Isamu Sakurai

Light Microscopic Localization of Hepatitis B Virus Antigens in the Human Pancreas Possibility of Multiplication of Hepatitis B Virus in the Human Pancreas

Hepatitis B virus has been considered to be strictly organotropic and to infect and multiply only the hepatocytes of humans and chimpanzees. The localization of hepatitis B surface antigen in extrahepatic tissues has been regarded as due to deposition or phagocytosis of hepatitis B surface antigen circulating in the blood. In the present study, however, we demonstrated hepatitis B virus antigens in the pancreases of autopsied subjects with hepatitis B surface antigenemia by Shikatas orcein stain, and immunoperoxidase, immunofluorescent studies; hepatitis B surface antigen and hepatitis B virus core antigen were localized within the cytoplasm of pancreatic acinar cells in 18 and 6 cases, respectively, out of 30 cases studied. In contrast, 25 autopsy cases with no hepatitis B surface antigenemia failed to stain hepatitis B surface antigen or hepatitis B core antigen in the pancreas and liver. Therefore, it may be reasonable to assume that hepatitis B virus can infect and replicate in the human pancreatic acinar cells; however no convincing hepatitis B virus-associated ultrastructures were detected in the present study. Although there were some cases demonstrating chronic inflammatory reaction or fatty necrosis, or both, in the pancreas with hepatitis B virus antigens, the causal relationship between these pathologic changes and hepatitis B virus infection awaits further clarification.

Second nation-wide study of atherosclerosis in infants, children and young adults in Japan

Abstract This paper reports the results of a nation-wide cooperative study of atherosclerosis in young, first generation Japanese with ages ranging from 1 month to 39 years, who were autopsied between 1978 and 1982 in hospitals distributed over the entire archipelago of Japan. Atherosclerotic lesions in 2320 aortas, 1620 coronary arteries and 344 cerebral arteries were classified into fatty streaks, fibrous plaques and complicated lesions and were then quantificated with the point-counting method. Atherosclerosis of aortas, coronary arteries and cerebral arteries, determined by surface involvement (SI) of atherosclerotic lesions and atherosclerotic index (AI), increased with age; the severest were seen in aortas, and then, with decreasing severity, in the coronary and cerebral arteries. Fatty streaks preceded the other lesions and accounted for the largest portion of the lesions in aortas and coronary arteries. Fibrous plaques and complicated lesions developed in the later decades of life. The patients with collagen diseases had a greater severity of aortic atherosclerosis in the 2nd and 3rd decades of life, than those without such disorders. Correlation of antemortem clinical data with SI and Al of each artery were analyzed, using simple correlation analysis and multiple regression analysis. 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 cases of early lesions of atherosclerosis in young Japanese.

Murine fetal resorption and experimental pre-eclampsia are induced by both excessive Th1 and Th2 activation

It has been proposed that immune responses in mammalian normal pregnancy are Th2-like, thereby protecting the fetus and placenta from being rejected. Administration of exogenous Th1 cytokines into pregnant mice is reported to induce feto-placental resorption. However, the effects of exogenous Th2 cytokines and Th2 directed responses in pregnant animals have not been well studied. In this study, we examined IL-4 and IL-12, which play decisive roles in the development of Th2 and Th1 responses, respectively, in the induction of fetal resorption and development of experimental pre-eclampsia. Transfer of either IL-4 and/or IL-12 stimulated splenocytes from BALB/C virgin female mice into BALB/C pregnant mice mated with either C57BL/6 or BALB/C male mice resulted in fetal resorption and glomerular nephritis associated with hypertension and proteinuria. In mice treated with IL-12 stimulated splenocytes, fatty liver degeneration associated with bile retention was observed. These results indicate that both excessive Th1 and Th2 activation contribute to the development of fetal resorption and pre-eclampsia, but that Th1 is critical to the development of liver degeneration.

Fluvastatin suppresses atherosclerotic progression, mediated through its inhibitory effect on endothelial dysfunction, lipid peroxidation, and macrophage deposition

Fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts an inhibitory effect on intimal thickening after mechanical injury in normocholesterolemic rabbit artery at a dose not enough to elicit a known action of lipid lowering. This study was designed to determine whether atherosclerotic progression triggered by hypercholesterolemia can be inhibited by fluvastatin under conditions without its hypocholesterolemic effect. Rabbits were fed a 0.5% cholesterol diet or normal diet for 17 weeks and were treated with either fluvastatin (0.3-2 mg/kg/day, p.o.) or pravastatin (2 mg/kg/day, p.o.). Atherogenic features manifested in the cholesterol-diet group, compared with the normal-diet group; they were the increase in serum lipid peroxide level, in the intraluminal lesion area of the aorta, and in macrophage content of the aortic cross-sectional lesion area; the attenuation of endothelium-dependent relaxing response to acetylcholine in the femoral artery; and the increase in serum lipid level. Treatment with fluvastatin, but not pravastatin, inhibited the manifestation of the atherogenic features without a serum lipid-lowering effect. Thus fluvastatin is likely to reduce the risk of atherosclerotic progression, to which endothelial dysfunction, lipid peroxidation, and macrophage accumulation in the vasculature may contribute, irrespective of changes in serum lipid levels.

Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery.

