Modern Japanese medical history and the European influence.

Before the first European visited Japan in 1549, traditional Chinese medicine was mainly employed in Japan. Francisco de Xavier, a missionary of the Society of Jesus, tried to promote the introduction of Christianity by providing a medical service for Japanese citizens. However, Japan implemented a national isolation policy in 1639 and cut off diplomatic relations with the rest of the world, except Holland and China. For over 200 years, until the American admiral Matthew Perry forced Japan to open its doors in 1853, Japan learned about western medicine only from doctors of the Dutch merchants' office or from Dutch medical books. After 1853, Western medicine was rapidly introduced into Japan, and great achievements by Japanese medical doctors soon followed, such as the serum therapy for tetanus, the discovery of the plague and dysentery bacilli, the invention of Salvarsan for the treatment of syphilis, and the demonstration of the neurosyphilis spirochete.

Alpha-adrenergic blockade with phenoxybenzamine enhances cerebrovascular CO2 reactivity.

The influence of sympathetic nervous activity on cerebral circulation and cerebrovascular CO2 reactivity was investigated by an alpha-adrenergic blockade with phenoxybenzamine (PBZ). Cerebral oxygen and carbon dioxide tension (BrPo2, BrPco2) and arterial blood pressure were continuously recorded before, during and after intracarotid infusion of 5 mg/kg of PBZ. The effects of 5% CO2 inhalation were measured before and after the infusion of PBZ. Following the intracarotid infusion of PBZ, BrPo2 and BrPco2 did not change significantly. After the alpha-adrenergic blockade the degree of the increase in BrPo2 during 5% CO2 inhalation was significantly enhanced. The increase in the cerebrovascular CO2 reactivity produced by low dose PBZ suggests that the sympathetic nervous system modifies cerebrovascular CO2 reactivity.

Effect of clonidine on the cerebrovascular system in cats.

The effects of clonidine, a potent alpha 2 adrenergic agonist and an imidazole/imidazoline receptor agonist, were examined in the cat cerebrovascular system, measuring cerebral oxygen and carbon dioxide tension (BrPo2, BrPco2) and arterial blood pressure. Intracarotid injection of clonidine (2 micrograms/kg) produced a gradual decrease in systemic blood pressure without initial hypertension, while BrPo2 decreased slightly but significantly. Before and after intracarotid administration of clonidine, cerebrovascular reactivity to carbon dioxide was estimated by changes in BrPo2 and BrPco2 during and after 3 min inhalation of 5% CO2. Clonidine significantly enhanced cerebrovascular reactivity to carbon dioxide. The data suggest that the alpha 2-adrenoceptor and/or imidazoline receptor play an important role in the regulation of cerebral circulation.

Role of cyclooxygenase system in cerebrovascular responsiveness: different effects of indomethacin on CO2 responsiveness and dilatation by Ca(2+)-channel blocker.

To investigate roles of prostaglandins in the regulation of cerebral blood flow, we compared effects of indomethacin, a cyclooxygenase inhibitor, on the cerebrovascular CO2 responsiveness with those on the cerebrovascular dilatory action of diltiazem, a Ca(2+)-channel blocker. Fifteen adult cats were used. The cerebral tissue oxygen tension, carbon dioxide tension, pH and blood pressure were measured continuously. Indomethacin (1 mg/kg) was infused into the carotid artery. In 8 cats, 3 min inhalation of 5% CO2 in air was performed before and after the indomethacin infusion. In 7 cats, diltiazem (100 micrograms/kg) was infused into the carotid artery for 3 min before and after the indomethacin infusion. The cerebrovascular CO2 responsiveness was significantly decreased (p < 0.05) after the administration of indomethacin. On the other hand, the cerebrovascular dilatation induced by the Ca(2+)-channel blocker was significantly increased (p < 0.05) after the administration of indomethacin. It is concluded that the products of cyclooxygenase system are involved in the cerebrovascular responsiveness both to CO2 and to Ca(2+)-channel blocker, but action mechanisms of prostaglandins may be different, that is, prostaglandians may enhanced cerebrovascular responsiveness to CO2 but diminish it to Ca(2+)-channel blocker.

