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Satoshi Suzuki, Neal F. Kassell, and Kevin S. Lee

✓ Hemin is a prominent breakdown product of hemoglobin, and high levels of hemin are found in the cerebrospinal fluid during subarachnoid hemorrhage—induced vasospasm. The possible role of hemin in modifying vascular function was examined in the present study by testing its effects on nitric oxide synthase (NOS) activity in cultured rat aortic smooth-muscle cells. Nitric oxide synthase activity was estimated from the amounts of accumulated nitrite and nitrate, which are oxidative products of nitric oxide (NO). Hemin (1–100 µM) increased the levels of nitrite and nitrate in culture medium in a dose- and time-dependent manner. The hemin-induced elevation of nitrite and nitrate was inhibited significantly by the NOS inhibitor, Nω-nitro-l-arginine (300 µM), and by the protein synthesis inhibitor, cycloheximide (5 µg/ml). These results indicate that hemin is capable of stimulating the expression of an inducible isoform of NOS (iNOS) in vascular smooth muscle. Transcriptional expression of iNOS is known to cause injurious effects on the maintenance of cellular homeostasis by generating extremely high levels of NO. The generation of hemin from methemoglobin during hemolysis of a subarachnoid blood clot could therefore stimulate an excessive production of NO in vascular smooth-muscle cells. It is postulated that this series of events contributes to the development of vascular injury associated with cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

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Satoshi Suzuki, Katsunobu Takenaka, Neal F. Kassell, and Kevin S. Lee

✓ The roles of hemoglobin (Hb) in the pathogenesis of cerebral vasospasm remain a matter of discussion. Hemoglobin is known to be released from extravasated red blood cells in a variety of pathological conditions, including subarachnoid hemorrhage. These conditions are often accompanied by infiltration of inflammatory cells and an associated release of multiple cytokines. Certain of these cytokines, including interleukin-1β (IL-1β), are capable of increasing nitric oxide (NO) production via the inducible form of nitric oxide synthase (NOS), and excessive NO production under these conditions may contribute to cellular dysfunction. This study further examines these questions by investigating the effects of Hb on the induction of NOS by IL-1β.

The effects of Hb on IL-1β-induced NO production were examined in cultured smooth-muscle cells of rat aorta (RA-SMC's). Production of NO was estimated from the accumulation of nitrite, an oxidative product of NO, in the culture medium. The synthesis of NO was induced by IL-1β in a concentration-dependent manner. This activation of NO production was inhibited by: 1) a general inhibitor of NOS (Nω-nitro-L-arginine); 2) a protein synthesis inhibitor (cycloheximide); and 3) two selective inhibitors of the inducible form of NOS (hydrocortisone and aminoguanidine). These results suggest that IL-1β promotes the expression of the inducible form of NOS in RA-SMC's. The effects of Hb on NO production were tested by adding purified human Hb to the culture medium of the cells in both the presence and absence of IL-1β. Nitrite accumulation was slightly but significantly increased by Hb in the absence of IL-1β. In contrast, Hb markedly augmented nitrite accumulation induced by IL-1β. This augmentation persisted even after the removal of Hb from the culture medium. The number of cells was not affected by Hb or IL-1β.

The findings demonstrate that Hb can modify cytokine-induced production of NO in RA-SMC's by increasing the inducible form of NOS. These observations suggest that Hb can also modify the action of inflammatory cells by facilitating NO production in target cells.

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Experimental cerebral vasospasm

Part 1: Factors contributing to early spasm

Hajime Nagai, Yoshiaki Suzuki, Mitsuo Sugiura, Satoshi Noda, and Hideo Mabe

✓The authors describe a model for making an experimental subarachnoid hemorrhage that closely simulates human aneurysmal rupture. A needle previously inserted into the posterior communicating artery is subsequently withdrawn by traction on a thread. Using this model they demonstrate biphasic spasm by measurement of cerebral blood flow and angiography after rupture of the artery; the early spasm lasted 60 minutes and the late spasm began 3 or 4 hours after subarachnoid hemorrhage and continued for several days. The authors discuss the pathogenesis of early and late spasm.

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Bernhard Sutter, Satoshi Suzuki, Neal F. Kassell, and Kevin S. Lee

✓ Increasing evidence suggests that disturbances in the modulatory influence of the vasoactive peptide, calcitonin gene—related peptide (CGRP), contribute to the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). However, only limited success has been achieved in trials attempting to ameliorate vasospasm by modifying CGRP function. To better understand the potential utility of targeting CGRP-mediated relaxation, it is important both to identify the interactions CGRP may have with other elements of the vasospastic response and to characterize the mechanisms through which CGRP elicits vasodilative effects. The present studies examined the effects of CGRP on vascular responsiveness using tension measurements of ring strips of rabbit basilar artery maintained in vitro. Pretreatment of vessels with CGRP (100 nM) inhibited vasoconstrictor responses to the potent protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDB). This particular contractile response was selected because PKC-mediated vasoconstriction is a critical component of the vasospastic response after SAH. In a posttreatment paradigm, CGRP was also found to reverse established constriction responses to PDB (2 nM) and histamine (3 µM) in a dose-dependent manner.

