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Biomedical subjects

R K Miller

Publications and source records attributed to R K Miller.

At least 109 records · Page 6Linked to original sources
PubMed1988

Enterovirus in pregnant women and the perfused placenta.

A survey of all nonpolio enterovirus infections in adults for a 10-year period revealed that most such infections will occur in the child-bearing age group during the third quarter of the year. Coxsackieviruses occurred more often than echovirus infection. Fourteen pregnant women, including four with meningitis, who had an enterovirus infection from 16 to 37 weeks of gestation delivered uninfected, healthy infants. Attempts to demonstrate transplacental passage of Coxsackie B-3 or ECHO-11 viruses by use of the dual, recirculating, in vitro perfusion of an isolated placental lobule were unsuccessful even with a maternal virus input of 200,000 median tissue culture infectious doses. This suggests that transplacental passage of virus does not occur readily, and that most neonates of infected mothers will be unharmed.

Adolescent↗
PubMed1988

Maternal toxicity and teratogenicity of tellurium dioxide in the Wistar rat: relationship to pair-feeding.

Tellurium dioxide (TeO2) induces hydrocephalus, edema, exophthalmia, ocular hemorrhage, umbilical hernia, undescended testes and small kidneys in day 20 Wistar rat fetuses when administered s.c. to pregnant dams from gestational day 15 to 19. At doses of 500 mumole/kg or greater, a 100% incidence of these findings and a reduction in maternal weight gain were observed. A pair-fed study at the dose of 500 mumole/kg of TeO2 was conducted to establish if the effects of tellurium were a result of a reduction in food intake or other maternal toxic responses. Two additional control groups of rats receiving tellurium or vehicle were fed ad libitum. After a comparable maternal weight gain from day 0 to 15, weight gain was significantly reduced in the treated groups and the pair-fed control. There was a reduction of fetal weight in the treated groups (p less than 0.01) and in the pair-fed control (p less than 0.02). There was a 100% incidence of the above anomalies in the litters of the two treated groups, but none in the pair-fed and control groups. No histological alterations other than a mild centrolobular fatty change in the liver were detected in the other organs from the tellurium exposed dams. Thus, tellurium induces both maternal toxicity and teratogenic effects in the rat where the teratogenicity is not mediated by alterations in the diet.

Abnormalities, Drug-Induced↗
PubMed1988

Magnetic resonance imaging: a noninvasive tool for fetal and placental physiology.

Nuclear magnetic resonance imaging (MRI), a technique that utilizes biochemical information reflected in nuclear magnetic moments, can be used to image the uterus, fetus, and placenta of the human and nonhuman primate. MRI studies during pregnancy in the human and nonhuman primate provide soft-tissue structural information of considerable detail. MRI also offers the opportunity for noninvasive pharmacokinetic and toxicokinetic studies during pregnancy. Paramagnetic ions (Cu, Ni, Gd, Fe, Mn) after spin-lattice (T1) and spin-spin (T2) relaxation times in reproductive tissues. Changes in T1 and T2 alter the MRI image, reflecting uptake of paramagnetic ions by the uterus, placenta, or fetus. MRI provides a noninvasive method of monitoring body burden of selected xenobiotics during gestation. The use of paramagnetic labels on endogenous substances may also allow noninvasive determination of physiological parameters such as intervillous blood flow, placental metabolism, and placental transport during gestation.

Animals↗
PubMed1988

The insanity defense for sex offenders: jury decisions after repeal of Wisconsin's Sex Crimes Law.

After repeal of a Wisconsin statute permitting hospitalization of defendants convicted of sexual crimes, the authors noted an increase in the percentage of sex offenders among persons hospitalized after being found not guilty by reason of insanity. They also found that a greater proportion of hospitalized sex offenders than of other kinds of offenders were diagnosed as nonpsychotic. Illustrating with three case studies, the authors argue that despite trends away from the therapeutic model of corrections, juries continue to make decisions that provide treatment for defendants perceived to need it, even if the legal criteria for those decisions do not appear to be met.

Adult↗
PubMed1987

Fetal toxicity of cadmium chloride: the pharmacokinetics in the pregnant Wistar rat.

