Intracellular neutral and acid protease activities in normal brain and brain tumors were measured. As compared with normal brain tissue, the malignant glioma tissue showed 2-to 8-fold increase in specific activity of Ca2+-dependent neutral protease. We partially purified this protease from rat brain and found that it required Ca2+ absolutely and cysteine obligatorily for its activity. It converted an inactive pre-protein kinase M in the brain to an active protein kinase M. On the other hand, S-100 protein, a brain-specific acidic protein, inhibited this protease activity. These results suggest that the Ca2+dependent neutral protease, S-100 protein and protein kinase M may have a close relationship with one another. The Ca2+-dependent neutral protease was inhibited by leupeptin, an actinomycete protease inhibitor. Leupeptin was then found to inhibit very strongly the cell growth of G203 glioma in vitro, suggesting that leupeptin could be used for therapeutic purposes.
Correlation between changes in epidural pressure, respiration and other related phenomena were studied in 7 patients with brain tumor by post-operative monitorings. Mutual changes in intracranial pressure (ICP) and respiratory pattern during rapid ICP variations were the main focus of our study. Occurrence of rapid ICP variations of A and B-waves was closely related to changes in respiratory pattern. In large plateau-like waves, suppression in respiration usually initiated the pressure rise, while hyperpnea or tachypnea accounted for the pressure decrease. Analysis on B-type pressure oscillation disclosed a clear phase relation that ICP rises during hypopneic phase of periodic respiration and its reduction coincides with the onset of hyperpnea. Noticeably such pressure variations as well as respiratory oscillations appeared dominant during sleep. Thus it is indicated that, under pathologic conditions, occurrence of oscillating respiration is provoked by depression in wakefulness of patients, presumably accompanying changes in the function of respiratory centers, and affects the changes in ICP.
CT findings in 59 cases of acute severe head trauma are presented. CT enabled an accurate differentiation between epidural and subdural hematomas in 100% of the cases. Not a small proportion of subdural hematoma cases was of the fulminant type which had a fatal outcome in one to 2 days after injury, in spite of intensive treatment. In some cases traumatic intracerebral hematomas were not formed within 6 hours after injury and were demonstrated by CT more than 12 hours after causative trauma. Cerebral contusion showed four types of CT findings, low density, high density, and isodensity with or without mass sign. Whereas many of the cases showing an area of high density on CT had poor outcomes, those with other types of CT findings had favorable prognosis. Traumatic intracerebral hematoma should not be dealt with as an independent entity distinct from cerebral contusion but should be regarded as a variety of the latter. Accordingly, these two conditions were designated together as traumatic intracerebral lesion (TIL).
Cranioplasty with homologous grafts was experimentally studied in the dog. Fresh and frozen-irradiated homologous bone flaps about 23 mm in diameter were comparatively studied. Each graft was examined at 3, 6, and 12 months after surgery. The irradiated grafts were penetrated by regenerating blood vessels and new bone matrix was formed around the revascularized Haversian canals; cellular infiltration and fibrotic changes were minimal in this group. Fresh grafts were only poorly vascularized and gave rise to massive fibrotic proliferations which finally lead to sequestration of the implants in some of the cases.
The authors report a unique case of infected cranioplasty with perforated air bubble cavities in the acrylic plate, which were acting as sites for recurrent and persistent infection. Computerized tomography was the most useful diagnostic measure to detect the subclinical fluctuating process of chronic epidural empyema.
Metastatic dural carcinomatosis secondary to gastric cancer is a rare complication. A case was experienced which demonstrated diffuse carcinomatous infiltration in the subdural membrane and in the scalp. The characteristic metastatic involvement of this membrane was of special interest in this case. There were numerous foci of carcinomatous infiltration within the lumen of markedly distended veins in the subdural membrane and there was marked proliferation of fibroblasts and capillaries around the carcinomatous infiltration.
To establish a definitive therapy for cerebral vasospasm, a basic study on the contractile mechanism of vascular smooth muscles of the cerebral artery was performed. Ultrastructural examination of smooth muscle cells in bovine basilar arteries revealed the existence of two types of myofilaments which correspond to thick and thin filaments. Also, the existence of an internal membrane system just inside of the surface membrane was confirmed. Experiments on the mechanical activity of basilar arterial strips showed that a K+ induced contraction was associated with a large increase of Ca2+ influx from outside of the muscle cell. On the other hand, 5HT induced tension without Ca2+ influx. A Ca antagonist (cinnarizine or verapamil) inhibited high K+ induced contractions, whereas its inhibitory effect on 5HT induced contraction was small. These facts suggest that 5HT can release Ca from intracellular store sites. The results shown here indicate that there are several kinds of bound Ca in the muscle cell, i.e.: 1) loosely; and 2) tightly bound Ca on the external surface of the cell membrane; 3) Ca bound in the internal surface of the cell membrane; and 4) Ca stored in the intracellular store sites, such as sarcoplasmic reticulum or mitochondria. It is suggested that such intracellularly immobilized Ca may play an important role in the regulation of mechanical activity of cerebral arterial muscle.
