Takao Hatakeyama

Evaluation of risk of hemorrhagic transformation in local intra-arterial thrombolysis in acute ischemic stroke by initial SPECT.

BACKGROUND AND PURPOSE Thrombolytic therapy was carried out on patients with acute ischemic stroke, and the risk of hemorrhagic transformation was evaluated from the residual cerebral blood flow (CBF) by pretherapeutic single-photon emission-computed tomography (SPECT). METHODS Local intra-arterial thrombolytic therapy was carried out using urokinase or recombinant tissue plasminogen activator (rt-PA) within 6 hours from the onset in 34 patients in whom no hypodensity areas were observed on the initial computed tomography examination. In the 20 patients with carotid territory occlusion who underwent 99mTc-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT, the residual CBF of the ischemic region was evaluated semiquantitatively by calculating two parameters: the ischemic regional activity to cerebellar activity ratio (R/CE ratio) and asymmetry index (AI). RESULTS The occluded vessels could be recanalized in 22 (92%) of the 24 patients in the urokinase group and in all 10 of the patients in the rt-PA group. Hemorrhagic transformation appeared in 4 patients in the urokinase group and 3 patients in the rt-PA group. Among the 20 patients who underwent SPECT before the treatment, the residual CBF was lower in the 5 patients who developed hemorrhagic transformation than in the 15 who did not (P < .05). Hemorrhagic transformation occurred in all patients with R/CE ratio of less than 0.35 and AI of more than 1.5. CONCLUSIONS The risk of hemorrhagic transformation after recanalization of occluded vessels by local intra-arterial thrombolytic therapy was considered to be high when the pretherapeutic residual CBF was markedly reduced.

Recovery of protein synthesis in tolerance-induced hippocampal CA1 neurons after transient forebrain ischemia

Protein synthesis at various recirculation times after 5-min transient forebrain ischemia was evaluated in gerbil hippocampal CA1 pyramidal neurons that had acquired tolerance to delayed-type ischemic injury. Evaluation was performed by observing polyribosomes under electron microscopy, and by [14C] leucine autoradiography. Hippocampal CA1 pyramidal neurons in the gerbils acquired stable and reproducible tolerance to delayed-type ischemic injury subsequent to a 5-min ischemia by pretreatment that consisted of loading two 2-min ischemic periods at a 1-day interval, followed by 48 h of recirculation. During the early phase following the 5-min ischemia, polyribosomal disaggregation, loss of dendritic microtubules, and significant suppression of radiolabeled leucine incorporation were observed in the tolerance-induced CA1 neurons as well as in the non-tolerance-induced neurons. While these findings persisted in the non-tolerance-induced neurons throughout the duration of the experiment, most of the tolerance-induced neurons demonstrated reaggregation of cytosomal ribosomes, increase in the number of dendritic microtubules, and restoration of impaired amino acid incorporation 24 h after the ischemia. These findings suggest that revovery of protein synthesis during the early post ischemic phase is essential for CA1 neuron survival after ischemic injury.

Endovascular treatment for acute thrombotic occlusion of the middle cerebral artery: local intra-arterial thrombolysis combined with percutaneous transluminal angioplasty

Abstract We report our experience in treating 15 patients with acute thrombotic occlusion of the M1 or M2 segment of the middle cerebral artery who underwent intra-arterial thrombolytic therapy alone or in combination with percutaneous transluminal angioplasty (PTA). The results were compared with those of 30 patients with acute embolic occlusion of the same artery. Intra-arterial thrombolysis was performed in 10 patients and thrombolysis combined with PTA in 5 in whom symptoms reappeared due to restenosis or reocclusion, or in whom recanalisation was not successfully accomplished by thrombolysis alone. In the patients with embolism recanalisation was observed in 28 (93 %) and there was no patient with reocclusion. In the patients with thrombosis recanalisation immediately after thrombolysis alone was observed in 9 of 15 (60 %). Restenosis, with reappearance of symptoms, occurred in 2 of these (22 %). In the patients who also underwent PTA, angiography after 1 month did not demonstrate any restenosis or reocclusion. Thrombolysis combined with PTA for acute thrombotic stroke may provide an effective procedure for restoring patency and preventing reocclusion of the occluded artery.

The role of early Ca2+ influx in the pathogenesis of delayed neuronal death after brief forebrain ischemia in gerbils

To examine the role of calcium influx in the early phase after brief forebrain ischemia and subsequent delayed neuronal cell death in the hippocampus, 45Ca autoradiography and electron microscopic cytochemistry, by a combined oxalate-pyroantimonate method, were carried out in gerbil brains after 5 min bilateral common carotid arterial occlusion. Further, neuronal damage during the ischemic and postischemic periods was determined by conventional or immunohistochemical staining for microtubule-associated protein 2 (MAP2) with and without calcium-entry blockers. 45Ca autoradiography showed a high peak of calcium in the hippocampus at 5 min of recirculation. Electron cytochemical microscopy also demonstrated accumulation of intracellular calcium pyroantimonate deposits in the neuronal cells in all regions. At 30 min of reperfusion, amounts of calcium in the hippocampus returned to the control levels, and intracellular dense calcium pyroantimonate deposits were reduced in these areas. Loss of the reaction for MAP2 was noted in the medial CA1 of the hippocampus immediately after 5 min ischemia and at 5 and 30 min after reperfusion. MK-801 (10 mg kg-1), an N-methyl-D-aspartate (NMDA) receptor antagonist, injected intraperitoneally 1 h before ischemia, suppressed the early increase of calcium in the forebrain and neuronal cell necrosis in the CA1. However, neither injection of MK-801 30 min after reperfusion nor preischemic treatment with 0.5 mg kg-1 Nimodipine or 1 mg kg-1 Nicardipine, voltage-sensitive calcium channel antagonists, prevented neuronal death. In immunohistochemical staining for MAP2, the ischemic lesion in the medial CA1 maintained after 5 min ischemia and the subsequent early reperfusion period in the untreated brains was protected by the preischemic injection of 10 mg kg-1 MK-801, but was not restored by the injection of 0.5 mg kg-1 Nimodipine or 1 mg kg-1 Nicardipine. In conclusion, it is suggested that an early excess of calcium influx could be caused mainly by excitatory amino acid overload through NMDA receptor-mediated calcium channels during the ischemic and early postischemic periods.

