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Shiro Isoe, Hirofumi Naganuma, Shin Nakano, Atsushi Sasaki, Eiji Satoh, Mitsuyasu Nagasaka, Shuichiro Maeda and Hideaki Nukui

Object. The aim of this study was to investigate the mechanism by which malignant glioma cells escape from growth inhibition mediated by transforming growth factor-β (TGF-β), a ubiquitous cytokine that inhibits cell proliferation by causing growth arrest in the G1 phase of the cell cycle.

Methods. The authors measured the response of eight malignant glioma cell lines to the growth-inhibiting activity of TGF-β in vitro and the expression of TGF-β Types I and II receptors in malignant glioma cells. The effect of TGF-β on the expression of a p27Kip1 cyclin-dependent kinase inhibitor was also investigated to assess the downstream signal transmission from TGF-β receptors. All malignant glioma cell lines were insensitive to growth inhibition by TGF-β1 and TGF-β2. Analyses of TGF-β receptors by means of affinity labeling in which 125I-TGF-β1 was used showed that six glioma lines had both TGF-β Types I and II receptors on their cell surfaces, whereas two lines had very small amounts of TGF-β Type I and/or Type II receptors. Northern blot analysis showed that all tumor lines expressed variable levels of messenger RNAs for both TGF-β Types I and II receptors. Flow cytometric analyses revealed that treatment of malignant glioma cells with TGF-β1 significantly downregulated the expression of p27Kip1 protein in all malignant glioma cell lines except one.

Conclusions. The authors suggest that most malignant glioma cells express TGF-β Types I and II receptors, which can transmit some signals downstream and that the loss of response to TGF-β growth inhibition may not be caused by an abnormality of the TGF-β receptors.

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Arata Watanabe, Tomohiro Omata, Hidehito Koizumi, Shin Nakano, Nobuyasu Takeuchi and Hiroyuki Kinouchi

Object

The natural history of moyamoya disease is not well known. We have observed that the bony carotid canal is hypoplastic in patients with adult onset moyamoya disease. Bony carotid canal development should represent internal carotid artery (ICA) development, and may stop with the beginning of ICA stenosis. The purpose of this study was to determine the onset of moyamoya disease by measuring the bony carotid canal.

Methods

The normal diameter of the bony carotid canal was evaluated on 4-mm thick bone window CT scans of the skull base in 60 Japanese patients aged 20–80 years, who had minor head trauma or headache considered to be unrelated to the skull base or arterial systems. The relationship between age and bony carotid canal development was assessed in a second group of 50 patients aged 0–19 years, including 10 under 2 years, using CT scans with the same parameters. The diameter of the bony carotid canal in 17 Japanese patients with moyamoya disease was measured.

Results

The normal diameter in adults was 5.27 ± 0.62 mm (mean ± SD). The bony carotid canal developed rapidly before approximately 2 years of age. After fusion of the bony suture, the bony carotid canal developed slowly. The mean diameter of the bony carotid canal was 3.31 ± 0.44 mm in 11 adult patients with adult-onset moyamoya disease. According to the apparent curve of bony carotid canal development, ICA stenosis was assumed to start in early childhood.

Conclusions

Our findings suggest that most cases of Asian moyamoya disease may arise in childhood and that many Asian adult patients with moyamoya disease may develop occlusive vasculopathy in childhood.

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Nobuo Senbokuya, Hiroyuki Kinouchi, Kazuya Kanemaru, Yasuhiro Ohashi, Akira Fukamachi, Shinichi Yagi, Tsuneo Shimizu, Koro Furuya, Mikito Uchida, Nobuyasu Takeuchi, Shin Nakano, Hidehito Koizumi, Chikashi Kobayashi, Isao Fukasawa, Teruo Takahashi, Katsuhiro Kuroda, Yoshihisa Nishiyama, Hideyuki Yoshioka and Toru Horikoshi

Object

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm.

Methods

Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population.

Results

Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period.

Conclusions

Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry.