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Biomedical subjects

J F Young

Publications and source records attributed to J F Young.

134 records · Page 8Linked to original sources
PubMedDate not supplied

Dose-response of retinoic acid induced stress protein synthesis and teratogenesis in mice.

Stress proteins are synthesized in response to a variety of stressors, including several teratogenic agents. However, their role, if any, in the teratogenic process is unknown. We have previously demonstrated that all-trans-retinoic acid administered to pregnant CD-1 mice on gestational day 11 or 13 produced limb defects and cleft palate near term in a dose-responsive manner. This chemical also induced the synthesis of several nuclear stress proteins in embryonic tissues within several hours of dosing. The stress proteins were only observed in tissues that eventually became malformed and not in tissues that appeared normal at term. In the current work, we examined the stress response in embryonic target tissues after several different doses of retinoic acid. The nuclear stress proteins were synthesized in a dose-related manner and at a lower retinoic acid dose than doses producing malformations in the corresponding tissue at birth. Each individual stress protein and the total stress protein response were highly correlated, across dose, with the respective malformations observed at term.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Kinetics and specificity at the clonal level of the cytotoxic T lymphocyte response to influenza pneumonia.

We have studied the kinetics and specificity of the cytotoxic T lymphocyte (CTL) response to influenza A/PR/8 (H1N1) virus pulmonary infection in the mouse detected using spleen cells from infected mice which were stimulated in bulk and limiting dilution cultures. A hybrid protein designated D-peptide, which contains the terminal 157 amino acids of the HA2 subunit of A/PR/8 virus, was used to stimulate influenza virus subtype-specific secondary CTL in vitro. Infection induced two specificities of precursor CTL, cross-reactive and subtype-specific. The kinetics of the subtype-specific CTL response detected by the D-peptide were similar to the cross-reactive CTL response detected by stimulation with live virus. The majority of the precursor CTL (CTL-p) are able to lyse virus-infected target cells in a cross-reactive fashion. The number of memory subtype-specific and cross-reactive CTL increased by approximately 2.5 logs10 during the first 3 weeks after infection.

Administration, Intranasal↗
PubMedDate not supplied

Publication of utilisation data. Its effect on clinical decisions.

During an 18-week period in 1978-1979, a weekly bulletin containing information about patients' stay in hospital and prescribing patterns in each unit was distributed to all doctors and senior nurses of six general medical and six general surgical units in the Royal Adelaide Hospital. For the first nine weeks, the bulletins contained information from half of the units, then crossed over in the second nine-week period. The mean stay in all units of 2251 persons discharged from hospital during the first nine weeks was 9.5 days, compared with 8.7 days for the 2234 patients in the second nine weeks (a reduction of more than 2000 bed-days (P less than 0.002)). The percentage of outpatients and discharged inpatients who were given prescriptions for more than two drugs fell from 15.3% to 13% (P less than 0.001). It is likely that publication of the bulletins influenced discharge and prescribing decisions by increasing general awareness that these matters were under review.

Australia↗
PubMedDate not supplied

Mathematical modeling of human embryonic and fetal growth rates.

A mathematical model for human embryonic/fetal growth data from implantation to birth is developed. In previous work, it was shown that an unbiased estimate for human fetal growth data from about day 50 post-conception until term could be calculated from the Gompertz equation. This period represents a range of embryonic/fetal weights from one to 3500 g. When the Gompertz equation is extended, with no change of parameters, to the prenatal period before 50 days, the predicted weights have a consistent bias which might have a biological basis. Early embryonic growth immediately following fertilization is exponential; i.e., one cell goes to 2, then 4, then 8... etc., with essentially no decrease in relative growth rate. Except for possible small changes in cell size and cell mitosis cycle time, such exponential growth can be considered as a special case of the Gompertz equation with a, the relative rate of decrease of the relative growth rate, equal to zero. The relative growth rate begins to decrease about 20 days post-conception, at the time of cell differentiation into organ precursors. Although the "Hayflick Limit" of the maximum of 50 to 60 cell divisions for human cells would tend to cause a decrease in growth rate, it can be shown that the effect is insignificant during embryonic/fetal growth. The observed decrease in the growth rate might be a result of a decreasing fraction of cells in the pool of dividing cells. For the Gompertz equation model, a at this time changes from zero to a positive number. Analysis of fetal growth data shows that a rapidly becomes large and then decreases over a period of several days to become a constant positive value for the remainder of the prenatal term. Good fits of empirical embryonic/fetal growth data were obtained by nonlinear regression with calculation of the embryonic/fetal weights through numerical integration of the differential Gompertz equations and the functionality of alpha.

