It has been known for many years that human benign prostatic hyperplasia (BPH) is composed predominantly of hyperplastic stromal cells rather than epithelial cells. In the present study the effects of a new steroidal aromatase inhibitor on hormone-induced and spontaneous canine BPH were investigated.(1) Effects of TZA-2237 on hormone-induced canine BPH. Ten castrated beagles were administered testosterone and androstenedione 6 days/week for 8 months, and divided randomly into three groups after 2 months of treatment as follows. Group I served as controls, Group II was given 0.5 and Group III was given 2.5 mg/kg/day TZA-2237 5 days/week for 6 months. (2) Effects of TZA-2237 on spontaneous canine BPH. Twenty aged beagles with BPH were divided into five groups, Group IV was untreated, Group V was treated with 1 and Group VI with 5mg/kg/day TZA-2237 5 days/week for 31 weeks. Group VII was treated with 5mg/kg/day Atamestane and Group VIII was treated with 0.3 mg/kg/day chlormadinone acetate (CMA) 5 days/week. (3) Effects of TZA-2237 combined with CMA on spontaneous canine BPH. Three aged beagles with BPH were treated with 1mg/kg/day TZA-2237 and 0.03 mg/kg/day CMA 5 days/week for 20 weeks (Group IX) and a further three aged beagles with BPH were treated with 0.3 mg/kg/day CMA alone 5 days/week (Group X).Hormone-induced prostatic growth was significantly suppressed in group III compared with that in other groups. In Group III, the intraprostatic aromatase activity, estradiol level and androgen receptor content decreased significantly in comparison with the values in Group I. The prostatic weights in Groups V, VI and VII increased significantly in comparison with the weight in Group IV. Serum LH and testosterone levels in Groups V, VI, and VII increased significantly in comparison with the level in Group IV. The prostatic weight in Group IX was decreased only slightly, but the smooth muscle component was decreased significantly.TZA-2237 is a new, unique and effective aromatase inhibitor that causes inhibition of both epithelial and stromal compartments in hormone-induced canine BPH. Dual inhibition of androgen and estrogen resulted in inhibition of smooth muscle growth, and should prove effective as a new method of treatment given the atrophic effects on not only the epithelium but also the stroma in human BPH.
Cerebrovascular reactivity to CO2 inhalation and voluntary hyperventilation was studied in seven normotensive subjects and nine hypertensive patients without clinical or angiographical signs of arteriosclerosis. Cerebral blood flow (CBF) was measured by the intracarotid 133Xe clearance method and calculated as the initial slope index. Three to five CBF measurements were made in each patient in the PaCO2 range of 20 to 55 mm Hg. No difference was observed in reactivity between hypertensive and normotensive patients, either during CO2 inhalation or during hyperventilation. The shape of the CBF:PaCO2 curve suggested a decrease in reactivity below a PaCO2 of 30 to 35 mm Hg in both groups. Above a PaCO2 of 35 mm Hg, exponential regression analysis yielded a mean reactivity of 6 +/- 2%, whereas below a PaCO2 of 30 mm Hg it was about 2%. The rise in CBF during CO2 inhalation was not influenced by the intravenous infusion of a small dose of trimethaphan which blocked the concomitant rise in blood pressure.
Neuronal nitric oxide synthase is involved in diverse signaling cascades that regulate neuronal development and functions via S-Nitrosylation-mediated mechanism or the soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway activated by nitric oxide. Although it has been studied extensively in vitro and in invertebrate animals, effects on mammalian brain development and underlying mechanisms remain poorly understood. Here we report that genetic deletion of “Nos1” disrupts dendritic development, whereas pharmacological inhibition of the sGC/cGMP pathway does not alter dendritic growth during cerebral cortex development. Instead, nuclear distribution element-like (NDEL1), a protein that regulates dendritic development, is specifically S-nitrosylated at cysteine 203, thereby accelerating dendritic arborization. This post-translational modification is enhanced by N-methyl-D-aspartate receptor-mediated neuronal activity, the main regulator of dendritic formation. Notably, we found that disruption of S-Nitrosylation of NDEL1 mediates impaired dendritic maturation caused by developmental alcohol exposure, a model of developmental brain abnormalities resulting from maternal alcohol use. These results highlight S-Nitrosylation as a key activity-dependent mechanism underlying neonatal brain maturation and suggest that reduction of S-Nitrosylation of NDEL1 acts as a pathological factor mediating neurodevelopmental abnormalities caused by maternal alcohol exposure.
