Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma.

Retinoic acid (RA) has been shown to induce neuronal differentiation and/or apoptosis, and is widely used as a chemotherapeutic agent for treating the patients with neuroblastoma. However, the therapeutic effect of RA is still limited. To unveil the molecular mechanism(s) inducing differentiation and apoptosis in neuroblastoma cells, we compared CHP134 and NB-39-nu cell lines, in which all-trans-RA (ATRA) induces apoptosis, with LA-N-5 and RTBM1 cell lines, in which it induces neuronal differentiation. Here, we found that Bcl-2 was strongly downregulated in CHP134 and NB-39-nu cells, whereas it was abundantly expressed in LA-N-5 and RTBM1 cells. ATRA-mediated apoptosis in CHP134 and NB-39-nu cells was associated with a significant activation of caspase-9 and caspase-3 as well as cytoplasmic release of cytochrome c from mitochondria in a p53-independent manner. Enforced expression of Bcl-2 significantly inhibited ATRA-mediated apoptosis in CHP134 cells. In addition, treatment of RTBM1 cells with a Bcl-2 inhibitor, HA14-1, enhanced apoptotic response induced by ATRA. Of note, two out of 10 sporadic neuroblastomas expressed bcl-2 at undetectable levels and underwent cell death in response to ATRA in primary cultures. Thus, our present results suggest that overexpression of Bcl-2 is one of the key mechanisms to give neuroblastoma cells the resistance against ATRA-mediated apoptosis. This may provide a new therapeutic strategy against the ATRA-resistant and aggressive neuroblastomas by combining treatment with ATRA and a Bcl-2 inhibitor.

Hepatitis C virus (HCV) infection as a risk factor for spontaneous intracerebral hemorrhage: hospital based case-control study.

Hepatitis C Virus (HCV) infection was investigated as a risk factor for intracerebral hemorrhage (ICH) by HCV antibody screening in 462 patients with ICH and 462 control patients with cerebral infarction matched by age and sex. Laboratory examinations of hemostatic parameters and cholesterol level were also performed in patients with ICH. HCV infection was significantly more frequent in patients with ICH than controls (8.7% vs 3.5%, P< 0.01). ICH patients with HCV infection had significantly higher L-alanine:2-oxoglutarate aminotransferase level (P< 0.001), lower cholesterol level (P< 0.05), lower platelet count (P< 0.05), and longer prothrombin time (P< 0.01) than ICH patients without HCV infection, although most of these values were within the normal range. These results demonstrate that HCV infection is a risk factor for spontaneous ICH. Subclinical clotting disorder and/or vessel wall friability resulting from hypocholesteremia may be associated with ICH in patients with HCV infection.

[A case of acute subdural hematoma in the posterior fossa with idiopathic thrombocytopenic purpura].

Intracranial bleeding is one of fatal complications in idiopathic thrombocytopenic purpura although its reported incidence is low. A case of spontaneous acute subdural hematoma complicated with idiopathic thrombocytopenic purpura was reported. He was hospitalized complaining of sudden onset of headache and nasal bleeding without neurological deficit. CT scan revealed subdural hematoma in the posterior fossa especially below the tentorium cerebelli. Further hematological examination proved very low platelet count (1,000/mm3) and antiplatelet antibody in confirmation of a diagnosis of idiopathic thrombocytopenic purpura. As his neurological status was good, he was treated medically. His symptoms and platelet count improved gradually with corticosteroid therapy. Reviewing the literature, acute subdural hematoma with idiopathic thrombocytopenic purpura was quite rare and only three cases reported.

[Aneurysms of the distal posterior inferior cerebellar artery; the report of 10 cases].

Non mycotic and non traumatic distal posterior inferior cerebellar artery (PICA) aneurysms are rare, but eleven aneurysms in ten cases were reported. They all originated from subarachnoid hemorrhage due to rupture of these aneurysms. The patients in these cases were all admitted within 5 days after the onset. The neurological state of four cases on admission was grade 4 or 5 in Hunt and Kosnik's grading system. Two patients of grade 5 died within 24 hours after the onset. The CT scan on admission revealed heavy subarachnoid hemorrhage mainly in the posterior fossa. In severe cases, ventricle hematoma, cerebellar hematoma and/or subdural hematoma were evident in the posterior fossa. The locations of these eleven aneurysms were as follows: On the bifurcation of the Telovelotonsillar segment in six cases. In the cortical segment in three cases. In the anterior medullary and tonsillomedullary segment in one case. Six saccular aneurysms were situated on bifurcations of parent arteries but three saccular aneurysms did not arise from bifurcations. Two of them were not from turning points of the arteries. One fusiform aneurysm situated on the bifurcation of telovelotonsillar segment was excised, and histologically shown to be a dissecting aneurysm with hypoplasia of elastic lamina and tunica media in the parent artery. Three cases were associated with small AVM located on the superior surface of the cerebellar vermis and fed mainly by the superior cerebellar artery (SCA) in two cases, and by SCA and PICA in one case. In these cases the hemodynamic stress on PICA did not seem to increase so remarkably.(ABSTRACT TRUNCATED AT 250 WORDS)

