Chikayoshi Masuda

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 (R2 = 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.

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%), χ2 = 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 (R2 = 0.468, p < 0.0001). In only the HD patient group, age and smoking were shown to be independent risk factors of SCI (R2 = 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.

Chemopreventive effects of bovine lactoferrin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis.

Chemopreventive effects of bovine lactoferrin (bLF), which is found at high concentrations in colostrum, on rat bladder carcinogenesis were investigated using a rat bladder medium‐term bioassay. In experiment 1, a total of 80 F344 male rats, 6 weeks old, were divided into 5 groups. Groups 1 and 2 were treated with 0.05%N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) in the drinking water for 8 weeks and after a 1‐week interval, received dietary supplementation with 2% and 0.2% bLF, respectively. Group 3 received 0.05% BBN for 8 weeks and then no treatment. Group 4 was administered 2% bLF alone from week 9, without prior carcinogen exposure. Group 5 was maintained without any treatment throughout the experiment. All rats were killed at the end of week 36. Group 1 demonstrated a significantly decreased multiplicity of the bladder tumors (carcinomas and papillomas) as compared with group 3, Maximum cut surface areas of bladder tumors were also significantly decreased in groups 1 and 2 compared with group 3. No bladder tumors were observed in groups 4 or 5. In experiment 2, a total of 60 rats were divided into two groups (30 rats each); both were treated with 0.05% BBN for 4 weeks and after a 1‐week interval, one received 2% bLF (group 1) and the other, basal diet (group 2) for 4 weeks. Group 1 demonstrated a tendency for decrease of the 5‐bromo‐2′‐deoxyuridine (BrdU) labeling index. bLF was detected in the urine of rats fed bLF by ELISA as well as western blot analysis. The findings indicate that 2% bLF can inhibit BBN‐induced rat bladder carcinogenesis, and that this may be due to bLF in the urine.

Presence of a no-observed effect level for enhancing effects of development of the α-isomer of benzene hexachloride (α-BHC) on diethylnitrosamine-initiated hepatic foci in rats

The dose dependence of the promoting effects of the alpha-isomer of benzene hexachloride (alpha-BHC) on hepatocarcinogenesis was investigated in a medium-term rat liver bioassay (Ito test). A total of 195 F344 male rats, 6 weeks old, were given a single intraperitoneal injection of diethylnitrosamine (DEN) at the start of the experiment and subjected to two-thirds partial hepatectomy at week 3. Two weeks after the administration of DEN, alpha-BHC were fed to rats at doses of 0, 0.01, 0.1, 0.5, 1, 2, 4, 7.5, 15, 30, 60, 125 and 500 ppm in diet for 6 weeks. All surviving animals were killed at week 8, and their livers were examined immunohistochemically for detection of glutathione S-transferase placental form (GST-P)-positive foci, surrogate preneoplastic lesions. Quantitative values for numbers and areas were dose-dependently increased in rats given alpha-BHC at 0.5-500 ppm. However, those for groups treated with 0.01 and 0.1 ppm were decreased, albeit not significantly in comparison to the controls. Cytochrome P450 3A2 (CYP3A2) protein levels and activities showed a good correlation to the number and area of GST-P-positive foci. These results support evidence of hormesis and indicate a no-observed effect level for alpha-BHC promoting potentials may exist regarding rat liver carcinogenesis, which correlates with expression of CYP3A2 in the liver.

Non-carcinogenicity, but Dose-related Increase in Preneoplastic Hepatocellular Lesions, in a Two-year Feeding Study of Phenobarbital Sodium in Male F344 Rats

Phenobarbital sodium (PB) was administered at dietary levels of 0 (control), 8, 30, 125 and 500 ppm to groups of 20 male F344/DuCrj rats for 104 weeks. There were no treatment-related clinical signs or adverse effects on survival rate, body weights, food consumption, and haematology or blood biochemistry data. Statistically significant increases of relative liver weights were found in the 500 and 125 ppm, but not the 30 and 8 ppm groups. Quantitative analysis of glutathione S-transferase placental form positive (GST-P+) hepatocyte foci/areas revealed clear increases limited to the 500 and 125 ppm groups. Western blotting revealed CYP2B1, 2C6 and 3A2 proteins to be also increased only with these high doses. In addition, significant increase of regenerative hepatocellular hyperplasias was noted in the 500 ppm group. No hepatocellular adenomas were observed, but a hepatocellular carcinoma arose in single rats of the 8 ppm and 125 ppm groups. No treatment-related changes were found in any other organs or tissues. Thus, under the experimental conditions used, the highest dose of PB (500 ppm) was not carcinogenic in male F344 rats. Furthermore, increase in putative preneoplastic proliferative hepatocytic lesions was only noted with 500 and 125 ppm.

Are tobacco use and urine pH indicated as risk factors for bladder carcinoma

Abstract Background: Many case‐control and cohort studies have shown a positive relationship between bladder carcinoma and tobacco use. Recently, urine pH has been reported to influence aromatic amine carcinogenesis, which have been implicated as potent carcinogens in bladder carcinoma patients. Herein the correlation between bladder carcinoma, tobacco use and urine pH is reported.

p53 status in multiple human urothelial cancers: assessment for clonality by the yeast p53 functional assay in combination with p53 immunohistochemistry.

Multifocal synchronous or metachronous tumor development is a common observation in human urothelial cancer cases. However, the underlying mechanism has remained obscure. We have employed a new tool to investigate the p53 gene status, the yeast p53 functional assay, in combination with immunohistochemistry in a total of 50 tumor samples from 32 cases with urothelial cancers, including 8 with multiple synchronous tumor development and 2 demonstrating metachronous tumors. p53 mutations were found in 13 cases (9 with missense mutations, 3 with deletion, 1 with splicing mutation) by the yeast p53 functional assay. p53 protein overexpression was seen in all 9 cases with missense mutations, but in only one of the 4 cases with nonsense mutations. Two tumors without p53 mutation also showed positive p53 immunoreactivity. Overall, p53 abnormalities including mutations and/or protein overexpression were found in 15 (47%) cases. p53 abnormalities were significantly more frequent in non‐papillary and in high grade tumors. Loss of the wild type allele in addition to a p53 mutation was suggested in 8 of the 15 (53%) cases. All 4 cases with mutations in multiple synchronous tumors had identical p53 mutations in the separate urothelial cancers, strongly suggestive of monoclonality. The one case with multiple metachronous tumors, in contrast, was characterized by variation in the p53 status, indicative of different clonal origins. In conclusion, combined assessment for p53 status as used here (yeast p53 functional assay plus immunohistochemistry) may provide insights into the molecular mechanisms of urothelial carcinogenesis.

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.

Comparative study of transurethral laser prostatectomy versus transurethral electroresection for benign prostatic hyperplasia.

Background: Transurethral resection of the prostate (TURP) is the gold standard treatment for benign prostatic hyperplasia (BPH). Recently, less invasive transurethral laser prostatectomy, such as visual laser ablation (VLAP) or interstitial laser coagulation (ILCP), have been developed. Herein, we investigated the efficacy of VLAP and ILCP compared to TURP.

Primary Retroperitoneal Pure Yolk-sac Tumor in an Adult Male

Pure extragonadal tumors are rare in adult males. A 24-year-old male with an extremely high level of serum f -fetoprotein (32.795 ng/ml) was diagnosed by abdominal computed tomography as having a retroperitoneal tumor. A case of primary retroperitoneal pure yolk-sac tumor in an adult male is described.Pure extragonadal tumors are rare in adult males. A 24-year-old male with an extremely high level of serum alpha-fetoprotein (32.795 ng/ml) was diagnosed by abdominal computed tomography as having a retroperitoneal tumor. A case of primary retroperitoneal pure yolk-sac tumor in an adult male is described.