Relationship between penile hemodynamic parameters assessed by color Doppler ultrasonography and penile rigidity recorded by the RigiScan Plus

OBJECTIVE: We studied the relationship between penile hemodynamic parameters assessed by color Doppler ultrasonography and penile rigidity estimated by objective measurement. PATIENTS AND METHODS: A total 37 patients with erectile dysfunction were examined. After intracavernous injection of 20 microg prostaglandin E1, we measured their penile hemodynamic parameters in the cavernous arteries by color Doppler ultrasonography. Simultaneously, the RigiScan Plus device was used for real-time evaluation of penile rigidity. Hemodynamic parameters were correlated with penile rigidity. RESULTS: Peak systolic velocity and resistive index were significantly correlated with penile tip (r = 0.54, r = 0.72, respectively) and base (r = 0.55, r = 0.76, respectively) rigidity; there was no significant correlation between end-diastolic velocity and penile rigidity. CONCLUSIONS: Peak systolic velocity and resistive index were strongly correlated with penile rigidity in patients with erectile dysfunction during intracavernous pharmacological testing. The resistive index in particular appeared to be the most valid parameter for assessment of penile rigidity.     

Oxidative DNA damage induced by a melatonin metabolite, 6-hydroxymelatonin, via a unique non-o-quinone type of redox cycle

Melatonin, an indolic pineal hormone, is produced primarily at night in mammals and is important in controlling biological rhythms. Although melatonin is known to be effective as a free radical scavenger and has an anti-cancer effect, carcinogenic properties have also been reported. In relation to its carcinogenic potential, we have examined whether 6-hydroxymelatonin, a major melatonin metabolite, can induce DNA damage in the presence of metal ion using [32P]-5'-end-labeled DNA fragments obtained from genes relevant to human cancer. 6-Hydroxymelatonin induced site-specific DNA damage in the presence of Cu(II). Formamidopyrimidine-DNA glycosylase treatment induced cleavage sites mainly at G residues of the 5'-TG-3' sequence, whereas piperidine treatment induced cleavage sites at T mainly of 5'-TG-3'. Interestingly, 6-hydroxymelatonin strongly damaged G and C of the 5'-ACG-3' sequence complementary to codon 273 of the p53 gene. These results suggest that 6-hydroxymelatonin can cause double-base lesions. DNA damage was inhibited by both catalase and bathocuproine, Cu(I)-specific stabilizer, suggesting that reactive species derived from the reaction of H2O2 with Cu(I) participate in DNA damage. Cytochrome P450 reductase efficiently enhanced 6-hydroxymelatonin-induced oxidative DNA damage and oxygen consumption, suggesting the formation of redox cycle. It is noteworthy that 6-hydroxymelatonin can efficiently induce DNA damage via non-o-quinone type of redox cycle. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in calf thymus DNA was significantly increased by 6-hydroxymelatonin in the presence of Cu(II). Furthermore, 6-hydroxymelatonin significantly increased the formation of 8-oxodG in human leukemia cell line HL-60 but not in HP100, a hydrogen peroxide (H2O2)-resistant cell line derived from HL-60. The 6-hydroxymelatonin-induced 8-oxodG formation in HL-60 cells significantly decreased by the addition of bathocuproine or o-phenanthroline. Therefore, it is concluded that melatonin may exhibit carcinogenic potential through oxidative DNA damage by its metabolite.     

Comparison of intraperitoneal continuous infusion of floxuridine and bolus administration in a peritoneal gastric cancer xenograft model

Purpose To identify the optimal schedule for intraperitoneal (i.p.) infusion of floxuridine (FUDR) against peritoneal micrometastases from gastric cancer.Methods The efficacy of continuous i.p. infusion of FUDR was compared with that of bolus i.p. administration in peritoneal gastric cancer (MKN45) xenografts. The FUDR continuous delivery system in this study was in the form of injectable poly(lactic-coglycolic) acid (PLGA) microspheres intended for i.p. injection. Animals were treated by continuous i.p. infusion using FUDR-loaded microspheres or bolus i.p. administration of FUDR.Results In vitro testing demonstrated that FUDR was released slowly from the microspheres at a rate of approximately 5% of the total encapsulated drug per day. In in vivo studies, the peritoneal level was found to persist and was approximately 5- to 50-fold higher than that of plasma for more than 2 weeks following a single injection of the microspheres. An in vitro MTT assay showed that exposure time clearly influenced the cytotoxic potency of FUDR. In vivo, continuous infusion was more effective against peritoneal tumor than bolus administration at equivalent doses. However, compared with bolus administration, toxicity was increased, resulting in a reduced maximum tolerated dose (MTD) with continuous infusion. When the treatment was carried out at each MTD (continuous 1 mg/kg, bolus 600 mg/kg), continuous infusion had no advantage in inhibiting tumor growth.Conclusions Owing to the higher toxicity and the equal efficacy of continuous infusion compared with bolus administration, continuous infusion is not recommended in i.p. FUDR treatment.This study was supported in part by a grant from the Japan Society for the Promotion of Science and by a grant from the Setsuro Fujii Memorial Osaka Foundation for Promotion of Fundamental Medical Research.     

Mechanism of carcinogenesis induced by a veterinary antimicrobial drug, nitrofurazone, via oxidative DNA damage and cell proliferation

Nitrofurazone, a veterinary antimicrobial drug, causes mammary and ovarian tumors in animals. We investigated the mechanisms of carcinogenesis by nitrofurazone. Nitrofurazone significantly stimulated the proliferation of estrogen-dependent MCF-7 cells. Nitrofurazone caused Cu(II)-mediated damage to 32P-5'-end-labeled DNA fragments obtained from human genes only when cytochrome P450 reductase was added. DNA damage was inhibited by catalase and bathocuproine. DNA damage was preferably induced at the 5'-ACG-3' sequence, a hotspot of the p53 gene. These findings suggest that nitrofurazone metabolites are involved in tumor initiation through oxidative DNA damage and nitrofurazone itself enhances cell proliferation, leading to promotion and/or progression in carcinogenesis.     

