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In glutamate-mediated excitatory neuronal cell death, immunosuppressants (FK506, Cys-A) are powerful agents that protect neurons from apoptosis. Immunosuppressants inhibit two types of enzyme, calcium/calmodulin-dependent protein phosphatase (calcineurin: CaN), and peptidyl-prolyl cis-trans-isomerase (PPIase) activity such as the FKBP family. In this study, we used a protein transduction approach to determine the functional role of CaN and to produce a potential therapeutic agent for glutamate-mediated neuronal cell death. We created a novel cell-permeable CaN autoinhibitory peptide using the 11 arginine protein transduction domain. This peptide was highly efficient at transducing into primary culture neurons, potently inhibited CaN phosphatase activities, and inhibited glutamate-mediated neuronal cell death. These results showed that CaN plays an important role in excitatory neuronal cell death and cell-permeable CaN autoinhibitory peptide could be a new drug to protect neurons from excitatory neuronal death.

We examined the effects of mild to moderate hypothermia and the influence of rewarming on electrophysiological function using somatosensory evoked potentials (SEPs) in transient focal ischemia in the brain. Nineteen cats underwent 60 min of left middle cerebral artery occlusion under normothermic (36 degrees-37 degrees C, n = 6) or hypothermic (30 degrees -31 degrees C, n = 13) conditions followed by 300 min of reperfusion with slow (120 min, n = 6) or rapid (30 min, n = 7) rewarming. Whole-body hypothermia was induced during ischemia and the first 180 min of reperfusion. SEPs and regional cerebral blood flow were measured before and during ischemia and during reperfusion. The specific gravity of gray and white matter was examined as the indicator of edema. During rewarming, SEP amplitudes recovered gradually. After rewarming, SEPs in the normothermic and rapid rewarming groups remained depressed (20%-40% of pre-occlusion values); however, recovery of SEPs was significantly enhanced in the slow rewarming group (p0.05). Hypothermia followed by slow rewarming reduced edema in gray and white matter. Rapid rewarming did not reduce edema in the white matter. The recovery of SEPs correlated with the extent of brain edema in transient focal ischemia. Rapid rewarming reduced the protective effect of hypothermia.

Delayed resistance to ischemic injury can be induced by a variety of conditioning stimuli. This phenomenon, known as delayed ischemic tolerance, is initiated over several hours or a day, and can persist for up to a week or more. The present paper describes recent experiments in which transient hypothermia was used as a conditioning stimulus to induce ischemic tolerance. A brief period of hypothermia administered 6 to 48 hours prior to focal ischemia reduces subsequent cerebral infarction. Hypothermia-induced ischemic tolerance is reversed by 7 days postconditioning, and is blocked by the protein synthesis inhibitor anisomycin. Electrophysiological studies utilizing in vitro brain slices demonstrate that hypoxic damage to synaptic responses is reduced in slices prepared from hypothermia-preconditioned animals. Taken together, these findings indicate that transient hypothermia induces tolerance in the brain parenchyma, and that increased expression of one or more gene products contributes to this phenomenon. Inasmuch as hypothermia is already an approved clinical procedure for intraischemic and postischemic therapy, it is possible that hypothermia could provide a clinically useful conditioning stimulus for limiting injury elicited by anticipated periods of ischemia.

Only small amounts of superoxide dismutase (SOD) are present in the extracellular space to scavenge excess amounts of superoxide anions (02-) released after traumatic brain injury (TBI). Experiments were performed in rats with cerebral contusion produced by weight-drop technique. We investigated the effects of exogenous lecithinized SOD (PC-SOD) on accumulation of 02- produced in our model, by measuring the level of SOD activity (using the NBT-reducing method) and the expression of copper, zinc-SOD (Cu, Zn-SOD) mRNA (by Northern blot analysis). As determined by tissue-specific gravity, administration of PC-SOD reduced brain edema in the periphery of the lesion 6 h after contusion. SOD activity increased in the peripheral region at 30 min after contusion, but returned to normal levels at 6 h after TBI. Administration of PC-SOD increased SOD activity up to 6 h after TBI. The expression of Cu, Zn-SOD mRNA increased in the core region, peripheral portion, and contralateral hemisphere up to 6 h after TBI, then was suppressed in all three regions by PC-SOD. Our results confirm the important role of 02- in the development of brain edema after TBI and indicate that PC-SOD diminishes brain edema through a protective effect against 02-.