Body Weight↗
PubMedDate not supplied

Influence of a purified diet and route of administration on the metabolism and disposition of estradiol in B6C3F1 mice.

The metabolism and disposition of [6,7-3H]estradiol ([3H]E2) given by gavage (po) or intravenously (iv) were examined in female B6C3F1 mice fed either the purified AIN-76A (AIN) or cereal-based NIH-07 (NIH) diet for a period of 8 weeks prior to treatment with E2. Initially, 40.6 Ci of [3H]E2 was given iv to each mouse. Subsequently, 45.6 Ci of [3H]E2 was given po to the same mice. Samples of blood, urine, and feces were obtained during a 48-hr period after each dosing. Total radioactivity was determined for each sample. Urine and plasma samples were analyzed by HPLC, and the radiolabeled metabolites were tentatively identified and quantified. Statistical comparisons were made of the effects of diet, route of administration, and interactions among groups. Analysis revealed: 1) greater fecal than urinary excretion of radioactivity regardless of route of administration or diet fed, 2) more radioactivity excreted in the urine of AIN-fed than in NIH-fed mice, significantly different only after iv administration (p less than 0.02), and 3) a greater feces:urine ratio of excreted radioactivity following iv than po administration and from NIH-than AIN-fed mice. Metabolite profiles showed: 1) no differences in urine due to route of administration, 2) estriol conjugates dominated urinary metabolites, 3) accumulation of radioactive material in plasma that apparently was tritiated water, with more rapid accumulation of tritiated water after po than iv administration, 4) relatively more plasma estradiol-17-glucuronide, estriol-3-sulfate, and estriol in po- than in iv-treated mice, 5) estradiol-3, 17-sulfate in plasma of iv- but not po-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMedDate not supplied

A pharmacokinetic model to predict exposure of the bladder epithelium to urinary N-hydroxyarylamine carcinogens as a function of urine pH, voiding interval, and resorption.

Estimation of urinary levels of N-hydroxyarylamines, which are believed to be ultimate carcinogens for the bladder epithelium, has been complicated by the rapid resorption of these metabolites across the bladder wall and by their formation in the urine upon hydrolysis of N-hydroxyarylamine N-glucuronide conjugates. Therefore, a three-compartment pharmacokinetic model was developed with an analog-digital hybrid computer to separate absorption, metabolism, and distribution in the whole animal from events in the bladder lumen (deposition, hydrolysis, and resorption). The total bladder exposure to the carcinogen, N-hydroxy-2-naphthylamine, was then simulated from experimental data; and urine pH and voiding interval, both of which differ widely among species, were tested as variables. For humans and dogs, urine pH was found to be considerably more acidic than monkeys or rats; while voiding intervals in rats were considerably shorter than in monkeys, dogs, or humans. The relative species susceptibilities, indicated by the model as total bladder exposure to the N-hydroxyarylamine metabolite under conditions of normal urine pH and frequency of micturition for each species, were in the order: human greater than or equal to dog greater than monkey greater than rat. This is consistent with the reported carcinogenic potency of 2-naphthylamine in these species and suggests that urine pH and voiding interval are important determinants in aromatic amine-induced bladder cancer.

Absorption↗
PubMedDate not supplied

Utility of pharmacokinetics in designing toxicological protocols and improving interspecies extrapolation.

Key terms such as pharmacokinetics, pharmacodynamics, time course-concentration, and dosimetry and how they apply to predictive toxicology are defined and differentiated. The importance of utilizing pharmacokinetic techniques in teratology and developmental toxicology are discussed from the viewpoints that (1) agent's access to target tissue is modulated by the placenta, (2) interspecies sensitivities differ, (3) dose-response curves are steep, and (4) dosimetry information improves the validity of regulatory standards. We review the teratology literature where attempts were made to correlate embryonal/fetal exposure to teratogenic endpoints. The strengths and weaknesses of these papers are discussed as well as our suggested changes in their protocols, which would have improved interspecies extrapolation.

Age Factors↗