[Dissecting aneurysm of distal posterior inferior cerebellar artery--case report and review of the literature].

A rare case of dissecting aneurysm of distal posterior inferior cerebellar artery (PICA) is reported. A 51-year-old woman was admitted to our hospital complaining of severe headache and nausea. CT scan revealed subarachnoid hemorrhage which was thicker in the posterior fossa. The vertebral angiography demonstrated an aneurysm on the telovelotonsillar segment (Lister's classification) of the left PICA. On the third day, the left suboccipital craniotomy was performed and the fusiform aneurysm was resected. The postoperative course was uneventful. Histological examination of the resected aneurysm showed a dissection between the ruptured elastic lamina and the tunica media. Dissecting aneurysm of distal PICA is still belong to a rare entity. In all three cases found in the literature, the dissecting aneurysms are sited in the anterior medullary segment of PICA. Probably, this is the first report described a dissecting aneurysm on the more distal part-telovelotonsillar segment of PICA. The clinical features, pathogenesis and treatment of intracranial dissecting aneurysms are briefly discussed with reviewing the literature.

Paroxysmal speech disorder following left frontal brain damage.

The patient was a 61-year-old female who suffered from the sudden attack of a speech disorder. The episodes of speech disorder lasted for less than 1 min, but occurred several times a day, paroxysmally. A CT revealed a low density area on the surface of the left frontal lobe and an EEG showed an abnormal wave at the frontoparietal area, more dominantly on the left. This condition was diagnosed as a kind of epilepsy. The paroxysmal speech disorder occurred very often during the 2 months after the first episode. However, with therapy using anticonvulsives and antibiotics, the condition began to improve after 4 months and disappeared completely after 6 months. It is assumed that the inflammatory change which occurred at the frontal lobe stimulated the supplementary motor area paroxysmally, and subsequently the speech disorder occurred as a kind of epilepsy.

[Superior petrosal sinus dural arteriovenous malformation with varix indenting brain stem--report of a case and review of the literature].

A rare case of the dural AVM mainly around the left petrosal sinus was reported. A 64 years old man was admitted just after the sudden onset of severe headache and nausea. The CT scan revealed subarachnoid hemorrhage in the left ambient cisterns. A small hematoma was also found in the left cerebellar peduncle. External carotid angiogram showed a dural AVM which nidus was located adjacent to the left superior petrosal sinus. Its feeding arteries were as follows; the middle meningeal artery, the artery of foramen rotundum, the accessory meningeal artery, the dural branch of occipital artery and the ascending pharyngeal artery. The voluminous petrosal vein and the dilated cortical veins were identified as drainers and, the portion of the latter appeared as "varix" embedded in the pons, which was clearly delineated by MRI. In the venous phase, stenotic straight sinus and residual Falcine sinus were illustrated. Superselective embolization of the feeding arteries was employed followed by the direct clippings of draining vein. Postoperative course was uneventful. The present case should be classified into the tentorial dural AVM. Only 26 cases of this rarely encountered entity was reported in the literature. Based on both the present and the previously reported cases, the clinical features, treatment and pathogenesis of this disease were briefly discussed.

[Encapsulated chronic intracerebral hematoma caused by venous angioma of the basal ganglia: a case report].