Mechanisms of CBF augmentation during hypoxia in cats: probable participation of prostacyclin, nitric oxide and adenosine.

To elucidate the mechanisms of CBF augmentation during hypoxemic hypoxia, we applied continuous monitoring of CBF and metabolism to examine the participation of prostacyclin, nitric oxide (NO), and/or adenosine in these mechanisms. Cats (n = 32) were anesthetized and ventilated artificially. Cerebrovascular reactivity to hypoxia was assessed by changes in CBF, brain tissue oxygen and carbon dioxide tensions, and mean arterial blood pressure (delta CBF, delta BrPO2, delta BrPCO2, and delta MABP) during a 3-min inhalation of 10% O2 + 90% N2 before and after the intracarotid administration of (1) indomethacin (1 mg/kg, a cyclooxygenase inhibitor, n = 11), (2) L-NG-monomethyl-arginine (LNMMA, 1 mumol/kg/min, an inhibitor of nitric oxide synthesis, n = 11), and (3) caffeine (20 mg/kg, an adenosine antagonist, n = 10). BrPO2 decreased significantly in all groups during the produced hypoxemic hypoxia. CBF significantly increased in this state before the administration of indomethacin, LNMMA, or caffeine, whereas it contrastively did not significantly increase after the administration of indomethacin or caffeine. In addition, CBF significantly decreased under hypoxia during the administration of LNMMA. Taken together, these results suggest that prostacyclin (PGI2), nitric oxide (NO), and adenosine may jointly participate in CBF augmentation during hypoxia.

Changes of pial vessel diameter and CO2 reactivity during insulin-induced hypoglycemia and in the recovery period following glucose administration.

The present study examined the changes of cerebrovascular CO2 reactivity during insulin-induced hypoglycemia and in the recovery period following glucose administration in cats. The diameters of pial vessels were continuously measured using the vidicon camera system. Hypoglycemia was induced by intraperitoneal injection of Actrapid insulin (100 IU/kg). Cerebrovascular CO2 reactivity was estimated by the changes of pial vessel diameters during 3 min inhalation of 5% CO2 in air at each stage of glucose level. CO2 reactivity was impaired in the hypoglycemic stage and this impairment was further enhanced in the early recovery stage. In the late recovery stage, CO2 reactivity was restored particularly in the small arteries which were less innervated by autonomic nerves. These results suggest that the sympathetic activity plays an important role in the impairment of cerebrovascular CO2 reactivity during hypoglycemia.

Role of the sympathetic system in impairment of the cerebrovascular CO2 responsiveness during moderate hypoglycemia.

We examined the mechanism of impairment of the cerebrovascular CO2 responsiveness in moderate hypoglycemia. Twelve fasted cats were used. The brain-PO2, brain-PCO2 and brain-pH were measured continuously with electrodes placed on the brain surface. Hypoglycemia was induced with insulin. Intravenous injection of hexamethonium (a sympathetic ganglion blocker, C6; 0.1 mg/kg) was performed at the following stages: Control, hypoglycemia and recovery. Before and after the C6 administration, 5% CO2 in air was inhaled for 3 min at the respective stages. The CO2 responsiveness (cerebrovascular dilatory response to increased PaCO2) at the control stage was not altered after the ganglionic blockade. At the hypoglycemic stage, the increase in BrPO2 by CO2 inhalation was significantly less than that at the control stage. This reduction of delta BrPO2 was significantly improved after the administration of C6. At the recovery stage, the CO2 responsiveness before and after the administration of C6 was not significantly different. An impaired CO2 responsiveness in the hypoglycemic state was improved by sympathetic ganglion blockade with C6 which did not alter the reactivity during normoglycemia. It is suggested that the sympathetic activity plays an important role in impairment of the cerebrovascular CO2 responsiveness during moderate hypoglycemia.

