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All-trans-retinoic acid (RA) in olive oil was given in doses of 0, 40, or 60 mg/kg of body weight to pregnant mice on day 8 of gestation, and 2-6 hr later embryos were fixed in solutions with or without cetylpyridinium chloride (CPC). The neuroepithelium of the presumptive midbrain was processed for light and electron microscopy. Distorted contours of the neuroepithelium were induced by both doses of RA and the incidence and the severity of the disorganized neuroepithelium showed dose-related results. Abnormal neuroepithelium showed wide intercellular spaces with degenerated cytoplasmic processes or cell debris, separation of the apical side from adjacent cells, retention of mitotic and/or postmitotic cells on the apical side, presence of mitotic cells on the basal side, and detachment of degenerated structures from the neuroepithelium. Ultrastructurally, the affected neuroepithelium showed (1) appearance of degenerating filamentous or tubular coagulating bundles in the cytoplasm and the cytoplasmic process of the neural crest cells, (2) dispersal of polysomes into monosomes especially in the degenerating neural crest cells, (3) and a collecting of microfilament-like structures at the contact area between the neural crest cell and the presumptive neuroblast. These morphological changes suggest that RA affects the nature of cytoskeletal elements and the protein synthesis of the neuroepithelial cells. The selective susceptibility of neural crest cells to RA causes more degenerating neural crest cells in the neuroepithelium, which causes nonapproximation of the neural folds and scantiness of the migrating neural crest cells; these results lead to neural tube defects and craniofacial anomalies, respectively.

The isopachics of a birefringent object were obtained as a moiré pattern, see Kihara et al., Appl. Opt. 15, 3025 (1976). This paper describes experiments that separate the isopachics of a birefringent object by using the immersion method real-time polarization holography. The sign of the isopachics is accurately determined in real time by inserting a wave front retarder in the optical path of the illuminating beam and observing the shift of the fringe pattern.

Pregnant ICR/JCL mice were given orally 0.02, 0.3, or 2.0 mg/kg body weight/day of ethinyl estradiol in olive oil or vehicle alone on day 11 through day 17 of pregnancy. Pregnant mice of another group received a single oral dose of ethinyl estradiol on day 8 or day 11 of pregnancy. A lethal effect on fetuses of both groups with single and continuous exposure to ethinyl estradiol was observed in a dose-response relationship. Growth suppression of fetuses was only found at term in a dose-response relationship following continuous exposure to ethinyl estradiol. Hypertrophic nipples were seen in 42% of surviving female fetuses prenatally exposed to 2.0 mg/kg of ethinyl estradiol singly on day 11 of gestation. There was not an increase in other congenital malformations in any of the treated groups. These findings indicate that administered ethinyl estradiol can affect the developing mouse embryo but the embryotoxic doses in the mouse are substantially greater than the usual therapeutic or contraceptive doses in the human.

The oxidation of reduced cytochrome c by ferricyanide has been studied over a wide range of ferricyanide concentrations using a continuous-flow apparatus. The formation of a ferrocytochrome c-ferricyanide complex has been demonstrated and the binding and electron transfer processes separated to give both the oxidation electron transfer rate and the binding rate parameters. The electron transfer rate has been found to be 1.86 . 10(3) s-1 in H2O buffer and 1.36 . 10(3) s-1 in 2H2O demonstrating that a deuterium isotope effect of similar magnitude (R = 1.37) to that found in the cytochrome reactions in photosynthetic bacteria [18] is also found in the reaction studied here. The binding association rate parameters also show a similar deuterium isotope effect suggesting that water rotation may be involved in both the binding of ferricyanide to reduced cytochrome c and the subsequent oxidation electron transfer.