A case is reported of venous angioma at the right basal ganglia simulating the encapsulated chronic intracerebral hematoma. A 29-year-old man was admitted to our hospital on July 14, 1988 with a two-month history of headache. Neurological examination revealed left homonymous lower quadrantic anopsia. CT scans showed a mosaic high density lesion at the right basal ganglia with extensive adjacent edema. MRI revealed that the high density lesion on CT scans was the combination of a reticulated core of mixed signal intensity with a surrounding rim of decreased signal intensity. The lesion was accompanied with extensive edema. Followed up CT scans showed the transformation of the lesion and ring-shaped enhancement. A right frontotemporal craniotomy was performed on August 9, 1988. After thorough dissection of the sylvian fissure and small corticotomy to the insula, a tough capsule was seen. There was blood in various stages of organization in the capsule. A histological examination gave a diagnosis of venous angioma in the membrane similar to the outer membrane of chronic subdural hematomas. Postoperatively, the patient showed slight left motor weakness, but it gradually improved and he was discharged on foot, on October 19, 1988. There have been a lot of reports about angiographically occult intracranial vascular malformation (AOIVM). But AOIVM at the basal ganglia is rare, and to our knowledge, only 8 cases have been reported. In our case, the presence of adjacent extensive edema, and ring-shaped enhancement on CT scans confused the preoperative diagnosis. Those findings might have been caused by encapsulation. By using CT scans and MRI, a complete and accurate diagnosis was impossible.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnetic detection of sleep spindles in normal subjects.

The magnetoencephalogram (MEG) and electroencephalogram (EEG) were recorded simultaneously from 3 normal subjects during light sleep. The extracranial magnetic field patterns associated with the ionic currents within the brain (MEG) were measured using a SQUID magnetometer in a magnetically shielded room. Although a previous report indicated that there are few sleep spindles in MEG records, we observed many in all 3 subjects. We believe this is because measurements were made vertically at the vertex region.

[Clinical analysis of etiology of spontaneous subarachnoid hemorrhage diagnosed by computed tomography].

In 575 cases with subarachnoid hemorrhage (SAH) diagnosed by computed tomography (CT) scan, four vessel cerebral angiography was performed several times at more than two-week intervals to investigate a source of the hemorrhage. The first four-vessel study on admission revealed 530 cases (92.2%) of ruptured cerebral aneurysms, four (0.7%) of ruptured arteriovenous malformation, 25 (4.3%) of unknown etiology. Repeated four vessel study showed eight (32.0%) aneurysms among 25 cases whose first studies were negative. Six of the eight cases had aneurysms in the vertebro-basilar system. In 11 cases, repeated four-vessel study failed to detect the hemorrhagic source; and no generalized diseases were noted. One of them had recurrence of SAH 19 months after the onset of the initial one. The patient was underwent operation, which showed thrombosed ruptured aneurysm. Our present investigation demonstrated that ruptured aneurysm was responsible for 94.8% of all 575 cases of SAH detected by CT scans and 10 cases (1.7%) were diagnosed as cases of SAH of unknown etiology.

Stereotactic aspiration of thalamic hematoma. Overall results of 75 aspirated and 70 nonaspirated cases.

Among 145 cases of spontaneous thalamic hemorrhage, stereotactic aspiration of the hematoma was done in 75 cases in which the hematoma was greater than 6 ml and the limbs on the affected side could not be elevated. Thirty-one of 40 operated cases with a long axis greater than 3.3 cm were capable of returning to useful activity 6 months postoperatively (excellent to fair). The results 6 months from onset in the 145 cases were as follows: 43% excellent or good, 32% fair, 11% poor and 13% dead. These results appear to indicate that stereotactic aspiration can produce improvements in therapeutic results for cases of thalamic hemorrhage.

Results of stereotactic aspiration in 175 cases of putaminal hemorrhage.

Believing that improved therapeutic results in cases of intracerebral hematoma might be obtained by minimal invasion of the brain, we used computed tomographic-guided stereotactic aspiration in 175 of 241 patients with putaminal hemorrhage. These patients, who were treated 6 or more hours after onset, had hematomas larger than 8 ml and were unable to raise an arm and/or leg on the affected side. Craniotomy was performed in 15 other patients, most of whom were brought to the hospital with large hematomas within 6 hours of onset. The remaining patients either had mild deficits of consciousness (33 patients) or severe deficits and/or were elderly (18 patients) and were treated conservatively. Thirteen patients (7.4%) showed rebleeding after stereotactic aspiration (6 instances of major and 7 instances of minor rebleeding). Craniotomy and removal of the hematoma were required in three of these patients. Aspiration should be avoided in patients who have a tendency for bleeding, even if mild, because rebleeding occurred in 6 of 23 such patients (26%) in these study. The consciousness level improved in 66 patients (38%), was unchanged in 103 patients (59%), and was worse in 6 patients (3%) 1 week postoperatively. Motor function of the arm improved in 55 patients (31%) and was worse in 23 patients (14%). Six months after surgery, the results for the 175 patients who underwent stereotactic aspiration were: 19% excellent, 32% good, 35% fair, 7% poor, 6% dead, and 1% unknown. For the entire series of 241 patients, the results were: 24% excellent, 26% good, 31% fair, 7% poor, 11% dead, and 1% unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental retrograde adriamycin trigeminal sensory ganglionectomy.

