A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome.

A novel causative variant (c.608G>A, p.Arg203Gln) in PACS1.

Intracellular pH in the brain following transient ischemia.

The objective of the present study was to discover whether or not intracellular alkalosis develops in the brain in the recovery period following transient ischemia. Forebrain ischemia of 15-min duration was induced by four-vessel occlusion in rats, with recovery periods of 15, 60, and 180 min. Intracellular pH was derived both by the HCO3- -H2CO3 method and from the creatine kinase equilibrium. The ischemia was associated with energy failure and marked accumulation of lactic acid in the cerebral cortex. Recirculation brought about rapid rephosphorylation of adenine nucleotides and gradual normalization of lactic acid levels. After 15 min of recovery, the HCO3- -H2CO3 method indicated persisting acidosis, but the creatine kinase reaction did not. After 60 min, a shift of pH in the alkaline direction was demonstrated in both methods. This alkalosis had disappeared after 3 h of recovery. It is concluded that resumption of ATP production after ischemia is followed by a rapid rise in intracellular pH, which transiently increases above normal.

Improvement of passive avoidance task after grafting of fetal striatal cell suspensions in ischemic striatum in the rat.

Behavioral recovery and cell survival/growth after grafting of fetal striatal cell suspensions in the ischemic striatum of rats were investigated. Ischemia was induced by one hour intraluminal occlusion of the right middle cerebral artery under halothane anesthesia. During the ischemia rats usually manifested signs of hemiparesis and sometimes rotations. Behavioral function was measured by a passive avoidance task and radial arm maze test at 1-2 weeks and 6-7 weeks after ischemia. The size of the ischemic lesions depended on each animal, but the ischemic animals showed deficits in both passive avoidance task and radial maze test. Two weeks after ischemia, fetal striatal cells, marked with DiI, were transplanted into the ischemic striatum. The transplantation improved the ischemia-induced deficit in the passive avoidance task but not in radial maze test. Although there were variations in the size of the grafts, many DiI-positive cells with dendritic outgrowth were detected under fluorescent microscopy. Immunohistochemical study revealed that many choline acetyltransferase (ChAT) positive cells and GABA-positive cells survived in the grafts. However, striosome-matrix compartments were not evident inside the grafts. Thus, partial recoveries in both cytoarchitectural and behavioral aspects were obtained by striatal cell grafts, suggesting that neural transplantation could be a useful approach in reconstructing ischemic brain function.

Striatal grafts in infarct striatopallidum increase GABA release, reorganize GABAA receptor and improve water-maze learning in the rat.

We grafted fetal striatal cells in ischemic rat models, and investigated graft survival/growth, GABA release, GABAA receptor reorganization and functional recovery. One hour intraluminal occlusion of the middle cerebral artery (MCA) induced ischemic infarct in the lateral part of the striatum and adjacent cortex. In ischemic rats, the acquisition of Morris' water-maze learning was significantly slower than that of control rats. In these animals GABA level in the globus pallidus, detected by microdialysis, was about the half of that of controls. However, after the grafts of fetal striatal cells in the striatopallidum, the acquisition was improved, thus no difference was observed in the time course of learning curves in control and grafted animals. GABA level recovered to almost normal level by the graft. It further increased by the treatment of a GABA uptake blocker (nipecotic acids) in the perfusion. In the grafts, GABAA receptor organization detected by autoradiography using [3H] labeled SR95531 was restored for more than 1 year after the graft. Data suggest that fetal striatal cell grafts in infarct striatum may partially reconstruct striatopallidal GABA projection and reorganize GABAA receptor. This might be a basis of improvement of function.

Dopamine has inhibitory and accelerating effects on ischemia-induced neuronal cell damage in the rat striatum.

