Tomio Sasaki

Cerebral microvessel endothelium is producing endothelin.

Endothelin, a potent vasoconstrictor peptide, was recently isolated from the supernatant of the cultured endothelia of the porcine aorta and is now supposed to be the most likely candidate for the endothelium-derived contractile factor (EDCF), which is responsible for the endothelium-dependent vasoconstriction by various stimuli. In this study, the production of endothelin by the endothelia of porcine cerebral microvessels was revealed by the Northern blot analysis with porcine endothelin cDNA probe and the enzyme-linked immunosorbent assay (ELISA) with anti-porcine endothelin antibody. Our results raise the possibility that the endothelia of cerebral microvessels regulate the local blood flow within the brain through the production of endothelin.

Lipid peroxidation as a cause of cerebral vasospasm.

In the present study, the vasocontractile activities of purified oxyhemoglobin, methemoglobin, peroxides of linoleic and arachidonic acid, and hydrogen peroxide were examined in vitro, using the canine basilar artery. It was shown that all of them possess a vasocontractile capacity in a dose-dependent fashion. Fresh canine arterial blood was incubated at 37 degree C for 2 weeks, and the daily change of its vasocontractile capacity and the amount of TBA-reactive substance was studied. This study revealed a gradual and parallel increase in both of them. In a clinical study with 32 SAH patients, the amount of TBA-reactive substance in the CSF was more elevated when angiographically confirmed vasospasm was present. The angiographical and histological responses of the basilar artery to the cisternal injection of 15-HPAA were studied in dogs. The cisternal injection of 15-HPAA (0.2 and 2.0 mg dissolved in bovine serum) caused a mild initial contraction of the basilar artery that lasted about 7 hours. On the third day, a stronger contraction occurred, persisting thereafter until sacrifice. Electronmicroscopy of those arterial samples revealed the disappearance of myofibrils, pyknotic changes of nuclei, and the appearance of vacuoles as well as electron-dense granules in the tunica media. The prolonged arterial contraction was always associated with remarkable destruction of the endothelial cells. These changes were essentially the same as those in experimental and clinical vasospasm. These data strongly indicate that free radical reactions initiated by clot lysis, represented by lipid peroxidation, plays an important role in the genesis of chronic vasospasm in subarachnoid hemorrhage.

Clinical and histopathological analysis of proliferative potentials of recurrent and non-recurrent meningiomas

Abstract Proliferative potentials of meningiomas from 127 patients were examined immunohistochemically using the anti-Ki-67 monoclonal antibody, MIB-1, on paraffin sections, and the correlation among MIB-1 staining index (SI), histopathological finding, and clinial course of the disease was analyzed retrospectively. The mean MIB-1 SI of 50 male patients with meningioma was 5.5%, whereas that of 77 female patients was 2.7%. Higher MIB-1 SI were observed for younger patients. These age- and sex-related differences in MIB-1 SI were statistically significant. The patients were assigned to one of three groups: those with non-recurrent meningioma (n = 73); those with recurrent meningioma in whom the specimens obtained during the initial surgery were used to calculate the MIB-1 SI (n = 21); and those with recurrent meningioma for whom the specimens obtained during the surgery for recurrent tumors were used to calculate the MIB-1 SI (n = 33). The mean MIB-1 SI in these patients were 1.6%, 3.6%, and 8.8%, respectively, and there were statistically significant differences among these three groups. Statistical analyses reveal that meningiomas with a MIB-1 SI of 3% or more have a significantly high tendency for recurrence during the clinical courses, especially within the first 10-year follow-up periods. Moreover, there is statistically significant correlation between MIB-1 SI and recurrence in each Simpson’s grade. The time interval to the next recurrence for recurrent meningiomas is associated with the proliferative potential represented by the MIB-1 SI, and a correlation equation has been proposed to predict the date of the next recurrence. Analyses on cellularity of meningiomas revealed no statistically significant difference in cellularity between non-recurrent and recurrent meningiomas. There was no statistically significant relationship between cellularity and MIB-1 SI of meningiomas. In conclusion, examination on proliferative potentials of meningiomas using MIB-1 SI is very important for biological and histopathologicl analyses and the prediction of future recurrence.