In our recent study, biochemical analysis of spasmegenic substances released from blood or a blood-CSF mixture has been performed. These vasoactive substances were applied in both in vitro and in vivo experiments and it was found that oxyhemoglobin or its allied polypeptide, produced in the process of clot lysis or during the breakdown of blood corpuscles, was the main causative substance for prolonged vasospasm. In this study, morphological examination using the fluorescent antibody and the ferritin antibody methods were undertaken to gain a better understanding of the mechanism of spasmogenic reaction of hemoglobin on cerebral vessels. Hemoglobin was found to be distributed in the adventitia and in the smooth muscle layer of the media. Haptoglobin, which is a normal constituent of serum, is known to bind with hemoglobin to form a chemically stable hemoglobin-haptaglobin compound. Vasospasm was released by the application of haptoglobin both in vitro and in vivo. Based on these experimental results, clinical use of haptoglobin was made in 27 patients with vasospasm. In 17 cases, angiographical spasm was progressively increased or decreased on the the day prior to surgery. Fourteen of the 17 cases showed angiographical improvement of vasospasm after use of haptoglobin. We also discuss the development of postoperative vasospasm due to the operation itself.
To investigate the spasmogenicity of hemoglobins, we have analyzed the amount of total hemoglobin, oxyhemoglobin and methemoglobin in bloody or xanthochromic cerebrospinal fluid (CSF) and in intracranial hematoma. Morphological changes of the endothelial surface of spastic arteries and their vasorelaxative responses to papaverine were also studied using rat basilar artery. Total hemoglobin was determined in 85 CSF samples obtained from patients with ruptured aneurysm. Vasospasm was seen most frequently in patients with bloody or xanthochromic CSF. However, it was also true in many cases that bloody or xanthochromic CSF was not accompanied by vasospasm. No significant correlation could be observed between vasospasm and the amount of hemoglobin. In analysis of 90 CSF samples, vasospasm was seen in 39% of those containing oxyhemoglobin and in 64% of those containing both oxyhemoglobin and methemoglobin. The relatively high frequency of vasospasm in the presence of methemoglobin in the CSF is likely attributable to the large amount of hemoglobin or blood clots in the subarachnoid space. In comparative studies of hemoglobin and barium chloride, vasorelaxative response to papaverine was found to be highly correlated to the severity and duration of vasospasm. Scanning electron microscopic studies demonstrated that endothelial cells were damaged after vasospasm induced by both hemoglobin and barium chloride. Endothelial alterations were observed initially as an increase of craters, blebs, and microvilli and poorly defined marginal folds, followed by separation of cell junctions and by detachment of endothelial cells. Adherence and aggregation of platelets were located at the denuded regions of the endothelium. These observations suggest that the organic changes of the arterial wall might be implicated in the pathogensis and pathophysiology of vasospasm.
Delayed cerebral vasospasm was studied in exposed basilar arteries 3 days after cisternal injection of blood in cats. Substances containing heme components such as oxyhemoglobin, methemoglobin, catalase, NADH and methemalbumin, induced profound vasospasm when applied topically. All products released from erythrocytes with heme components may be responsible for delayed cerebral vasospasm. Vasospasm produced by incubated blood-CSF mixture was relieved by topical application of fusaric acid, methylprednisolone, salbutamol, o-phenanthroline or ascorbic acid. Levels of cyclic AMP in cerebral vessels were slightly increased after cisternal injection of ascorbic acid (100 mg), as well as aminophylline (25 mg). Patients with vasospasm following subarachnoid hemorrhage were treated with intrathecal administration of ascorbic acid (200-1, 000 mg). Of 5 treatment trials, there were 2 definite beneficial responses. Certain improvements were obtained in patients who were treated with ascorbic acid within 16 hours after the onset of symptoms.
The luminal surface of the cerebral arteries was examined by scanning electron microscopy. Preliminary findings of the cases which succumbed to the aneurysmal rupture are reported with those obtained by light microscopic examinations of old autopsy specimens of the ruptured aneurysm. On SEM, the endothelial cells were lost on the luminal surface of the cerebral arteries and some were covered with fibrin meshwork confining red blood cells and other corpuscles. These findings were interpreted as endothelial injury with denudation of elastica and resulting mural thrombus formation. Light microscopic examination revealed that cerebral arteries which had had narrowing after SAH showed concentrically thickened intimal layer and the presence of rich vascularization partly in the subintimal layer. These histological pictures were interpreted as organized mural thrombus. Possible role which mural thrombosis plays in the pathogenesis of prolonged narrowing after SAH from the rupture of an aneurysm and its clinical significance, especially in connection with antifibrinolytic treatment, is discussed.
Serial angiograms, CT scans and clinical courses of 40 patients with vasospasm are analyzed. Angiographic vasospasm has a tendency to develop on arteries adjacent to ruptured aneurysms. The configuration of spasm changes from smooth narrowing into irregular narrowing. The former is observed after the 5th day and the latter after the 9th day of the rupture. Resolution of spasm follows irregular narrowing. Angiographic vasospasm, neurological symptoms, and low density areas on CT scan develops at intervals of 2 to 3 days. Optimal timing for direct aneurysmal surgery is discussed in relation to the time course of vasospasm.
The authors have analyzed the clinical characteristics of vasospasm following subarachnoid hemorrhage (SAH) secondary to rupture of cerebral aneurysms in 110 cases that demonstrated vasospasm during their hospital stay. It was concluded that subarachnoid clot surrounding cerebral arteries is the most important factor for initiating vasospasm.