Direct destruction of the sensory ganglion or its root, by either surgical transection or injection of phenol, has been employed as preferred treatment for a variety of neuralgic pain syndromes. In this report, the suicide axoplasmic transport of adriamycin is described as a novel approach to sensory ganglionectomy. When injected into a branch of the trigeminal nerve in the cat, adriamycin was swiftly transported by way of retrograde axoplasmic flow to the sensory neurons parental to the injected nerve, where adriamycin-specific autofluorescence was observed. Trigeminal sensory evoked potentials became unobtainable 24 to 48 hours after injection of adriamycin in concentrations of 1% to 10%. The sensory neurons underwent subacute degeneration within a week due to the delayed action of adriamycin, and consequently the primary afferents degenerated in a restricted projection field of the brain-stem trigeminal sensory nuclei. These results indicate that retrograde axoplasmic transport of adriamycin is a unique approach to noninvasive sensory ganglionectomy with strict, albeit simple, safe targeting of sensory neurons and little likelihood of regeneration.

Influence of liver dysfunction on volume of putaminal hemorrhage.

We studied the relations of age, sex, hypertension, alcohol consumption, liver dysfunction, and thrombocyte count to the volume of the hematoma in 141 patients with spontaneous putaminal hemorrhage. Hematomas were significantly larger in men, regular alcohol consumers, those with liver dysfunction, and those with low platelet counts. Our findings reflect the fact that almost all of the alcohol consumers were men, most of them had liver disorders, and the volume of hematoma in such patients was relatively large.

Spontaneous intracerebral hemorrhage and liver dysfunction.

We evaluated liver function and coagulation parameters in 117 patients with spontaneous intracerebral hemorrhage (68 men and 49 women) admitted to our clinic within 24 hours after onset. Liver dysfunction was more common among men than women due to differences in alcohol consumption. Number of thrombocytes and fibrinogen concentrations were lower, especially among men with elevated concentrations of glutamic oxaloacetic transaminase or glutamic pyruvic transaminase and/or elevated gamma-globulin fraction. Five of the 78 patients undergoing stereotactic hematoma aspiration and one of the 39 treated nonsurgically rebled. All six of the patients who rebled were men, heavy alcohol consumers with liver dysfunction. Fibrinogen concentration was abnormally low in four of the six and at the lower end of the normal range in one. Two showed thrombocytopenia and one case showed prolonged prothrombin time. These facts suggest that liver disorders produce a state in which hemorrhage occurs more readily and that this hemorrhagic tendency may be one of the causal factors of spontaneous intracerebral hemorrhage.

Intracerebral hemorrhage from a metastatic brain tumor. Importance of differential diagnosis preceding stereotaxic hematoma aspiration.

Three cases of sudden intracerebral hemorrhage, which were diagnosed as hemorrhage from metastatic brain tumors following stereotaxic aspiration of a hematoma, are reported. Two cases had subcortical hemorrhage and one had cerebellar hemorrhage. Neither contrast-enhanced computed tomography scans nor angiograms revealed any findings other than those indicating the hematoma in all three cases. However, retrospective study of the anamnesis showed very mild symptoms due to metastasis to the brain or spinal cord in one case each. In cases of intracerebral hematoma located at atypical sites, extreme care is required for the differential diagnosis.

Stereotactic aspiration of putaminal hemorrhage using a double track aspiration technique.

Double track aspiration was used to remove the hematoma between 6 and 24 hours from onset in nine cases of putaminal hemorrhage. This technique was used in cases where an approach along the long axis of the hematoma was not feasible. With this method, aspiration is done at two target points lying anterior and posterior of the somewhat harder central region, at which aspiration is not attempted. This technique allows aspiration of most of the serum components, which are depicted as low density areas in computed tomographic (CT) scans, and some 53 to 85% of the main mass of the hematoma, which is seen on CT as high density areas. There was no rebleeding among these nine patients, and the remaining hematoma in all cases was located between two target points--a fact that is thought to indicate that the central portion of the hematoma is in fact somewhat harder than the peripheral portions. Although the double track aspiration technique has the disadvantage of producing two tracks, it is thought to be an effective method in such cases because it allows safe and thorough hematoma aspiration.