Dopaminergic (DAergic) influence on ischemic neuronal cell damage in the dorsolateral striatum was studied. Intact and 6-hydroxydopamine (6-OHDA) lesioned rats, with and without pretreatment by D1 and D2 DA antagonists, were subjected to 20 min forebrain ischemia. Extracellular DA and glutamate (Glu) were measured using microdialysis technique. Histological examination was performed on the dorsolateral striatum and the hippocampal CA1 area 24 h after ischemia. DA increased 400-500 times the control level during ischemia among the groups except the 6-OHDA lesioned group. No significant changes were observed in the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC), but a transient decrease was seen in homovanillic acid (HVA). Due to ischemia, Glu increased up to about 5 times the control level among the groups. Neuronal damage in the dorsolateral striatum was slightly attenuated by 6-OHDA lesion. Treatment by spiperone (D2 antagonist, 7 micrograms/kg IP) alone attenuated the damage strongly. Treatment by SCH23390 (D1 antagonist, 2.5 mg/kg IP) alone or both D1 and D2 antagonists had no effects. Data suggest that excessive Glu and DA are involved in neuronal cell damage. DA might enhance the damage via D2 but inhibit via D1 receptor.

Spontaneous disappearance of a cerebral arteriovenous malformation in infancy. Case report.

The authors report a case of the disappearance of an arteriovenous malformation in infancy, demostrated by follow-up angiography performed 7 months after the original angiograms. Some possible mechansims whereby a cerebral arteriovenous anomaly is thrombosed are discussed.

Experimental cerebral vasospasm. Part 2: effects of vasoactive drugs and sympathectomy on early and late spasm.

The authors report the effects of vasoactive drugs and sympathectomy on experimental spasm using vertebral angiography. Papaverine and isoxsuprine injections into the vertebral artery released both early and late spasm. The antiserotonin agent, methysergide, adn the alpha adrenergic blocking agent, phentolamine, released early but not late spasm. In sympathathectomized dogs, early spasm was milder than in untreated dogs; however, late spasm was the same as in untreated dogs. The authors discuss an etiological difference between early and late spasm.

Action of phospholipases A2 and C on free fatty acid release during complete ischemia in rat neocortex. Effect of phospholipase C inhibitor and N-methyl-D-aspartate antagonist.

The levels of brain free fatty acids rapidly increase after the onset of ischemia. The purpose of this study was to investigate the action of phospholipases A2 and C during complete ischemia based on the effects of a phospholipase C inhibitor (phenylmethylsulfonyl fluoride) and the N-methyl-D-aspartate antagonist MK-801 on the release of free fatty acids in rat neocortex. Complete brain ischemia was induced in rats with cardiac arrest by intracardiac injection of KCl. Free fatty acid levels in the neocortex were measured 0, 2, 4, and 8 minutes after cardiac arrest. Phenylmethylsulfonyl fluoride inhibited the release of free fatty acids primarily from phosphatidylinositol during the first 2 minutes of ischemia and from phosphatidylcholine and phosphatidylethanolamine at 4 to 8 minutes of ischemia. Conversely, MK-801 inhibited free fatty acid release mainly from phosphatidylcholine and phosphatidylethanolamine at 2 to 4 minutes of ischemia. These results indicate that the release of free fatty acids during the first 2 minutes of ischemia can be attributed mostly to the action of phospholipase C, and that the activation of phospholipase C further influences the activation of phospholipase A2 in the subsequent course, while phospholipase A2 predominantly acts after 2 minutes of ischemia.

Role of brain tissue leukotriene in brain oedema following cerebral ischaemia: effect of a 5-lipoxygenase inhibitor, AA-861.

It has been postulated that lipoxygenase metabolites of arachidonic acid play a role in the pathogenesis of cerebral ischaemia. Severe forebrain ischaemia in rats was induced by four-vessel occlusion with mild hypotension. After 30 min of ischaemia, circulation was restored by removing the arterial clamps and increasing blood pressure to preischaemic levels. During 30 min of cerebral ischaemia, free arachidonic acid increased by approximately 8.5 times compared with the preischaemic level. This accumulation was reversed within 60 min of reperfusion. The concentration of leukotriene C4 in brain tissue increased significantly during reperfusion: treatment with a 5-lipoxygenase inhibitor, AA-861, decreased the increase of brain water content associated with reperfusion. This study demonstrated that the increased arachidonic acid resulting from cerebral ischaemia in rats is metabolized to leukotrienes via the lipoxygenase pathway once circulation is restored, and these leukotrienes may play some role in the development of postischaemic cerebral oedema.

Serum neuron-specific enolase levels after subarachnoid hemorrhage.