The role of endothelin in the pathogenesis of vasospasm following subarachnoid haemorrhage

The purpose of the present study was to evaluate the vasocontractile activity of endothelin, a newly isolated endothelium-derived constrictor peptide, in canine basilar arteries in vitro and in vivo. Endothelin at concentrations of 10(-12) M approximately 3 X 10(-8) M elicited dose-dependent contractions of canine basilar arteries in vitro. The maximum tension was larger than that induced by 40 mM KCl. The EC50 value was 1.9 +/- 0.6 X 10(-9) M (mean +/- SEM). The endothelin-induced contraction was reversed by 10(-8) M nicardipine or 10(-5) M approximately 10(-4) M papaverine. An intracisternal injection of 0.6 approximately 1.2 X 10(-12) mol/kg of endothelin caused biphasic contraction of the basilar artery lasting for more than 24 h. The initial phase of the contraction accompanied remarkable changes in vital signs such as an acute rise of blood pressure, bradycardia and respiratory arrest. An intracisternal injection of 2.0 X 10(-12) mol/kg of endothelin also induced acute contraction of the basilar artery. However, all of the dogs which received an intracisternal injection of 2.0 X 10(-12) mol/kg of endothelin died from sustained respiratory insufficiency. The present results demonstrate that endothelin induces strong and long-lasting contractions of cerebral arteries. Therefore, endothelin may play an important role in the pathogenesis of vasospasm.

Postoperative residual tumor growth of meningioma can be predicted by MIB‐1 immunohistochemistry

Meningiomas are benign tumors that can be cured by surgical removal. However, tumors located deeply within or close to vital structures cannot be removed completely and require repeated surgery. This study was designed to clarify whether immunohistochemical study using MIB‐1 monoclonal antibody is useful for determining the rate of regrowth for this tumor.

Analyses of neuro-otological complications after radiosurgery for acoustic neurinomas

PURPOSEnTo find out the optimum treatment parameters and the proper indications for treatment of acoustic neurinomas, univariate and multivariate actuarial analyses of neuro-otological complications after stereotactic radiosurgery for acoustic neurinomas were performed.nnnMETHODS AND MATERIALSnThe subjects were 46 patients with acoustic neurinomas who underwent unilateral radiosurgery between June 1990 and June 1994 and were followed up at the University of Tokyo. Age ranged from 13 to 77 years (median, 54 years). Tumor diameter ranged from 0 to 25 mm (mean, 12 mm) at the cerebellopontine angle and from 2 to 15 mm (mean, 8.3 mm) in the internal auditory meatus. Maximum tumor doses ranged from 20 to 40 Gy (mean, 31.4 Gy), and peripheral doses from 12 to 25 Gy (mean, 16.8 Gy). One to eight isocenters were used (mean, 3.2). Median follow-up was 39 months. Eight events concerning neuro-otological complications were chosen, and the potential risk factors for them were analyzed by the actuarial analyses (univariate and multivariate). The events examined include hearing loss, vestibular function loss, facial palsy, and trigeminal nerve dysfunction. In order to point out potential risk factors for neuro-otological complications, univariate analyses were performed using both the Wilcoxon test and the log rank test, and multivariate analyses were performed with the Cox proportional hazards model. Variables nominated as potential risk factors were 1) demographic variables such as patient age and sex, 2) tumor dimensions, 3) treatment variables such as tumor doses and number of isocenters, and 4) pretreatment hearing levels. A variable with significant p-values (p < 0.05) in two or more of the three actuarial analyses (two univariate and one multivariate) was considered a possible risk factor.nnnRESULTSnThe possible variables that increase the risk for each event analyzed were: neurofibromatosis type II (NF2) and the number of isocenters for total hearing loss; experience of prior operation, the tumor diameter in the internal auditory meatus, and NF2 for hearing threshold elevation; peripheral tumor dose for vestibular function loss; patient age or midporus transverse tumor diameter (the two variables were correlated), and the number of isocenters for facial palsy; and the number of isocenters for trigeminal neuropathy.nnnCONCLUSIONnNF2 and the tumor diameter were the common risk factors for hearing loss in previous studies and ours. For the 5th/7th nerve dysfunction, the tumor diameter was the common risk factor. The risk of using more isocenters remains controversial. The difference in risk factors for hearing impairment and vestibular function loss suggests different mechanisms for the two. Further studies with larger populations and longer follow-up periods are required in order to draw conclusions on the risk factors in radiosurgery.

The role of endothelin and nitric oxide in modulation of normal and spastic cerebral vascular tone in the dog.

