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Hiroki Ohkuma, Takahiro Nakano, Hiroshi Manabe and Shigeharu Suzuki

Object. Subarachnoid hemorrhage (SAH) caused by the rupture of a dissecting aneurysm of the internal carotid artery (ICA) has been considered rare. Based on data from cooperatively collected cases, the clinical features of patients with dissecting aneurysms of the ICA who presented with SAH were examined.

Methods. Data from 18 patients with dissecting aneurysms of the ICA who presented with SAH diagnosed on the basis of clinical signs, neuroradiological findings, and intraoperative findings from 41 institutions were collected during a 5-year period between 1995 and 1999. The authors found that 0.3% of all cases of SAH and 3.1% of cases of SAH of unverified cause were attributable to a dissecting aneurysm of the ICA. Eleven patients (61%) were middle-aged women, and eight patients (44%) had hypertension. Rebleeding before admission was demonstrated in 13 patients (72%), and intraoperative bleeding was exhibited in half of the patients who underwent surgery during the acute stage. Postoperative growth of an aneurysm bulge or recurrent SAH was seen in five of 10 patients who had undergone wrapping or clipping of the aneurysm bulge in the acute phase. Trapping with or without bypass, which resulted in no postoperative recurrence, was performed in three patients in the acute stage and in two patients in the chronic stage. Twelve patients (67%) had a poor prognosis, primarily attributed to intraoperative bleeding and postoperative recurrence.

Conclusions. Generally, dissecting aneurysms of the ICA are not thought of as frequent causes of SAH. Nonetheless, the presence of these aneurysms should be considered when dealing with SAH because they have a susceptibility to bleeding that can lead to a poor prognosis. Careful surgical planning is necessary to decrease intraoperative bleeding and to avoid postoperative recurrence.

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Hiroki Ohkuma, Ian Parney, Joseph Megyesi, Aziz Ghahary and J. Max Findlay

Object. The purpose of this study is twofold: 1) to test antisense genetic techniques used in the prevention of cerebral vasospasm in a canine model of subarachnoid hemorrhage (SAH), targeting the endothelin-1 (ET-1) gene; and 2) to determine if fibrinolysis of subarachnoid clot with recombinant tissue plasminogen activator (rtPA) could enhance the effect of antisense treatment.

Methods. A total of 39 dogs were studied in this experiment. Placebo (six animals), rtPA (six animals), antisense preproET-1 oligodeoxynucleotide (ASOD; five animals), or rtPA plus ASOD (combined treatment; six animals) was injected into the cisterna magna 30 minutes after a second SAH was induced on the 2nd day of the experiment. The animals were observed until Day 7, when they underwent follow-up angiography and then were killed; their basilar arteries were removed for analysis. Control animals included in this study (two animals in each group) received placebo, rtPA, ASOD, or rtPA plus ASOD without induction of SAH, or rtPA with mismatched (nonsense) preproET-1 oligodeoxynucleotide following SAH. Six additional dogs were analyzed earlier following SAH.

Dogs that received placebo developed severe vasospasm (51 ± 8% of baseline caliber). Administration of ASOD alone resulted in a mild reduction in vasospasm (64 ± 13% of baseline caliber) and rtPA alone resulted in a moderate reduction in vasospasm (81 ± 5% of baseline caliber); however, the combined therapy of rtPA plus ASOD almost completely prevented vasospasm (95 ± 6% of baseline caliber), which was significantly different from all other groups (p < 0.05). Morphological analysis of the basilar arteries yielded results similar to angiography with respect to vasospasm severity. The ASOD treatment combined with rtPA resulted in reduced ET-1 expression, as demonstrated by immunohistochemical staining of the arteries, and reduced preproET-1 levels on Day 4, as measured by reverse transcription—polymerase chain reaction. Nonsense DNA sequences had no effect on the vessels.

Conclusions. Antisense preproET-1 oligodeoxynucleotide treatment, when combined with clot lysis caused by rtPA, reduced vasospasm in the canine model of SAH, and this effect appeared to be related to reduced ET-1 synthesis. The results of this experiment support a causative role for ET-1 early in the course of vasospasm development in dogs. The apparent additive therapeutic effects of antisense and fibrinolytic treatments could be due to clot lysis, which allows better delivery of oligodeoxynucleotides to arteries within the subarachnoid space.