Significance of working environment improvement based on determination of source of harmful substance--example of an endoscope syringe room using glutaraldehyde

Because a worker complained of irritated eyes and throat due to glutaraldehyde (GA) in an endoscope syringe room, the automated endoscope washers and GA liquid stored in reserve were isolated in a separate room. A ventilation system was installed in this room, and the packing of the automated endoscope washers was changed. However, since the obnoxious smell of GA still remained in the endoscope syringe room, we had to determine the source of the smell. A plastic bucket with a cap was found to be filled with GA for disinfection of the endoscope apparatus. GA had evaporated when dispersed around the bucket, resulting in the obnoxious smell. The plastic bucket was replaced with a different type of container. Moreover, GA from the separate room did not affect the concentration of GA in the working area because the separate room for the automated endoscope washers had twice the ventilation volume proposed by the guidelines of the Society of Gastroenterology Nurses and Associates of the USA and the Healthcare Engineering Association of Japan. Consequently, we reconfirmed the significance of working environment improvement after clarifying the source of the harmful substance.     

Diagnostic significance of serum soluble transferrin receptors in various anemic diseases: the first multi-institutional joint study in Japan

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 +/- 7.04 mg/l, n = 52, p < 0.0001), anemia of chronic disorders (ACD) (3.45 +/- 1.38 mg/l, n = 20, p < 0.0001), hemolytic anemia (HA) (5.57 +/- 3.26 mg/l, n = 17, p < 0.0001), and myelodysplastic syndrome (MDS) (4.03 +/- 2.83 mg/l, n = 20, p < 0.0001). There were significant differences between IDA and ACD (p < 0.0001), between aplastic anemia (AA) (1.58 +/- 1.26 mg/l, n = 16) and MDS (p < 0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 +/- 3.40 mg/l, n = 9) (p < 0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p < 0.0001) and the sTfR/F index (p < 0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p < 0.0001) compared with serum sTfR (p < 0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.     

Laparoscopic ablation of peripelvic renal cysts

Recently, laparoscopic surgery has been reported for symptomatic renal cysts. A 60-year-old female was referred to Toyama Medical and Pharmaceutical University Hospital with a chief complaint of general fatigue and left back pain. CT demonstrated bilateral peripelvic renal cysts, and DIP demonstrated left hydronephrosis and a medical shift of the left renal pelvis. Laparoscopic ablation of bilateral peripelvic renal cysts was performed under general anesthesia and a round excision was made in the cyst wall via the peritoneum. After surgery, the left back pain disappeared and CT demonstrated resolution of peripelvic renal cysts. Laparoscopic ablation of peripelvic renal cyst is a highly effective and minimally morbid procedure.     

Metastatic prostate cancer with normal level of serum prostate-specific antigen

The clinical and pathological features of metastatic prostate cancer with normal level of serum prostate-specific antigen (PSA) were investigated. Four patients with metastatic prostate cancer had serum PSA within the normal range at the diagnosis. All tumors were poorly-differentiated adenocarcinoma. Endocrine therapy was performed as the initial therapy in all patients. Despite subsequently treatment, all cases died of prostate cancer at 2, 8, 9 and 38 months. During disease progression, 3 of 4 patients had elevated serum markers such as carcinoembryonic antigen (CEA), CA19-9, CA15-3, CA125, neuron-specific enolase and pro-gastrin releasing peptide. Immunohistochemical examination of the initial biopsy specimens revealed that 4 and 3 cases were positive for CEA and chromogranin A, respectively. In advanced prostate cancer patients with low PSA level, those markers may aid in the follow up of disease.     

Oxidative DNA damage induced by benz[a]anthracene metabolites via redox cycles of quinone and unique non-quinone

Benz[a]anthracene (BA) is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) that are ubiquitous environmental pollutants. PAH carcinogenesis is explained by DNA adduct formation by PAH diol epoxide and oxidative DNA damage by PAH o-quinone. Benz[a]anthracene-trans-3,4-dihydrodiol (BA-3,4-dihydrodiol) is a minor metabolite but shows higher mutagenicity and tumorigenicity than parent BA. We confirmed that a BA o-quinone type metabolite, benz[a]anthracene-3,4-dione (BA-3,4-dione), induced oxidative DNA damage in the presence of cytochrome P450 reductase. Interestingly, we found that BA-3,4-dihydrodiol nonenzymatically caused Cu(II)-mediated DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation and the addition of NADH enhanced DNA damage. BA-3,4-dihydrodiol induced a double-base lesion of C and G at the 5'-ACG-3' sequence complementary to codon 273 of the human p53 tumor suppressor gene, which is known as a hotspot. The DNA damage was inhibited by catalase and bathocuproine, indicating the involvement of H(2)O(2) and Cu(I). Time-of-flight mass spectroscopic study suggested that BA-3,4-dihydrodiol undergoes Cu(II)-mediated autoxidation leading to the formation of its hydroxylated form of BA-3,4-dihydrodiol, capable of causing oxidative DNA damage. It is noteworthy that BA-3,4-dihydrodiol can nonenzymatically induce DNA damage more efficiently than BA-3,4-dione with metabolic activation. In conclusion, oxidative DNA damage induced by BA-3,4-dihydrodiol not only via quinone-type redox cycle but also via a new type of redox cycle participates in the expression of carcinogenicity of BA and BA-3,4-dihydrodiol.