[CT-guided stereotaxic implantation of the Ommaya reservoir for cystic brain tumors].

We report the use of CT-guided stereotaxic system to implant Ommaya reservoir in 26 patients with cystic brain tumors consisting of 16 gliomas, 3 craniopharyngiomas, 3 metastatic brain tumors and 5 other and unknown pathologies, on the way of their biopsy. The entire procedure was carried out in the CT room using Leksell's CT stereotaxic system. In 24 cases with supratentorial tumors, it was at the option of the operator to take any approach such as frontal, posterior temporal and parietal approaches. Especially in 3 cases of craniopharyngioma, we inserted the tube into their cyst directly so that the ventricle should not be open to the cyst. Also in cases of a pontine glioma and a C-P angle metastatic tumor, we used retromastoid approach to the posterior fossa by making patient's heads turned about 30 to 40 degrees to contralateral side of the approach, with slight flexion of the neck. Minimal bleeding occurred during operation in one case, however, it showed no clinical symptoms. Advantages of this method are as follows: Operative invasion is minimal; The surgeon can check the course of the cannula and position of the tip of Ommaya tube even at operation, and can modify it, if necessary.

[CT-guided stereotaxic biopsy in 104 cases of brain tumor].

Biopsy of suspected brain tumor was performed on 104 cases using Leksell's CT-guided stereotaxic system. The entire operation was performed in the CT room. A Backlund's spiral biopsy needle was advanced to the target point in a stepwise fashion and two to nine tissue samples were obtained from one to three biopsy tracks. Tissue sampling was impossible in two cases because the tumors were too hard for biopsy needle to advance. Also, sampling was sometimes difficult in the case of soft and necrotic tumor, cystic tumor, already treated (irradiated) tumor and the lesion including old blood clot. After the biopsy, minimal bleeding occurred in nine cases, however, stopped within 10 minutes by controlling the blood pressure. A minimum sized hematoma was visible on the postoperative CT in four cases. Postoperative neurological deterioration was seen in two cases. One case was transient and the other seemed to be in his natural course. Anyway, there were neither cases of operative mortality nor severely complicated cases in these series. Useful pathological diagnosis was possible in 83 cases (80%). Accurate diagnosis was not possible in the remaining 21 cases, however, their histological datum such as necrosis, blood clot, and so on were very useful to estimate the lesions. In summary, accurate diagnosis rate of CT-guided stereotaxic needle biopsy was 80%. However, it appeared to be a safe and useful procedure in the diagnosis of intracranial mass lesions.

The development and morphogenesis of the human pituitary gland.

In order to clarify the environmental factors which are involved in the development of the primordium of the pituitary gland such as cell-cell interactions, a three-dimensional reconstruction of this organ and its surrounding tissues was carried out. Pituitary material was obtained from human fetuses mainly during the period of organogenesis. Rathke's diverticulum was found to stretch rostrally from the stomodeal epithelium to the middle of the mesoderm, and already by the 5th week of fetal growth, it was clearly seen to be involved with the diencephalon. The area of contact between Rathke's pouch and the diencephalon gradually moved from the rostral to caudal regions and, after 13 weeks of development, had a position similar to that found in the newborn infant. Among the cells forming Rathke's pouch, it was found that the closer their relationship was to the diencephalon, the greater were their epithelial characteristics. When the relationship of such cells to the diencephalon was weaker, their differentiation to endocrine cells occurred earlier. Immunohistochemically, that portion of the pituitary primordium which has a close relationship with the diencephalon, later to become the pars intermedia, showed an adrenocorticotropic hormone (ACTH) immunoreactivity later than that of the pars anterior. On the other hand, in the 21st fetal week, nearly all of the cells of the pars intermedia were found to be ACTH-positive. This finding is thought to indicate a close connection between the physical contact between the brain (diencephalon) and the pituitary primordium and the development of the pars intermedia; the differentiation of ACTH cells. The surface of the epithelium of Rathke's cavity continues to increase at least until the 21st fetal week, so the growth of the epithelium of Rathke's pouch is thought to be heavily involved in the growth of the primordium of the pituitary gland in the early stages of development.