The pharmacological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent, on the peripheral nervous system and peripheral organs were studied in various laboratory animals in comparison with those of disopyramide and mexiletine, and the following results were obtained. 1. Large doses (50 or 100 mg/kg p.o.) of SUN 1165 as well as mexiletine had little effects on the pilocarpine-induced hypersalivation and the pupil size in mice. At higher concentration (10(-5) g/ml), SUN 1165 had no effects on the various spasmogen acetylcholine (ACh)-, histamine- or BaCl2-induced contractions in the isolated guinea pig ileum, tracheal smooth muscle and urinary bladder. Disopyramide caused mydriasis, inhibited the pilocarpine-induced hypersalivation at antiarrhythmic doses (10-30 mg/kg p.o.), and suppressed ACh-induced contractions in the various organs. 2. SUN 1165, like disopyramide and mexiletine, decreased the contractile amplitude and diastolic tone of the isolated rabbit ileum. SUN 1165 as well as disopyramide had no effect on the intestinal propulsion even at a large dose (100 mg/kg p.o.). Mexiletine inhibited it at antiarrhythmic doses (10-30 mg/kg p.o.). SUN 1165 only at a large dose (100 mg/kg i.d. or p.o.) inhibited volume of pepsin output in the gastric juice in pylorus-ligated rats and caused a damage to the gastric mucosa. 3. SUN 1165, like disopyramide and mexiletine, slightly potentiated the norepinephrine-induced contraction of the rat vas deferens in vitro. Moreover, SUN 1165 as well as disopyramide and mexiletine slightly potentiated the serotonin-induced contraction of the rat isolated fundus.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral ethinyl estradiol (0.01 or 0.02 mg. per kilogram) administered prenatally to ICR-JCL strain mice before the development of the uterine and ovarian blastemata induced cystic glandular hyperplasia with epidermization in the endometrium and excessive formation of degenerating follicles in the ovaries at 10 to 14 weeks of age. To the evidence for the production by estrogen of malignant uterine neoplasms in rodents and the clinical data showing that cystic glandular hyperplasia develops after prolonged estrogen administration in postmenopausal women and adenocarcinoma in premenopausal or menopausal women using oral contraceptives including ethinyl estradiol, we add the present results which suggest that ethinyl estradiol administered transplacentally can cause malignant transformation of the uterine endometrium in mice.

Tissue distribution of radioactive carbon from [U-14C]glucose in the mouse in vivo was studied by whole-body autoradiography. The mice were frozen with Dry-Ice-acetone at 0.5, 1, 5 and 30 min, 1 and 24 hr and 1 and 3 weeks after intraperitoneal injection of [U-14C]glucose. Whole-sagittal sections of the frozen mouse, obtained by using a microtome in a cryostat, were dried in a cryostat and autoradiographed. The resulting dry autoradiographs are called untreated autoradiographs in the present work. The sections were then fixed in cold 6% (w/v) HClO4, dried at room temperature and again autoradiographed. Autoradiographs that have undergone this process are referred to as treated autoradiographs. In both untreated and treated autoradiographs, within 1 min following injection of the labeled glucose, the abdominal cavity had the highest autoradiographic density. At 1 hr, density became highest in Harder's, sublingual and duodenal glands, large intestinal mucosa and tongue, and after 3 weeks, no autoradiographic denisty was present.

The involvement of a catecholaminergic mechanism in the production of morphine analgesia and the development of tolerance to the effect has been suggested. Here, using various adrenergic blockers, the role of adrenergic function in the mechanism was examined. Phentolamine (alpha 1 + alpha 2-blocker, 10, 1 and 0.5 mg/kg), prazosin (alpha 1-blocker, 0.1 and 0.02 mg/kg), propranolol (beta 1 + beta 2-blocker, 10, 1 and 0.5 mg/kg), metoprolol (beta 1-blocker, 10 and 1 mg/kg) did not affect morphine analgesia, but dose-dependently suppressed the development of tolerance to morphine. Yohimbine (alpha 2-blocker, 5 and 1 mg/kg) dose-dependently antagonized morphine analgesia in naive animals and delayed the development of tolerance to morphine. Pindolol (beta 1 + beta 2-blocker but is devoid of membrane stabilizing activity) suppressed the development of tolerance to morphine analgesia; however, d-propranolol, which possesses membrane stabilizing activity but lacks beta-blocking activity, could not prevent the development of tolerance. Thus, the suppressive effect of propranolol on the development of tolerance is not due to membrane stabilizing properties. Not only the non-selective adrenergic blockers, phentolamine and propranolol, but also the selective blockers of each receptor subtype, prazosin and metoprolol, suppressed the development of tolerance. This fact may suggest the importance of the equilibrated state of adrenergic functions in the mechanism for the development of tolerance to morphine.

Whether or not the suppressive effect of alpha- and beta-adrenergic blockers, phentolamine and propranolol, on the development of tolerance to morphine could be substituted for each other was investigated in mice. Daily co-administration of either one of the blockers with morphine suppressed the development of analgesic tolerance to morphine as far as the treatment was continued without affecting the analgesic effect per se; however, the suppressive effect was lost from the day of the substitution for the other blocker and tolerance developed as rapidly as in the control group treated with morphine alone. Co-administration of both blockers with morphine also maintained the analgesic effect on the 1st day for 10 days, but when the administration of either one or both blockers was eliminated from the 6th day, the development of tolerance was initiated. These results suggest that the mechanisms of alpha- and beta-blockers for the suppression of the development of analgesic tolerance to morphine are different from each other and that adrenergic blockers may produce a specific alteration in the mechanism for the development of tolerance to morphine.