Evaluation of the basic properties of the BANGkit gel dosimeter.

We evaluated the basic properties of a commercially available BANGkit gel dosimeter, which is a normoxic type of BANG gel. This gel-kit has the same composition as the BANG 3 gel, but is fully oxygenated. To exclude oxygen, oxygen scavenging ascorbic acid and copper sulfate as a catalyst are used. The properties that we examined are the effects of the concentrations of copper sulfate and ascorbic acid on the response, the reproducibility, the long-term stability, the temperature effect at irradiation and the dose-rate effect. In our results, the excellent linear fit of the R2-dose response in a dose range for clinical use and its reproducibility were observed. The precision of a linear fit was preserved for about 3 weeks. The temperature at irradiation showed a significant effect on the dose response. Although the dose-rate dependence in the high-dose range was observed, it was negligible for the clinical dose range up to 270 cGy. In conclusion, this gel dosimeter is thought to be utilizable in clinical practice, while we have to pay attention to the temperature during the entire measurement processes, and additionally there is room for improvement in the linearity and the dose-rate dependence in the high-dose range.

Surgical treatment for intractable epilepsy caused by cavernous angioma in the temporal lobe of the dominant hemisphere--three case reports.

The surgical treatment modality for intractable epilepsy with cavernous angioma in the dominant hemisphere is still unclear. Three patients with medically intractable seizures associated with cavernous angioma in the dominant hemispheric temporal lobe underwent tailored resection based on magnetic resonance (MR) imaging, single photon emission computed tomography (SPECT), electroencephalography monitoring (from scalp and sphenoidal electrodes), and neuropsychologic assessment. Epileptogenic zones were located in the area surrounding the angioma in all patients and mesial temporal dysfunction in two patients. The adjacent cortex and gliotic tissues containing hemosiderin were resected, in conjunction with either total or partial resection of the nidus. Intraoperative electrocorticography (ECoG) was then performed. Additional resection of the mesial temporal structures or multiple subpial transection was performed as indicated by the ECoG findings. All three patients have been seizure free and showed no language or cognitive deterioration for 30, 18, and 14 postoperative months, respectively, while receiving tapered antiepileptic medication. Tailored resection based on electrophysiological data, MR imaging, SPECT, and intraoperative ECoG is effective for the treatment of medically intractable seizure associated with cavernous angioma in the temporal lobe of the dominant hemisphere.

Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system.

The tremor rat is a mutant that exhibits absence-like seizure and spongiform degeneration in the CNS. By positional cloning, a genomic deletion was found within the critical region in which the aspartoacylase gene is located. Accordingly, no aspartoacylase expression was detected in any of the tissues examined, and abnormal accumulation of N-acetyl-L-aspartate (NAA) was shown in the mutant brain, in correlation with the severity of the vacuole formation. Therefore, the tremor rat may be regarded as a suitable animal model of human Canavan disease, characterized by spongy leukodystrophy that is caused by aspartoacylase deficiency. Interestingly, direct injection of NAA into normal rat cerebroventricle induced 4- to 10-Hz polyspikes or spikewave-like complexes in cortical and hippocampal EEG, concomitantly with behavior characterized by sudden immobility and staring. These results suggested that accumulated NAA in the CNS would induce neuroexcitation and neurodegeneration directly or indirectly.

Epileptic seizures induced by N-acetyl-L-aspartate in rats: in vivo and in vitro studies.

