Lack of preventive efficacy of FK228, a histone deacetylase inhibitor, against N-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder carcinogenesis in p53+/- and p53+/+ mice.

BACKGROUND: The efficacy of FK228, a histone deacetylase inhibitor that is currently under early clinical trials for cancer therapy, against N-butyl-N-(4-hydroxybutyl)- nitrosamine (BBN) -induced mouse urinary bladder carcinogenesis was examined. MATERIALS AND METHODS: Heterozygous p53-deficient (p53+/-) and wild-type (p53+/+) mice were given FK228 (0, 0.01 and 0.1 mg/kg i.p., 3 times/week, respectively) after 10 weeks of 0.05% BBN treatment, and were sacrificed at 22 and 24 weeks after the start, respectively. RESULTS: There was no significant difference in the incidence of urinary bladder tumors among groups in the p53+/- or p53+/+ mice, although the high dose of FK228 increased the p21WAF1 mRNA expression in urinary bladder cancers in animals of both genotypes. CONCLUSION: The present data indicate a lack of any inhibitory effects of FK228 on BBN-induced mouse urinary bladder carcinogenesis under the present conditions.

The prognostic role of atrial natriuretic peptides in hemodialysis patients.

BACKGROUND: It is well known that plasma atrial natriuretic peptide (ANP) is an indicator of extracellular fluid volume expansion and that plasma ANP is considered to be a marker for setting the proper dry weight of HD patients. Although the plasma ANP is a prognostic predictor of cardiac death, the prognostic role of ANP in HD patients has yet to be elucidated. In this study, we investigated the prognostic role of ANP in HD patients. METHODS: Plasma ANP concentrations were measured in 105 HD patients after HD. Multiple regression analysis was performed to determine the major factors causing increased plasma ANP concentrations. Cardiac mortality was monitored for 24 months after baseline analysis, and the prognostic role of ANP was examined by Cox proportional hazards regression analysis. RESULTS: Multiple regression analysis showed that cardiovascular disease (CD) and age were independent factors for elevated ANP (R2 = 0.298, p < 0.0001). During a 24-month follow-up period, cardiac death occurred in 11 patients. Kaplan- Meier survival estimates of patients from varying plasma ANP levels (<50 and >50 pg/ml) differed between the two groups (p < 0.0001). The group with the higher ANP level (>50 pg/ml) had the lower survival. When compared with patients with ANP <50, the hazard ratios for cardiac death of patients with ANP of >50 pg/ml were 32.0 (95% confidence interval (CI) 4.1 to 252.4). Univariate Cox proportional hazards model showed that ANP, left ventricular ejection fraction (LVEF), LVMI, age, serum albumin and C-reactive protein (CRP) were significantly associated with the risk of cardiac mortality. By stepwise multivariate Cox proportional hazards analysis, only ANP, LVMI and CRP remained powerful independent predictors of cardiac death. The relative risk ratios were 3.483 (95% CI 1.640-7.397) for ln ANP, 1.023 (1.008-1.038) for LVMI, and 1.379 (1.115-1.705) for CRP. CONCLUSION: High plasma ANP level of post-HD were strongly associated with CD and age. Post-HD ANP level may be a reliable parameter for assessing the risk for cardiac death in HD patients by providing prognostic information independent of other variables previously reported.

No inhibition of urinary bladder carcinogenesis in rats with intravesical instillation of alpha-galactosylceramide.

The immunostimulatory a-galactosylceramide, KRN 7000 ((2S,3S,4R)-1-O-(a-D-galactopyranosyl)-2-(N-hexacosnoylamino)-1,3,4-octadecatrienol), may be anticipated to have antitumor activity in vivo apart from any direct toxicity to cancer cells. In this experiment, inhibition of rat bladder carcinogenesis by intravesically instillated KRN7000 was investigated. Male Fischer 344 rats, 6-weeks-old at the start, were divided into 4 groups, all first receiving the carcinogen, 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine, in their drinking water for 12 weeks. Then groups 1 and 2 respectively were administered 500 and 50 mg/kg of KRN7000 intravesically once weekly for 17 weeks. Group 3 similarly received only 0.3 micro/l of saline (vehicle control). Group 4 did not undergo bladder catheterization. On macroscopic examination at 30 weeks, multiplicities and sizes of bladder tumors in the KRN 7000 high and low-dose groups were not significantly different from those of the vehicle control group. Histologic examination confirmed no significant variation in incidences of carcinomas or preneoplastic lesions in the bladder among groups 1 to 4. Thus the results indicate that intravesical instillation of KRN7000 does not inhibit bladder carcinogenesis in rats.

Asymptomatic occlusive lesions of cerebral arteries in Japanese hemodialysis patients.