We examined serum levels of neuron-specific enolase by enzyme immunoassay in 29 patients with subarachnoid hemorrhage due to ruptured cerebral aneurysm. Serum neuron-specific enolase levels were significantly higher in patients with a poor neurological status than in patients with a good neurological status on admission, and the greater the amount of subarachnoid blood, the higher the serum neuron-specific enolase level. Patients with a good outcome had low serum neuron-specific enolase levels throughout their courses. Serum neuron-specific enolase levels increased with development of delayed ischemic neurological deficits and, especially in poor outcome patients, high levels persisted until 3 weeks after the subarachnoid hemorrhage.

Atypical Moyamoya disease associated with brain tumor.

A 4-year-old boy with right retinal hemorrhage, mental retardation, and multiple minor anomalies was referred to our hospital. Computed tomography scanning revealed a cystic brain tumor at the vermis. Angiography showed stenosis of both internal carotid arteries at the supraclinoid portion and the Moyamoya vessels. The right ophthalmic artery was dilated as wide as the internal carotid artery. Stenosis of the basilar artery was also observed. Collateral circulation via the posterior inferior cerebellar artery and Moyamoya vessels in the area of the posterior cerebral artery was observed.

Glioblastoma multiforme in the left frontal lobe subsequent to malignant lymphoma in the right orbit.

A 62-year-old male presented with glioblastoma multiforme in the left frontal lobe manifesting as motor aphasia, subsequent to a malignant lymphoma in the right orbit. He underwent subtotal removal of the right orbital mass presenting as right exophthalmos which was shown by histological examination to be non-Hodgkin's lymphoma. He received 30 Gy Lineac irradiation to the right orbit. His post-operative course was satisfactory. Magnetic resonance (MR) imaging with gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) 7 months later demonstrated a small spotty enhanced lesion in the left frontal lobe. He developed motor aphasia 1 year after irradiation. MR imaging disclosed an enhanced mass in the left frontal lobe, which was totally removed. Histological examination revealed glioblastoma multiforme. Patients with malignant lymphoma may develop a subsequent second malignant tumor. MR imaging with Gd-DTPA is quite useful for early detection of a second brain tumor.

[The role of sympathetic nerve and vasoactive amines in experimental cerebral vasospasm in dogs (author's transl)].

In order to study the role of sympathetic nervous system and vasoactive amines in cerebral arterial spasm, the following experiments were performed in dogs. In the first experiment, two weeks after bilateral removal of the superior cervical ganglion subarachnoid hemorrhage was produced by the puncture of the posterior communicating artery in six dogs. Second, the arterial blood of non-reserpinized dog was injected into the cisterna magna of another six reserpinized dogs. Diameter changes of the cerebral basal arteries before and after the experimental subarachnoid hemorrhage were observed utilizing the magnified vertebral angiography. Vasoconstriction 30 minutes after the puncture of the artery in the sympathectomized dogs was milder than that seen in the non-sympathectomized dogs, while vasoconstriction 24 hours after the subarachnoidal hemorrhage was induced similarly in degree in both groups. In reserpinized dogs, vasconstriction 30 minutes after the experimental subarachnoidal hemorrhage was somewhat milder than that seen in control dogs, and angiograms taken 24 hours after the hemorrhage showed that vasoconstriction was remarkably milder than in control dogs. Noradrenergic fluorescence of the arterial wall after the puncture of the posterior communicating artery was examined using Falck's fluorescence histochemical method. Noradrenergic fluorescence in the arterial wall did not disappear 15 minutes, 24 hours and three weeks after the experimental subarachnoid hemorrhage. From these experimental results, it was suggested that the sympathetic innervation to cerebral arteries might contribute to induce early spasm, but not to late spasm. Moreover, it was speculated that vasoactive amines released from the damaged brain tissue might play a role in inducing late spasm.

[Role of arachidonic acid metabolites on development of ischemic cerebral edema in rat middle cerebral artery occlusion].

