Hidetaka Wagayama

Atherosclerosis and ω-3 fatty acids in the populations of a fishing village and a farming village in Japan

The effect of different dietary habits on atherosclerosis was investigated by examining the content of ordinary diets and relevant risk factors through a mass health survey on two village populations in Japan. In total, 261 inhabitants in the fishing village and 209 in the farming village were examined for body build, blood pressure, and blood chemistry. Information on smoking habits and food consumption was obtained using a semi-quantitative item-frequency questionnaire. Pulse wave velocity of the aorta, intima-media thickness of the carotid artery, and atherosclerotic plaques as obtained by ultrasonography were used as measures of atherosclerosis. All measures of atherosclerosis are lower in the fishing village than in the farming village in both men and women. There is a striking 5-8-fold difference in the number of atherosclerotic plaques (P < 0.0001) between the populations. The observed differences in atherosclerosis parallels differences in dietary habits and differences in the serum essential fatty acids. Evaluation of the omega-3 fatty acids over the combined populations reveals a negative association with the number of plaques in the common carotid while the omega-6 fatty acids shows a weak positive association with plaques.

Association of remnant-like particle cholesterol with coronary artery disease in patients with normal total cholesterol levels.

BACKGROUND Limited information is available as to whether there is a difference in the association of lipid and fibrinolytic variables with coronary artery disease according to the presence or absence of elevated serum total cholesterol. We examined the levels of various lipid and fibrinolytic variables including remnant-like particle cholesterol (RLP-C). RLP-C is a recently established simple assay method for the estimation of triglyceride-rich lipoprotein remnants. METHODS AND RESULTS Levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride, lipoprotein(a), RLP-C, uric acid, blood glucose, tissue plasminogen activator, tissue plasminogen activator inhibitor type 1, antithrombin III, and protein C were measured in 208 patients who underwent diagnostic coronary angiograms. Of these 208 patients, 57 were hypercholesterolemic (> or =220 mg/dL) and 151 were normocholesterolemic. HDL-C showed significant differences between patients with and those without angiographically determined coronary artery stenosis in both hypercholesterolemic and normocholesterolemic patients (P =.0025 and P =.0003, respectively). Both RLP-C and uric acid showed significant differences only in the normocholesterolemic subgroup (P =.0006 and P =.0060, respectively). This difference in uric acid was not significant by multivariable analysis. The ratio of RLP-C/HDL-C was demonstrated to be highly significantly (P <.0001) associated with coronary artery stenosis in patients with normal total cholesterol, whereas there was no statistically significant association in the hypercholesterolemic patient subgroup. CONCLUSIONS Our current study disclosed that RLP-C levels are strongly associated with coronary artery disease, especially in patients with normal total cholesterol levels. Moreover, RLP-C/HDL-C ratio may be even more significantly associated with the presence of coronary artery stenosis in normocholesterolemic patients.

p21WAF1/CTP1 expression and hepatitis virus type.

Since p21WAF1/CIP1 (p21) is a universal inhibitor of cyclin-dependent kinases and is regulated transcriptionally by p53, which is activated by DNA stress, its expression reflects DNA stress in chronic hepatitis. Recently an association with both hepatitis B and C virus and the expression of p53 or p21 was reported. We analyzed p21 expression in 18 cases of HBV-associated chronic liver diseases and 32 cases of HCV-associated chronic liver diseases by immunohistochemical analysis, and investigated the possible association between hepatocyte p21 expression and hepatic inflammation, fibrosis, and especially hepatitis virus type. The p21-positive hepatocytes were more numerous in areas of intense inflammation and spotty necrosis and areas close to fibrosis, and they increased according to the degrees of grading and staging. The p21 labeling index (LI) in patients with liver cirrhosis was significantly higher than that in patients with chronic hepatitis of both hepatitis viral types (5.84 ± 0.61 vs 12.0 ± 0.83, P < 0.0001 in hepatitis B, 10.28 ± 0.80 vs 15.6 ± 1.09, P = 0.0004 in hepatitis C), Furthermore, the p21 LI was significantly higher in HCV-associated liver disease than in HBV-associated liver disease in every group (4.02 ± 0.48 vs 7.74 ± 0.96, P = 0.021 in low grade group, 7.35 ± 0.46 vs 12.8 ± 0.57, P < 0.0001 in high grade, 12.0 ± 0.83 vs 15.6 ± 1.09, P = 0.034 in liver cirrhosis). In, conclusion, p21 expression was up-regulated by the stress of inflammation and fibrosis and might be influenced by viral proteins in human chronic liver disease.