Improvement in local cerebral blood flow measurement in gerbil brains by prevention of postmortem diffusion of [14C]iodoantipyrine.

Postmortem diffusion of [14C]iodoantipyrine, which distorts the image of cerebral blood flow, can occur in at least three steps; from decapitation until the brain is frozen, while frozen sections on coverslips are thawed, and when dried sections are applied to x-ray film. In the present study, the first two steps were modified to reduce the time during which brain tissue was wet. When the brains of gerbils were taken out of the skulls and immersed in chilled isopentane (–45°C), 90–95 s elapsed between decapitation until the brain tissues were frozen. However, immersion of whole heads in liquid nitrogen after decapitation decreased the time to 25 s. The autoradiograms had better contrast after the freezing procedure with liquid nitrogen than after that with chilled isopentane. The drying time of the thawed sections was markedly reduced by blowing hot air across the sections on a hot plate, and this resulted in clearer images on autoradiograms. In most of the tissues with values of cerebral blood flow over 100 ml 100 g−1 min−1 as measured using the conventional drying method, the corresponding values were higher if the modified method was used. In contrast, in tissues with values less than 100 ml 100 g−1 min−1, the corresponding values were lower. Moreover, the differences between flows in adjacent small brain structures were less clear if the sections were dried by the conventional method. Reducing the time during which postmortem brains or sections are wet can help prevent [14C]iodoantipyrine diffusion artifacts.

Single photon emission computed tomography (SPELT) using N-isopropyl-p-(123I)iodoamphetamine (IMP) in the evaluation of patients with epileptic seizures

To evaluate the clinical usefulness of IMP SPECT in the diagnosis of epilepsy, 6 normals and 52 patients in the interictal phase were studied. Thirty min after an intravenous injection of 111 MBq IMP, SPECT was performed using a rotating gamma camera. Of 21 patients with simple partial seizures, a localized decrease of uptake was shown in 16, and an increase in 3. Topologically, these findings corresponded well to the ictal symptoms. Nine of 13 patients with localized epileptic EEG had a good correspondence between the findings on EEG and IMP SPELT. In 20 of 23 with complex partial seizures, the coronal images showed laterality of uptake in the temporal lobes, whereas the CT was normal in 14. However, these findings on IMP SPECT agreed with the EEG in the temporal leads in only 5 cases. Of 8 patients with primary generalized seizures, a diffuse cerebral decrease was shown in 3 of 4 patients with convulsive seizures (grand mal), and a normal uptake in 3 of 4 patients with non-convulsive seizures (petit mal). However, 2 patients showed a localized decrease, therefore, we determined that they suffered from partial seizures evolving to secondarily generalization. From these data, we concluded that IMP SPELT could be a useful method in the diagnosis of epilepsy.

A strategy for selective anti-cancer drug concentration increase in rat glioma tissue with Ca2+-channel blocker co-administration: calcium kinetics in intra-glioma arteriolar smooth muscle cells

SummaryA rat glioma model was employed to estimate the Ca2+ kinetics in the tumor arteriolar smooth muscle cells. Electron microcytochemistry revealed that the density of intracellular Ca2+ deposits in the intra-tumor arteriolar smooth muscle cells was significantly greater, with slightly higher membrane Ca2+-adenosine triphosphatase (ATPase) activity, compared to the contralateral cerebral arterioles. Furthermore, the administration of tyrphostin, a tyrosine kinase inhibitor, specifically increased only the intra-tumor blood flow. These findings suggest that the condition of the intra-tumor arteriole alters the susceptibility to contraction by the accelerated Ca2+ influx into the cytoplasm mediated through the tyrosine kinase pathway. After the administration of diltiazem, which also has a blocking effect on the Ca2+-channel mediated through this pathway, the local intra-tumor blood flow showed an increase of 39% with a marked decrease of intracellular Ca2+ concentration of the arteriolar smooth muscle cells in the tumor, while the blood flow in the basal ganglia increased by only 8%. The intra-tumor concentration of Nimustine-HCI (ACNU) with co-administration of diltiazem was significantly increased compared to that without the co-administration. Co-administration of diltiazem may be a valuable strategy in chemotherapy for glioma in affording the selective increase of intra-tumor concentration of the anti-cancer drug.

Intraarterial infusion of urokinase using superselective catheterization for patients with acute cerebral arterial occlusion.

CTscanにて低吸収域の出現していない脳梗塞急性期15症例に対して, 超選択的カテーテルを用いて計16回のウロキナーゼ (UK) による局所動脈内注入を行い, その効果および副作用について検討した.UKは24万～30万単位ずつ計24～150万単位注入した.発症よりUK注入までの時間は3.5～9時間 (平均5.8時間) で, 閉塞部位は中大脳動脈13例, 脳底動脈2例, 内頸動脈先端部1例であった.再開通は12例 (81.3%) に, 臨床症状の回復は11例に認められ, そのうち7例は完全回復をきたした.出血性梗塞は3例に出現したが, 症状の悪化は認められなかった.発症より6時間以内に治療を開始した11例中では, 出血性梗塞は出現しなかった.以上のことから, 本療法は厳密な適応選択の上に行えば, 安全で有用な治療法であると考えられる.