Objective To investigate the degree to which ionising radiation confers risk of mortality from heart disease and stroke. Design Prospective cohort study with more than 50 years of follow-up. Setting Atomic bomb survivors in Hiroshima and Nagasaki, Japan. Participants 86 611 Life Span Study cohort members with individually estimated radiation doses from 0 to >3 Gy (86% received <0.2 Gy). Main outcome measures Mortality from stroke or heart disease as the underlying cause of death and doseresponse relations with atomic bomb radiation. Results About 9600 participants died of stroke and 8400 died of heart disease between 1950 and 2003. For stroke, the estimated excess relative risk per gray was 9% (95% confidence interval 1% to 17%, P=0.02) on the basis of a linear dose-response model, but an indication of possible upward curvature suggested relatively little risk at low doses. For heart disease, the estimated excess relative risk per gray was 14% (6% to 23%, P<0.001); a linear model provided the best fit, suggesting excess risk even at lower doses. However, the dose-response effect over the restricted dose range of 0 to 0.5 Gy was not significant. Prospective data on smoking, alcohol intake, education, occupation, obesity, and diabetes had almost no impact on the radiation risk estimates for either stroke or heart disease, and misdiagnosis of cancers as circulatory diseases could not account for the associations seen. Conclusion Doses above 0.5 Gy are associated with an elevated risk of both stroke and heart disease, but the degree of risk at lower doses is unclear. Stroke and heart disease together account for about one third as many radiation associated excess deaths as do cancers among atomic bomb survivors.

Background and Purpose-A traditional diet that is poor in animal products is thought to explain the high rate of stroke in Asian populations. The purpose of the present study was to examine the effect of a diet rich in animal protein, animal fat, and cholesterol on the risk of cerebral infarction mortality in a Japanese population. Methods-A prospective study of 3731 Japanese men and women aged 35 to 89 years was conducted from 1984 to 2001.Nutrient intake was estimated at baseline from the responses to a 24-hour diary. During the follow-up period, cases of cerebral infarction deaths (as entered on death certificates) were monitored. Results-During the follow-up period, 60 deaths were attributed to cerebral infarction. A high intake of animal fat and cholesterol was significantly associated with a reduced risk of cerebral infarction death. The risk was reduced by 62% (CI, 82% to 18%) for those in the third tertile of animal fat intake, compared with those in the first tertile, with a significant linear dose-response relationship (Pϭ0.0073). The risk of death from infarction was reduced by 63% (CI, 82% to 22%) in the high cholesterol consumption group, compared with the low consumption group. A significant linear dose-response relationship was observed. Animal protein was not significantly associated with infarction mortality after adjustment for animal fat and cholesterol. Conclusions-This study suggests that in Japan, where animal product intake is lower than in Western countries, a high consumption of animal fat and cholesterol was associated with a reduced risk of cerebral infarction death.

The association between green-yellow vegetables and fruit consumption and risk of cancer death was investigated in a prospective study of 38 540 men and women who were atomic-bomb survivors in Hiroshima and Nagasaki, Japan. Study participants completed a dietary questionnaire in 1980 -1981 and were followed-up for cancer deaths until March 1998, during which time 3136 cancer deaths were identified. Daily or almost daily fruit consumption was associated with a significant 12% reduction in total cancer mortality (RR ¼ 0.88; 95% CI, 0.80 -0.96 for daily intake compared with intake once per week or less). Daily or almost daily greenyellow vegetables consumption was associated with a marginally significant 8% reduction in total cancer mortality (0.92; 0.94 -1.01). Green-yellow vegetables consumption was associated with a significant reduction in liver cancer mortality (0.75; 0.60 -0.95). Fruit consumption was associated with a significantly reduced risk of stomach cancer and lung cancer mortality (0.80; 0.65 -0.98). Greenyellow vegetables and fruit consumption was associated with a reduction in oesophageal cancer, but these associations were not statistically significant. Neither green-yellow vegetables nor fruit consumption was associated with colorectal cancer or breast cancer mortality. These results support the evidence that daily consumption of fruit and vegetables reduces the risk of total cancer, and specifically cancers of the stomach, liver, and lung.

Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1and HER4 expression and the prognosis of patients with gastric cancers. Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T 1 versusT 2 -T 4 ; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.