The pharmacokinetics of a single subcutaneous injection of 40 mumol/kg CdCl2 in pregnant rats on day 18 were studied during an 18-hour time period. Previous studies demonstrated that this dose of CdCl2 induced fetal death, placental necrosis, and a reduction of uteroplacental blood flow without maternal lethality; direct fetal injections of CdCl2 indicated that the site of toxic action was not in the fetus. Cadmium was rapidly absorbed from the intrascapular subcutaneous depot with the highest blood levels occurring within 5 minutes of injection. The release from the depot appeared to be multiphasic with both rapid and slow absorption components observed in the blood. Uptake of cadmium was greatest in the liver, followed by the placenta, kidney, and pancreas. The best fit to the data was obtained by assuming the existence of two pools of cadmium in the organs: one freely exchangeable with the blood and the other nonexchangeable. Deviations from model predictions were observed for the placenta and adrenals; these deviations are consistent with the concomitant diminished blood flow to these organs. Cadmium uptake by the fetus was also investigated, and the results support the hypothesis that the placenta is relatively impermeable to the toxicant. It is concluded that the rapid and extensive accumulation of cadmium by the placenta may play a role in the development of early placental cellular damage and the eventual induction of fetal death through uteroplacental dysfunction.

Animals↗
PubMed1987

Kinetic assessment of manganese using magnetic resonance imaging in the dually perfused human placenta in vitro.

The transfer and distribution of paramagnetic manganese was investigated in the dually perfused human placenta in vitro (using 10, 20, 100 microM Mn with and without 54Mn) using magnetic resonance imaging (MRI) and conventional radiochemical techniques. The human placenta concentrated 54Mn rapidly during the first 15 min of perfusion and by 4 hr was four times greater than the concentrations of Mn in the maternal perfusate, while the concentration of Mn in the fetal perfusate was 25% of the maternal perfusate levels. Within placentae, 45% of the 54Mn was free in the 100,000g supernatant, with 45% in the 1,000g pellet. The magnetic field dependence of proton nuclear spin-lattice relaxation time (T1) in placental tissue supports this Mn binding. Mn primarily affected the MRI partial saturation rather than spin-echo images of the human placenta, which provided for the separation of perfusate contributions from those produced by Mn. The washout of the Mn from the placenta was slow compared with its uptake, as determined by MRI. Thus, Mn was concentrated by the human placenta, but transfer of Mn across the placenta was limited in either direction. These studies also illustrate the opportunity for studies of human placental function using magnetic resonance imaging as a noninvasive biomarker.

Female↗
PubMed1986

Comparison of the disposition of diethylstilbestrol and estradiol in the fetal rat. Correlation with teratogenic potency.

The dispositions of radiolabeled diethylstilbestrol (DES) and estradiol (E2) in the fetal rat were compared to determine whether kinetic differences accounted for their differences in teratogenic potency. 14C (from DES) was concentrated in fetal tissues relative to plasma, whereas 3H (from E2) was largely retained protein-bound in fetal plasma. Both compounds were rapidly metabolized in the fetus (and mother) to less or non-estrogenic products. Fetal levels of E2 declined faster than those of DES (E1 was the primary circulating estrogen within 1-3 hr of E2 injection) so that exposure to unchanged DES was of longer duration than to E2. The unchanged compounds were retained longer and at higher concentrations in the target genital tissue compared to other tissues. Although these differences were consistent with the potencies, the concentration of the unchanged estrogen in fetal genital tract was lower after a teratogenic dose of DES than after a threshold teratogenic dose of E2. However, the 3H in fetal plasma and genital tract cytosol at 1 hr after injection of [3H]E2 at 2 ng or 10 micrograms/fetus was found to be highly protein-bound. DES competed poorly for these binding sites. It is suggested that the concentration of E2 which is "free" in the cell (as DES is), rather than the total content, correlates with its teratogenicity. Thus, in the rat, rapid metabolism and extensive protein-binding, both extra- and intracellularly, reduce the teratogenicity of the natural estrogen compared to the synthetic estrogen.

Abnormalities, Drug-Induced↗
PubMed1986

The antiestrogen LY117018 is estrogenic in the fetal rat.

LY117018 (LY) has high affinity for the adult rat uterine estrogen receptor, has little uterotrophic activity, and inhibits many estradiol (E2)-induced responses in the adult or immature uterus. In these studies, LY was injected into day 19 rat fetuses, with and without diethylstilbestrol (DES) or E2, to determine whether it could block the estrogen-induced teratogenesis. LY at 1, 25, or 50 micrograms/fetus failed to decrease the 15-70% incidences of oviduct malformation and cleft phallus induced by DES (2.5 micrograms/fetus) or E2 (50 micrograms/fetus). However, LY alone (1-50 micrograms/fetus) was more potent than E2 in eliciting these same urogenital malformations. LY also failed to compete in vitro for plasma protein-bound 3H-E2, and therefore, like DES, is more available than E2 for uptake into fetal tissues. Thus, in the fetus, unlike the adult, LY was an estrogen agonist, which indicates that the fetus has a very different sensitivity than the adult to estrogenic compounds.

