiation 2 days after exposure to Ad5CMV-p53, dl312, or DMEM. Infection with Ad5CMV-p53 alone increased p53 levels compared with DMEM- or dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in a further increase in p53 that reached a maximum at 2 hours postirradiation. To determine whether exogenous p53 provided by Ad5CMV-p53 had transactivating activity, U87MG cells were treated as described earlier and p21 messenger RNA levels were determined. Infection of U87MG cells with Ad5CMV-p53 only resulted in an increase in p21 compared with DMEM- and dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in an additional time-dependent increase in p21 expression. Conclusions. These data indicate that adenovirus-mediated delivery of p53 may enhance the radioresponse of brain tumor cells containing wild-type p53 and that this radiosensitization may involve converting from a clonogenic to the more sensitive apoptotic form of cell death. Although the mechanism underlying this enhanced apoptotic susceptibility is unknown, the Ad5CMV-p53—infected cells have a higher level of p53 protein, which increases further after irradiation, and this exogenous p53 is transcriptionally active. Thus, it is possible that the combination of Ad5CMV-p53 infection and radiation treatment increases p53 protein to a level that is sufficient to overcome at least partially the block in apoptosis existing in U87MG cells.

scholarly journals MxA Mediates SUMO-Induced Resistance to Vesicular Stomatitis Virus

2016 ◽  
Vol 90 (14) ◽  
pp. 6598-6610 ◽  
Author(s):  
Ghizlane Maarifi ◽  
Zara Hannoun ◽  
Marie Claude Geoffroy ◽  
Faten El Asmi ◽  
Karima Zarrouk ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Mrna Synthesis ◽  
Restriction Factors ◽  
Viral Protein Synthesis ◽  
Independent Manner ◽  
Content Type ◽  
Intracellular Pool ◽  
Vesicular Stomatitis ◽  
Cellular Pathways ◽  
Opposing Effects

ABSTRACTMultiple cellular pathways are regulated by small ubiquitin-like modifier (SUMO) modification, including ubiquitin-mediated proteolysis, signal transduction, innate immunity, and antiviral defense. In the study described in this report, we investigated the effects of SUMO on the replication of two members of theRhabdoviridaefamily, vesicular stomatitis virus (VSV) and rabies virus (RABV). We show that stable expression of SUMO in human cells confers resistance to VSV infection in an interferon-independent manner. We demonstrate that SUMO expression did not alter VSV entry but blocked primary mRNA synthesis, leading to a reduction of viral protein synthesis and viral production, thus protecting cells from VSV-induced cell lysis. MxA is known to inhibit VSV primary transcription. Interestingly, we found that the MxA protein was highly stabilized in SUMO-expressing cells. Furthermore, extracts from cells stably expressing SUMO exhibited an increase in MxA oligomers, suggesting that SUMO plays a role in protecting MxA from degradation, thus providing a stable intracellular pool of MxA available to combat invading viruses. Importantly, MxA depletion in SUMO-expressing cells abrogated the anti-VSV effect of SUMO. Furthermore, SUMO expression resulted in interferon-regulatory factor 3 (IRF3) SUMOylation, subsequently decreasing RABV-induced IRF3 phosphorylation and interferon synthesis. As expected, this rendered SUMO-expressing cells more sensitive to RABV infection, even though MxA was stabilized in SUMO-expressing cells, since its expression did not confer resistance to RABV. Our findings demonstrate opposing effects of SUMO expression on two viruses of the same family, intrinsically inhibiting VSV infection through MxA stabilization while enhancing RABV infection by decreasing IFN induction.IMPORTANCEWe report that SUMO expression reduces interferon synthesis upon RABV or VSV infection. Therefore, SUMO renders cells more sensitive to RABV but unexpectedly renders cells resistant to VSV by blocking primary mRNA synthesis. Unlike the interferon-mediated innate immune response, intrinsic antiviral resistance is mediated by constitutively expressed restriction factors. Among the various anti-VSV restriction factors, only MxA is known to inhibit VSV primary transcription, and we show here that its expression does not alter RABV infection. Interestingly, MxA depletion abolished the inhibition of VSV by SUMO, demonstrating that MxA mediates SUMO-induced intrinsic VSV resistance. Furthermore, MxA oligomerization is known to be critical for its protein stability, and we show that higher levels of oligomers were formed in cells expressing SUMO than in wild-type cells, suggesting that SUMO may play a role in protecting MxA from degradation, providing a stable intracellular pool of MxA able to protect cells from viral infection.

Cerebral oxygen and microdialysis monitoring during aneurysm surgery: effects of blood pressure, cerebrospinal fluid drainage, and temporary clipping on infarction

2002 ◽  
Vol 96 (6) ◽  
pp. 1013-1019 ◽  
Author(s):  
Rupert Kett-White ◽  
Peter J. Hutchinson ◽  
Pippa G. Al-Rawi ◽  
Marek Czosnyka ◽  
Arun K. Gupta ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Total Duration ◽  
Wilcoxon Test ◽  
Fisher Exact Test ◽  
Content Type ◽  
The Impact ◽  
Temporary Clipping ◽  
Fine Print

Object. The aim of this study was to investigate potential episodes of cerebral ischemia during surgery for large and complicated aneurysms, by examining the effects of arterial temporary clipping and the impact of confounding variables such as blood pressure and cerebrospinal fluid (CSF) drainage. Methods. Brain tissue PO2, PCO2, and pH, as well as temperature and extracellular glucose, lactate, pyruvate, and glutamate were monitored in 46 patients by using multiparameter sensors and microdialysis. Baseline data showed that brain tissue PO2 decreased significantly, below a mean arterial pressure (MAP) threshold of 70 mm Hg. Further evidence of its relationship with cerebral perfusion pressure was shown by an increase in mean brain tissue PO2 after drainage of CSF from the basal cisterns (Wilcoxon test, p < 0.01). Temporary clipping was required in 31 patients, with a mean total duration of 14 minutes (range 3–52 minutes), causing brain tissue PO2 to decrease and brain tissue PCO2 to increase (Wilcoxon test, p < 0.01). In patients in whom no subsequent infarction developed in the monitored region, brain tissue PO2 fell to 11 mm Hg (95% confidence interval 8–14 mm Hg). A brain tissue PO2 level below 8 mm Hg for 30 minutes was associated with infarction in any region (p < 0.05 according to the Fisher exact test); other parameters were not predictive of infarction. Intermittent occlusions of less than 30 minutes in total had little effect on extracellular chemistry. Large glutamate increases were only seen in two patients, in both of whom brain tissue PO2 during occlusion was continuously lower than 8 mm Hg for longer than 38 minutes. Conclusions. The brain tissue PO2 decreases with hypotension, and, when it is below 8 mm Hg for longer than 30 minutes during temporary clipping, it is associated with increasing extracellular glutamate levels and cerebral infarction.

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