Development of glucagon sensitivity in neonatal rat liver.

The ontogenesis of the hepatic glucagon-sensitive adenylate cyclase system has been studied in the rat. With a partially purified liver membrane preparation, fetal adenylate cyclase was less responsive to glucagon than the enzyme from neonatal or adult livers. Similar results were obtained in gently prepared liver homogenates, suggesting that destruction of essential components of the fetal liver membrane did not account for the relative unresponsiveness of the adenylate cyclase enzyme to glucagon. Investigation of other factors that might account for diminished fetal hepatic responsiveness to glucagon indicate (a) minimal glucagon degradation by fetal membranes relative to 8-day or adult tissue; and (b) available adenylate cyclase enzyme, as suggested by a 13-fold increase over basal cyclic AMP formation with NaF in fetal liver membranes. These results indicate that neither enhanced glucagon degradation nor adenylate cyclase enzyme deficiency accounts for the relative insensitivity of the fetal hepatic adenylate cyclase system to glucagon. In early neonatal life, hepatic adenylate cyclase responsiveness to glucagon rapidly developed and was maximal 6 days after birth. These changes were closely paralleled by a fivefold increase in glucagon binding and the kinetically determined Vmax for cyclic AMP formation. These observations suggest that (a) fetal hepatic unresponsiveness to glucagon may be explained by a limited number of glucagon receptor sites; (b) during the neonatal period, the development of glucagon binding is expressed primarily as an increase in adenylate cyclase Vmax; (c) the ontogenesis of hepatic responsiveness to glucagon may be important in the resolution of neonatal hypoglycemia.

Black teachers' perceptions of the ideal pupil.

Torrance's Ideal Child Checklist was administered to 76 black teachers. A comparison of their 10 most and least valued traits with those of the expert panel on the creative personality showed that the two groups agreed only once on the 10 most valued traits and three times on the 10 least valued traits.

Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant.

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.

Developmental toxicity of gemcitabine, an antimetabolite oncolytic, administered during gestation to CD-1 mice.

Gemcitabine was given intravenously to female mice on gestation days (GD) 6-15 at doses of 0, 0.05, 0.25, or 1.5 mg/kg/day (0, 0.15, 0.75, or 4.5 mg/m2/day, respectively). Animals assigned to the teratology segment (25/group) were killed on GD 18 for examination of maternal hematologic parameters and organ weights, as well as fetal viability, weights, and morphology. The postnatal segment females (20/group) were allowed to deliver, and offspring physical, behavioral, and reproductive parameters were monitored. After offspring weaning, these dams were killed for hematologic and organ weight evaluations. At necropsy, 3 days after the final dose, the teratology segment dams showed dose-related increases in spleen and thymus weights. These changes were accompanied by a dose-related decrease in leukocytes and modest increases in mean corpuscular volume (MCV) and hemoglobin (MCH) at the two higher doses. On postpartum day (PPD) 21, the dams in the postnatal segment showed no treatment-related effects on these organ weights or hematologic parameters, indicating recovery of these maternal parameters within 3.5 weeks following termination of treatment. The decreases in maternal body weight and food consumption observed during gestation, and in liver and uterine weights at term in the 1.5 mg/kg/day group, were considered to be secondary to a high rate of prenatal mortality, evidenced by increased resorptions in the teratology segment and decreased live litter size in both segments of the study. Additional indications of developmental toxicity in this dose group were an increased incidence of malformations, primarily cleft palate, decreased fetal weights in the teratology segment, and decreased neonatal survival in the postnatal segment.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple cranial neuropathies associated with leprosy.

We report on a Samoan man with dysphagia, voice hoarseness, facial erythema, and edema. Neurologic examination revealed hypesthesia at the site of the facial rash, enlarged auricular nerves, a right facial palsy, decreased gag reflexes, and voice hoarseness. Laryngoscopic examination showed paralysis of the left vocal cord, and a barium swallow revealed a possible compressive lesion. A skin biopsy specimen was diagnostic of tuberculoid leprosy. This patient has an unusual case of leprosy with multiple cranial neuropathies.

Preclinical toxicology studies with nizatidine, a new H2-receptor antagonist: acute, subchronic, and chronic toxicity evaluations.

Nizatidine (NIZ), a new antiulcer drug, was evaluated for toxicity in acute, subchronic, and chronic tests. Acute toxicity studies were conducted in rats, mice, dogs, and monkeys. Median lethal doses (MLD) in rodents were greater than 1600, 230, and 1000 mg/kg by oral (po), iv, and sc administration, respectively. No deaths occurred in dogs given single doses of 800 mg/kg (po), 75 mg/kg (iv), or 225 mg/kg (im) or in monkeys given 1200 mg/kg (po) or 200 mg/kg (iv). Rats survived up to 1.0% dietary NIZ (daily intake ranging from 24 to 800 mg/kg/day) for 1 year. Slight decreases in body weight gain and increases in liver and kidney weights occurred. Slight decreases in erythrocytic parameters at 3 months were not present at 6 or 12 months. Mice survived up to 1.5% dietary NIZ for 3 months and effects were limited to slight decreases in body weight gain and increases in relative liver weight. Dogs survived oral doses up to 800 mg/kg/day for 3 months but had numerous clinical signs of toxicity and body weight loss. All dogs given oral NIZ doses up to 400 mg/kg/day survived except for one high-dose dog that was killed in a moribund condition following convulsions in the 41st week of treatment. Effects in dogs included miosis, body weight loss, increased thrombocyte counts, and decreased hepatic microsomal enzyme activity and P450 content. The increase in thrombocyte counts was unaccompanied by changes in thrombocyte function and did not reoccur in a subsequent study. A decrease in plasma testosterone in two of three surviving male dogs given 400 mg/kg/day for 1 year was unaccompanied by effects on the size or morphology of testes or prostate. Peak plasma levels of NIZ in all species tested were in excess of human plasma levels after therapeutic doses. In conclusion, there was no evidence of significant toxicity in organs or tissues including those sites (gastric mucosa, male sex organs, and liver) that have been affected by some agents of this therapeutic class.