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A case of leiomyosarcoma of the spermatic cord, occurring in a 79-year-old male patient, is reported. The tumor was resected with high inguinal ligation and orchiectomy. It was located at the scrotal part of the spermatic cord on the left side and was shown to have originated from the spermatic duct using the dissecting method. Histologically, it was identical to leiomyosarcoma showing a typical morphological appearance of smooth muscle cell tumor in the conventional histochemical preparations as well as a focal positive reaction to antidesmin antibody, a marked nuclear pleomorphism, and abundant mitotic figures. The patient had been untroubled for six months after the resection of the tumor. Leiomyosarcoma arising in spermatic cord is quite rare.

Using a computed image analyser, coronary arteries from 50 autopsied patients with systemic lupus erythematosus (SLE) were examined on the three vessels (RCA, LAD, LCX) and compared with those of age-matched controls. The intima of coronary artery was significantly thickened much more in the case of SLE than in the case of age-matched controls. This was statistically significant (p less than 0.01). Hypertension and glomerulonephritis did not but corticosteroid therapy had an influence on the development of intimal thickening ratio of the coronary arteries in SLE patients. The mean intimal thickening ratio of the coronary arteries in the patients with SLE and without corticosteroid therapy was larger than that of patients with corticosteroid therapy (p less than 0.1). It appears possible to conclude that inflammatory change of SLE itself is one of the promoting factors of coronary atherosclerosis.

One hundred and ninety-one patients with disseminated intravascular coagulation syndrome (DIC) or its prodromal stage (preDIC) were treated with only gabaxate mesilate (FOY) (group G) or a combination of gabaxate and unfractionated heparin (group GH), and the efficacy of gabaxate was evaluated in a multicenter study. Following the treatment, the mean DIC score, which was evaluated on the basis of clinical symptoms and hemostatic parameters, decreased significantly to 5.58 +/- 3.48 from 6.75 +/- 3.14 in group G (p0.001) and to 6.34 +/- 3.33 from 7.31 +/- 3.00 in group GH (p0.05). In patients with overt DIC, the mean score decreased to 6.71 +/- 3.54 from 8.42 +/- 2.84 (p0.001). In DIC, the rate of overall efficacy was 46.2% in group G and 35.1% in group GH. In preDIC, it was 41.5% in group G and 27.3% in group GH. No side effects, including severe bleeding, were found in this study. The results indicate that gabaxate mesilate is clinically effective for patients with DIC and preDIC.

A 56-year-old Japanese man without asthma was admitted with cough, excessive sputum, and abnormalities on the chest X-ray film. The lung biopsy material showed necrotizing granulomas centered upon bronchioles. Serial sections of the material revealed a mass of well-oriented, uniform, viable-appearing aspergillus hyphae in the center of the granulomas. There was no evidence of blood eosinophilia, tissue infiltration of eosinophils, or deposition of immunoglobulins or complement in the granulomatous lesion. Thus, we obtained no direct evidence of an allergic reaction. After treatment with the antifungal drug, 5-flucytosine, the patient is in good health. This may be the first documentation of pulmonary aspergillosis showing predominantly bronchocentric granulomas in a nonasthmatic patient who was not immunocompromised.

A 32-year-old Japanese man with chronic granulocytic leukemia died of respiratory failure. Autopsy revealed alveolar proteinosis and pulmonary fibrosis, complicated by disseminated atypical mycobacteriosis. Epithelial hyperplasia caused by busulfan therapy was probably responsible for the induction of excessive surfactant production, resulting in alveolar proteinosis, and the immunosuppressive state due to chronic granulocytic leukemia was probably related to the induction of disseminated atypical mycobacteriosis.

This paper reports the results of the second nation-wide cooperative study of atherosclerosis in young Japanese, aged from 1 month to 39 years, who were autopsied between 1991 and 1995. Atherosclerotic lesions in 1066 aortas and 974 coronary arteries were classified into fatty streaks, fibrous plaques and complicated lesions and quantificated with the point-counting method. The results of this study were compared with those of the former study, which was conducted 13 years earlier in almost the same fashion as this study. Atherosclerosis of aorta, which was determined by surface involvement (SI) of atherosclerotic lesions and atherosclerotic index (AI), increased with age in both sexes of the former and the present studies and their tendency for the progression of the extent of atherosclerotic lesions appeared to be similar. In the coronary arteries, the mean values of SI and AI in the males of the present study were greater significantly than those in the male of the former studies and in the female of the both studies in the third and fourth decades. This difference suggests that atherosclerotic lesions are increasing in young Japanese males. It also suggests that these subjects may be increasingly susceptible to atherosclerotic cardiovascular disease with increasing age.

