Search PubMed⌕ Search

Biomedical subjects

F A Smith

Publications and source records attributed to F A Smith.

At least 37 records · Page 2Linked to original sources
PubMed1993

The uptake and metabolism of urea by Chara australis: IV. Symport with sodium--a slip model for the high and low affinity systems.

We have previously investigated the electrogenic influx of urea in Chara, and the urea- and sodium-dependent membrane current. We have shown that there is a sodium-stimulated component of urea influx and a urea-stimulated component of sodium influx, and that these are of the same size. We conclude that the electrogenic inward transport of urea, and of its analogues acetamide and acrylamide, is by sodium symport, with a stoichiometric ratio of 1:1. The kinetics of the fluxes and currents show two different KM values for sodium in different cells and two different kinds of kinetics for the effect of urea on membrane current, one of which fits the Michaelis-Menten equation, while the other shows a maximum and fits the difference of two Michaelis-Menten terms, suggesting a phenomenon like cis-inhibition. Similarities in kinetic characteristics between the inhibitory site and the electrically silent uptake site (System II) lead us to suggest that the same protein may be responsible for both the low-KM, electrogenic influx of urea (System I) and the high-KM, electrically silent influx by System II. We suggest a "slip" model for urea uptake in Chara.

Acetamides↗
PubMed1992

Regulation of Calcium Influx in Chara: Effects of K, pH, Metabolic Inhibition, and Calcium Channel Blockers.

Measurements were made of (45)Ca influx into isolated internodal cells of Chara corallina and also into internodal cells of intact plants. (45)Ca influx was closely related to growth. In rapidly expanding internodal cells, the influx was approximately 1.4 nmol m(-2) s(-1) compared to the influx in mature cells from slow-growing cultures of 0.2 nmol m(-2) s(-1). Isolated internodal cells had influxes in the range 0.2 to 0.7 nmol m(-2) s(-1), but this increased to approximately 2 nmol m(-2) s(-1) in high calcium solutions and to 4 nmol m(-2) s(-1) in high potassium solutions. No significant effects on calcium influx were observed for changes in external pH or for treatments that changed internal pH, except that NH(4) was slightly inhibitory. Severe metabolic inhibition by carbonylcyanide-m-chlorophenyl-hydrazone stimulated influx, whereas dicyclohexylcarbodiimide had no effect and darkness inhibited influx. La(3+) also inhibited influx, but the organic channel blockers nifedipine and bepridil stimulated influx. Verapamil had no effect. The results are generally consistent with voltage regulation of calcium channels as in animal cells.

Journal Article↗
PubMed1991

Disposition and metabolism of [14C]1,2-dichloropropane following oral and inhalation exposure in Fischer 344 rats.

The objective of this study was to compare the disposition and metabolism of [14C]1,2-dichloropropane [( 14C]DCP) following oral and inhalation exposure since these two routes are of interest with regards to occupational and accidental exposure. [14C]DCP was administered orally to groups of four rats of each sex as a single dose of 1 or 100 mg/kg and as a multiple 1 mg/kg nonradiolabeled dose for 7 days followed by a single 1 mg [14C]DCP/kg dose on day 8. In addition, four rats of each sex were exposed to [14C]DCP vapors for a 6-h period in a head-only inhalation chamber at target concentrations of 5, 50 and 100 ppm. [14C]DCP was readily absorbed, metabolized and excreted after oral or inhalation exposure. For all treatment groups the principal routes of elimination were via the urine (37-65%) and expired air (18-40%). The tissues, carcass, feces and cage wash contained less than 11, 9.7 and 3.8% of the dose, respectively. The major urinary metabolites, as a group, from the oral and inhalation exposures were identified as three N-acetylcysteine conjugates of DCP, N-acetyl-S-(2-hydroxypropyl)-L-cysteine, N-acetyl-S-(2-oxopropyl)-L-cysteine and N-acetyl-S-(1-carboxyethyl)-L-cysteine. The majority (61-87%) of the expired volatile organic material was found to be parent DCP in all samples analyzed. Increasing the dose/concentration of [14C]DCP resulted in an increase in the amount of exhaled [14C]-volatile organics. The peak DCP blood concentrations (inhalation exposure) were not proportional to dose, indicating a dose-dependency in the blood clearance of DCP. Nonetheless, upon termination of exposure, DCP was rapidly eliminated from the blood. In all treatment groups, following oral and inhalation exposure the majority of the radioactivity was eliminated by 24 h postdosing and no differences were noted between sexes. Therefore, it can be concluded that in the rat the pharmacokinetics and metabolism of [14C]DCP are similar regardless of route of exposure or sex.

Administration, Inhalation↗
PubMed1991

A PAC study of the binding of 111In to a monoclonal antibody via the macrocyclic molecule 1,4,7-triazacyclononanetriacetic acid.