Background Laparoscopic distal gastrectomy (LDG) is an established procedure for the treatment of early gastric cancer. Roux-en-Y (R-Y) or Billroth-I (B-I) reconstruction is generally performed after LDG in Japan. The aim of this retrospective cohort study was to compare the effectiveness of R-Y and B-I reconstructions and thereby determine which has better clinical outcomes. Methods We analyzed data from 172 patients with gastric cancer who underwent LDG. Reconstruction was done by R-Y in 83 patients and B-I in 89. All patients were followed up for 5 years. Evaluated variables included symptoms, nutritional status, endoscopic findings, gallstone formation, and later gastrointestinal complications. Results Scores for the amount of residue in the gastric stump, remnant gastritis, and bile reflux, calculated according to the ''residue, gastritis, bile'' scoring system, were significantly lower in the R-Y group (score 0 vs. 1 and more; p = 0.027, \0.001, and \0.001, respectively). The proportion of patients with reflux esophagitis was significantly lower in the R-Y group (p \ 0.001). Relative values (postoperative 5 years/preoperative) for body weight, serum albumin level, and total cholesterol level were similar in the two groups (p = 0.59, 0.56, and 0.34, respectively). Gallstone formation did not differ between the groups (p = 0.57). As for later complications, the incidence of gastrointestinal ulcer was 4.5 % in the B-I group, and that of ileus was 3.6 % in the R-Y group, but differences between the groups were not significant (p = 0.12, 0.11, respectively). Conclusions As compared with B-I, R-Y was associated with lower long-term incidences of both bile reflux into the gastric remnant and reflux esophagitis.

We evaluated the performance of a 22-item food frequency questionnaire (FFQ) administered in 1980-81 to 3,005 members of the Adult Health Study cohort, part of the Life Span Study. The questionnaire was compared with the records of a 24-hour dietary survey that was performed in 1984-85. From the dietary records, food and nutrient intakes were estimated. The association between the two measures of dietary intake was assessed using Mantel-Haenszel chi-square test and the Spearman's rank correlation coefficient. The frequency of food intake as measured by the FFQ was linearly associated with food intake as measured by the 24-hour diary, with the exception of dry fish. The highest correlations were observed for beverages, including coffee (0.51), milk (0.32) and black tea (0.26). Foods such as fruit (0.27), confectionery (0.23), rice (0.34) and bread (0.28) were also moderately correlated. These results show that, with the exception of dry fish, the FFQ is moderately correlated with the 24-hour diary and can be used to assess diet intake in this cohort. J Epidemiol2002;12:394-401.Key words: food frequency questionnaire, validity, dietary record, JapanThe development of methods to measure habitual, long-term dietary intake in epidemiologic studies has been a considerable challenge over the past two decades. The semi-quantitative food frequency questionnaire (FFQ) is the method most commonly used, and usually includes questions on the average frequency of consumption during the past year for a given number of food items. In order to evaluate the performance of a FFQ, dietary intake is often compared with a more objective or detailed measurement, such as biomarkers, an interviewer-assisted 24-hour recall, or self-reported dietary records.The Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan is following the Life Span Study cohort, a large cohort of atomic-bomb survivors recruited in 1958.1 Several mail surveys have been carried out to examine lifestyle factors among the Life Span Study cohort members2-4 and a self-administered food-frequency questionnaire based on the frequency of consumption of 22 dietary items (FFQ22) was conducted in 1980-81. Since then, two decades have passed and the number of chronic diseases cases among the respondents has become sufficient to allow statistical analysis. Recently, three studies on diet and cancer have been published, based on the questionnaire.5-7 However, the validity of the FFQ22 was not considered in these reports, since no study has been specifically designed to measure its per-

Forkhead box protein O1 (FoxO1) is a transcription factor and a critical regulator of angiogenesis. Various environmental stimuli, including growth factors, nutrients, shear stress, oxidative stress and hypoxia, affect FoxO1 subcellular localization and strongly influence its transcriptional activity; however, FoxO1-localization patterns in endothelial cells (ECs) during development have not been clarified in vivo. Here, we reported that FoxO1 expression was observed in three layers of angiogenic vessels in developing mouse retinas and that among these layers, the front layer showed high levels of FoxO1 expression in the nuclei of most tip ECs. Because tip ECs migrate toward the avascular hypoxic area, we focused on hypoxia as a major stimulus regulating FoxO1 subcellular localization in tip cells. In cultured ECs, FoxO1 accumulated into the nucleus under hypoxic conditions, with hypoxia also inducing expression of tip-cell-specific genes, including endothelial-specific molecule 1 (ESM1), which was suppressed by FoxO1 knockdown. Additionally, in murine models, EC-specific FoxO1 deletion resulted in reduced ESM1 expression and suppressed tip-cell migration during angiogenesis. These findings indicated roles for FoxO1 in tip-cell migration and that its transcriptional activity is regulated by hypoxia.

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