Intimal thickening in the aorta and carotid artery of rats was induced by repeated intraperitoneal injections of ovalbumin, 2.5 mg/kg BW, given weekly 5 times after initial subcutaneous sensitization, and/or feeding with a cholesterol-rich diet. The intimal thickening was apparent in immune-challenged rats fed with either a cholesterol-rich or a basal diet (p less than 0.01), whereas it was mild in non-immunized rats fed a cholesterol-rich diet. The ultrastructural changes in the thickened intima were characterized by leukocytic (mainly monocytic) adhesion and migration, and minor endothelial cell damage. Morphometric evaluation of leukocyte adhesion to the intima of the thoracic aorta revealed that the immunized rats fed either a cholesterol-rich or a basal diet showed greater leukocytic adhesion (p less than 0.01 and p less than 0.001, respectively) than that in non-immunized rats fed a cholesterol-rich diet, which in turn also showed an increased degree of leukocyte adhesion (p less than 0.05) than control rats. This immunological approach to the arteriosclerotic process could explain the earlier and more severe arteriosclerosis found in patients with immunological disorders, and the development of arteriosclerosis in the absence of hypercholesterolemia, hypertension and other risk factors.

One hundred eleven autopsy cases of dissecting aneurysm were collected from western Japan. The ratio of males to females was 3:2 and the sixth and seventh decades of life were most frequently affected. All 11 cases of Marfan's syndrome were in patients under 40 years of age. DeBakey's type III dissections showed a male predilection and more severe atherosclerosis than in control cases. Many patients with types I and II dissections died of hemorrhage in the acute phase, while many patients with type III dissection died in the subacute or chronic phase, and half of the patients died of diseases other than hemorrhage. Hypertension was recognized in 73.7% of the 95 cases which showed no other obvious risk factors. Histologic examinations suggested that cystic medial necrosis was related to the pathogenesis of the disease in Marfan's syndrome, but was not so apparent in non-Marfan's syndrome. Laminar medial necrosis was found in many cases, but was considered to be a secondary ischemic change following dissection, as supported by other investigators. There were only a few cases in which dissection seemed to be directly caused by atherosclerosis.

1) The incidence of myocardial infarction, as well as thrombosis, has been increasing recently in the consecutive autopsy cases over 40 years old in Kyushu University, but is still less frequent than those in the autopsy cases in Boston around 1960. Increased fat intake might play a significant role in the increasing frequency of myocardial infarction in Japanese. 2) In a nationwide cooperative study of atherosclerosis in young Japanese, atherosclerotic changes were observed to begin developing in childhood. Primary prevention of atherosclerosis should be initiated in the pediatric age group. We should pay more attention to subclinical atherosclerosis. Age, serum cholesterol, and blood pressure were significantly and positively correlated with SI and AI of aortas and coronary arteries. Serum cholesterol was more strongly correlated with the extent of fatty streaks than was mean blood pressure and vice versa with that of fibrous plaques. Atherosclerosis of cerebral arteries, however, showed a significant correlation only with the factor of mean blood pressure. Therefore the susceptibility to risk factors varies with the artery in the case of early lesions of atherosclerosis in young people. More attention should be paid to the fact that atherosclerosis is a multifactoral disease. 3) Deposition of fibrinogen in the intima might precede LDL deposition and possibly play a more important role than LDL in the development of atherosclerotic lesions in the cerebral arteries, especially in their early stage. 4) The proliferation of smooth muscle cells is stimulated by fibrin and later inhibited by FDP, as produced by fibrinolytic activity of smooth muscle cells. The metabolism of fibrin in the arterial wall may be of importance in the regulation of smooth muscle cell proliferation, and the coagulation-fibrinolysis system may play a significant role in atherosclerosis with the effect of other risk factors such as cholesterol and hypertension.

A clinicopathological study of coronary atherosclerosis was performed on adult autopsied cases of a Japanese community (about 7000 population) with autopsy rate of approximately 82%. Grading of atherosclerosis of the coronary artery was made by the degree of luminal stenosis. Atherosclerosis was found in the left anterior descending branch, in the right coronary artery, and in the left circumflex branch in decreasing order of severity. This trend was significant for females and also when both sexes were combined. The frequency of cases, where at least one of the three major coronary branches had luminal stenosis of 50% or more, increased significantly with age in both sexes, and was higher in males than in females in all 10 yr age groups of 40–99. Coronary atherosclerosis showed closer correlation to systolic blood pressure than to diastolic blood pressure.

Fibrinolytic activity in the inner ear of human beings and guinea pigs was assayed qualitatively and quantitatively. It was found that fibrinolytic activity of the stria vascularis was caused by a conversion of plasminogen to plasmin by tissue plasminogen activator and was moderate in degree compared with that of other organs in both species. In human beings, endolymph showed higher plasminogen activator activity than that of CSF. Plasminogen activator activity was not detected in either endolymph or perilymph of guinea pigs. Thrombin infusion diminished plasminogen activator activity in the stria vascularis of guinea pigs.

Fifty male rats were made diabetic by a single injection of streptozotocin and were killed at periods varying from 1 to 12 mo. Ten saline-injected rats and three rats treated with 3-O-methylglucose and streptozotocin served as controls. Intraluminal changes in retinal vessels were studied by electron microscopy. In diabetic rats maintained for 9–12 mo, microthrombus formation was observed in the various sized retinal vessels at the histologic and ultrastructural level. The microthrombi were mainly composed of aggregated platelets and fibrin strands. However, there was no definite evidence of detachment or loss of the endothelial cells. This microthrombus formation may play an important role in the development of diabetic retinopathy.

The significance of endothelial damage in thrombogenesis was studied by scanning and transmission electron microscopy. Intimal injury was induced by inserting polyethylene tubing into the aorta and inferior vena cava of albino rabbits. Denudation of the endothelial cells and direct exposure of the subendothelial materials, mainly of microfibrils, was apparently necessary for initiation of in vivo mural thrombosis in the aorta as well as in the inferior vena cava. The initial event of thrombus formation was platelet adhesion and subsequent aggregation on the injured surface where the endothelium was completely absent. Adhesion of platelets was not found on the disintegrated endothelial cell itself. Adhesion, aggregation and dissociation of the platelets on the injured areas appeared to took place repeatedly. Thrombus was further developed by formation of fibrin nets around the platelet aggregates and appeared to be settled as a mural one. Other cellular components of blood than platelets might play little role in the primary event of thrombogenesis. Retardation of the blood flow appeared to enhance the platelet adhesion on the injured vessel walls.

The incidence and mortality from stroke during the period 1961 to 1976, among 1,621 subjects aged 40 and over at entry, in Hisayama community, Kyushu Island, Japan, were analyzed. A major age-related decline in the incidence of cerebral infarction occurred in both sexes. The average annual incidence of cerebral infarction also fell continuously in both sexes throughout the whole observation period. The 5-year annual mortality rate from cerebral hemorrhage also showed a decrease in men, but fluctuated in women. The 5-year mortality from cerebral infarction slightly increased in both sexes.

The present report describes a rare prostatic tumor occurring in a 78-year-old Japanese male. The histological features were those of carcinosarcoma involving an adenocarcinoma and a chondrosarcoma, with metastasis to the liver. The carcinomatous component stained positively for prostatic acid phosphatase (PAP) by an immunoperoxidase technique. The literature is reviewed. ACTA PATHOL. JPN. 35 : 481–487, 1985.

When Lewis lung carcinoma cells were transplanted into the foopad of mice, exponential growth of tumour was seen from the 4th day. Intravasation of tumour cells was first seen at this time, then increased steadily up to the 10th day. Tumour cells entered the circulation by destructive degeneration of the vascular endothelium and also by transcellular passage, mainly through capillaries, venules and thin-walled tumour vascular channels. Multiple sites of entry of tumour cells into the circulation were frequently found. The rate of intravasation of tumour cells into the circulation was the same at the proximal, middle and distal portions of the tumour.

The permeability pattern of iridial blood-aqueous barrier in streptozotocin-diabetic rats, maintained for 1-6 months, was studied with the light and electron microscopes, using horseradish peroxidase as a tracer. A reaction product of horseradish peroxidase was confined to the vascular lumina and to a small number of vesicles on the luminal portion of the endothelial cells in control rats and diabetic rats maintained for 1 month. In diabetic rats maintained for 2-6 months, endothelial cells contained a large number of horseradish peroxidase-labeled vesicles which opened into the basement membrane, and intercellular junctions of the endothelial cells were filled with horseradish peroxidase. Horseradish peroxidase was consistently found in the stroma around the vessels, and seemed to reach the anterior chamber through the intercellular spaces between the fibroblasts. However, the passage of horseradish peroxidase was blocked by the posterior epithelial cells.

Three cultured cell lines of human lung cancer with varied degrees of thromboplastic and fibrinolytic activities were injected subcutaneously or intravenously into congenitally athymice nude mice, and their fate was observed with light and electron microscopes. All the cell lines formed solid tumor masses at the sites of subcutaneous injection. When the cancer cells with high or moderate thromboplastic activity were injected intravenously, marked platelet aggregation and fibrin deposition, followed by neutrophilic infiltration, were seen around the cancer cells arrested in pulmonary arterioles or capillaries. Platelet aggregation and fibrin deposition were less conspicuous, when the cancer cells with low thromboplastic activity were injected. No metastatic foci were found 2 weeks after the intravenous injection of each cancer cell line. These results suggest that thromboplastic activity of human cancer cells is closely related to thrombus formation at the sites of lodgement and that thrombus develops without participation of immunological mechanisms.

Prostacyclin (PG I 2 ) generated by vascular endothelium is a strong antiaggregating substance. As platelet aggregation and release of humoral factor(s) have been reported to be crucial in the pathogenesis of acute lung injury following pulmonary microembolization, PG I 2 could have a protective effect against microembolic lung vascular injury. Following unilateral microembolization, we have observed a large increase in the filtration coefficient in the nonembolized lung with a significant increase in 6-keto PG F 1α , the stable metabolite of PG I 2 , in arterial blood. The pretreatment with indomethacin (10 mg/kg) prevented the increase in 6-keto PG F 1α and potentiated the lung injury after microembolization. Exogenously administered PG I 2 (20 ng/kg/min) prevented completely the increase in the filtration coefficient without any effects on hemodynamics, although these effects of indomethacin and PG I 2 did not relate to their effects on platelet aggregation. Based on these results, we could conclude that prostacyclin could play an important role in preserving cell integrity of the lung and in prevention of increased lung vascular permeability following pulmonary microembolization.

✓ Dissecting intracranial arterial aneurysms were identified in a 16-year-old girl and a 48-year-old man with moyamoya disease. Hemiplegia or tetraplegia rapidly developed. Angiography revealed bilateral stenoses or occlusion of the bifurcation of the internal carotid arteries (ICA's) and an unusual vascular network at the base of the brain. Autopsy confirmed massive hemorrhage from the thalamus and putamen, with intraventricular extension. The intracranial segments of both ICA's were markedly stenotic in both patients, due to eccentric fibroelastic intimal thickening. In one patient, a dissecting aneurysm was identified microscopically, involving the proximal segment of the left anterior cerebral artery. In the other patient, the right middle cerebral artery (MCA) was dissected beneath the internal elastic lamina along the entire length of the horizontal segment of the MCA. Thus, cerebral dissecting aneurysms may be present in patients with moyamoya disease.

A clinicopathological study of myocardial infarction was made in a Japanese community with autopsy rate of approximately 82% during 10 yr (from 1 November 1961 to 31 October 1971). Myocardial infarct (1 cm or more in 1 dimension) was found in 12.4 and 10.8% of 193 males and 167 females, aged 20 yr or over, respectively. Frequency of myocardial infarct among the autopsied cases remained almost constant in the 6th through 9th decade of life in both sexes. Approximately one half of the larger infarcts (5 cm or more in 1 dimension) and all of the smaller infarcts were found initially by postmortem examination. Unequivocal cardiac pain was found in one half of the patients with larger infarcts. Approximately one fourth of the larger infarcts and more than one half of the smaller infarcts were asymptomatic. This emphasizes the importance of close follow-up of cohorts in the epidemiological study of coronary heart disease.

To investigate a possible role of a nonadrenergic inhibitory nervous system in airway hyperreactivity, we measured changes in R l and C l caused by electrical stimulation of cervical vagus nerve during the infusion of 5-HT, after treatment with atropine and propranolol in 18 cats. R l decreased to 56 ± 3% (mean ± SE) and C l increased to 186 ± 13% of the prestimulated values, respectively, after stimulation. Hexamethonium diminished these responses significantly. Airway reactivity to 5-HT was reduced by continuous electrical stimulation of cervical vagus nerve in cats pretreated with atropine and propranolol. Hexamethonium potentiated airway reactivity to 5-HT. These results suggest that a nonadrenergic inhibitory nervous system could play an important role in the control of the bronchomotor tone and contribute to airway hyperreactivity.

Nineteen fatal cases of occlusion of the circle of Willis, so-called Moyamoya disease, were examined clinicopathologically. Fresh and massive cerebral haemorrhage was confirmed in 14 and cerebral infarcts of 4 of 19 patients. Among these 14 patients, massive haemorrhage was found in the basal ganglia, thalamus and hypothalamus of 9, and in the thalamus, cerebral peduncle and midbrain of 5. Pathologically, fibrosing stenoses or occlusions involved the circle of Willis and its major branches in all cases. In 13 of 17 patients numerous collateral channels, muscular in type, paralleled the circle, bypassing the occluded natural passages, Rupture of dilated small muscular collateral arteries was demonstrated in fresh and old haemorrhagic lesions in 3 of the 14 patients. Saccular aneurysm of cerebral arteries in the subarachnoid spaces was present in two of the 19. No rupture involved the perforating arteries in the subarachnoid space. These findings strongly suggest that in patients with Moyamoya disease rupture of overgrown perforating arteries as collaterals in brain may be main cause of single or repeated cerebral haemorrhage. Stenoses or occlusions of these perforators are presumably an important factor in the occurrence of cerebral infarcts.

Six hundred and fifty-eight autopsy cases of both sexes in a general population of Hisayama town (autopsy rate 85%) were examined to determine the frequency and causes of sudden and unexpected death. Seventy-three sudden deaths. (11.1%) were identified when sudden death was defined as death occurring within 24 hours after the onset of clinical symptoms. Thirty-nine deaths (54%) were due to intracranial hemorrhage (cerebral and subarachnoid) and 17 (23%) were due to coronary heart disease. An instantaneous death occurred within one hour was observed in 20 of the 73 cases (27%), of which 8 were attributed to coronary heart disease (40%) and one (0.5%) to subarachnoid hemorrhage. Pathologic evidence of recent myocardial infarcts or coronary thrombosis was found less frequently in cases who died within one hour than in those who died between one and 24 hours. An annual incidence of sudden death due to various etiologies, calculated from the population study on Hisayama residents who were aged 40 or over, was 1.7/1, 000. Deaths from coronary heart disease in this community were much less common as compared with those reported in Western communities.

This study of autopsy cases in the general population of the town, Hisayama, describes the incidence and severity of aortic and cerebral atherosclerosis in Japan. Atherosclerosis was more severe in the aorta than in the cerebral arteries of all age groups and its disparity became more conspicuous with age. In hypertensive cases, atherosclerosis was more severe in both the aorta and the cerebral arteries from and beyond the 6th decade of age. The severity of atherosclerosis in the aorta in those with systolic hypertension was lower under the age of 79 and higher after the age of 80 than in diastolic hypertension; the cerebral arteries were afflicted similarly by the two forms of hypertension. The serum cholesterol level correlated better with the severity of aortic than cerebral atherosclerosis.

Permeability pattern of retinal capillaries in streptozotocin-diabetic rats, maintained for 1–6 months, was studied with the electron microscope, using horseradish peroxidase as a tracer. A reaction product of horseradish peroxidase was confined to the capillary lumina and to a small number of vesicles on the luminal portion of the endothelial cells in control rats and diabetic rats maintained for 1 month. In diabetic rats maintained for 2–6 months, reaction product was observed in the basement membrane of endothelial cells and pericytes and extended to the extracellular spaces around the capillaries. The number of reaction product-labeled vesicles in the capillary endothelial cells was greatly increased in diabetic rats maintained for 2 months, as compared with that in control rats and diabetic rats maintained for 1 month. Reaction product was also found in the intercellular junctions of capillary endothelial cells from the luminal to the abluminal portion in diabetic rats maintained for 3–6 months. The increased permeability in retinal capillaries of diabetic rats preceded the thickening of the basement membrane, and seemed to play an important role in the development of diabetic retinopathy.

X-irradiation to the nude mouse lung and the ensuing pulmonary metastasis of the injected human cancer cells were investigated. Human cancer cells were injected intravenously into nude mice following 20 Gy right hemithoracic irradiation. The right lungs showed evidence of metastasis while metastasis was slight in the non-irradiated left lung. Platelet aggregation and fibrin deposition occurred around the arrested cancer cells in the capillaries of the right lung. The fibrinolytic activity of the irradiated right lung was lower than that of the non-irradiated contralateral lung. Natural killer cell activity was lower in the right-lung-irradiated mice than in the non-irradiated mice. We conclude that when the target organ is exposed to X-irradiation, there will be a decrease in fibrinolytic activity, a condition paving the way toward a metastasis.

Squamous cell carcinoma is the commonest type of bladder malignancy in most areas of northern Tanzania. Of 172 cases of bladder cancer recorded in 9 years, 72% were squamous cell carcinomas. Of these, 46% had Schistosoma haematobium eggs in sections taken from tumour tissue. The geographical distribution of this tumour closely corresponded to the prevalence of S. haematobium infection. The Mt Kilimanjaro area is free of schistosomiasis and virtually lacks squamous cell carcinoma. Although transitional cell carcinoma is rare in all regions of northern Tanzania, the relative frequency of bladder cancer in the Mt Kilimanjaro area was only one-third of that seen in other regions; population-based incidence rates were also very low in this area.

To evaluate the potential beneficial effect of a thromboxane synthetase inhibitor, OKY-1581, on increased pulmonary vascular permeability in pulmonary microembolization, we have measured the filtration coefficient in the nonembolized lung after unilateral microembolization in dogs. The unilateral microembolization caused marked elevations in pulmonary artery pressure and blood flow to the nonembolized lung, while pulmonary venous pressure in nonembolized lung did not change. The pulmonary vascular resistance in nonembolized lung did not increase significantly. The filtration coefficient (K f ) in nonembolized lung increased to 0.14 ± 0.02 from the baseline value of 0.07 ± 0.01 ml/min/mmHg/100g at 30 min after microembolization when the initial hemodynamic changes reduced toward the baseline value. In OKY-1581 treated dogs, similar hemodynamic changes did not result in the increase in the filtration coefficient in nonembolized lung. Platelet aggregation was also inhibited after microembolization in OKY-1581 treated dogs. Based on these results, we could conclude that OKY-1581 could prevent the increase in pulmonary vascular permeability following pulmonary microembolization by inhibiting platelet aggregation and possibly by preventing the release of thromboxane A 2 .

This paper reports the occurrence of renal cell carcinoma, hepatoma and malignant hepatic mixed tumor in a 22-year-old male with ataxia-telangiectasia (AT). Incidence of various malignant neoplasms is high in the patients with AT. The majority of these are lymphoreticular tumors and leukemia, and epithelial tumors are rare. This report is the first case with renal cell carcinoma and the second with hepatoma. The reason for a low incidence of epithelial tumors in AT is still obscure. It is possible that as the result of abnormal aging the tumors expected in the aged will occur in longer survivors with AT.

A 70-year-old man, with regional herpes zoster (C2) of 10 weeks duration, died following subarachnoid hemorrhage caused by the rupture of an aneurysm in the basilar artery. Granulomatous angiitis, with multinucleated giant cells, was found at autopsy in the wall of the aneurysm. Electron microscopy of the basilar artery disclosed intracytoplasmic viral particles with an envelope which measured 150-220 nm in diameter. Immunohistochemistry studies revealed varicella-zoster-virus-related antigen in the cytoplasm and/or in the nucleus of histiocytes in the vessel wall. These findings suggest that varicella-zoster virus may be linked to the development of granulomatous angiitis.

To study the effect of monocrotaline on the pulmonary alveolar-capillary membrane permeability, cardiac catheterization, extravascular lung water content and absorption of 14C-compounds from the rat lungs in combination with morphological observations were studied in the early stage of monocrotaline intoxications. Purified monocrotaline or its pyrrole was administered to rats with various doses. Single dose of 50 mg/kg of monocrotaline was enough to induce pulmonary hypertension 4 weeks later, but neither immediate nor direct pressor effect was observed by monocrotaline or active pyrrole. Only 3 to 5 mg/kg of pyrrole was enough to produce alveolar flooding with increased extravascular lung water content and accelerated absorption of 14C-mannitol and 14C-inulin from lungs 24 hours after administration. In contrast with fast and potent effect of pyrrole, effect of monocrotaline was mild and delayed in development. These findings suggested that monocrotaline increased the porosity of not only endothelial but also alveolar membrane by active metabolite.

SummaryThe release and the local activity of plasminogen activator (PA) were studied in isolated perfused dog hearts, without or with intimal injury induced by means of a balloon catheter inserted into the left anterior descending coronary artery (LAD). Thrombin but not DFP-thrombin induced a dose-dependent PA release in doses of 8 to 32 units. ADP 20 or 200 μmol but not ergonovine 20 or 200 μg induced a weak PA release. The local PA activity was much lower in the LAD at 1 or 4 weeks after this injury than in the intact LAD. However, the release of PA from the hearts after intimal injury was similar to findings in the intact hearts.We conclude from this study that thrombin plays an important role in regulating the coagulation-fibrinolysis system in endothelial cells and that changes in the properties of the endothelial cells may lead to initiation and enhancement of atherosclerosis.

Interactions between fibrin and arterial endothelial cells of rat iliac arteries in vivo were studies electron microscopically using a newly devised method. The microvilli became attached to the fibrin threads in an initial period of fibrinolysis. These threads had a fine granular appearance in the lysed areas. Fibrinolytically active endothelial cells had an active vesicular transport for ferritin particles injected concomitantly with the fibrinogen-thrombin mixture, thereby implying the enhancement of endothelial permeability in the lysed areas. However, fibrinolytically inactive endothelial cells coexisted in the same arteries. The denuded intima showed no lytic changes in the fibrin threads. These results indicate that the microvilli of the endothelial cells may plan an important role in releasing plasminogen tissue activator from the endothelial cells and that there is a heterogeneity with regard to reactivity of each endothelial cell to fibrin.

In this multiinstitute cooperative study, 143 patients were treated with either urokinase (UK) or combination of urokinase and dextran sulfate (UK-DS) within one to seven days following acute onset of cerebral thrombotic infarction. Of these, 81 randomized cases received a single dose of UK (2.83 x 105 units) by six-hour intravenous drip infusion and the remaining 62 received a combined dose of UK (2.84 x 105 units) and DS (3000mg) for only one day. Moderate to marked clinical improvements assessed during the seven-day study period were observed in 30.9% of the patients treated with UK and in 61.3% of those with UK-DS, the latter being significantly higher. Hemorrhagic phenomena appeared in 3.2% of the cases treated with UK-DS and in none of those with UK alone, but mortality was 1.6% in the former and 2.5% in the latter. UK-DS produced a prompt and sustained increase in plasma fibrinolytic activity with transient and relatively minor disturbance of the blood coagulation system. The results indicate that combined therapy with UK and DS is more effective than UK alone for acute cerebral thrombotic infarction.

Prostacyclin (PG I2) generated by vascular endothelium is a strong antiaggregating substance. As platelet aggregation and release of humoral factor(s) have been reported to be crucial in the pathogenesis of acute lung injury following pulmonary microembolization, prostacyclin could have a protective effect against microembolic lung vascular injury. Following unilateral microembolization, the filtration coefficient in the nonembolized lung increased significantly to 0.14 +/- 0.02 from the base line value of 0.07 +/- 0.01 ml/min/mmHg/100g. Prostacyclin as measured as 6-keto PG F1 alpha in arterial blood increased significantly to 4.15 +/- 1.76 at 30 min from the base line value of 1.90 +/- 0.45 ng/ml and increased further to 5.67 +/- 1.49 ng/ml at 60 min following microembolization. Exogenously administered PG I2 methylester (20 ng/kg/min) prevented completely the increase in the filtration coefficient without any effects on hemodynamics, although the effects of PG I2 methylester did not depend on its action on platelet aggregation. Based on these results, we conclude that prostacyclin could play an important role in preserving cell integrity of the lung and prevention of increased lung vascular permeability following pulmonary microembolization.

Frequency of cerebrovascular diseases (CVD) and their underlying vascular lesions were analyzed in 724 autopsy cases, aged 40 years and over, in the community of Hisayama, Japan during the period 1961 to 1981. Cerebral infarction (CI) was more frequently found at autopsy than cerebral hemorrhage (CH) with a ratio of infarction and hemorrhage of 4.4. Small CI occupied 75.7% of the cases with CI. The cases with any type of CVD showed more severe atherosclerosis of the major cerebral arteries than did those without CI or CH. Cerebral atherosclerosis of those with large and medium CI was the greatest, and with decreasing severity in those with small CI and with CH sequentially. Fibrinoid necrosis of the intracerebral small arteries was frequently found in cases with hypertension and particularly associated with CH. The decline in frequency of CH was confirmed; however, changes in frequency of CI were not evident. Fibrinoid necrosis was also reduced, although the severity of cerebral atherosclerosis showed no definite change. The decline of CH seemed to be ascribed to the reduction of fibrinoid necrosis of the intracerebral small arteries.

Summary An autopsy case was presented of brain stem encephalitis diagnosed clinically. A patient was taken ill with headache and double vision. He developed character change, dysphagia, dysarthria, nuchal rigidity and spastic quadriparesis with intermittent fever, following the disappearance of double vision. These symptoms and signs progressed slowly with transient remissions. He died at the age of thirty-five years, three years and six months after the onset. On neuropathological examination, there were chronic inflammatory lesions together with demyelination and gliosis in the hypothalamus, lower end of the internal capsule, optic chiasm, midbrain, pons, medulla oblongata and spinal cord. The clinicopathological features of our case were most similar to those of brain stem encephalitis described by Iizuka. However, the spinal cord involvement was severe in our case. Viral studies examined were all negative, despite that the neuropathological findings were suggestive of some viral infection.

Purified diets containing cholesterol, cholic acid and different levels of magnesium with or without glycyrrhizin and Mg-K-Aspartate were fed to young growing rats for 138 days. The mild diet-induced magnesium deficiency resulted in poor growth, hypomagnesemia, an increased production of atheromatosis of aorta and heart valves, a profound calcification of kidney, an increase of calcium concentration of kidney, a slight decrease of magnesium concentration in kidney and myocardium, increases of cholesterol, glycerol and phosphorus in lipid fraction of serum, and an increase of weight of the liver and spleen. Rats receiving a dietary glycyrrhizin showed an increase of magnesium concentration of myocardium, decrease of magnesium in serum, a decrease of cholesterol in serum, increase of glycerol and phosphorus in lipid fraction from liver and decrease of glycerol and phosphorus in lipid fraction from serum.Rats fed a diet containing 24mg. of magnesium per 100Gm. of diet without cholesterol and cholic acid, showed a conspicuous calcification of kidney, suggesting that 24mg. of magnesium per 100Gm. of diet is insufficient. Rats receiving a dietary magnesium in a form of Aspartate instead of MgO, had a decreased concentration of glycerol and phosphorus of lipid fraction in serum, and an increase of magnesium in myocardium.

A case of localized form of desquamative interstitial pneumonia is presented. The patient is well and shows no recurrence of disease after a lobectomy. No corticosteroids were given.

Thromboplastic and Abrinolytic activities in various organs of congenitally athymic nude mice were estimated. These activities varied from one organ to another and the organs were divided into six groups of possible combinations of these activities. The lung revealed high thromboplastic and high Abrinolytic activities, while the liver showed low thromboplastic and low Abrinolytic activities. The pattern of distribution of these activites in various organs of nude mice was almost similar to that of rats and mice with normal thymus. No plasmin activity was found in all organs. ACTA PATH. JAP. 29: 409–411, 1979.

Sequential changes in the kidney during the generalized Shwartzman reaction were studied electron microscopically. The first anatomical change was infiltration of neutrophils into the glomerular capillaries. Endothelial damage was not noticeable until the capillaries were filled with fibrin deposits. Fibrin appeared in the mesangium at almost the same time as in the capillary lumina, traversing through the endothelial fenestrae. Endothelial damage was more common in the mesangial portion than in the peripheral portion of the capillaries. Severe mesangiolysis developed after loss of endothelial cells had been followed by massive penetration of intracapillary contents. Later, signs of repair were evident in some parts of the damaged endothelium. The development of cortical necrosis coincided with the appearance of mesangiolysis and arteriolar thrombotic lesions.

Morphologic alterations in the gastric microcirculation in cirrhosis were investigated following infusion of a silicone rubber compound into vessels of the excised stomach which was then cleared with methyl salicylate. In cirrhosis, arteriovenous anastomoses 15 to 50 micron in diameter were present in 5 of 10 patients; spiral arterioles were less than one-tenth as numerous as in stomachs from noncirrhotic patients. The arterioles mainly had a straight pattern and precapillaries, capillaries, and submucosal and subserosal veins were dilated in cirrhotics (p less than 0.05). The number of arteriovenous anastomoses was unrelated to the degree of vascular dilatation and the number of spiral arterioles. These morphological alterations are consistent with decreased arteriovenous flow resistance in the stomach of cirrhotic patients.

In order to clarify the ultrastructural change of initial phase of thrombosis, an autologous clot Injection or one shot of thrombin was performed via an auricular vein of each rabbit. In the groups of clot injection, platelets located between an inserted thrombus and endothelial cells show viscous metamorphosis. Degeneration and disappearance of the endothelial cells are followed by invasion of platelets and dense liquid materials into the subendothelial space and the media of the muscular arteries in both experimental groups. There is no detectable morphological difference between thrombosis in rivo induced by an injection of thrombin and thromboembolism induced by an injection of autologous whole blood clots coagulated in vitro. Phagocytosis in the course of thrombosis is mainly derived from the activity of subendothelial cells and partly from that of endothelial cells. Ultrastructural features of the subendothelial edema are based on the detachment of endothelial cells from the elastic lamina or on the edematous swelling of subendothelial cell cytoplasm. The initial stage of the organization of thrombus, showing smooth muscle cells arranged in the vertical position towards the thrombus, is noted three days after a clot or thrombin administration. Myofilamentous structures with dotted density are detected in the endothelial cells of muscular artery, not only of experimental groups but also of control ones.

Monocrotaline, an alkaloid obtained from Crotalaria spectabilis, provides an experimental model for studies of mesangiolysis as seen in Habu venom poisoning and hemolytic-uremic syndrome. Renal lesions induced in rats by a single intraperitoneal administration of monocrotaline were examined by light and electron microscopy. Two weeks after the injection glomerular capillaries showed focal endothelial cell detachment and adhesion of platelets to the basal lamina. At 3 weeks there was no endothelial denudation but the mesangium was severely edematous. Mesangiolysis occurred at 4 weeks, accompanied by dilatation or obliteration of capillaries and necrosis and hemorrhage in the mesangium. Insudation of plasma constituents facilitated by the endothelial injury appeared important in the pathogenesis of mesangiolysis. Fusion of capillaries seemed to lead to capillary aneurysmata and necrosis of the mesangium. These glomerular lesions induced by monocrotaline were similar to those of Habu venom poisoning or hemolytic-uremic syndrome.

The effect of the lysosomal contents of hog kidney cortex, especially of the fraction not bound by concanavalin A (Fraction A) on the permeability of the coronary and cerebral arteries of rats was studied ultrastructurally using H.R. peroxidase. This fraction was devoid of renin activity by bioassay. The coronary arteries of the experimental rats displayed fibrinoid degeneration: e.g., degeneration and disappearance of medial smooth muscle cells and deposition of electron dense materials containing fibrin. A large amount of reaction product of peroxidase was present in the subendothelial space and media where fibrinoid degeneration was evident. Transendothelial passage of the marker occurred by both junctional and vesicular transport. There was no evidence of separation or discontinuity of the endothelial cells. Occasionally, increased permeability of the intima was noted in the coronary arteries without medial damage. By contrast, neither fibrinoid degeneration nor increased permeability was noted in the cerebral arteries. The difference in the response of the two arteries seems attributable to the barrier effect of cerebral arterial intima.

Using a polyclonal antibody against human epidermal keratins and a monoclonal antibody against cytokeratins characteristic of simple epithelia, and the Avidin-Biotin system of immunohistochemistry, we have demonstrated cytokeratin expression in 46% and in 60% of small cell carcinomas of the lung at autopsy respectively. The latter gave a diffuse stronger reaction product than the polyclonal antibody. The results suggest that there is a cytokeratin rich and a cytokeratin poor type of small cell carcinoma. Neuron-specific enolase immunohistochemistry was positive in 60% of the cases. Coexpression with cytokeratin was seen in ten cases (30%). The expression of cytokeratin and neuronspecific enolase in small cell carcinomas strongly suggests that they are of an epithelial origin, but are capable of neuroendocrine differentiation.

The incidence of cerebral amyloid angiopathy in a general population was evaluated in brains of 400 consecutive autopsies of residents of Hisayama, Japan (November 1971-October 1983). Six samples taken from frontal lobe, parietal lobe, temporal lobe, occipital lobe, hippocampus, and basal ganglia of the same side of each brain were stained with both hematoxylin and eosin and Congo red. The specimens were surveyed microscopically with polarized light for deposition of amyloid in the vascular wall. In 26 cases with brain hemorrhage, the region surrounding the hemorrhagic sites was further examined to study the probable causal relation between cerebral amyloid angiopathy and brain hemorrhage. Cerebral amyloid angiopathy was found in 40 of 218 men (18.3%) and 51 of 182 women (28.0%). The incidence increased with age in both sexes. The frontal lobe was most frequently affected (66 cases), followed by parietal lobe (65), occipital lobe (49), temporal lobe (44), and hippocampus (32); the putamen was never affected. The incidence of cerebral amyloid angiopathy did not correlate with blood pressure or with the severity of cerebral atherosclerosis. Among the 26 cases in which there was brain hemorrhage, only one cerebellar hemorrhage, in an 85-year-old man, was attributed to cerebral amyloid angiopathy. This case showed four microaneurysms in vessels, with cerebral amyloid angiopathy surrounding the hemorrhagic site. Thirty similar lesions were observed in eight cases without brain hemorrhage. Cerebral amyloid angiopathy may play an etiologic role in the development of brain hemorrhage through formation of angionecrosis and microaneurysm.