Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice

In this study, we investigated the carcinogenic response oftransgenic mice carrying the human prototype c-Ha-ras gene,namely Tg rasH2/CB6F1 mice, to various genotoxic carcinogensand compared it with that of control non-transgenic CB6F1 mice(non-Tg mice). The present studies were conducted as the firststep in the evaluation of the Tg rasH2/CB6F1 mouse as a modelfor the rapid carcinogenicity testing system. Short-term (     

Gonadal toxicity of an ethanol extract of Psoralea corylifolia in a rat 90-day repeated dose study

Ethanol extracts of seeds of Psoralea corylifolia are proposed as food additives for processed food preservation. An extract was administered by admixing into diet at concentrations of 0, 0.375, 0.75, 1.5 or 3.0% to 10 male and 10 female F344 rats each for 90 days to evaluate its toxicity. Body weight gain, food consumption and food conversion efficiency (body weight gain per food consumption) were lower in the extract-treated animals, except for the 0.375% males, as compared to the control animals. Absolute and/or relative testes weights in the 1.5 and 3.0% groups and those of ovaries in the 3.0% group were significantly (p < 0.01) lower than in the control group. On histopathological examination, seminiferous tubular atrophy and Leydig cell atrophy in the testes, and epithelial cell atrophy in the seminal vesicles and prostate were observed in the 1.5 and 3.0% males. Decrease in the number of corpora lutea associated with frequent necrotic follicles in the ovaries in the 1.5 and 3.0% females and less frequent endometrial glands in the uterus in the 3.0% females were also detected. These results might suggest disruption of the hypothalamus-pituitary-gonadal axis in Psoralea corylifolia-treated rats as possible mechanisms underlying this gonadal toxicity.     

Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis

BACKGROUND: Pulse pressure (PP) has been shown as a risk factor for mortality or cardiovascular events in several studies. However, the impact of PP on prognosis in a cohort of chronic hemodialysis patients has not been sufficiently studied. We examined the effect of PP on total mortality and cardiovascular events in chronic hemodialysis patients, and whether PP adds useful value to systolic blood pressure (SBP) or diastolic blood pressure (DBP) for predicting total mortality and cardiovascular events in chronic hemodialysis patients. METHODS: Chronic hemodialysis patients (N=1243, 720 men, 523 women) alive on January 1, 1991 at baseline were involved in this study. Cox regression, adjusted for age, sex, and other risk factors, was used to assess the relation between blood pressure components and risk of death and cardiovascular events over a nine-year follow-up. RESULTS: The association with the risk of total mortality was positive for PP (P=0.002) and SBP (P=0.04), but not significant for DBP (P=0.4), considering each pressure individually (single blood pressure component model, SPM); of the three measurements, PP yielded the highest chi2 value. When SBP and DBP were jointly entered into the Cox regression model (dual blood pressure component model, DPM), the association with the risk of total mortality was positive for SBP (HR, 1.083; 95% CI, 1.030 to 1.137) and negative for DBP (HR, 0.886; 0.808 to 0.970). After the addition of diabetes mellitus as an adjusted variable to the model, PP was not a significant predictor for total mortality; PP was a significant predictor for total mortality in non-diabetic patients, but not in diabetic patients. PP was positively associated with the risk of stroke, and stroke and AMI; however, predictive value of PP for each endpoint was not superior to SBP and DBP in SPM. In DPM with SBP and DBP, the association with the risk of stroke and acute myocardial infarction (AMI) was positive for SBP (P=0.02) but not significant for DBP (P=0.5). In DPM with SBP and PP, the association with the risk of stroke and AMI was positive for SBP (P=0.01) but not significant for PP (P=0.5). CONCLUSIONS: In non-diabetic patients on chronic hemodialysis, PP was an independent predictor of total mortality. PP was more potent predictor of total mortality than SBP or DBP. For predicting cardiovascular events, SBP was superior to PP or DBP.     

Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients

BACKGROUND: Although hypocholesterolemia is common in chronic hemodialysis patients, its effect on survival has not been studied in a large patients population. METHODS: A cohort of chronic hemodialysis patients (N = 1167) was prospectively followed from January 1991 to January 2001. The survival impact of this cohort, who were divided according to different baseline levels of serum cholesterol, were calculated with the multivariate Cox proportional hazard analysis after adjusting for baseline clinical and laboratory variables. RESULTS: During the study period, 567 (48.6%) patients died. The mean (SD) baseline level of serum cholesterol was 171.0 (40.8) mg/dL and ranged from 76 to 378 mg/dL. The five-year survival rate was highest (0.812) in the subgroup that had a serum cholesterol range of 200 to 219 mg/dL and was lowest (0.608) in the subgroup with serum cholesterol values of <140 mg/dL. The five-year survival rate was 0.735 in the subgroup with serum cholesterol of > or =220 mg/dL. Serum cholesterol was a significant predictor of death with an adjusted hazards ratio (95% confidence interval) was 0.939 (0.891 to 0.989). In a subgroup of patients with serum albumin values > or =4.5 g/dL (N = 128), the adjusted hazards ratio was even greater at 1.370 (1.105 to 1.692). Other than sex, body mass index and serum albumin were significant determinants of baseline levels of serum cholesterol. CONCLUSIONS: Hypocholesterolemia was an independent predictor of death in patients on chronic hemodialysis. This impact of hypercholesterolemia on survival was only evident in a subgroup of patients whose serum albumin was more than 4.5 g/dL.     

Season of birth in Japanese patients with schizophrenia

A number of North American and European studies have observed a higher proportion of winter births in schizophrenia patients. Fewer studies have investigated this issue in Asian populations, and the findings are not as consistent as in the studies of Western populations. A statistically significant excess of winter births has not been observed in Japanese or Korean studies, while some of the studies found a decreased number of summer births among their patients. We further investigated the issue in Japanese patients with schizophrenia (n=2985). No significant excess of winter births was observed. Spearman correlation between schizophrenia births and ambient temperature was not significant. However, a decrease in the summer births was found, consistent with most of the previous Japanese studies. When analyzed by gender, a decrease in summer births was found in males, but not in females. In addition, a trend towards an increase in winter births was observed and Spearman correlation between low ambient temperature and schizophrenia births was significant in male subjects. More significant seasonality of birth in male patients than in female patients might be related to more susceptibility to pre- or perinatal disturbances in neurodevelopment in males than in females.     

Ribozyme mediated suppression of vascular endothelial growth factor gene expression enhances matrix metalloproteinase 1 expression in a human hepatocellular carcinoma cell line

The levels of expression of various genes were altered in cellular transformants with manipulation of expression of single genes. Vascular endothelial growth factor A (VEGF-A) is a key molecule for tumor progression, although it is unclear how VEGF-A expression regulates various genes. Multiple gene expression levels were evaluated using cDNA arrays in a human hepatocellular carcinoma cell line (HLF) with suppression of the VEGF-A gene by anti-VEGF-A ribozyme (alphaVRz). The ribozyme-mediated suppression of VEGF-A gene solely up-regulated matrix metalloproteinase 1 (MMP1) gene level in HLF/alphaVRz. Levels of expression of other members of MMP family or tissue inhibitors of MMPs did not show any alteration. These results suggested that intracellular suppression of VEGF-A gene was specifically linked to up-regulation of MMP1 in human hepatocellular carcinoma cells.     

Assessment of renal toxicity by analysis of regeneration of tubular epithelium in rats given low-dose cadmium chloride or cadmium-polluted rice for 22 months

To determine whether low-dose oral administration of cadmium (Cd) induces renal toxicity, six groups of female Sprague-Dawley rats were fed a diet containing low amounts of CdCl2 or Cd-polluted rice at concentrations up to 40 ppm, and were killed after 12, 18, and 22 months (experiment 1). In addition to the determination of cortical Cd levels and histopathological assessment of kidneys, labeling indices (LIs) for proliferating cell nuclear antigen (PCNA) in the renal cortical tubular epithelium of Cd-treated rats were determined as a measure of regenerative activity. For comparison, the kidneys of rats given diets containing small to large amounts of CdCl2 up to 600 ppm for 4 months were similarly examined (experiment 2). Animals in experiment 1 demonstrated spontaneous chronic nephropathy and fluctuation in the tubular PCNA LI, but these findings were not correlated with renal Cd levels at 22 months. PCNA LI on the other hand, appeared to be linked to the severity of chronic nephropathy. In experiment 2, levels of CdCl2 of 200 ppm or more clearly induced degeneration and apoptosis of proximal tubules with high correlations between renal Cd levels, PCNA LI, and the severity of tubular degeneration. The results demonstrated that, in contrast to high-dose Cd administration, treatment with 40 ppm or less for 22 months did not influence tubular regeneration as a component of nonspecific chronic nephropathy, suggesting that long-term oral administration of low levels of Cd does not injure renal tubules in female rats.     

