Effects of a new analog of thyrotropin-releasing hormone, N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate (YM-14673) on spinal reflex potentials and flexor reflexes in spinalized rats

Experiments were performed on spinalized rats, transected at the Cl level. The intravenous administration of TRH and its analog YM-14673 (N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate) produced marked increases in the amplitude of mono- and polysynaptic reflex potentials and those of the withdrawal flexor reflexes. The effects of YM-14673 were stronger and longer-lasting than those of TRH. The stimulant action of TRH and YM-14673 on the flexor reflexes was not antagonized by prazosin, chlorpromazine, haloperidol or cyproheptadine, suggesting no involvement of the release of catecholamines or serotonin in the stimulant effects of TRH and its analog. Therefore, YM-14673 may be beneficial for the treatment of several spinal motor neuron diseases.     

Impact of unilateral interposition sural nerve graft on the recovery of sexual function after radical prostatectomy in Japanese men: A preliminary study

PURPOSE: To determine the effect of an interposition nerve graft on sexual function after radical prostatectomy. METHODS: This study includes 64 patients, without hormonal therapy, who underwent a radical prostatectomy and intraoperative electrophysiological confirmation of cavernous nerve preservation. Twelve patients underwent a unilateral interposition sural nerve graft (UNG) for the resected neurovascular bundle. Twenty-one and 31 patients underwent bilateral nerve-sparing (BNS) and unilateral nerve-sparing (UNS) surgery without a nerve graft, respectively. As the age of patients was significantly younger in the UNG group than in the other groups, age-matched analysis also was conducted. Sexual function, evaluated by a self-administered questionnaire using the University of California Los Angeles-Prostate Cancer Index, was compared statistically among the three groups. RESULTS: In the age-matched analysis, the postoperative sexual function (SXF) score of the UNG group showed an intermediate level of recovery between those of the BNS and UNS groups at 12 months and reached the same level as the score at 12 months of the BNS group at 18 months postoperatively. The difference in the SXF score between the UNG and UNS groups began to appear after 6 months postoperatively and increased steadily with time. However, the background factors, such as the baseline SXF score, the usage rate of phosphodiesterase 5 inhibitors, and the rate of comorbidities were different between the UNG and UNS groups. CONCLUSIONS: The difference of the SXF score between the UNG and UNS groups increased with time after 6 months postoperatively. However, it might be difficult at present to attribute a better recovery of the SXF score to the nerve graft because of the difference in the background factors between the groups.     

A female case with Down syndrome and non-neurogenic neurogenic bladder

Although the prevalence of a learned voiding dysfunction and non-neurogenic neurogenic bladder (NNB), which is one type of dysfunctional elimination syndrome, is considered to be relatively rare, the association of NNB with Down syndrome (DS) has been elucidated in male patients. We herein describe the occurrence of NNB in an adult female with DS. The diagnosis was confirmed after completely ruling out any neurological or anatomical anomalies that could be related to a lower urinary tract dysfunction. She had renal dysfunction and multiple obstructive uropathies for which clean intermittent catheterization was successfully introduced.     

The Japan Morning Surge-1 (JMS-1) study: protocol description.

Morning blood pressure is reported to be more closely related to hypertensive organ damages such as left ventricular mass index, microalbuminuria and silent cerebral infarcts, than blood pressure at other times of the day. Morning blood pressure may play an important role in the pathogenesis of hypertensive target organ damage. Increased sympathetic nerve activity is reported to be one of the mechanisms of morning hypertension; however, there are no available data that show whether strict home blood pressure control, especially in the morning period, can reduce target organ damage. The Japan Morning Surge-1 (JMS-1) study includes hypertensive outpatients with elevated morning systolic blood pressure (>or=135 mmHg) as assessed by self-measured blood pressure monitoring at home. All enrolled patients are under stable antihypertensive medication status. Exclusion criteria are arrhythmia, chronic inflammatory disease, and taking alpha-blockers or beta-blockers. The target number of patients to be enrolled in the JMS-1 study is 600, and the aim is to evaluate differences in the markers of hypertensive target organ damage, such as brain natriuretic peptide and the urinary albumin excretion/creatinine ratio. All of the patients are randomized to an experimental group or a control group, with randomization to be carried out by telephone interviews with the patients' physicians. In the experimental group, patients begin taking additional antihypertensive medication just before going to bed. This consists of doxazosin 1 mg/day, which then is increased to 2 mg/day and 4 mg/day, with a beta-blocker added after a 1-month interval until the morning systolic blood pressure is controlled to less than 135 mmHg. Patients in the control group continue the treatment they are receiving at the enrollment for 6 months. Blood pressure levels, adverse effects, and hypertensive target organ damage before and after the study are evaluated. In the JMS-1 study, we will evaluate whether strict morning blood pressure control by sympathetic nervous system blockade using an alpha-blocker, doxazosin, and with the addition of a beta-blocker if needed, can reduce hypertensive target organ damage.     