While cerebrovascular diseases (CVD) are very common in hemodialysis (HD) patients, the prevalence and risk factors of asymptomatic occlusive lesions (AOL) of cerebral arteries in HD patients have not yet been elucidated. We performed cerebral magnetic resonance angiography (MRA) on 123 HD patients without symptomatic cerebrovascular disease and on 52 control subjects. On the basis of these images, we investigated the prevalence and risk factors of AOL. Stenosis greater than 25% narrowing of the cerebral arteries was found in 27 HD patients. The prevalence of AOL of cerebral arteries in HD patients was significantly higher than in the control group [27 (22.0%) versus 4 patients (7.7%), chi.2=4.2, p=0.0411]. Multiple logistic regression analysis showed that independent risk factors of AOL of cerebral arteries were uremic state, dyslipidemia, and age in all subjects and dyslipidemia and age in HD patients (R.2=0.162, p=0.0004; R.2 =0.138, p=0.0145, respectively). Our findings suggest that chronic renal failure maintained by hemodialysis increases the prevalence of AOL, and that age and dyslipidemia are also significantly associated with AOL in HD patients.

Silent cerebral infarction in hemodialysis patients.

BACKGROUND: Cerebrovascular diseases are very common in hemodialysis (HD) patients. Silent cerebral infarction (SCI) has not been investigated in HD patients although it may be a significant risk factor for cerebrovascular diseases. HYPOTHESIS: Chronic renal failure may be an independent risk factor for SCI and cerebrovascular diseases. METHODS: Cranial magnetic resonance imaging (MRI) was performed on 123 HD patients without symptomatic cerebrovascular disease and on 52 control subjects. We investigated the prevalence of SCI and performed cross-sectional study using multiple logistic analysis to assess the relationship between SCI and the risk factors. RESULTS: The prevalence of SCI was significantly higher in HD patients than in the healthy control group (60 patients (48.8%) vs. 5 patients (9.6%), chi(2) = 22.4, p < 0.0001). Multiple logistic regression analysis with all subjects showed that independent risk factors of SCI were chronic renal failure, hypertension, smoking and age (R(2) = 0.468, p < 0.0001). In only the HD patient group, age and smoking were shown to be independent risk factors of SCI (R(2) = 0.378, p < 0.0001) while HD duration and hypertension were not. CONCLUSIONS: The findings of the present study indicate that chronic renal failure maintained by hemodialysis increases the prevalence of SCI and that age and smoking habits are also significantly associated with SCI in HD patients.

Unruptured intracranial aneurysms in haemodialysis patients.

While the mortality rate of subarachnoid haemorrhage is very high in haemodialysis (HD) patients, the prevalence of unruptured intracranial aneurysms in HD patients has not yet been elucidated. We performed cerebral magnetic resonance angiography (MRA) on 123 HD patients who did not have symptomatic cerebrovascular disease, and on 52 control subjects. On the basis of these images, the prevalence of unruptured intracranial aneurysms was evaluated. Unruptured aneurysms were found in three HD patients (2.4%). There were no aneurysms found in the healthy control group. There was no significant difference in the prevalence of unruptured aneurysms between HD patients and healthy controls. Therefore, the incidence of intracranial aneurysms is not associated with chronic renal failure.

The prognostic role of brain natriuretic peptides in hemodialysis patients.

BACKGROUND: Although plasma concentrations of brain natriuretic peptides (BNP) increase in hemodialysis (HD) patients as well as patients with cardiovascular diseases (CD), the clinical significance of BNP in HD patients has yet to be elucidated. In this study, we investigated the pathophysiological significance of BNP in HD patients. METHODS: Plasma BNP concentrations were measured in 164 HD patients after HD and 14 healthy volunteers. In 12 patients without CD, BNP was also measured before HD. Multiple regression analysis was performed to determine the important factors causing increased plasma BNP concentrations. Cardiac mortality was monitored for 36 months after baseline analysis, and the prognostic role of BNP was examined by Cox proportional hazards regression analysis. RESULTS: Plasma BNP concentrations of HD patients without CD decreased significantly during HD session (124.5 +/- 90.7 vs. 91.4 +/- 67.6 pg/ml, mean +/- SD, p = 0.004), but were still significantly higher than those of the healthy subjects (9.7 +/- 9.2 pg/ml, p = 0.0002). Plasma BNP concentrations of patients with CD were significantly higher than of those without CD (579.6 +/- 564.3 vs. 204.0 +/- 241.5 pg/ml, p < 0.0001). Plasma BNP concentrations were also significantly higher in diabetes mellitus (DM) patients than in non-DM patients (514.1 +/- 585.4 vs. 296.0 +/- 347.0 pg/ml, p = 0.0031). Multiple regression analysis showed that left ventricular mass index (LVMI), CD and DM were independent factors for the elevated BNP (R(2) = 0.303, p < 0.0001). During a 36-month follow-up period, cardiac death occurred in 13 patients. Kaplan-Meier survival estimates of patients from varying plasma BNP quartiles (<200, 200-450, 450-700 and >700 pg/ml) differed between the four groups (p < 0.0001). The group with the highest BNP level (>700 pg/ml) had the lowest survival. When compared with patients with BNP <200, the hazard ratios for cardiac death of patients with BNP of 200-450, 450-700 and >700 pg/ml were 2.3 [95% confidence interval (CI) 0.14-36.7], 18.7 (1.9-183.4) and 51.9 (6.5-416.3), respectively. The univariate Cox proportional hazards model showed that BNP, left ventricular ejection fraction, LVMI, age, DM, serum albumin and C-reactive protein (CRP) were significantly associated with the risk of cardiac mortality. By stepwise multivariate Cox proportional hazards analysis, only BNP, LVMI and CRP remained powerful independent predictors of cardiac death. The relative risk ratios were 1.002 (95% CI 1.001-1.002) for BNP, 2.192 (1.532-3.135) for CRP and 1.027 (1.013-1.042) for LVMI. CONCLUSION: High plasma BNP concentrations in HD patients were associated with volume overload, left ventricular hypertrophy, CD and DM. Plasma BNP concentration may be a useful parameter for assessing the risk of cardiac death in HD patients by providing prognostic information independently of other variables previously reported.

