Role of supraspinal alpha1-adrenoceptors for voiding in conscious rats with and without bladder outlet obstruction

PURPOSE: Previous studies have shown that spinal alpha1-adrenoceptors can influence voiding in normal rats and in rats with outlet obstruction. Also, at the supraspinal level such receptors may be involved in voiding control. Therefore, we studied in rats the effects on cystometrography of intracerebroventricular administered alpha1-adrenoceptor antagonists. MATERIALS AND METHODS: Continuous cystometry was performed in conscious, freely moving rats with and without bladder outlet obstruction. Cystometric parameters were evaluated before and after intracerebroventricular drug administration. RESULTS: In normal rats intracerebroventricular administration of 8 nmol. kg.-1 prazosin (Pfizer Central Research, Sandwich, United Kingdom) or terazosin (Abbott Laboratories, Abbott Park, Illinois) (nonsubtype selective) caused no change in cystometric parameters. At 24 or 80 nmol. kg.-1 the 2 drugs significantly decreased voiding pressure and increased bladder capacity, voided volume and post-void residual urine volume. Administering vehicle had no effect. In rats with outlet obstruction the drug effects were significantly more pronounced than in normal animals (p <0.05), and urinary retention was produced in 50% of rats receiving prazosin. In normal rats the selective alpha1A-adrenoceptor antagonists KMD 3213 (0.8, 8 and 24 nmol. kg.-1) dose dependently depressed voiding pressure, and increased bladder capacity and voided volume, whereas BMY 7378 (selective for alpha1D-adrenoceptors) and A322312 (selective for alpha1B-adrenoceptors) at doses up to 80 nmol. kg.-1 had no effect. CONCLUSIONS: The results suggest that in normal rats and in rats with outflow obstruction volume induced bladder activity involves supraspinal alpha1-adrenoceptors. Bladder outlet obstruction seems to enhance the importance of these receptors. At least in normal rats the alpha1A-adrenoceptor subtype seems to mediate the effect.     

Importance of transition zone biopsies in patients undergoing ultrasound-guided prostate systemic biopsies for the first time

INTRODUCTION: We analyze the efficacy of routine transition zone biopsies in patients undergoing ultrasound-guided systemic prostate biopsies for the first time because of a suspicious digital rectal examination or an elevated serum prostate-specific antigen (PSA) level. PATIENTS AND METHODS: During systemic prostate biopsy two or four additional transition zone biopsies were performed in 192 consecutive patients: in 182 because of a serum PSA concentration >4.1 ng/ml and in 10 because of a suspicious digital rectal examination and a serum PSA level <4.0 ng/ml. RESULTS: The overall prostate cancer detection rate was 37.5% (72/192). In 24 patients (33.3%), cancer was only detected in the peripheral zone, in 3 (4.2%) only in the transition zone, and in 45 (62.5%) in both zones. CONCLUSION: Transition zone biopsies performed at the first time of systemic prostate biopsy seem to have a low efficacy.     

Hepatic recurrence after prophylactic hepatic arterial infusion of 5-fluorouracil for Dukes' C colorectal cancer--correlation with the expression of dihydropyrimidine dehydrogenase in the primary tumor

PURPOSE: The purpose of this study was twofold: (1) to disclose the intermediate outcome of a non-randomized trial of prophylactic hepatic arterial infusion chemotherapy (PHAI) for curatively resected Dukes' C colorectal cancer performed between November 1996 and April 2000, and (2) to examine the relationship between the expression of dihydropyrimidine dehydrogenase (DPD) in tumor tissue and the efficacy of this chemotherapy. PATIENTS AND METHODS: The oncological outcomes were compared between patients (n = 28) receiving PHAI (5-FU: 500 mg/body/w x 50 cycles) plus oral administration of UFT-E (400 mg/body/day, for 24 months) and those (n = 21) receiving UFT-E alone. The levels of tumoral DPD were determined in a total of 43 patients (n = 25, PHAI group; n = 18, control group) by an enzyme-linked immunosorbent assay. RESULTS: Seven (25%) in the PHAI group and four (19%) in the control group developed liver metastasis postoperatively. The liver metastasis-free survival was not different between the groups (p = 0.94). When the analysis was restricted to patients who developed liver metastasis, the duration from surgery to detecting liver metastasis tended to be longer in the PHAI group (p = 0.09). In addition, the overall survival tended to be better in the PHAI group (p = 0.12). In the control group, the level of DPD was higher in patients who developed liver metastases (n = 4) than in those who did not (n = 14, p = 0.04). However, in the PHAI group, the level of DPD was not different regardless of the occurrence of liver metastases (p = 0.30). CONCLUSIONS: These results suggest that (1) PHAI is unlikely to improve the prognosis of Dukes' C patients remarkably, and (2) the efficacy of this regimen cannot be predicted by determining the levels of tumoral DPD.     

Evaluation of the developing human visual system using flash-visual evoked potential

Flash visual evoked potential (Flash-VEP) is easily recorded in preterm infants. However, its clinical application has not been established due to its great variability in response. Our longitudinal studies on the two components of the N1 wave facilitated peak definition and established normal ranges that are clinically valuable. The N1a (early component of the N1) peak latency decreases at about 4.6 msec/week between 30 and 40 weeks postmenstrual age. A flash-VEP study in the preterm period enables us to observe the neuronal development in the human visual system that normally proceeds in utero. Flash-VEP analyses on preterm infants demonstrated that the decrease in the N1a peak latency reflects the progress of myelination in the visual pathway according to the developmental program irrespective of preterm birth. The developmental changes of the N1 wave configuration reflect the maturation of the neuronal networks in the visual cortex, which is accelerated by extrauterine visual experience. Using improved methodology and peak denomination that we proposed, flash-VEP can be applied to preterm infants safely, and should provide us with neuro-developmental information of the human cerebrum.     