Superacute phase blood pressure elevation may relate to massive hematoma in hypertensive putaminal hemorrhage.

A restrospective clinical investigation has been performed to elucidate the relationship between hematoma size in putaminal hemorrhage and blood pressure (BP) changes during the immediate post-hemorrhagic phase in the emergency room (ER). Thirty-seven adult patients brought to the emergency department by ambulance within 6 hours after onset of symptoms with a confirmed diagnosis of acute putaminal hemorrhage on CT have been involved. Two BP measurements during the superacute phase in the ER have been studied: immediately after arrival at the ER (BP-I), and immediately prior to CT examination (BP-II). Patients have been divided into 6 categories: 1) those whose BP decreased with treatment (D+), 2) those whose BP decreased without treatment (D-), 3) those whose BP increased in spite of treatment (I+), 4) those whose BP increased without treatment (I-), 5) those whose BP remained unchanged in spite of treatment (U+), and 6) those whose BP remained unchanged without treatment (U-). Hematoma size has been compared among 5 categories (D+, D-, I-, U+, U-) using factorial ANOVA (analysis of variance). The hematoma sizes have been found to be (D+) 54 +/- 44 ml, (D-) 22 +/- 25 ml, (I-) 102 +/- 58 ml, (U+) 11 +/- 5 ml, (U-) 21 +/- 9 ml (mean +/- S.D.), respectively. (I-) has been significantly larger than any of the other categories (p < 0.001 - 0.05). Additional ANOVA has shown that BP-II in category (I-) was significantly higher than that of the other categories. Patients with putaminal hemorrhage whose BP was elevating during the superacute phase in the ER were shown to have massive hematomas.

Rapid changes in pial arterial diameter and cerebral blood flow caused by ipsilateral carotid artery occlusion in rats.

We investigated rapid changes in pial arterial diameter and in cerebral blood flow (CBF) caused by transient ipsilateral common carotid artery occlusion (CCA-O) in anesthetized rats in order to elucidate how the cerebral circulation reacts to acute stem artery occlusion. In separate groups of rats, pial arterial diameter was recorded through a closed cranial window and CBF was recorded by laser-Doppler flowmetry. CCA-O was performed for 5 minutes under normotension and normocapnia (control) and under graded hypotension, hypercapnia and hypocapnia. In the control condition, pial arterial diameter increased rapidly, triggered by CCA-O. It took 12 +/- 3 s to reach the maximum of 204 +/- 42% of the value before CCA-O, and 60 +/- 24 s to become stable at 131 +/- 11%. CBF decreased rapidly to 66 +/- 11%, then increased reactively to 135 +/- 9%, and again decreased to 91 +/- 3%. The reactive increase in CBF caused by CCA-O decreased in parallel with the degree of hypotension, and also became barely detectable under hypercapnia. Our data suggest that active vascular dilation in the territory of the occluded artery is important for inducing collateral circulation.

Cerebral ischemia-induced amplification phenomenon of somatosensory evoked potentials in cats.

We elucidate the amplification phenomenon of median nerve somatosensory evoked potentials (SEPs) induced in cats by cerebral ischemia and also analyse the relationship between such amplification and cerebral blood flow (CBF). Transient focal cerebral ischemia was carried out by inducing only middle cerebral artery occlusion or jointly with bilateral common carotid artery occlusion. Various SEP alteration patterns were observed with CBF changes; with our overall results suggesting for the first time that the SEP amplification phenomenon occurs only under relatively mild cerebral ischemia.

Controlled ultraviolet irradiation generates endothelial damage without affecting the nerve terminals of the cerebral artery in cats.

