YM116, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole, decreases adrenal androgen synthesis by inhibiting C17-20 lyase activity in NCI-H295 human adrenocortical carcinoma cells

The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1H-imidazol-4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17Alpha-hydroxyprogesterone, a product of 17alpha-hydroxylase, was increased by YM116 (1-30 nM) and by ketoconazole (10-300 nM) and then was decreased at higher concentrations of both agents (IC50: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17alpha-hydroxylase. Compatible with these findings, progesterone, a substrate of 17alpha-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC50: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC50: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity.     

Discovery of orally active nonpeptide bradykinin B2 receptor antagonists

Orally active nonpeptide bradykinin (BK) B2 receptor antagonists have been discovered by using directed random screening and chemical modification. These compounds displaced [3H]BK binding to B2 receptors in guinea-pig ileum membranes, rat uterus membranes and human lung fibroblasts with nanomolar IC50s. They did not inhibit different specific radio-ligand bindings to other receptor sites including B2 receptors. In isolated guinea-pig ileum preparations, these compounds had no agonistic effect on smooth muscle contraction at 10(-6) M, and caused parallel rightward shifts of the concentration-response curves to BK on contraction with higher p A2 values. They also blocked human B2 receptor-mediated phosphatidylinositol hydrolysis without agonistic effect. In vivo, the oral administrations of these antagonists potently inhibited BK-induced bronchoconstriction in guinea-pigs. They also reduced carrageenin-induced paw edema and caerulein-induced pancreatitis in rats. Moreover, these compounds alleviated kaolin-induced pain in mice by oral administration. These results show that our compounds are potent, selective, and orally active BK B2 receptor antagonists and that they may have therapeutic potential against inflammatory diseases and pain.     

Car seatbelt use during pregnancy in Japan: determinants and policy implications

CONTEXT: Pregnant women are exempted from the current seatbelt legislation in Japan despite the fact that seatbelt use is essential to reduce the risk of fatalities for these women and their fetuses in car crashes. OBJECTIVE: To examine factors that might influence seatbelt use during pregnancy. METHODS: A cross sectional study, with data collected via an anonymous, self administered questionnaire at obstetric clinics in suburban areas of Japan. Altogether 880 pregnant women receiving prenatal care in July 2001 were recruited. The relative effects of factors that might influence seatbelt use during pregnancy were estimated using logistic regression analysis. RESULTS: Almost 70%-80% of pregnant women were consistent seatbelt wearers before pregnancy but seatbelt compliance was reduced by about half at 20 weeks or more gestation. Only 20% had received information on maternal seatbelt use, with one third reporting that seatbelt use is beneficial during pregnancy. Those who perceived that maternal seatbelt use is beneficial tended to maintain use, but daily car users and those who knew that they were exempted from seatbelt legislation were more likely to reduce use. CONCLUSIONS: Knowledge of the legislative exemption for pregnant women, misunderstanding of the benefits, and daily car use contributed to the reduction in seatbelt use after pregnancy.     

The role of the sentinel lymph node in gastrointestinal cancer

Evaluation of the clinical significance of the sentinel node concept in GI cancer has just begun. The authors' preliminary data, using intraoperative radiation techniques and the gamma probe, suggest that it is worthwhile to continue the evaluation of this procedure to determine its role in an accurate staging and a minimally invasive approach to GI cancers.     

Bronchiolar disease: spectrum and radiological findings

Two types of bronchiole, the terminal bronchiole and the respiratory bronchiole, have structural and functional differences. The former is characterized as a conducting airway and the latter is closely related to a gas-exchange function as it has numerous alveoli on the wall. Therefore, the diseases occurring at bronchiole demonstrate different pathological, radiological and clinical pictures depending on which bronchiole is mainly involved. The disease that mainly involves the conducting airway is appreciated as a small airway disease. Constrictive bronchiolitis is a well-recognized entity classified in this category. Whereas the disease mainly involves the respiratory bronchiole and distal alveolar space, it is recognized as an interstitial and parenchymal disease. BOOP or RB-ILD is classified in this category. These two types of bronchiolar diseases reveal the contrast clinical pictures, including incidence, causative disease, response to the treatment, prognosis, respiratory function test as well as the radiological findings. This pictorial essay will illustrate the radiological features of the varieties of bronchiolitis.     

Development of micro mechanical device having two-dimensional array of micro chambers for cell stretching

This paper presents a novel cell stretching micro device having two-dimensional array of micro chambers. It enables an in situ time-lapse observation of stretched cell by using an optical microscope with high measurement efficiency. The presented device consists of a cell culture dish and the array of micro chambers made of silicone elastomer and extension structures made of photocurable resin, and is fabricated with MEMS technology. The fabrication process of the thin micro chamber array combines photoresist mold and lift-off process based on conventional photolithography. The fabricated device has 134 micro chambers in 5μm or less thickness. It was demonstrated that the fabricated micro device could be used to make in-situ time-lapse observation of cell responses to stretching under optical microscopy. In addition, the influence of the chamber thickness to the quality of the microscope image observed was evaluated. It is confirmed that the proposed device having two-dimensional array of the thin micro chambers makes it possible to observe cell response for stretch stimuli with high quality and efficiency.