The products resulting from arachidonic acid metabolism of the both cyclo-oxygenase and lipoxygenase pathways possess strong physiological activities, such as vasoconstriction and the enhancement of vascular permeability. Therefore, it is likely that these metabolites are involved in cerebral circulatory disturbance and the formation of brain edema in cerebral ischemia. It is reported that intracerebral injection of leukotriene B4, C4, and E4 increased blood-brain barrier permeability. Thus, it is suggested that leukotrienes may induce vasogenic cerebral edema. We examined role of the products resulting from arachidonic acid of the cyclo-oxygenase and lipoxygenase pathways on the formation of ischemic cerebral edema in rats with focal cerebral ischemia. Focal cerebral ischemia was induced by the occlusion of right middle cerebral artery. Acyclo-oxygenase inhibitor, indomethacin (4mg/kg), was given intravenously 30 minutes before the occlusion of the middle cerebral artery. Also, azerastine hydrochloride (8mg/kg), which has an inhibitory effect on the production and release of leukotrienes from human neutrophil as well as an antagonistic action on leukotrienes and another inhibitory effect on the production of superoxide anion, was given intravenously 5 minutes prior to occlusion. Concentrations of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene C4 (LTC4) measured by radioimmunoassay. The percent water content of a cerebral hemisphere was determined by the wet-dry weight method. In the occluded hemisphere, PGE2, 6-keto-PGF1 alpha, TxB2 and LTC4 significantly increased at 2, 6, 12 hours respectively, following the MCA occlusion as compared to the control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of FO-1561 on postischemic cerebral functional and metabolic recovery in experimental cerebral ischemia].

Effects of S-adenosyl-L-methionine sulfate tosylate (FO-1561) on postischemic cerebral functional and metabolic recovery in experimental cerebral ischemia were investigated. Severe bilateral forebrain ischemia in rats was induced by four-vessel occlusion with reducing the mean arterial pressure to 100-110 mmHg. After forebrain ischemia had been maintained for 30 minutes, recirculation was started by removal of the arterial clamps of bilateral common carotid arteries and by increasing systemic arterial pressure to the preischemic level. The EEG was continuously recorded from gold-coated screws inserted bilaterally in the parietal bones with the tips in extradural position, against a reference inserted prefrontal bone. Analysis of power spectrum of EEG activity was done by Berg Fourier Analyser. The brains were frozen in situ with liquid nitrogen before, during and after ischemia and then chiselled out during irrigation with liquid nitrogen. Concentrations of ATP in brain tissue were determined with high performance liquid chromatography. FO-1561, 100 mg/kg, was given intravenously, immediately after recirculation. After recirculation there was a tendency that EEG power spectrum in FO-1561-treated animals contained higher percentage of beta wave compared to that in control animals, while delta wave was lesser in FO-1561-treated animals. At 90 minutes following recirculation, ATP level in control animals was 2.17 +/- 0.05 mumol/g (mean +/- SE) and 2.42 +/- 0.03 mumol/g (mean +/- SE) in FO-1561-treated animals. Thus, recovery of ATP level was significantly better in FO-1561-treated animals than in control animals (p less than 0.01).

[Effect of calcium entry blocker, nimodipine, on the cerebral function and metabolic recovery following experimental cerebral ischemia].

Ischemic deporalization of cell membranes is associated with a precipitous influx of calcium from the extracellular to the intracellular compartment, and it is suggested that increased intracellular calcium in ischemic brain leads to an activation of phospholipase and to increase of the concentration of free fatty acids, in particular arachidonic acid, with energy depletion. The objective of the present study is to test whether calcium entry blocker, nimodipine, prevent increase of free fatty acids and metabolic disturbances during ischemic period, and promote functional and metabolic recovery after recirculation. Severe forebrain ischemia in rats was induced by four-vessel occlusion with reducing the systolic arterial pressure to 100 mmHg. After forebrain ischemia had been maintained for 30 minutes, recirculation was started by removal of the arterial clamps of bilateral common carotid arteries and by increasing systemic blood pressure to the preischemic level. The EEG was continuously recorded from gold-coated screws inserted bilaterally in the parietal bones with the tips in extradural position, against a reference inserted prefrontal bone. Analysis of power spectrum of EEG activity was done by Berg Fourier Analyser. The brain were frozen in situ with liquid nitrogen before, during and after ischemia and then chiselled out during irrigation with liquid nitrogen. Concentrations of ATP, ADP, AMP and free fatty acids in brain tissue were determined with high performance liquid chromatography. Nimodipine, 10 micrograms/kg, was given intravenously 2-3 minutes before induction of ischemia, and an infusion of 1 microgram/kg/min was continued during ischemic and postischemic periods.(ABSTRACT TRUNCATED AT 250 WORDS)

[Brain tissue leukotrienes in cerebral ischemia and the effect of inhibitor of SRS-A release on postischemic cerebral edema].