Tremor rat (tm/tm), the parent strain of spontaneously epileptic rat (SER: zi/zi, tm/tm), exhibits absence-like seizures characterized by 5-7 Hz spike-wave-like complexes on cortical and hippocampal electroencephalograms (EEG) after 10 weeks of age, prior to development of convulsive seizures. Recently, this animal model has been demonstrated to display a genomic microdeletion within the critical region of tm, where aspartoacylase hydrolyzing N-acetyl-L aspartate (NAA) is located, besides showing the ability to accumulate NAA in the brain. Therefore, the present study was performed to determine the involvement of NAA in the induction of epileptic seizures. When NAA (4 micromol) was applied intracerebroventricularly (i.c.v.) to normal Wistar rats, 4-10 Hz polyspikes and/or spike-wave-like complexes followed by absence-like seizure before persistent 1-5 Hz waxing high-voltage after-discharges were observed on cortical and hippocampal EEG. At a higher dose (8 micromol), NAA induced convulsive seizures. The absence-like seizures with polyspikes and/or spike-wave-like complexes on the EEG were also observed with i.c.v. NAA in premature tremor rats without seizures. The NAA-induced seizures in normal rats were antagonized by i.c.v. glutamic acid diethyl ester, a non-selective glutamate receptor antagonist. In addition, NAA applied to the bath rapidly induced a long-lasting depolarization concomitantly with repetitive firings in hippocampal CA3 neurons of normal rat brain slice preparations. These findings suggest that NAA is involved in the induction of absence-like seizures and/or convulsion, probably via glutamate receptors.

[Significance and pitfall of diffusion weighted image in super acute cerebral ischemia: investigation by questionnaire study].

We investigated the findings in diffusion weighted image (DWI) of super acute ischemia examined within 6 hours after onset by questionnaire study. The magnitude of magnetic field of MR machine, method of diffusion weighted imaging, the total number of cases, the number of cases with high signal intensity area on DWI and the number of decrease or disappearance of signal intensity were investigated. Answers were obtained from 16 institutes (64%). Totally, 232 cases of super acute ischemia examined within 6 hours after onset were imaged by DWI. High signal intensity area were detected in 189 cases (81.5%) of all, which disappeared or decreased in 10 cases (4.3%). Follow up DWI revealed a decrease in the area of high signal intensity in 5 (17.9%) of 28 cases who underwent thrombolysis by endovascular treatment. However, 6 (21.4%) or 28 cases resulted in hemorrhagic infarction. We must recognize the diffusion anisotropy, apparent diffusion coefficient, and b value in reading the DWI. In conclusion, high signal intensity area on DWI include not only irreversible infarction but also the reversible ischemia.

Noninvasive assessment of the cardiac baroreflex: response to downward tilting and comparison with the phenylephrine method.

OBJECTIVES: We studied the relation between changes in systolic blood pressure and RR interval during downward tilting in comparison with assessment of baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) and with measures of heart rate variability (HRV). BACKGROUND: The method most extensively used for assessing BRS involves bolus injections of phenylephrine. Several noninvasive methods proposed to assess BRS have not been widely applied in the clinical setting. METHODS: Sixteen healthy male volunteers were studied (mean age +/- SD 27.5+/-4.6 years). Arterial blood pressure using tonometry and electrocardiogram was simultaneously recorded. After 20 min of 70 degrees upright tilting, the table was returned to supine position at a speed of 3.2 degrees/s. Subsequently, BRS was assessed using an intravenous bolus injection of phenylephrine (2 to 3 microg/kg). Heart rate variability under resting conditions also was analyzed. RESULTS: In all subjects, a beat to beat systolic blood pressure increase associated with corresponding RR interval lengthening was observed during downward tilting as well as during phenylephrine administration. During both testing procedures, these two variables showed linear correlation, and the slope of regression line during downward tilting (DT-BRS) correlated significantly with Phe-BRS (r = 0.79, p = 0.0003). The DT- and Phe-BRS also correlated significantly with the high frequency component of resting HRV (r = 0.70, p = 0.0023 for DT-BRS; r = 0.58, p = 0.0185 for Phe-BRS). CONCLUSIONS: We conclude that in a small homogeneous group DT-BRS provided an assessment of reflex cardiac vagal function comparable to that obtained by the phenylephrine method.

Subsidence of seizure induced by stereotactic radiation in a patient with hypothalamic hamartoma. Case report.

The authors report on a patient who exhibited intractable epilepsy due to an inaccessible hypothalamic hamartoma and subsequently underwent stereotactic radiosurgery. This 25-year-old man had a 24-year history of intractable gelastic and tonic-clonic seizures. Magnetic resonance (MR) imaging performed at examination as well as that performed 30 months earlier demonstrated a nonenhancing and nonprogressive spherical mass, approximately 10 mm in diameter, located on the patient's right side at the floor of the third ventricle. Focal radiation treatment performed with a gamma knife unit administered 36 Gy to the center and 18 Gy to the periphery of the lesion. This treatment resulted in an improvement in seizure control. Before the patient underwent radiosurgery, he suffered from three to six generalized seizures per month in spite of attentive compliance with an anticonvulsant medication regimen. After irradiation of the harmatoma, the frequency of the seizures transiently increased and then subsided 3 months posttreatment. The patient has been free of seizures for the last 21 months, with no neurological or endocrinological complications. Magnetic resonance imaging performed 12 months posttreatment demonstrated complete disappearance of the lesion.

Induction of convulsive seizures by acoustic priming in a new genetically defined model of epilepsy (Noda epileptic rat: NER).

Noda epileptic rat (NER) is a mutant rat, found in a Crj: Wistar colony, which exhibits a tonic clonic convulsion spontaneously about once per 30 h from 14 weeks of age. We performed modified acoustic priming, that is, repeated weekly sound stimulations from 3 weeks of age. In addition, characteristics of audiogenic seizure (AGS), and ictal/interictal electroencephalograms (EEGs) were examined. We also studied the effect of repeated weekly stimulations from 14 weeks of age on AGS susceptibility in another NER. From 9 weeks of age, the NER primed from 3 weeks of age had a high incidence (100%) of AGS: a typical seizure was composed of sudden wild running and/or jumping (WRJ) followed by clonic or tonic-clonic convulsion. The severity and the duration of the AGS were intensified and prolonged with an increase in age, respectively. By contrast, the NER repeatedly stimulated from the age of 14 weeks, rarely showed AGS (20-40(%). The majority of the seizures in this NER were WRJ. The cortical and hippocampal EEG during the tonic convulsion showed a low-voltage spike-wave (5-7 Hz). This evolved into a high-amplitude spike- or polyspike-waves associated with the clonic convulsion. Immediately after cessation of the seizures, the EEG showed a flattening or diffuse slowing. In interictal EEG analysis, sporadic spikes predominantly in the hippocampus and spike-wave bursts in both the cortex and hippocampus occurred from 11 and 20 weeks of age, respectively. These results indicate that AGS susceptibility in NER can be induced consistently by modified acoustic priming and this rat strain is a new genetic model useful for experimental studies of human epilepsy.

Suppression by topiramate of epileptiform burst discharges in hippocampal CA3 neurons of spontaneously epileptic rat in vitro.

Topiramate, a novel antiepileptic drug, inhibits the seizures of spontaneously epileptic rat (SER), a double mutant (zi/zi, tm/tm) which exhibits both tonic convulsion and absence-like seizures from the age of 8-weeks. Hippocampal CA3 pyramidal neurons in SER show a long-lasting depolarization shift with accompanying repetitive firing when a single electrostimulation is delivered to the mossy fibers in vitro. The effects of topiramate on the excitability of CA3 pyramidal neurons in SER were examined to elucidate the mechanism underlying the antiepileptic action. Intracellular recordings were performed in 23 hippocampal slice preparations of 16 SER aged 8-17 weeks. Topiramate (10-100 microM) dose-dependently inhibited the depolarizing shifts with repetitive firing induced by mossy fiber stimulation without affecting the first spike and resting membrane potentials in hippocampal CA3 neurons of SER. Higher dose of topiramate (100 microM) sometimes inhibited the first spike, and decreased excitatory postsynaptic potentials in the SER CA3 neurons. However, topiramate up to 100 microM did not affect the single action potential elicited by the stimulation in the hippocampal CA3 neurons of age-matched Wistar rat devoid of the seizure. Application of topiramate (100 microM) did not significantly affect the firing induced by depolarizing pulse applied in the CA3 neurons of the SER. In addition, topiramate (100 microM) had no effects on the Ca2+ spike induced by intracellularly applied depolarizing pulse in the presence of tetrodotoxin and tetraethylammonium. In contrast, a dose-dependent inhibition of depolarization and repetitive firing induced by bath application of glutamate in CA3 pyramidal neurons was obtained with topiramate (10-100 microM). Furthermore, topiramate (100 microM) decreased the number of miniature postsynaptic potential of CA3 pyramidal neurons of SER. In patch clamp whole cell recording using acutely dissociated hippocampal CA3 neurons from SER aged 8-weeks and age-matched normal Wistar rats, there were no remarkable effects on voltage dependent Ca2+ current with topiramate up to 300 microM in either animal; the current was completely blocked by Cd2+ at a concentration of 1 mM. These findings suggest that topiramate inhibits release of glutamate from the nerve terminals and/or abnormal firing of the CA3 pyramidal neurons of SER by mainly blocking glutamate receptors in the neurons.