Chemical pleurodesis is performed in pneumothorax patients to treat nonresolving air leakage or prevent recurrence. However, factors that might predict the need for chemical pleurodesis remain unknown. Therefore, this study investigated predictive factors for the application of chemical pleurodesis for pneumothorax.We retrospectively analyzed 401 adult pneumothorax patients who underwent chest tube drain insertion during hospitalization at Fukujuji Hospital from January 2016 to December 2020. The patients were divided into 3 groups: the pleurodesis group, comprising 89 patients treated with chemical pleurodesis; the nonpleurodesis group, comprising 206 patients treated without chemical pleurodesis; and the surgical group, comprising 106 patients treated surgically. Data for patients in the pleurodesis group were compared to those in the nonpleurodesis or surgical group, and a predictive score of the application of chemical pleurodesis for pneumothorax was developed.Compared with the nonpleurodesis group, in the pleurodesis group, patient age was higher (P < .001), emphysema (n = 33 (37.1%) vs 70 (34.0%), P = .045), and interstitial pneumonitis (n = 19 (21.3%) vs 19 (9.2%), P = .022) were more common causes, and chest tube suction was more common (n = 78 (87.96%) vs n = 123 (59.7%), P < .001). Similar results were found between the pleurodesis and surgical groups. We developed a score for predicting the application of chemical pleurodesis for pneumothorax, including the following factors: age ≥55 years; presence of emphysema and/or interstitial pneumonitis; and use of chest tube suction. The score for the pleurodesis group showed a high area under the receiver operating characteristic curve compared with that for the nonpleurodesis group (0.776 [95% confidence interval]: 0.725-0.827). With a score of 2 as the cutoff value, the sensitivity was 91.0% and the specificity was 52.4%. In a comparison between the pleurodesis and surgical groups, the predicting score showed the high AUC of 0.904 (95% confidence interval: 0.863-0.945).This study reveals predictive factors for the application of chemical pleurodesis and provides a predictive score including 3 factors.
Effects of KB-2413 on experimental asthma and respiration were examined in comparison with ketotifen and chlorpheniramine in guinea pigs. Anaphylactic bronchoconstriction in guinea pigs were measured by two methods. One is the method measuring increase of airway resistance and the other is the method measuring change of volume and rate of respiration. KB-2413 (0.003-0.1 mg/kg p.o.) showed a dose-dependent inhibition on antigen-induced increase in airway resistance in passively sensitized guinea pigs. The ED50 value of KB-2413 was 0.012 mg/kg p.o. and the inhibitory effect of KB-2413 was 24.9 and 3.3 times more potent than those of chlorpheniramine and ketotifen, respectively. On the other hand, disodium cromoglycate did not show any inhibitory effect on this reaction at a dose of 30 mg/kg i.v. KB-2413 (0.003-0.03 mg/kg p.o.) also showed a dose-dependent inhibition on antigen-induced disorder of the respiration in passively sensitized guinea pigs. KB-2413 itself did not induce respiratory disorder at doses of 1 and 3 mg/kg i.v. and 30 mg/kg i.d. On the other hand, ketotifen and diphenhydramine induced respiratory disorder distinctly at a dose of 1 mg/kg i.v. Thus, KB-2413, by oral administration, has a very strong inhibitory effect on anaphylactic bronchoconstriction, and does not induce respiratory disorder even at about 2500 times the dose as that which showed a 50% inhibitory effect on anaphylactic bronchoconstriction.