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Kenichiro Asano, Takahiro Nakano, Tetsuji Takeda and Hiroki Ohkuma

Object

In elderly patients with brain tumors, the prevention of postoperative systemic complications is extremely important, and identification of the risk factors would be useful for planning therapy. The authors investigated ways to avoid postoperative complications by identifying risk factors.

Methods

The study population included 84 patients, 70 years of age or older, who underwent surgical brain tumor removal. The following independent factors were assessed by univariate and multivariate analyses: sex, age, preoperative underlying diseases and complications, histopathological findings, preoperative Karnofsky Performance Scale (KPS) score, preoperative whole blood hemoglobin (Hb) level, preoperative serum total protein (TP) level, operation time, intraoperative blood loss, change in Hb level (difference between pre- and postoperative values), and change in TP level (difference between pre- and postoperative values). The cutoff values for significant independent factors were also determined.

Results

Overall, 35 (41.7%) of the 84 patients had a total of 56 postoperative systemic complications. Univariate analysis identified the preoperative KPS score, intraoperative blood loss, change in Hb level, and change in TP level as risk factors for postoperative complications, and multivariate analysis extracted the following risk factors: the preoperative KPS score (p = 0.0450, OR 4.020), intraoperative blood loss (p = 0.0104, OR 6.571), and change in Hb levels (p = 0.0023, OR 9.301). The cutoff values were: KPS score < 80%, intraoperative blood loss ≥ 350 ml, and change in Hb level ≥ 2.0 g/dl.

Conclusions

In elderly patients with brain tumors, low preoperative KPS score, high intraoperative blood loss, and a large difference between pre- and postoperative Hb levels are significant risk factors for postoperative systemic complications.

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Naoya Matsuda, Hiroki Ohkuma, Masato Naraoka, Akira Munakata, Norihito Shimamura and Kenichiro Asano

Object

Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication. Free radicals derived from subarachnoid clotting are recognized to play an important role. Oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) have been shown to be related to the pathogenesis of atherosclerosis and may increase in cerebral arteries after SAH, due to the action of free radicals derived from a subarachnoid clot. These molecules may also affect the pathogenesis of vasospasm, generating intracellular reactive oxygen species and downregulating the expression of endothelial NO synthase (eNOS). If so, apple polyphenol might be effective in the prevention of vasospasm due to an abundant content of procyanidins, which exhibit strong radical scavenging effects, and the ability to suppress ox-LDL and LOX-1. The purposes of this study were to investigate changes in levels of ox-LDL and LOX-1 after SAH and whether administering apple polyphenol can modify cerebral vasospasm.

Methods

Forty Japanese white rabbits were assigned randomly to 4 groups: an SAH group (n = 10); a shamoperation group (n = 10), which underwent intracisternal saline injection; a low-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 10 mg/kg per day from Day 0 to Day 3; and a high-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 50 mg/kg per day. At Day 4, the basilar artery and brain was excised from each rabbit. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar artery, and the expression of ox-LDL, LOX-1, and eNOS was examined for each basilar artery by immunohistochemical staining and reverse transcriptase polymerase chain reaction. In addition, neuronal apoptosis in the cerebral cortex was evaluated by TUNEL.

Results

Compared with the sham group, the expression of ox-LDL and LOX-1 in the basilar arterial wall was significantly increased in the SAH group, the expression of eNOS was significantly decreased, and the cross-sectional area of basilar artery was significantly decreased. Compared with the SAH group, the cross-sectional area of basilar artery was increased in the polyphenol groups, together with the decreased expression of ox-LDL and LOX-1 and the increased expression of eNOS. In the high-dose polyphenol group, those changes were statistically significant compared with the SAH group. In the low-dose polyphenol group, those changes were smaller than in the high-dose polyphenol group. No apoptosis and no changes were seen in the cerebral cortex in all groups.

Conclusions

This is the first study suggesting that ox-LDL and LOX-1 increase due to SAH and that they may play a role in the pathogenesis of vasospasm. It is assumed that procyanidins in apple polyphenol may inhibit a vicious cycle of ox-LDL, LOX-1, and ROS in a dose-dependent manner. Apple polyphenol is a candidate for preventive treatment of cerebral vasospasm.