The anti-atherosclerotic effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors at doses insufficient to lower serum cholesterol was investigated in rabbit femoral artery denuded by balloon catheter. Fluvastatin and pravastatin were given orally at doses of 4 and 8 mg/kg per day, respectively, for 2 weeks after the catheterization. There was little change in serum cholesterol, triglyceride and phospholipid by chronic treatment with the drugs. The cross-sectional area of the intima, expressed as relative values to media (I/M ratio), was increased by the catheterization, showing intimal thickening in the denuded arteries. The I/M ratio was reduced by fluvastatin but not pravastatin: 0.327 +/- 0.060 for control, 0.116 +/- 0.035 for 4 mg/kg fluvastatin, 0.088 +/- 0.027 for 8 mg/kg fluvastatin and 0.22 +/- 0.069 for 8 mg/kg pravastatin. Fluvastatin (8 mg/kg)-induced effect on the I/M ratio, was prevented by the combined administration with 40 mg/kg per day mevalonate, a metabolite in the HMG-CoA reductase pathway. These results suggest that fluvastatin inhibits intimal thickening after catheterization-induced injury through percutaneous transluminal coronary angioplasty (PTCA) and that the inhibition is presumably attributed to reduced migration and proliferation of smooth muscle cells but not secondarily to a lowering of serum lipid.

DETECTION OF HBsAg IN THE PANCREAS

Hepatitis B surface antigen (HBsAg) has been reported to be present in other organs than the liver.3,9 So far as our knowledge is concerned, however, any report of cases dealing with pancreatic diseases induced by hepatitis B virus (HBV) has not been described in the English and Japanese literature. We report an autopsy case with a pancreatic lesion characterized by damage of both exocrine and endocrine epithelial cells with inflammatory response, which were immunohistochemically found to be positive for HBsAg, and electron‐microscopically to possess core‐like particles In the nucleus and cytoplasm.

Expression of apoptosis and its related protein in astrocytic tumors

The relationship between malignant potential and apoptosis in astrocytic tumors has not been clearly defined, and further classification of astrocytic tumors is necessary. To elucidate the relationship between the histopathological grade of astrocytic tumors and apoptosis, we studied 25 cases of astrocytic tumors, comprising 10 cases of glioblastoma (GB), 7 cases of anaplastic astrocytoma (AA), and 8 cases of astrocytoma (AC). We detected apoptosis using the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. We studied immunohistochemical expression of bcl-2 protein and p53 protein, which are apoptosis-related factors, and cell proliferative activity using Ki-67 antibody. No significant change was noted between apoptotic index and the histological grade of the tumors. In GB, apoptotic cell-rich foci were present at the pseudopalisading necrosis. No correlation between histopathological grades and expression of either p53 or bcl-2 was observed. In GB, however, poor distribution of bcl-2 was found in the areas of pseudopalisade formation. bcl-2 is one of the regulatory factors in the cell cycle and inhibits apoptosis. Expression of apoptosis had no correlation with histopathological grade. However, in GB, the distribution of apoptotic cells showed a correlation with bcl-2-poor foci. It was thought that apoptosis was one of the regulatory factors in the formation of pseudopalisading necrosis in GB.

SQUAMOUS CELL CARCINOMA OF GALLBLADDER

Two cases of a well‐differentiated keratinizing squamous cell carcinoma of the gallbladder were reported. Pathologic analysis of this rare neoplasm was made in conjunction with cases of the gallbladder carcinoma of a squamous cell variety reported in literatures. The squamous cell carcinoma is characterized by a well‐localized growth and a rarity or lack of metastasis. These characteristics make a good contrast with an adenosquamous carcinoma of the gallbladder which usually infiltrates rather extensively and metastasizes widely. Thus the adenosquamous carcinoma should be sequestered from group of squamous cell carcinoma. Radical operative procedures may well be encouraged on selected cases of squamous cell carcinoma.

Development of Antibody Against Epitope of Lipoprotein(a) Modified by Oxidation Evaluation of New Enzyme-Linked Immunosorbent Assay for Oxidized Lipoprotein(a)

BackgroundRecently, the biological effects of oxidized lipoprotein(a) [Lp(a)] have been reported to be more potent than Lp(a), the arteriosclerosis-relevant lipoprotein. Thus, investigations with oxidized Lp(a) are expected to provide viewpoints different from the conventional ones based on Lp(a). Methods and ResultsAn anti-Lp(a) monoclonal antibody (161E2) was produced against synthetic peptide antigen (Arg-Asn-Pro-Asp-Val-Ala-Pro). This epitope was characterized as having various properties because its external exposure was induced as a result of oxidative modification. Using 161E2 antibody, we developed a new enzyme-linked immunosorbent assay to measure Lp(a) modified by oxidative stress. The present data demonstrated that oxidized Lp(a) that contains the epitope of 161E2 antibody was present in the serum of humans. Therefore, we used this new enzyme-linked immunosorbent assay to evaluate the role of oxidized Lp(a) in patients with hypertension, which induces oxidative stress . Interestingly, hypertensive patients with complications showed a significantly higher level of oxidized Lp(a) in serum than did normotensive subjects (P <0.01), whereas there was no significant difference in native Lp(a) between normotensive and hypertensive subjects. Importantly, positive immunostaining with 161E2 monoclonal antibody was found in the human arteriosclerotic tissue. ConclusionsWe developed a new antibody against an epitope in Lp(a) as a result of oxidation treatment but not in native Lp(a). The present data demonstrated in vivo the presence of oxidized Lp(a) in the atherosclerotic tissue and its elevation in hypertensive patients. The presence of oxidized Lp(a) may be important in understanding the role of Lp(a) in cardiovascular disease.

Benign osteoblastoma of the temporal bone of an infant

Benign osteoblastoma is a rare neoplasm of bone tissue most commonly involving the vertebral column and long bones. Occurrence in the calvarium is extremely rare, and no cases in infants have previously been described. We report a case of benign osteoblastoma occurring in the temporal squama of an infant. The clinical features of this type of tumor occurring in the calvarium are briefly discussed.