Evaluation of preoperative chemoembolization using ethiodized oil, cisplatin and gelatin sponge (sandwich therapy) for hepatocellular carcinoma

The significance of preoperative chemoembolization using ethiodized oil, cisplatin and gelatin sponge (Sandwich therapy) for resectable hepatocellular carcinoma (HCC) was evaluated. One hundred and thirteen patients with solitary and less than 10 cm sized HCC who underwent radical hepatic resection were chosen for this study. Fifty-three patients received Sandwich therapy before surgery (Group A), and the remaining 60 patients under-went surgery without any preoperative treatments (Group B). Any background factors between two groups were not significantly different. The anticancer effects of this therapy were evaluated by histologic examination in 31 patients who had preoperative Sandwich therapy. In 22 of 31 patients (71%), the main nodules were completely necrotic. The ratios of patients with complete necrosis in daughter nodules were 7/12 (58%), in portal vein tumor emboli, 7/10 (70%), in intracapsular invasions, 11/21 (52%), in extracapsular invasions, 4/11 (36%). The 4-year disease-free survival rates in Group A and Group B were 56% and 27% respectively, and the rate of the former was significantly higher than that of the latter (p less than 0.05). The 4-year survival rates in Group A and Group B were 83% and 53% respectively. The rate of Group A was also significantly higher than that of Group B (p less than 0.01). We concluded that preoperative Sandwich therapy was very significant to obtain successful long-term disease-free survival and survival in regard to relatively early stage HCC.     

Transient Brain Ischaemia Provokes Ca2+, PIP2 and Calpain Responses Prior to Delayed Neuronal Death in Monkeys

To clarify the mechanism of postischaemic delayed cornu Ammonis (CA)-1 neuronal death, we studied correlations among calpain activation and its subcellular localization, the immunoreactivity of phosphatidylinositol 4,5-bisphosphate (PIP₂) and Ca²⁺ mobilization in the monkey hippocampus by two independent experimental approaches: in vivo transient brain ischaemia and in vitro hypoxia-hypoglycaemia of hippocampal acute slices. The CA-1 sector undergoing 20 min of ischaemia in vivo showed microscopically a small number of neuronal deaths on day 1 and almost global neuronal loss on day 5 after ischaemia. Immediately after ischaemia, CA-1 neurons ultrastructurally showed vacuolation and/or disruption of the lysosomes. Western blotting using antibodies against inactivated or activated μ-calpain demonstrated μ-calpain activation specifically in the CA-1 sector immediately after ischaemia. This finding was confirmed in the perikarya of CA-1 neurons by immunohistochemistry. CA-1 neurons on day 1 showed sustained activation of μ-calpain, and increased immunostaining for inactivated and activated forms of μ- and m-calpains and for PIP₂. Activated μ-calpain and PIP₂ were found to be localized at the vacuolated lysosomal membrane or endoplasmic reticulum and mitochondrial membrane respectively, by immunoelectron microscopy. Calcium imaging data using hippocampal acute slices showed that hypoxia-hypoglycaemia in vitro provoked intense Ca²⁺ mobilization with increased PIP₂ immunostaining specifically in CA-1 neurons. These data suggest that transient brain ischaemia increases intracellular Ca²⁺ and PIP₂ breakdown, which will activate calpain proteolytic activity. Therefore, we suggest that activated calpain at the lysosomal membrane, with the possible release of biodegrading enzyme, will cause postischaemic CA-1 neuronal death.     

Effects of proton pump inhibitor on gastric mucosa hemodynamics and tissue oxygenation in anesthetized rats.