Cytoplasmic p21WAF1/CIP1 expression in human hepatocellular carcinomas

To the editor: We read with great interest the articles ‘Interleukin-6 inhibits cell proliferation in a rat model of hepatocellular carcinoma’ by Moran et al. (1) and ‘Hepatocellular carcinoma – survival and clinical characteristics in relation to various histologic molecular markers in Western patients’ by Schoniger-Hekele et al. (2). These articles focused on expression of p21 in hepatocellular carcinomas (HCCs). These studies, together with previous reports, suggest that p21 plays an important role in HCC development and that p21 expression may represent dysfunction of the cyclin-dependent kinase inhibitor involved in tumorgenecity. p21 protein is a universal inhibitor of cyclindependent kinases (CDK) and is regulated transcriptionally by p53, which is activated by DNA stress. In chronic hepatitis, lymphocytes and Kupffer cells induce DNA stress in hepatocytes. Therefore, we suggested that p21 expression is present in hepatocytes in chronic liver diseases and that p21 is involved in hepatocarcinogenesis. We previously found that p21 was upregulated by inflammation and fibrosis in hepatitis C virus (HCV)-associated chronic liver diseases and that high p21 expression may be related to hepatocarcinogenesis in cirrhotic patients (3). These results indicated that p21 plays a critical role in nontransformed cells during the development of HCC. However, most papers describing the expression of p21 have focused on its nuclear expression. Despite the function of p21 as a cell cycle inhibitor, which implies that p21 is a tumor suppressor, elevated levels of p21 in the cytoplasm have been reported to be critical for promoting cell transformation and survival. Levels of p21 expression are also elevated in various human cancers. Therefore, we immunohistochemically investigated the localization of p21 expression in chronic liver diseases and HCCs. Briefly, sections were deparaffinized, and endogenous peroxidase activity was blocked. They were then stained using the immunoperoxidase technique with monoclonal primary antibody (anti-p21 clone 187 against full-length p21 of human origin; Santa Cruz Biotechnology, Santa Cruz, CA) at a 1:100 dilution. Secondary antibody application and peroxidase staining were performed using a Biotin-conjugated goat anti-mouse secondary antibody and the ABC horseradish peroxidase method (Elite ABC kit, Vector laboratories, Burlingame, CA). p21 was mainly expressed in the nuclei of nontumor tissues (Fig. 2A). We previously demonstrated that p21 is upregulated by inflammation and fibrosis in chronic liver diseases and that high p21 expression is related to hepatocarcinogenesis in cirrhotic patients (3). However, we found that, in most HCCs, p21 is largely expressed in the

CASE REPORT: Pancreatic Cancer with Chylous Ascites Demonstrated by Lymphoscintigraphy: Successful Treatment with Peritoneovenous Shunting

A 60-year-old woman was admitted to our hospital because of abdominal distension caused by massive chylous ascites. Six months earlier, she was diagnosed with inoperative pancreatic head cancer and biliary tract stenting and radiation therapy were performed due to obstructive jaundice. The chylous ascites was observed by lymphoscintigraphy with 99mTc-labeled human serum albumin. It showed upper abdomen accumulation and leakage into the abdominal cavity, and a diagnosis of chylous ascites caused by obstruction or rupture of lymphocele due to pancreatic cancer was made. Chylous ascites did not improve with a conservative therapy, including low-fat diet and administration of flousemide, but was successfully treated with a peritoneovenous shunt using a Denver shunting tube. In association with the placement of the shunt, she lived for 15 months after the first diagnose of pancreatic cancer without pancreatoduodenectomy.

Difference in atherosclerosis between the populations of a fishing and a farming village in Japan.

Epidemiological studies from Greenland’ and Japan2 suggest that high dietary consumption of marine fats may prevent the development of atherosclerosis and thrombosis. Fish oils rich in n-3 polyunsaturated fatty acids suppress platelet aggregation, vascular prostaglandin production, hepatic triglyceride and very low density lipoprotein cholesterol formation, and intimal smooth muscle cell proliferation. These antiatherosclerotic effects may be important in preventing the development of cardiovascular diseases.