Antiepileptic effects of 20-hydroxyecdysone on convulsive seizures in spontaneously epileptic rats.

We examined the effect of 20-hydroxyecdysone (20-HE), a neurosteroid found in insects that is involved in their developmental process, on both tonic convulsion and absence-like seizure in spontaneously epileptic rat (SER). When 20-HE was given orally to SER at 25-200 mg/kg, significant decreases of the tonic convulsion were observed with 100 and 200 mg/kg. Pretreatment of the animal with bicuculline (1 mg/kg, i.p.) antagonized the inhibitory effects of 20-HE. However, absence-like seizures were not affected by 20-HE. These findings indicate that 20-HE produces antiepileptic effects on tonic convulsion by acting on the modulatory site of GABA(A) receptors.

[A novel epilepsy animal model (NER)].

A mutant showing convulsive seizures spontaneously in a CJ: Wistar colony was named the Noda epileptic rat (NER). The NER exhibits tonic-clonic convulsion without any external stimuli once every 30 h. However, we succeeded in inducing similar convulsive seizures by applying priming sound stimuli (95 dB, 8 kHz, 30 sec) from 3 weeks of age in all 24 NER examined. When the effects of clinically available antiepileptics were tested on the seizures of such primed NER, the most potent agents were carbamazepine, diazepam, valproate, phenobarbital and trimethadione, while phenytoin and zonisamide showed lower potency. Furthermore, ethosuximide was not effective in inhibiting the seizures. In hippocampal slices of NER with convulsive seizures, repetitive firing accompanied by long-lasting depolarization was observed when a single stimulation was delivered to the mossy fibers in the CA3 pyramidal cell. This depolarization shift was completely blocked with a Ca2+ antagonist (nicardipine 10 nM). The long-lasting hyperpolarization that followed the repetitive firing was also observed with mossy fiber stimulation in the hippocampal CA3 pyramidal cells of the NER. These findings suggest that Ca2+ channel abnormality of the hippocampal CA3 pyramidal cells may be involved in the convulsive seizures.

Ischemic preconditioning attenuates postischemic leukocyte adhesion and emigration.

Intravital microscopy was used to determine whether ischemic preconditioning (IPC; 5 min ischemia and 10 min reperfusion) would attenuate leukocyte adhesion and emigration induced by subsequent prolonged ischemia (60 min) and reperfusion (60 min) (I/R) in murine cremaster muscle and whether adenosine produced during IPC and/or reperfusion contributed to these beneficial effects. I/R elicited a marked increase in the number of adherent and emigrated leukocytes compared with the nonischemic control muscles, an effect that was largely prevented by IPC. Superfusion of the cremaster with adenosine deaminase only during IPC or only during 60-min reperfusion attenuated the inhibitory effect of IPC on postischemic leukocyte adhesion and emigration. However, the beneficial effects of IPC were mimicked in cremaster muscles preconditioned with adenosine (topical application for 10 min beginning 20 min before the onset of prolonged ischemia). Similar results were obtained in experiments in which adenosine was topically applied to the cremaster only during the 60-min reperfusion period. Our findings suggest that the ability of IPC to attenuate postischemic leukocyte adhesion and emigration may be mediated by adenosine released during IPC and during reperfusion after prolonged ischemia.

Caffeine induces ventricular tachyarrhythmias possibly due to triggered activity in rabbits in vivo.