Arachidonic acid metabolites are postulated to play a role in the pathogenesis of cerebral ischemia. In order to test the development of lipoxygenase metabolites of arachidonic acid in cerebral ischemia, we measured free arachidonic acid and slow reacting substance of anaphylaxis (SRS-A) and leukotriene C4 in the brain tissue. Moreover, we studied the influence of inhibitor of SRS-A release on postischemic cerebral edema. Severe forebrain ischemia in rats was induced by the modification of the method described by Pulsinelli and Brierley. Both vertebral arteries were electrocauterized through the alar foramen and then bilateral common carotid arteries were clamped by aneurysmal clips and mean arterial pressure was reduced to 80-90 mmHg. EEG activity was isoelectric throughout the period of carotid clamping. After forebrain ischemia had been maintained for 30 minutes, recirculation was started by removal of the arterial clamps and by increasing blood pressure to the preischemic level. Following the desired ischemic or postischemic periods, the brains were frozen in situ with liquid nitrogen. The brains were then chiselled out during irrigation with liquid nitrogen and stored at -80 degrees C until analysis. The brain extracts were analysed by high performance liquid chromatography for free arachidonic acid, by bioassay using the ileum of guinea pig for SRS-A and by radioimmunoassay for leukotriene C4. Brain water content was calculated with dry weight method. Inhibitor of SRS-A release, tranilast, was given intraperitoneally, 100 mg/kg 30 minutes before induction of ischemia and 50 mg/kg immediately before recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of occlusion and reperfusion on free fatty acid levels and eicosanoid metabolism in a rat model of focal ischemia].

Focal brain ischemia was induced in rats by inserting a silicone rubber cylinder attached to a nylon surgical thread from the common carotid artery into the middle cerebral artery bifurcation. Reperfusion was achieved by removing the cylinder. In the ischemic area, free fatty acids were measured. Arachidonic acid lipoxygenase metabolites: leukotriene C4 (LTC4), and cyclooxygenase metabolites: thromboxane B2 (TXB2), prostaglandin E2 (PGE2) and 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) were measured during ischemia and after reperfusion. There were five ischemia groups. The rats in these groups were killed 1, 2, 3, 4 or 6 hours after occlusion. In the reperfusion group, rats exposed to 1, 2, 3 and 4 hours of ischemia were killed 5, 4, 3 and 2 hours after reperfusion, respectively. The free fatty acids, which had increased due to occlusion, decreased after reperfusion from 1 hour of ischemia. With 2 or more hours of ischemia, however, the free fatty acids increased after reperfusion, indicating cell membrane destruction. Eicosanoids showed almost the same changes in all groups. The eicosanoid level was high only after 1 hour of ischemia and it stayed low if the ischemia time exceeded 2 hours and after reperfusion. Therefore, we suggested that eicosanoids are not a main cause of tissue damage in the ischemic area after 2 or more hours of ischemia.

[Correlation between local cerebral blood flow and EEG in experimental cerebral ischemia].

Varying degrees of cerebral ischemia were produced in adult Wistar rats by clipping of bilateral common carotid arteries with or without induced hypotension. Local cerebral blood flow was measured from bilateral caudate nuclei and parietal cortices using the hydrogen clearance method. EEG was recorded from the same electrode as used for the hydrogen clearance method. The delta power of EEG increased along with decreasing local cerebral blood flow. There was an inverse correlation between the delta power of EEG and local CBF values, ranging from normal to extremely low (10 ml/100 g/min). When local CBF was reduced below 6-8 ml/100 g/min, EEG became isoelectric. Continuous EEG recording might contribute to predict rCBF value in the ischemic lesion.

[A case of extraneural metastasis of medulloblastoma successfully treated with cisplatin and etoposide].

A patient who had been treated for cerebellar medulloblastoma presented progressive abdominal distension and tachypnea. Metastases of the tumor in the abdominal and thoracic cavity were confirmed by cytology. The authors treated the metastasis with a combination of intravenous administration of 20 mg/m2/day cisplatin and 60 mg/m2/day etoposide for two 5-day cycles. After chemotherapy, the patient recovered fully with time and follow-up radiological studies demonstrated no evidence of tumor recurrence. Combination chemotherapy with cisplatin and etoposide is to be considered effective for extraneural metastasis of medulloblastoma.