Abnormalities, Drug-Induced↗
PubMed1986

Operant behavior in transition reflects neonatal exposure to cadmium.

Male Long-Evans rats were injected with 0, 1, 3, or 6 mg/kg of cadmium chloride on the first day of life. Animals free of morphological stigmata at weaning were selected for study. Tissue concentrations of cadmium and operant behavior under various fixed-ratio (FR) schedules of reinforcement were evaluated when these rats were adults. Dose-related increases in cadmium were present in the brains, livers, and kidneys. Dose-related differences in behavior were most evident during the transition from fixed ratio 25 (FR 25 or 25 responses/reinforcer) to FR 75. An inverted U describes the relationship between response output during the transition to FR 75 and cadmium chloride dose response output increased at 3 mg/kg and decreased at 6 mg/kg. The rate decreases were not correlated with weight loss that appeared after some of the animals exposed to 6 mg/kg reached 60 days of age. Challenge doses of d-amphetamine revealed no interaction between neonatal exposure to cadmium and d-amphetamine. The occurrence of alterations in operant behavior in animals that appeared normal on a number of preweaning evaluations suggests that operant behavior in transition was sensitive to subtle effects not observed with other commonly used tests. The data provide evidence for delayed effects in the adult that are due to neonatal exposure to cadmium.

Animals↗
PubMed1985

The influence of maternal cadmium exposure or fetal cadmium injection on hepatic metallothionein concentrations in the fetal rat.

The ability of Cd to induce the synthesis of fetal hepatic metallothionein (MT) was investigated in rat fetuses exposed to Cd throughout gestation via the mother's drinking water or injected directly with Cd through the uterine wall on Day 18 of gestation. On Day 21 all dams were killed and fetal and maternal tissues were removed. Tissue MT, Zn, Cu, and Cd concentrations were measured. Fetal hepatic Cd concentration was increased only at the high maternal Cd exposure, whereas Zn concentration was significantly reduced by Cd exposure. Both fetal liver and kidney MT were reduced following maternal Cd exposure. Unlike maternal hepatic MT, fetal hepatic MT was not increased after maternal Cd exposure nor did the direct injection of Cd into the 18 days of gestation fetus induce fetal MT synthesis. These data suggest that fetal rat liver is incapable of synthesizing MT in response to Cd, possibly because Cd is not transported to the site of MT synthesis in the fetal system. Furthermore, neither the route of exposure, the duration of prenatal Cd exposure, nor the stage of gestation appear to account for the differences observed between fetal and adult hepatic MT induction by Cd.

Administration, Oral↗
PubMed1985

The pharmacokinetics of phenytoin in perfused human placenta.

In vivo phenytoin (PHT) and its metabolites are present in the fetal plasma. In order to determine the transfer kinetics and biotransformation characteristics for phenytoin in the human placenta, a dual recirculating perfused human placental lobule preparation was utilized. A single bolus of 14C-PHT with or without tritiated water (3H2O) was injected into the maternal reservoir. Peak concentrations of 3H2O and PHT appeared simultaneously in the maternal artery at 4 minutes and in the maternal vein at 9 minutes, whereas the peak concentrations of 14C-PHT and 3H2O in the fetal vein were at 9 and 7 minutes, respectively. After 4 hours of perfusion, the total phenytoin concentration in the fetal perfusate was only 73% of the maternal perfusate level. Protein-bound PHT was 37 +/- 8% and 7 +/- 3% of the total phenytoin in the maternal and fetal perfusate. The concentrations of free phenytoin in the maternal and fetal compartments were identical by 60 minutes and were maintained for the remainder of the experiment. The concentration of total PHT in perfused placenta was more than 3.5 times greater than the total maternal perfusate levels. In the placenta, PHT concentration was highest in the cytosolic fraction, and 57% of the placental PHT was in the free form. There was no evidence of parahydroxylation, oxidation, or conjugation of PHT. Phenytoin was also concentrated in nonperfused placental tissue. Thus the transfer of PHT by the human placenta is rapid and dependent upon protein binding and flow in both maternal and fetal circulations. Even though the human placenta does concentrate PHT, it does not metabolize PHT under these conditions.