The vesicles of adventitial autonomic nerve terminals were examined quantitatively under an electron microscope in controlled ultraviolet ray (UV)-irradiated cerebral vessels. Five cats whose basilar arteries were irradiated with UV (UV group) and 5 cats whose basilar arteries were irradiated with visible rays (control group) were compared. Endothelial vacuolation was observed only in the UV group. There was no statistically significant difference in the diameters of the dense-cored vesicles, related to noradrenaline, and clear vesicles, related to acetylcholine, between the two groups. It is concluded that controlled UV irradiation which generates endothelial damage does not affect the vascular adventitia ultrastructurally.

Cerebrovascular NADPH diaphorase-containing nerve fibers in the rat.

Recently, neuronal nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase has been elucidated to be the nitric oxide synthase (NOS) per se. In order to examine the existence and distribution of cerebrovascular nerve fibers containing these substances, NADPH-diaphorase histochemistry was applied to the cerebral blood vessels and the cranial ganglia known to innervate the cerebral vessels in the rat. Numerous nerve fibers with varicosities forming plexuses were observed in the circle of Willis and its branches. In addition, thick nerve bundles were seen to run along the wall of the internal ethmoidal artery. NADPH-diaphorase reaction was prominent in neurons of the sphenopalatine, otic and internal carotid ganglia. This study demonstrated, for the first time, the NADPH-diaphorase-containing nerve fibers in the cerebral vessels and ganglion cells in the parasympathetic and sensory ganglia known to innervate the cerebral vessels.

Moderate hypoglycemia induces ultrastructural changes in perivascular nerve terminals of cat cerebral arteries.

A quantitative morphological analysis of the perivascular nerve terminals of cerebral arteries during moderate hypoglycemia was performed. 5-Hydroxydopamine (5-OHDA) was applied to discriminate dense-cored vesicles, related to noradrenaline, and clear vesicles, related to acetylcholine, under the electron microscope. Five hypoglycemic and 5 normoglycemic cats, all receiving 5-OHDA, were compared. In both the middle cerebral artery and vertebral artery, the dense-cored vesicles were significantly smaller and clear vesicles were significantly larger in hypoglycemia than in normoglycemia. These morphological changes in the vesicles may indicate hyperactivity of the sympathetic system and hypoactivity of the parasympathetic system of the cerebral vessels during hypoglycemia.

Effects of locus ceruleus lesions on the pericapillary nerve terminals in the feline brain.

The effects of bilateral locus ceruleus (LC) lesions on the pericapillary nerve terminals were investigated in the feline brain parenchyma using electron microscopy. LC lesions were induced stereotaxically and the animals were sacrificed after intravenous administration of 5-hydroxydopamine (5-OHDA). The diameter and number of dense-cored vesicles (DCVs) and clear vesicles (CVs) in the pericapillary nerve terminals were measured. The number of DCVs in the nerve terminal was significantly decreased by bilateral LC lesions. The diameters of the DCVs and CVs decreased significantly as compared with those in the non-operated control group. These data suggest that the LC is closely related to the pericapillary nerve terminals in the brain parenchyma and that not only nerve terminals with DCVs but also those with CVs are affected by LC lesions.

A MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) mtDNA mutation that induces subacute dementia which mimicks Creutzfeldt-Jakob disease.

A 50-year-old woman with subacute dementia and brain atrophy on CT showed periodic synchronous discharge (PSD) on electroencephalogram (EEG) and myoclonus. She was initially suspected of suffering from Creutzfeldt-Jakob disease (CJD), but dramatically recovered over 5 months. Based on further investigations, the final diagnosis was mitochondrial encephalomyopathy with an A-to-G substitution at nucleotide position 3243 in mitochondrial DNA (mtDNA), commonly seen in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This case suggests that patients suspected of suffering from CJD should be evaluated for mitochondrial encephalomyopathy.

Distribution of brain oedema in the contralateral hemisphere after cerebral infarction: repeated MRI measurement in the rat.