Caffeine induces delayed afterdepolarizations (DADs) and triggered activity in isolated cardiac tissue. We investigated the ability of caffeine to induce triggered ventricular arrhythmias in rabbits in vivo. During continuous infusion of caffeine at doses of 0.3 or 1.0 mg/kg per min, ventricular pacing was performed with 50 stimuli with a cycle length of 220 msec (basic pacing train) every 5 min until ventricular tachycardia (VT) was induced. The effects of programmed stimulation and pharmacologic agents on the induction of ventricular ectopic beats (VEBs) were examined. Pacing protocols were carried out in the presence of vagal-induced slowing of sinus rhythm. VT was induced by a basic pacing train during the infusion of caffeine at 1.0 mg/kg per min, but not at 0.3 mg/kg per min. An increase in the pacing rate or the number of stimuli resulted in 1) a decrease in the first postpacing interval, and 2) an increase in the number of postpacing VEBs. Induction of VT was suppressed by intravenous bolus injections of verapamil, propranolol and adenosine. At the time of the initial induction of VT, the plasma concentration of caffeine was 87 +/- 2 micrograms/ml and the plasma level of norepinephrine increased from 666 +/- 166 pg/ml at baseline to 1121 +/- 245 pg/ml. These results suggest that catecholamine-associated triggered activity may be responsible for caffeine-induced VT.

Fructose-1,6-diphosphate or adenosine attenuate leukocyte adherence in postischemic skeletal muscle.

The purpose of this study was to determine whether fructose-1,6-diphosphate (FDP) or adenosine (Ado), administered at the onset of reperfusion, would prevent ischemia/reperfusion (I-R)-induced leukocyte adherence and microvascular dysfunction in skeletal muscle. Changes in vascular permeability and tissue neutrophil content were assessed by measurement of the solvent drag reflection coefficient (delta) for total plasma proteins and muscle myeloperoxidase (MPO) activity, respectively, in continuously perfused, isolated canine gracilis muscles and in muscles subjected to I-R alone, I-R + FDP, and I-R + Ado. To determine whether FDP or Ado would attenuate leukocyte-endothelial cell adhesive interactions induced by I-R, leukocyte adherence and emigration were assessed in postischemic mouse cremaster muscles, using intravital microscopy in the presence and absence of FDP or Ado during reperfusion. I-R was associated with a marked increase in microvascular permeability and muscle MPO activity relative to nonischemic controls. These increases were attenuated by FDP and Ado. I-R also increased the number of adherent and emigrated leukocytes relative to control. I-R-induced leukocyte adherence and emigration were significantly attenuated by either FDP or Ado. These results indicate that FDP and Ado attenuate postischemic microvascular barrier dysfunction in skeletal muscle by a mechanism that may be related to their ability to inhibit leukocyte adhesion and emigration.

Ischemic preconditioning attenuates capillary no-reflow induced by prolonged ischemia and reperfusion.

Ischemic preconditioning (IPC) refers to a phenomenon in which a tissue is rendered resistant to the deleterious effects of prolonged ischemia and reperfusion by prior exposure to brief, repeated periods of vascular occlusion. The purposes of this study were to determine whether IPC would reduce the extent of capillary no-reflow in postischemic skeletal muscle and whether the protective effect of IPC was due to activation of ATP-sensitive potassium (KATP) channels. To address the first aim, capillary perfusion was assessed in vascularly isolated canine gracilis muscles subjected to 4.5 h of continuous perfusion, 4 h of ischemia followed by 30 min of reperfusion (I-R), and IPC (4 periods of 5 min ischemia followed by 5 min reperfusion) before I-R. I-R was associated with a reduction in the number of patent capillaries per fiber (0.6 +/- 0.1) relative to nonischemic control muscles (2.5 +/- 0.1), an effect that was attenuated by IPC (1.3 +/- 0.1 patent capillaries fiber). A role for KATP channels in the protective effect of IPC is supported by the observation that administration of a KATP channel antagonist (glibenclamide) 10 min before induction of IPC abolished the protective effect of preconditioning (0.6 +/- 0.1 patent capillaries/fiber). On the other hand, treatment of nonpreconditioned muscles with a KATP channel agonist (pinacidil) mimicked the protection afforded by IPC (1.2 +/- 0.1 patent capillaries/fiber). Moreover, the protective effect of pinacidil treatment was reversed by prior administration of glibenclamide (0.5 +/- 0.1 patient capillaries/fiber). These data indicate that IPC improves postischemic capillary perfusion by a mechanism that involves activation of KATP channels.

Leukocyte adhesion induced by inhibition of nitric oxide production in skeletal muscle.

Superfusion of rat cremaster muscles with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) elicited significant leukocyte adhesion to postcapillary venules (20- to 30-microns diameter), an effect that was attenuated by pretreatment with L-arginine (an NO precursor) or sodium nitroprusside (SNP) (an exogenous source of NO). In contrast to the effects of pretreatment, addition of SNP or L-arginine to the superfusate 30 min after the initiation of NO synthase inhibition failed to reverse the L-NAME-induced leukocyte adherence. However, this effect was reversed by administration of an anti-CD18 monoclonal antibody or 8-bromoguanosine 3',5'-cyclic monophosphate 30 min after L-NAME superfusion was initiated. These findings indicate that L-NAME promotes leukocyte adhesion to venular endothelium by a CD18-dependent mechanism in skeletal muscle and suggest that the failure of L-arginine or SNP to reverse L-NAME-induced leukocyte adherence is not due to a defect in signaling events that occur subsequent to activation of guanylate cyclase by NO derived from these agents. Because the simultaneous administration of superoxide dismutase (scavenges superoxide radicals) and SNP or L-arginine, but not superoxide dismutase alone, decreased L-NAME-induced leukocyte adherence, our results suggest that leukocyte adhesion caused by NO synthase inhibition may result in the generation of superoxide.

Leukocyte adhesion, edema, and development of postischemic capillary no-reflow.

The aim of this study was to determine whether the formation of edema that occurs secondary to the neutrophil-dependent increase in microvascular permeability contributes to the genesis of no-reflow in postischemic skeletal muscle. To address this issue, four experimental approaches were used. In the first group, capillary perfusion was assessed in nonischemic canine gracilis muscles in which interstitial fluid volume was increased to a level similar to that in postischemic muscle. In the second and third groups, edema formation was prevented in postischemic skeletal muscles by administration of phalloidin or a hypertonic hyperosmotic saline-dextran solution (HSD; 7.5% saline-6% Dextran 70), and the extent of capillary no-reflow was assessed. In the final group of experiments, a monoclonal antibody (MAb) that binds to the common beta-subunit of the leukocyte integrin CD11/CD18 (MAb IB4) was administered after the development of postischemic edema, and capillary perfusion was determined. Formation of edema in nonischemic preparations and ischemia-reperfusion (I-R) were associated with marked reduction in the number of patent capillaries per fiber (1.2 +/- 0.1 and 0.4 +/- 0.1, respectively) compared with nonedematous nonischemic controls (2.5 +/- 0.3). Treatment with phalloidin or HSD prevented edema formation and attenuated the reduction in the number of patent capillaries per fiber (1.62 +/- 0.2 and 1.71 +/- 0.2, respectively) induced by I-R, whereas administration of MAb IB4 after the formation of edema in reperfused muscles failed to limit capillary no-reflow (0.5 +/- 0.1 patent capillaries/fiber).(ABSTRACT TRUNCATED AT 250 WORDS)

Pure progressive autonomic failure presenting severe orthostatic hypotension.

A 59-year-old woman showed chronic progressive autonomic failure consisting of orthostatic hypotension and dyshidrosis. No signs of Parkinsonism, cerebellar or peripheral neuropathy were observed. Autonomic nervous function tests and findings of biopsied sural nerve suggested that this case had both sympathetic and parasympathetic dysfunctions, mainly postganglionic. A decrease in the total peripheral resistance and no increase in the heart rate on standing seemed to be the mechanism of orthostatic hypotension in this case. We conclude that pure PAF can be recognized as a distinct clinical syndrome of systematic degeneration of the autonomic nervous system.