When tested against the maximum effective dose of PDB (30 nM) in the posttreatment paradigm, CGRP (100 nM) did not elicit significant relaxation. However, after washing both of these drugs out of the test chamber, a persistent effect of CGRP was revealed: the decay of PDB-induced contraction was accelerated in vessels that had previously been treated with CGRP. These findings indicate that CGRP elicits both immediate and sustained influences on contractile responses mediated by PKC.

Finally, two potential mechanisms for the vascular response to CGRP were examined. Adenosine triphosphate (ATP)—sensitive K+ channels do not appear to participate in CGRP-mediated dilation; inhibitors of these channels, glibenclamide and tolbutamide, did not block CGRP-induced relaxation. In contrast, a possible role for the nucleotide cyclic adenosine monophosphate (cAMP) in the vascular response to CGRP was indicated by the dose-dependent elevation of cAMP levels by CGRP.

Together these studies indicate that CGRP can modulate the contractile response to PKC activation. These effects are associated with increases in the levels of cAMP, but occur independently of fluxes through ATP-sensitive K+ channels.

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Satoru Shimizu, Satoshi Utsuki, Sachio Suzuki, Hidehiro Oka, and Kiyotaka Fujii

✓Although the Codman-Hakim programmable valve is popular, several problems arising from its design have been described. The authors report an additional cause of shunt obstruction in the system. A 6-year-old girl who had received a ventriculoperitoneal shunt with the Codman-Hakim programmable valve system presented with worsening consciousness. The valve proved hard to flush, and emergency revision of the valve was performed. Examination of the extracted valve revealed that the pressure control cam had migrated into the outlet of the valve, thus causing the obstruction. A crack in the plastic housing surrounding the cam suggesting a past impact to the system was also revealed. These factors should thus be kept in mind as potential sources of obstruction of the valve system, especially in patients susceptible to episodes of head impact.

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Satoshi Utsuki, Hidehiro Oka, Sumito Sato, Sachio Suzuki, Satoru Shimizu, Satoshi Tanaka, and Kiyotaka Fujii

✓The response of nonfluorescing infiltrating tumors that had been exposed to 5–aminolevulinic acid and irradiated using a laser at a wavelength of 405 nm was analyzed intraoperatively using spectroscopy. Histological analyses demonstrated that neoplastic cells were present in the tissue region that displayed a peak at 636 nm, whereas no neoplastic cells were present in the region that exhibited only the excitation light peak. The authors conclude that the intraoperative use of laser spectroscopy can allow the diagnosis of infiltrating tumor and the detection of boundaries of the infiltrate when standard fluorescence techniques fail.

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Satoshi Suzuki, Junichi Omagari, Shunji Nishio, Eiichiro Nishiye, and Masashi Fukui

Object. The authors assessed the efficacy of gamma knife radiosurgery (GKS) in the treatment of patients with 10 or more simultaneous metastatic brain tumors.

Methods. Gamma knife radiosurgery was performed for the treatment of 10 or more simultaneous metastatic brain tumors in 24 patients. The performance status before and after GKS was expressed using the Karnofsky Performance Scale (KPS). The cumulative survival rate was analyzed using the Kaplan—Meier method. The level of satisfaction with the procedure was assessed by telephone interview.

No patient has died due to brain metastasis—related symptoms, and all patients and/or their families were satisfied with the GKS. In 12 patients who had brain metastasis—related symptoms, five improved, six were unchanged, and one deteriorated, as reflected by the KPS scores. The cumulative survival rate calculated by the Kaplan—Meier method was 70.4%, 49.3%, and 12.3% at 12 weeks, 24 weeks, and 36 weeks, respectively. The median survival time was 11 weeks.

Conclusions. Single-fraction GKS can achieve acceptable tumor control, low morbidity, and good quality of life in the treatment of multiple metastatic brain tumors even in cases with 10 or more simultaneous metastases.

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Koji Yoshimoto, Shunji Nishio, Satoshi Suzuki, Masashi Fukui, and Kanehiro Hasuo

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Satoshi Utsuki, Hidehiro Oka, Kimitoshi Sato, Satoru Shimizu, Sachio Suzuki, and Kiyotaka Fujii

Peritumoral hemangioblastoma cysts are usually composed of fibrous tissue without tumor cells. The authors describe the first case in which fluorescence with 5-aminolevulinic acid (5-ALA) was used to diagnose a hemangioblastoma tumor in a peritumoral cyst wall. A 27-year-old woman with a homogeneous, enhanced nodular lesion in the right hemisphere of the cerebellum underwent surgical treatment. After the nodular lesion was removed, the cyst region was observed with the aid of a semiconductor laser with a peak wavelength of 405 ± 1 nm, which was powered using a fiberoptic cable. The cyst region was visualized with strong fluorescence, which disappeared after tissue removal. The fluorescent cyst consisted of tumor cells. The authors conclude that fluorescence diagnosis performed using 5-ALA can inform the choice of removing hemangioblastoma cysts.