Biotransformation↗
PubMed1984

Prenatal exposure to diazepam alters central and peripheral responses to stress in adult rat offspring.

Central and peripheral responses to restraint stress were evaluated in 90-day-old rats exposed prenatally to diazepam (1.0, 2.5, or 10.0 mg/kg/day) over gestational days 13-20. As a measure of a central response to stress, the utilization of norepinephrine (NE) by hypothalamic NE neurons was assessed by determining the effect of stress on the loss of NE after synthesis inhibition. The stress-induced changes in plasma corticosterone and prolactin levels were evaluated as a physiologic index of stress. While stress increased the loss of NE after synthesis inhibition in the non-exposed control animals, it totally prevented any loss of NE after synthesis inhibition in offspring prenatally exposed to DZ. Additionally, the stress-induced change in plasma corticosterone was attenuated in a dose-related manner by prenatal exposure to DZ. The stress-induced change in plasma prolactin was also altered in a dose-related manner by the prenatal exposure. Both the altered response to stress within hypothalamic NE neurons and the attenuated change in plasma corticosterone induced by prenatal exposure to DZ (2.5 mg/kg) were prevented by concurrent administration of the centrally acting benzodiazepine antagonist Ro15-1788 to the pregnant dam, indicating that the effects of DZ were mediated via binding of the drug to central sites during gestation. These results indicate that activation of specific binding sites during early development can induce neural alterations in the adult offspring which can be reflected in functional changes which may compromise the organism.

Animals↗
PubMed1984

Prenatal diazepam exposure in rats: long-lasting, receptor-mediated effects on hypothalamic norepinephrine-containing neurons.

The concentration and turnover of catecholamines (CAs) were measured in the cortex, hippocampus, and hypothalamus of rats exposed in utero to diazepam (DZ, 1.0, 2.5, or 10.0 mg/kg/day) over gestational days 13-20. Prenatal DZ induced a regionally specific, dose-related decrease in the level of norepinephrine (NE) (maximum decrease, 65%) and turnover rate of NE (maximum decrease, 85%) in the hypothalamus of 90-day-old adult rats. Dopamine levels were not altered in this region and neither of the CAs were altered in the other regions. Dividing the prenatal exposure period into two shorter periods revealed that late gestation (days 17-20) was the period when factors influencing NE function in the hypothalamus were most sensitive to DZ. Analysis of the development of the CA in the hypothalamus demonstrated that the effect of the prenatal exposure on NE levels did not become apparent until after 28 days of age. However, at 28 days, there was a dose-related increase in turnover rate of NE (maximum increase, 52%). Concurrent administration of the specific benzodiazepine (BZ) antagonist RO15-1788 with DZ (2.5 mg/kg) to pregnant rats effectively reversed the effects of DZ in the hypothalamus of the adult offspring, suggesting that the effects were mediated via the BZ receptor. These data have provided insight into the intricate processes of neuronal development; in particular the importance of target cell-nerve terminal interactions and the role of early developing receptors.

Animals↗
PubMed1984

Direct fetal injections of diethylstilbestrol and 17 beta-estradiol: a method for investigating their teratogenicity.

The synthetic estrogen, diethylstilbestrol (DES), causes urogenital malformations in humans, primates, and rodents. This study was designed to determine whether these effects of DES are related to its estrogenicity. Therefore, DES (0.1, 1, and 10 micrograms) or the natural estrogen, estradiol (E2) (10 and 100 micrograms) was injected directly into day 19 rat fetuses. In the 6- to 7-week-old female offspring exposed to DES, a dose-related incidence of cleft phallus, hypospadias, and incomplete coiling of oviducts was observed. The single fetal injection of E2 elicited similar urogenital malformations, but was approximately 100-fold less potent than DES. A single subcutaneous dose of either DES (0.025, 0.25, or 2.5 mg/kg) or E2 (2.5 or 25 mg/kg) to dams on day 19 of pregnancy induced a spectrum of malformations similar to that following fetal injection. The offspring of treated dams, but not those injected directly as fetuses, had nonfunctioning ovaries (no corpora lutea) yet vaginal signs of estrous were present. It is concluded that DES can act directly in the fetus and its teratogenicity does not require maternal mediation. Since a high dose of E2 produced similar malformations when given to fetuses, it appears that excess estrogen during prenatal life is teratogenic. Thus, at least those endpoints of the teratogenicity of DES that were measured are accounted for by its estrogenic activity.

Animals↗