Involvement of apoptosis in the rat germ cell degeneration induced by nitrobenzene

Nitrobenezene (NB) produces germ cell degeneration, especially of spermatocytes in rats. To examine the possible involvement of apoptosis in this process, the extent and nature of nuclear DNA fragmentation after NB dosing were assessed using both terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and DNA gel electrophoresis, in addition to conventional histological and electron microscopic procedures. Adult Sprague Dawley rats were treated with a single oral dose of NB (250 mg/kg) and euthanized subsequently at 6, 12, and 24 h and 2, 3, 5, and 7 days. The earliest morphological signs of germ cell degeneration in testes were found in pachytene spermatocytes 24 h after dosing. Electron micrographs of degenerating spermatocytes showed marked nuclear chromatin condensation at the nuclear periphery and crowding of cytoplasmic constituents, which are characteristic of apoptosis. Coincident with the appearance of such morphological changes, degenerating spermatocytes contained fragmented DNA as revealed by TUNEL. The presence of DNA laddering, a hallmark of apoptosis on gel electrophoresis, was first apparent and most prominent at 24 h, gradually becoming less detectable. No such changes were observed up to 12 h after dosing or in control animals. These results demonstrated unequivocal involvement of apoptosis in the induction of germ cell degeneration caused by NB. Received: 29 September 1997 / Accepted: 6 January 1998     

Possible enhancing effects of atrazine on growth of 7,12-dimethylbenz(a) anthracene-induced mammary tumors in ovariectomized Sprague-Dawley rats

Atrazine, one of the most commonly used herbicides in the world, has been reported to have endocrine disrupting effects in vivo. In the present experiment, influence of dietary atrazine on the late promotion/progression stage of mammary carcinogenesis in ovariectomized female Sprague-Dawley rats was examined after a single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA). When the incidence of palpable mammary tumors reached about 50%, the animals were subjected to ovariectomy and divided into tumor bearing [DMBA-Tumor(+)] and non-tumor bearing [DMBA-Tumor(-)] groups, with subgroups of each fed a soybean-free diet containing 0, 5, 50, or 500 p.p.m. atrazine for 34 weeks. At the completion of the study, the tumor volume in the 50 and 500 p.p.m. treatment Tumor(+) subgroups was greater than in the 0 p.p.m. control case. In the DMBA-Tumor(-) group, higher incidences and volumes of the mammary tumors, with or without statistical significance (P <0.05), were observed in the 50 and 500 p.p.m. subgroups. Atrazine treatment tended to increase proportion of estrogen receptor alpha-positive tumors and stimulated cell proliferation in the DMBA-Tumor(+) group, but with no clear effects on serum hormone levels. The present study indicates that atrazine has a potential for enhancing the growth of mammary tumors, partly through increasing cell proliferation in the promotion/progression stage in female rats under ovarian hormone-free conditions.     

Factors influencing the development of end-stage renal disease

Epidemiological evidence is needed to design effective strategies for preventing chronic kidney disease (CKD) and end-stage renal disease (ESRD). Several types of health check are routinely performed in Japan, including the screening of asymptomatic individuals, but the potential benefits of these procedures remain unknown. We evaluated the predictors of ESRD, using community-based mass screening and a dialysis registry. This approach revealed the significance of proteinuria, hypertension, obesity, anemia, and high fasting plasma glucose levels (which indicate diabetes mellitus; DM), for the risk of developing ESRD. Lifestyle-related factors, such as smoking, alcohol consumption, and low levels of exercise, are also associated with these conditions and, in particular, with a high risk of ESRD. Over-nutrition and low levels of exercise can ultimately lead to DM, hypertension, hyperlipidemia, and obesity, and are important risk factors worldwide for cardiovascular diseases, CKD, and ESRD. The early detection and treatment of predictors of ESRD, along with appropriate treatment for CKD, may decrease the incidence of ESRD. In addition, the economic burden caused by the costs of dialysis presents a compelling argument for implementing a cost-effective preventive strategy against ESRD.