To determine the effect of hypothermia on superoxide injury after cerebral contusion, the induction of Cu,Zn-superoxide dismutase was examined 6 h after contusion in rats using Northern blotting. Cu,Zn-superoxide dismutase gene expression increased at the periphery of the contusion, which may indicate the severity of the superoxide stimulus. This increase was preserved after contusion under hypothermia, which may show that superoxide injury is still severe although brain edema is decreased.

Brain surface elastance, defined as the pressure needed to compress the cortex 3 mm, was measured using the ophthalmodynamometer in six cats using three burr holes (frontal, parietal, and occipital) on each side. An intracranial mass was then used to compress the right side for 3 hours, and cardiac arrest was induced after the mass was removed. Elastance was measured four times: before insertion of the mass, 10 and 70 minutes after removal of the mass, and 60 minutes after cardiac arrest. The results showed that: brain surface elastance does not change between sides, but varies among regions with the parietal region having the highest elastance; elastance increases after compression by an intracranial mass, but not after cardiac arrest; and stiff brain tends to restore poorly. Elastance is apparently increased by the formation of edema. Measuring brain elastance may be useful in predicting brain restoration subsequent to removal of mass lesions.

Progressive multifocal leukoencephalopathy (PML) is caused by opportunistic infection by JC virus and presents with progressive demyelinating lesions in the central nervous system. A 59-year-old man with a history of alcoholic liver dysfunction presented with progressive weakness of his left leg over a period of one month. MRI showed multiple white matter lesions that were of low intensity on the T1 image and high intensity on the T2 image, heterogeneously high intensity on the diffusion image, and were not enhanced with contrast media. The patient underwent open biopsy of the right parietal lesion. The histological findings were the demyelination and the enlargement of nuclei of oligodendrocytes. Electron microscopic examination showed numerous viral particles in the nuclei of the oligodendrocytes. Infection by JC virus in the central nervous system was diagnosed with the polymerase chain reaction (PCR) products sampled from the cerebrospinal fluid. The incidence of PML has significantly increased in immunosuppressive patients, such as AIDS (acquired immunodeficiency syndrome). We presented the first case of PML in an immune-compromised state with alcoholic liver dysfunction.

We report a rare case with polycystic kidney disease (PKD) having an intracranial internal carotid artery aneurysm associated with extracranial occlusion of the ipsilateral internal carotid artery. A 55-year-old man with chronic renal failure due to PKD presented with headache. CT scan and MRI showed no abnormal findings. MRA showed cervical occlusion of the right internal carotid artery and an ipsilateral intracranial carotid aneurysm. At surgery, the saccular aneurysm protruded anterolaterally at the C2 portion of the right internal carotid and was clipped. Hemodynamic stress of the blood flow through the posterior communicating artery and the fragility of arteries because of PKD were considered to be two main causes of aneurysmal formation in this case.