Role of supraspinal tachykinins for volume- and L-dopa-induced bladder activity in normal conscious rats

To clarify the roles of tachykinins in volume-induced micturition and in bladder hyperactivity, presumed to originate from supraspinal structures, normal, female Sprague-Dawley rats were investigated cystometrically before and after intracerebroventricular (i.c.v) administration of RP 67,580, a selective antagonist of NK-1 receptors, and/or SR 48,968, a selective antagonist of NK-2 receptors. The effects of RP 67,580 and SR 48,968 on intra-peritoneal (i.p.) L-dopa-induced bladder hyperactivity were also investigated. I.c.v. administration of RP 67,580 (20 nmol) SR 48,968 (20 nmol) suppressed micturition. Combination of i.c.v. RP 67, 580 (2 nmol) and SR 48,968 (2 nmol) significantly decreased micturition pressure (18%), and increased bladder capacity (26%), micturition volume (18%), and residual volume (223%). In rats pretreated with i.p. carbidopa 50 mg/kg, i.p. L-dopa 50 mg/kg caused bladder hyperactivity that was attenuated by the combination of i.c. v. RP 67,580 (2 nmol) and SR 48,968 (2 nmol). The results suggest that tachykinins, via stimulation of NK receptors in supraspinal structures, are involved in both volume and L-dopa-induced stimulation of bladder activity. This may imply that tachykinins can influence both the supraspinal and spinal control of the urinary bladder. It also implies that supraspinal NK receptors are a possible target for drugs aimed for elimination of bladder hyperactivity mediated via these pathways. Neurourol. Urodynam. 19:101-109, 2000.     

Phase II study of twice-daily high-dose thoracic radiotherapy alternating with cisplatin and vindesine for unresectable stage III non-small-cell lung cancer: Japan Clinical Oncology Group Study 9306.

PURPOSE: To evaluate the efficacy and toxicity of high-dose thoracic radiotherapy (TRT) alternating with chemotherapy (CH) for unresectable stage III non--small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-one patients received TRT with 1.5 Gy twice daily, 5 days a week, on weeks 1, 2, 5, 6, and 9, up to a total dose of 66 to 72 Gy, alternating with cisplatin 80 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1 and 8, repeated every 4 weeks, for two or three courses beginning on week 3. RESULTS: The median (range) total dose of TRT and number of CH courses were 72 Gy (16.5 to 72 Gy) and three (zero to three), respectively. Delay in TRT > or = 5 days was observed in 24 (75%) of 32 patients who completed the projected treatment, due to leukopenia in 12, esophagitis in seven, infection in two, and other causes in three patients. Partial responses were obtained in 36 patients (88%). The median survival time and 3- and 5-year survival rates were 18.4 months, 24%, and 10%, respectively. Grade 3 or 4 leukopenia and esophagitis developed in 32 and seven patients, respectively. Grade 3 or 4 late esophageal toxicity developed in two patients. CONCLUSION: Alternating high-dose TRT and CH for stage III NSCLC produced a high response rate with median and long-term survival comparable to prior trials utilizing standard approaches in this population. Acute and late esophageal toxicity was observed and interruption of TRT was required in most of the patients.     

Increased mutant frequency and altered mutation spectrum of the lacI transgene in Wilson disease rats with hepatitis

The mutant strain Long-Evans Cinnamon (LEC) rat, which accumulates copper in the liver because of a mutation in the Atp7b gene, encoding a copper-ATPase, is a model of Wilson disease. It spontaneously develops hepatitis, and subsequently hepatocellular carcinoma and cholangiofibrosis. Excess intracellular copper has been thought to induce DNA damage through reactive oxygen species produced by Cu (II)/Cu (I) redox cycling, and also by direct interaction with DNA. We have developed lacI transgenic Wilson disease (WND-B) rats by mating LEC with Big Blue F344 rats carrying a lambda shuttle vector harboring the lacI gene. lacI mutations of the livers of C-B heterozygous (Atp7b w/m, lacI) and WND-B homozygous (Atp7b m/m, lacI) rats at 6, 24, and 40 weeks of ages were analyzed. Mutant frequencies in the WND-B rats were 2.0 +/- 0.7 x 10(-5), 5.3 +/- 0.9 x 10(-5), and 5.3 +/- 1.0 x 10(-5), respectively, significantly higher than those of C-B rats. Nucleotide sequence analysis revealed that the frequency of deletion mutations of more than two nucleotides were much higher, 15% in WND-B rats, but only 2% in C-B rats. In addition, the average size of deletion was larger in the former. Loss of oligonucleotide-repeat units was specific and relatively frequent in WND-B rats. This type of mutation might be implicated in the induction of DNA strand scissions by reactive oxygen species. These findings suggest that the increase in mutant frequencies and/or the specific type of mutation according to copper accumulation play a crucial role in hepatocarcinogenesis in LEC rats.