To investigate the roles of endothelin and nitric oxide (NO) in the regulation of cerebral vascular tone under basal conditions and in cerebral vasospasm following subarachnoid hemorrhage in dogs, we used BQ-123 (cyclo(-D-Trp-D-Asp-L-Pro-D-Val-L-Leu-) sodium salt), an endothelin ETA receptor antagonist, L-arginine, a substrate for the formation of NO, and NG-nitro-L-arginine methyl ester, an NO synthesis inhibitor, and measured the angiographic diameter of the basilar artery in vivo. In normal dogs, intracisternal (i.c.) injection of BQ-123 (0.6 mg/kg) produced a 29.4 +/- 6.11% (P < 0.01) increase in the basal diameter 24 h after injection. NG-nitro-L-arginine methyl ester (0.6 mg/kg i.c.) produced a 19.3 +/- 2.93% (P < 0.05) decrease in the basal diameter 2 h after injection. This decrease was significantly attenuated by both BQ-123 (0.06-0.6 mg/kg i.c.) and L-arginine (6 mg/kg i.c.), but not by D-arginine. In the two-hemorrhage canine model, BQ-123 significantly inhibited the development of cerebral vasospasm (36.9 +/- 4.11% decrease on day 5 and 42.0 +/- 4.54% decrease on day 6 in controls vs 21.7 +/- 4.75% decrease (P < 0.05) on day 5 and 20.8 +/- 4.14% decrease (P < 0.05) on day 6 for 0.6 mg/kg i.c.) significantly attenuated the cerebral vasospasm on day 4 from a mg/kg i.c.). Furthermore, in this model, L-arginine (6 30.9 +/- 5.78% decrease (before)) to a 12.6 +/- 5.99% decrease (after). The immunoreactive endothelin-1 levels in the endothelial layer and the adventitia of the basilar artery were much higher on days 3 and 7 after the injection of autologous blood than on day 0 before blood injection. These results suggest that endogenous endothelin and NO both participate in regulating the basal tone of cerebral arteries, and, therefore, the development of cerebral vasospasm following subarachnoid hemorrhage may be at least partially attributed to an impairment of the balanced action of endothelin and NO. Furthermore, endothelin ETA antagonists or NO products may be useful in the treatment of cerebral vasospasm following subarachnoid hemorrhage.

Experimental evaluation of the beneficial effect of an antioxidant on cerebral vasospasm

Based on the previously suggested hypothesis that generation of free radicals leading to lipid peroxidation is involved in the genesis of vasospasm following SAH, the therapeutic effect of an antioxidant on experimental vasospasm was examined. As an antioxidant suitable for this purpose, AVS(1,2-bis(nicotinamide)-propane) was used. Experimental SAH was induced in dogs by intracisternal injection of blood and subsequent changes in the basilar artery diameter was evaluated by angiography. First, intrathecal administration of AVS 3 days after SAH caused prompt resolution of pre-existing chronic vasospasm for 3-4 h. Next, the effect of continuous intravenous administration of saline (control) or AVS was started and continued for 4 days. In the control group, early and chronic spasm was observed on the daily angiography. In the AVS-treated group, early spasm was only moderately inhibited, but the occurrence of chronic spasm was remarkably suppressed in a dose-dependent manner. In these experiments, no adverse effect of AVS on the neurological or systemic conditions was observed. The data indicate that AVS may be beneficial in the treatment of vasospasm following SAH, thereby reinforcing the concept that generation of free radicals is involved in the genesis of vasospasm.

A Phase II Clinical Trial of Recombinant Human Tissue-type Plasminogen Activator against Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage

The results of a Phase II clinical trial of intrathecal recombinant tissue-type plasminogen activator for the prevention of vasospasm were reported. The subjects were 53 patients with aneurysmal subarachnoid hemorrhage (SAH), Groups 2 to 4 in Fishers preoperative computed tomography classification and Grades II to IV in the Hunt-Kosnik classification. Twenty-four hours after surgery, tissue-type plasminogen activator (TD-2061) was intracisternally administered via a catheter (0.1, 0.2, or 0.4 mg, three times daily for 5 days). The clot-dissolving effects assessed as effective and markedly effective were virtually the same in the 0.1- and 0.2-mg groups (66.7% and 64.3%, respectively) but slightly lower (53.3%) in the 0.4-mg group, suggesting an adequate effect in the 0.1- and 0.2-mg groups. Severe angiographic vasospasm was not observed in any of three groups. No intergroup differences were noted in the incidence of symptomatic vasospasm, low density on computed tomography 1 month after SAH, and functional prognosis. Bleeding complications were noted in 4 patients (7.5%), including 1 case of SAH in the low 0.1-mg group, 2 cases of SAH in the 0.2-mg group, and 1 case of epidural hematoma in the 0.4-mg group. In overall safety rating, 3 cases with increased SAH and 1 case of epidural hematoma were assessed as safety doubtful. Other minor side effects such as headache and hepatic dysfunction attributed to the effect of other simultaneously used drugs were assessed as almost safe, and the rate of almost safe and better for all dose groups was about 90%, suggesting a safe dose level for all groups. These results suggest that repeated intrathecal administration of tissue-type plasminogen activator is useful for preventing vasospasm even in the low dose of 0.1 mg.

Intramedullary cavernous angioma with trigeminal neuralgia: a case report and review of the literature.

A case of intramedullary cavernous angioma of the upper cervical spinal cord, initially associated with trigeminal neuralgia, is reported. Magnetic resonance imaging precisely depicted the entire extent of the lesion. The angioma was totally removed and the operation was successful in relieving the patient of neuralgia. The previously reported 23 cases of intramedullary cavernous angiomas are reviewed, and the clinical symptoms, diagnosis, and treatment of this rare condition are discussed.