High b-value diffusion-weighted (DW) imaging obtained with a b-value of 2,000 s/mm2 offers theoretical advantages over DW imaging obtained with a b-value of 1,000 s/mm2 for detection of acute brain infarction. The purpose of this study was to determine whether high b-value DW images (b=2,000) are better than b=1,000 images for detection of diffusion change in patients with acute brain infarction. We compared diffusion-weighted (DW) images obtained with a b-value of 1,000 s/mm2 with those obtained with a b-value of 2,000 s/mm2 in 84 patients with small lesions (brain stem infarction, lacuna infarction) examined within 24 hours of clinical onset. Qualitative analysis was performed concerning lesion conspicuity. In quantitative analysis, contrast ratios (CR) were measured and findings of b=1,000 and b=2,000 images were compared. False-negative rate of b=1,000 and b=2,000 images were 23.8% and 3.6%, respectively, relative to the presense or absense of infarction on the follow-up MR or CT images. On qualitative analysis, lesions were more conspicuous on b=2,000 images. On quantitative analysis, as the b-value increased, mean CR increased. DW images aquired with a b-value of 2,000 s/mm2 were better than DW images aquired with a b-value of 1,000 s/mm2 for detection of diffusion change in patients with acute brain infarction.

Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects on dopaminergic (DA) neurons. In this study, we investigated whether the effects of VEGF were dose-dependent or not. First, VEGF was shown to be neuroprotective on 6-hydroxydopamine (6-OHDA)-treated murine DA neurons in vitro, although the 1 ng/ml of VEGF displayed more neuroprotective effects than 100 ng/ml. Furthermore, using 2 sizes of capsules (small/large) with different secreting quantities, 6-OHDA-treated rats receiving the small capsule filled with VEGF-secreting cells (BHK-VEGF) into the striatum showed a significant decrease in amphetamine-induced rotational behavior in number and a significant preservation of TH-positive fibers compared to those receiving the large BHK-VEGF capsule as well as those receiving BHK-Control capsule. Rats receiving the large BHK-VEGF capsule showed much more glial proliferation, angiogenesis, and brain edema around the capsule than those with the small one. High-dose administration of VEGF might cause poor circulation related to brain edema, although low-dose administration of VEGF displays neuroprotective effects on DA neurons. Our results demonstrate the importance of administration dose of VEGF, suggesting that low-dose administration of VEGF might be desirable for Parkinson's disease.

In glutamate-mediated excitatory neuronal cell death, immunosuppressants (FK506, Cys-A) are powerful agents that protect neurons from apoptosis. Immunosuppressants inhibit two types of enzyme, calcium/calmodulin-dependent protein phosphatase (calcineurin: CaN), and peptidyl-prolyl cis-trans-isomerase (PPIase) activity such as the FKBP family. In this study, we used a protein transduction approach to determine the functional role of CaN and to produce a potential therapeutic agent for glutamate-mediated neuronal cell death. We created a novel cell-permeable CaN autoinhibitory peptide using the 11 arginine protein transduction domain. This peptide was highly efficient at transducing into primary culture neurons, potently inhibited CaN phosphatase activities, and inhibited glutamate-mediated neuronal cell death. These results showed that CaN plays an important role in excitatory neuronal cell death and cell-permeable CaN autoinhibitory peptide could be a new drug to protect neurons from excitatory neuronal death.

Stressful, preconditioning stimuli can elicit rapid and delayed forms of tolerance to ischemic injury. The identification and characterization of preconditioning stimuli that are effective, but relatively benign, could enhance the clinical applicability of induced tolerance. This study examines the efficacy of brief hypothermia as a preconditioning stimulus for inducing rapid tolerance. Rats were administered hypothermic preconditioning or sham preconditioning and after an interval of 20-120 min were subjected to transient focal ischemia using a three-vessel occlusion model. The volume of cerebral infarction was measured 24 h or 7 days after ischemia. In other experiments, the depth or duration of the hypothermic stimulus was manipulated, or a protein synthesis inhibitor (anisomycin) was administered. Twenty minutes of hypothermia delivered 20 or 60 (but not 120) min prior to ischemia significantly reduces cerebral infarction. The magnitude of protection is enhanced with deeper levels of hypothermia, but is not affected by increasing the duration of the hypothermic stimulus. Treatment with a protein synthesis inhibitor does not block the induction of rapid tolerance. Hypothermic preconditioning elicits a rapid form of tolerance to focal ischemic injury. Unlike delayed tolerance induced by hypothermia, rapid tolerance is not dependent on either de novo protein synthesis or the duration of the preconditioning stimulus. These findings suggest that the mechanisms underlying rapid and delayed tolerance induced by hypothermia differ fundamentally. Brief hypothermia could provide a rapid means of inducing transient tissue protection in the context of predictable ischemic events.