Significance of brain natriuretic peptides in patients on continuous ambulatory peritoneal dialysis.

It is well known that plasma brain natriuretic peptide (BNP) concentration is elevated in cardiovascular diseases such as congestive heart failure. However, although it has been reported to increase in hemodialysis (HD) patients, little is known about plasma BNP in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Plasma BNP concentrations were measured and compared among CAPD patients (n=32), HD patients (n=63) and healthy volunteers (n=14) as well as those patients without cardiovascular disease. In addition, the correlation between plasma BNP concentration and parameters of echocardiography was examined. Plasma BNP concentration was significantly higher in CAPD patients without cardiovascular disease (n=23) than in healthy volunteers (n=14) (62.1+/-60.6 pg/ml versus 9.7+/-9.7 pg/ml, mean +/- SD, P<0.0001). Furthermore, it had a positive correlation with LVMI (CAPD: r=0.37, P=0.0354; HD: r=0.49, P<0.0001) but a negative correlation with LVEF (CAPD: r=-0.39, P=0.0277; HD: r=-0.40, P=0.0010) in both CAPD and HD patients. When all patients were compared, plasma BNP concentration was significantly lower in CAPD patients (n=32) than in HD patients (n=63) (114.8+/-142.7 pg/ml versus 296.8+/-430.4 pg/ml, P<0.0001). When those patients without cardiovascular disease was compared, it was also significantly lower in CAPD patients (n=23) than in HD patients (n=40) (62.1+/-60.6 pg/ml versus 151.8+/-102.2 pg/ml, P<0.0001). In conclusion, plasma BNP concentration was elevated in CAPD patients and correlated with LVMI and LVEF, suggesting that plasma BNP in CAPD patients may be associated with left ventricular hypertrophy (LVH) and left ventricular systolic dysfunction. In addition, plasma BNP concentration was significantly lower in CAPD patients than in HD patients, suggesting that cardiac load in CAPD patients may be lower than that of HD patients.

Formation of 8-hydroxydeoxyguanosine and cell-cycle arrest in the rat liver via generation of oxidative stress by phenobarbital: association with expression profiles of p21(WAF1/Cip1), cyclin D1 and Ogg1.

To evaluate the risk of exposure to so-called non-genotoxic chemicals and elucidate mechanisms underlying their promoting activity on rat liver carcinogenesis the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), cytochrome P-450 (P-450) and hydroxyl radicals induction, DNA repair and alteration to cellular proliferation and apoptosis in the rat liver were investigated during 2 weeks of phenobarbital (PB) administration at a dose of 0.05%. Significant increase of hydroxyl radical levels by day 4 of PB exposure accompanied the accumulation of 8-OHdG in the nucleus and P-450 isoenzymes CYP2B1/2 and CYP3A2 in the cytoplasm of hepatocytes. Conspicuous elevation of 8-OHdG and apoptosis in the liver tissue were associated with reduction of the proliferating cell nuclear antigen (PCNA) index after 8 days of PB application. Thereafter, 8-OHdG levels decreased with an increase in mRNA expression for the 8-OHdG repair enzyme, DNA glycosylase 1 (Ogg1). Analysis with LightCycler quantitative 2-step RT-PCR demonstrated induction of cyclin D1 (CD1) and p21(WAF1/Cip1) mRNA expression on days 4 and 6, respectively, preceding marked elevation of PCNA and apoptotic indices. These results suggest that similar to genotoxic, non-genotoxic chemicals might induce reversible alteration to nuclear 8-OHdG in the rat liver after several days of continuous application; however, by a different mechanism. Increased 8-OHdG formation is caused by developing oxidative stress or apoptotic degradation of DNA and coordinated with enhanced expression of CD1 mRNA and cell proliferation, subsequent increase of p21(WAF1/Cip1) mRNA expression, cell-cycle arrest and apoptosis, while activation of 8-OHdG repair mechanisms contributes to protection of tissue against reactive oxygen species-induced cell death.