The appearance of local cerebral dysfunction at remote regions from the focus in the acute stage of stroke (diaschisis) is well known, but its mechanism has not been established. We have analysed serial MR images of the infarcted brain of rats to evaluate the distribution of oedema. Forty-seven Sprague-Dawley rats were anaesthetized with halothane, and the right middle cerebral artery (MCA) was permanently occluded via the intraluminal approach using a nylon 2-0 suture. At 3, 6, 9 and 24 hours after the occlusion, coronal T(2)-weighted MR images were taken and the signal intensity (SI) was computed at each region of the brain. After occlusion of the right MCA, SI increased diachronically up to 24 hours on the occluded side of the cortex (52.9+/-3.2 to 104.8+/-22.4) and striatum, which are within the perfusion territory of the MCA. SI increment was also observed at the hippocampus, alveus hippocampi and pyriform lobe, which are not within the territory of the MCA, and at some regions of the contralateral side (52.5+/-4.8 to 69.4+/-14.8 at the cortex). These changes were prominent in ischaemia-vulnerable portions, mild in the cortex, and minimal in the striatum. This contralateral side SI increment indicates remote oedema, which corresponds to diaschisis. We suggest that the mechanism of this remote contralateral oedema is the movement of extravasated protein from the lesion.

[A case of posttraumatic spinal pseudomeningocele which caused spinal cord compression 20 years after injury].

We reported an extremely rare case of posttraumatic spinal pseudomeningocele which caused spinal cord compression 20 years after getting injury, and demonstrated that sequelae of an injury may occur many years after the original wound. A 39-year-old man, who got left cervical root avulsion due to a traffic accident when he was 17 years old, began to complain of progressive muscle atrophy and weakness of left lower extremity 1 year ago. Myelography demonstrated pseudomeningocele at left C6-C8 level, and MRI and CT myelography revealed that the pseudomeningocele extends through the intervertebral foramen and compresses the spinal cord to the right side in the spinal canal. Bilateral functional compression of spinal cord dorsal and lateral column was also verified with SEP and MEP electrophysiologically.

[A case of codon 232 mutation-induced Creutzfeldt-Jakob disease visualized by the MRI-FLAIR images with atypical clinical symptoms].

A 50-year-old man was admitted to our hospital because of disorientation and nocturnal restlessness. The patient presented chronically progressive dementia. No myoclonus or periodic synchronous discharge (PSD) was found over time, with abnormal evidence in MRI-FLAIR (fluid-attenuated inversion recovery) images alone. Brain biopsy and prion protein gene analysis led to the final diagnosis of Creutzfeldt-Jakob disease (CJD) induced by the point mutation at codon 232 (Met to Arg). To date the cases of M232R mutation-induced CJD have been reported to present clinical symptoms and pathological evidences similar to sporadic CJD cases, and differential diagnosis between the types has been believed to be difficult. Our case suggests that some types of CJD induced by point mutation at codon 232 cannot be easily inferred from clinical findings.

Experimental models and treatment trials for cerebral infarction.

Recent progress in both experimental and clinical studies of cerebral infarction is outlined, and research on delayed neuronal death and ischemic penumbra is described. Development of animal models to study clinical pathophysiology is reviewed, and our focal cerebral ischemia model which has been used for many years is introduced. With elucidation of the pathophysiology of cerebral ischemia, various pharmaceutical agents have appeared recently in the clinical setting and our experimental trials on the treatment of cerebral ischemia are also introduced. From the clinical aspect, practical methods of treatment including antiplatelet therapy are explained. Cerebrovascular dementia and its prevention are also described.

How to use cerebral vasodilators and metabolic activators.

Cerebral vasodilators and metabolic activators (enhancers) for the treatment of cerebrovascular disorders (CVD) have been categorized and introduced into clinical practice according to their pharmacological actions and clinical indications. The main therapeutic goal of these drugs is to relieve residual subjective symptoms and neuropsychological dysfunction, which reduce the quality of life of patients in the chronic stage of stroke. Selection of the most suitable drug for the individual symptoms of each patient is an important therapeutic principle.