Proton pump inhibitors have been reported to have a cytoprotective action in addition to the anti-secretory action of acid. The precise mechanism, however, remains obscure. In this study, the effects of proton pump inhibitors (omeprazole and NC-1300) on gastric mucosa hemodynamics and tissue oxygenation were investigated using organ reflectance spectrophotometry in a hemorrhagic shock-reperfusion model involving anesthetized rats. Neither drug affected gastric mucosa hemodynamics nor tissue oxygenation in the basal state before hemorrhage. During the hemorrhagic shock state, however, these drugs maintained tissue oxygenation and reduced ulcer formation, although they did not show a significant effect on gastric mucosa blood volume. The results suggest that both proton pump inhibitors have an anti-ulcer action by maintaining mucosal oxygenation in addition to the anti-secretory activity of acid.     

Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis.

PURPOSE: The association of BRCA2 polymorphisms at codon 372 [Asn (N)/His (H)]and codon 784 [Met (M)/Val (V)] with breast cancer risk was evaluated in Japanese women. In addition, the prognostic significance of these polymorphisms was studied in breast cancer patients. EXPERIMENTAL DESIGN: A case-control study was conducted to examine the association of the BRCA2 N/H372 polymorphism and M/V 784 polymorphism with breast cancer risk (cases = 149, controls = 154). The prognostic significance of these polymorphisms was evaluated in 139 patients with primary breast cancer. RESULTS: No significant association was observed between the N/H372 polymorphism and breast cancer risk. In contrast, a significant increase in breast cancer risk (odds ratio, 2.03; 95% confidence interval, 1.07-3.87) was observed in carriers of the variant allele (V784) of the M/V784 polymorphism as compared with noncarriers after adjustment for the classical risk factors, age, family history, parity, body mass index, and so forth. Among breast cancer patients, various clinicopathological parameters including menopausal status, tumor size, lymph node status, histological grade, and estrogen-receptor status were not significantly different between the carriers and noncarriers of the variant allele with regard to both N/H372 and M/V784 polymorphisms. The N/H 372 polymorphism was not significantly associated with patient prognosis. On the other hand, breast cancer patients carrying the variant allele of M/V784 polymorphism showed a significantly (P = 0.014) lower 3-year disease-free survival rate (63%) than noncarriers (92%). Multivariate analysis has revealed that the M/V784 polymorphism is a significant prognostic factor, being independent of the other conventional prognostic factors such as lymph node status and estrogen receptor status. CONCLUSION: These results suggest that the M/V784 polymorphism, but not the N/H372 polymorphism, would be useful in the selection of women at high risk for developing breast cancer and would also serve as a clinically useful prognostic factor in breast cancer patients.     

Changes in the distribution of filipin-sterol complexes in the boar sperm head plasma membrane during epididymal maturation and in the uterus.

The distribution of filipin-sterol complexes (FSCs) and intramembranous particles (IMPs) in the plasma membrane of the late spermatid of the boar and of the sperm obtained from the epididymides, ejaculates, and uterus 2 hours after mating was examined by a freeze-fracture replica technique. In the late spermatid, the FSC density was found to be very low. A majority of the FSCs in the acrosomal plasma membrane (APM) appeared as protuberances on the E face in the epididymal, ejaculate, and uterine sperm. The density of the FSCs in the principal segment (PS) of the APM was 291 +/- 44 FSC/microns2 (mean +/- standard deviation, S.D.), 322 +/- 41 FSC/microns2 and 355 +/- 31 FSC/microns2 in the caput, corpus, and cauda epididymidis, respectively. In comparison with the cauda epididymal sperm, the FSC density gradually decreased in the PS of the ejaculated (277 +/- 39 FSC/microns2) and uterine sperm (243 +/- 50 FSC/microns2). The reduction was especially remarkable in the equatorial segment (ES), where the density of FSCs in ejaculated and uterine sperm decreased to about half and less than half of that in the cauda epididymal sperm, respectively. Large (13 nm) and small (8 nm) IMPs were distributed evenly and densely in the P face of the APM in the late spermatid, epididymal, and ejaculated sperm. In the uterine sperm, IMP-free areas were observed in the P face of the plasma membrane, a feature thought to represent one of the capacitation changes of the boar sperm.