Object. A brief period of hypothermia has recently been shown to induce delayed tolerance to ischemic brain injury. This form of tolerance is initiated several hours after hypothermic preconditioning (HPC) and persists for a few days. Hypothermia-induced tolerance could provide a means for limiting cellular injury during predictable periods of ischemia, such as those that occur during many surgical procedures. The purpose of this study was to characterize the parameters of HPC that regulate the induction of delayed tolerance. Methods. The general design of the experiments was to perform HPC or a sham procedure on adult Sprague-Dawley rats. Twenty-four hours later, the animals were subjected to a transient period of ischemia induced by a 1-hour period of three-vessel occlusion. Infarct volume was assessed 24 hours postischemia. In the first series of experiments, the depth of global (that is, whole-body) HPC was set at 25.5, 28.5, or 31.5°C, and the duration of HPC was fixed at 20 minutes. In the second series of experiments, the duration of global HPC was set at 20, 60, 120, or 180 minutes, and the depth of HPC was set at 33 or 34.5°C. In the third series of experiments, focal HPC was administered by selectively cooling the head to achieve a cortical temperature of 28.5 or 31.5°C for 20 minutes, with the duration of HPC fixed at 20 minutes. The magnitude of tolerance induced by HPC was dependent on the depth and duration of the hypothermic stimulus. The parameters of hypothermia that are capable of inducing tolerance are similar to, or less severe than, those already in clinical use during intraoperative procedures. Focal cooling was as effective as global cooling for eliciting tolerance, indicating that it is possible to establish tolerance while limiting the potential complications of systemic hypothermia. Conclusions. The results of these experiments indicate that HPC may provide an effective and safe means for limiting cellular injury resulting from predictable periods of central nervous system ischemia.

Authors have developed proper polyhedron models to enable people to learn the concept of three-dimensional symmetry. Touching and operating the symmetry elements of the proper polyhedron enables people to understand symmetry. In this study, authors made three-dimensional tessellation models. Certain polyhedra can be stacked in a regular periodic pattern to fill three-dimensional space completely. Figures show our models. The cube (Fig. (a)) is the only regular polyhedron to fill three-dimensional space completely. The cube is a Voronoi region of the simple cubic lattice (sc). The truncated octahedron (Fig. (b)) is the only Archimedean solid to fill three-dimensional space completely. The truncated octahedron is a Voronoi region of the body-centered cubic lattice (bcc). The rhombic dodecahedron (Fig. (c)) is the only Catalan solid (or Archimedean dual) to fill three-dimensional space completely. The rhombic dodecahedron is a Voronoi region of the face-centered cubic lattice (fcc). Figs. (a), (b), and (c) show three kinds of their aggregate respectively. In each of left-hand aggregate, there is a two-fold rotational axis along a vertical direction. In each of central aggregate, there is a three-fold rotational axis along a vertical direction. In each of right-hand aggregate, there is a four-fold rotational axis along a vertical direction. Fig. (d) is a nontrivial polyhedron to fill three-dimensional space completely. The external shape of the polyhedron was designed as a tree shape. We call such a model three-dimensional Escher shape (3DES) [1]. This can be stacked in a regular periodic pattern too.

Object. Ischemic neuronal damage associated with neurological and other types of surgery can have severe consequences for functional recovery after surgery. Hypothermia administered during and/or after ischemia has proved to be clinically beneficial and its effects often rival or exceed those of other therapeutic strategies. In the present study the authors examined whether transient hypothermia is an effective preconditioning stimulus for inducing ischemic tolerance in the brain.Methods. Adult rats were subjected to a 20-minute period of hypothermic preconditioning followed by an interval ranging from 6 hours to 7 days. At the end of this interval, the animals were subjected to transient focal ischemia induced by clamping one middle cerebral artery and both carotid arteries for 1 hour. The volume of cerebral infarction was assessed 1 or 7 days postischemia. In the first series of experiments, hypothermic preconditioning (28.5°C) with a postconditioning interval of 1 day reduced the extent of cerebral infarction measured 1 and 7 days postischemia. In the second series, hypothermic preconditioning (31.5°C) with postconditioning intervals of 6 hours, 1 day, or 2 days (but not 7 days) reduced the extent of cerebral infarction measured 1 day postischemia. Treatment with the protein synthesis inhibitor anisomycin blocked the protective effect of hypothermic preconditioning. In a final series of experiments, in vitro brain slices prepared from hypothermia-preconditioned (nonischemic) animals were shown to tolerate a hypoxic challenge better than slices prepared from unconditioned animals.Conclusions. These findings indicate that hypothermic preconditioning induces a form of delayed tolerance to focal ischemic damage. The time course over which tolerance occurs and the ability of a protein synthesis inhibitor to block tolerance suggest that increased expression of one or more gene products is necessary to establish tissue tolerance following hypothermia. The attenuation of hypoxic injury in vitro following in vivo preconditioning indicates that tolerance is due, at least in part, to direct effects on the brain neuropil. Hypothermic preconditioning could provide a relatively low-risk approach for improving surgical outcome after invasive surgery, including high-risk neurological and cardiovascular procedures.

To analyze the effect of lecithinized superoxide dismutase (SOD) on superoxide accumulation after traumatic brain injury (TBI) in rats, we studied the SOD activity by NBT-reducing method and the expression of Cu,Zn-SOD mRNA by Northern blot analysis. As determined by the specific gravity method, the administration of lecithinized SOD decreased brain edema in the periphery of the lesion at 6 hr after contusion. SOD activity, without lecithinized SOD administration, increased at the peripheral portion at 30 min after contusion, but decreased to the normal level at 6 hr after TBI. By administration of lecithinized SOD, the increase of SOD activity was preserved until 6 hr after TBI. The expression of Cu,Zn-SOD mRNA increased in the core lesion, peripheral portion, and contralateral hemisphere until 6 hr after TBI, then was suppressed in all three areas by lecithinized SOD. These results support the hypothesis that superoxide anions may play an important role in the development of brain edema after TBI, and that leciyhinized SOD appears to prevent brain edema through a protective effect against superoxide anions.

To examine the relationship between the free radicals and brain tissue damage, we investigated the intensity of brain hydroxyl (OH) radical generation and lipid peroxidation in the rat contusion injury model. A unilateral contusion was induced by a weight-drop method. All rats were decapitated six hours after the injury, and brain samples were taken from three portions (core, peripheral, and distal) to examine the specific gravity as an indicator of brain edema, generation of OH using an electron paramagnetic resonance spectrometer (EPR), and malondialdehyde (MDA) and 4-hydroxyalkenals production. Analysis of the specific gravity revealed cerebral edema on the ipsilateral side in the injured group. The signal intensity of EPR in the core and peripheral portions in the contusion group was significantly higher than that in the distal portion of the contusion group and that of all portions in the control animals.

To analyze the effect of lecithinized superoxide dismutase (SOD) on superoxide accumulation after traumatic injury, the expression of Cu,Zn-SOD mRNA was examined after contusion in rat using Northern blotting. As determined by specific gravity, lecithinized SOD decreased brain edema. The expression of Cu,Zn-SOD mRNA increased at the core, peripheral and contralateral hemisphere of injury. These increases were then suppressed by lecithinized SOD. Our results support the hypothesis that superoxide may play an important role in edema formation after contusion, and that lecithinized SOD appears to prevent brain edema through a protective effect against superoxide injury.