Time integral and time differential PAC measurements have been made from samples of 111In bound to the functionalized 9N3 macrocycle, and 111In bound to the monoclonal antibody AUA1 via the macrocycle, over the temperature range 80-350 K. Values obtained for the integrated perturbation coefficient G22 (infinity) clearly illustrate the effects which the antibody has on the angular correlation of the gamma-rays emitted by the 111In decay. Measurements of the quadrupole frequency in the 111In-9N3-AUA1 samples show a transition temperature between 250 and 275 K which was not detected in the 111In-9N3. An arrhenius plot of the temperature dependence of the correlation time for the 111In-9N3 yielded a value of 0.10 +/- 0.01 eV for the activation energy associated with molecular re-orientation, whilst a Debye plot indicated an effective volume of (10 +/- 1) x 10(-27) m3 for the same sample. Extrapolation of the Debye plot suggests a high relaxation constant which may be attributed to internal vibrational modes in the macrocycle. Comparisons are made with similar work on the plasma protein transferrin.

Antibodies, Monoclonal↗
PubMed1990

Development of a physiologically based pharmacokinetic model for chloroform.

A physiologically based pharmacokinetic model describing the disposition of chloroform in mice, rats, and humans was developed. This model was designed to facilitate extrapolations from high doses, such as those used in chronic rodent studies, to low doses that humans may be exposed to in the workplace or the environment. Kinetic constants for mice and rats were derived from in vivo experiments. Enzymatic studies conducted with samples of rodent and human tissues provided a rational basis for estimating human in vivo metabolic rate constants. Incorporation of physiological descriptions of the processes of absorption, distribution, metabolism, and excretion allowed extrapolation between different routes of exposure as well. The model was validated by comparing model predictions with experimental data gathered in mice, rats, and humans after inhalation, oral, or intraperitoneal administration of chloroform. Consistent with previous reports, the metabolic activation of chloroform to toxic intermediates was shown to occur most rapidly in the mouse, less rapidly in the rat, and most slowly in humans. Estimates of the "delivered dose" of chloroform metabolites to internal organs sensitive to chloroform toxicity were calculated. This model may be used to develop refined dose estimates for human populations exposed to low levels of chloroform in the environment.

Administration, Inhalation↗
PubMed1990

Day-to-day variability of serum cholesterol, triglyceride, and high-density lipoprotein cholesterol levels. Impact on the assessment of risk according to the National Cholesterol Education Program guidelines.

The National Cholesterol Education Program has recently published guidelines for the assessment of cardiovascular risk and goals for laboratory accuracy. To test the impact of biologic and analytic variability on the ability of a single lipid measurement to assess risk accurately, lipids were measured on three occasions in 51 volunteers. Notable day-to-day variability of total cholesterol (5%), triglyceride (20%), high-density lipoprotein cholesterol (10%), and calculated low-density lipoprotein cholesterol (8%) levels was found. Analytic variability contributed significantly to total variability of high-density lipoprotein cholesterol levels and calculated low-density lipoprotein cholesterol levels. Confidence intervals constructed around National Cholesterol Education Program cutoff points suggested that classification was reliable from a single measurement if total cholesterol value was below 4.78 (less than 185 mg/dL), between 5.56 and 5.81 (215 and 225 mg/dL), or above 6.59 mmol/L (greater than 225 mg/dL). Low-density lipoprotein cholesterol value classification from a single measurement was only accurate at below 3.00 (greater than 116 mg/dL) or above 4.50 mmol/L (greater than 174 mg/dL). This study documents significant day-to-day variability of serum lipids and suggests that patients near the National Cholesterol Education Program cutoff points may require repeated measurements to assign risk accurately.

Adult↗
PubMed1989

Evidence of conformational changes in the non-equivalent binding sites of human serum transferrin.

Samples of monoferric human serum transferrin have been prepared in which the iron occupies predominantly the N-site (sample A) and the C-site (sample B). 111In was then added in concentrations small enough to ensure that there was always an excess of specific binding sites. Because of the presence of apo-transferrin in both the samples, the occupancy by 111In in the two sites was only 75-78% C-site in sample A and only 61-65% N-site in sample B. Time differential PAC spectra showed a transition in the quadrupole frequency which took place at different temperatures, approximately 275 K in sample A and between 290 and 305 K in sample B. Debye and Arrhenius plots of the temperature dependence of the correlation time associated with molecular reorientation indicated an effective molecular volume about 50% larger than that of the hydrated diferric molecule determined by "biochemical" methods, and an activation energy for re-orientation of approximately 0.065 eV.

Binding Sites↗
PubMed1988

Some optimum conditions for proton induced ultrasoft x-ray production.

The proton beam from an AN700 van de Graaff accelerator has been used to bombard solid targets of C, TiB2, SiC, SiN, Al and Au in the energy range 250-700 keV. A study of target surface contamination, the nature of the angular dependence in the x-ray emission and the dependence of the x-ray yield on proton energy has been undertaken. Our findings suggest that the optimum target angle is 30 degrees with respect to the incident proton direction and the detector angle 90 degrees to the target surface. In a vacuum of 10(-5) Torr (approximately 1.33 mPa) and at proton currents of 50-100 muA, a carbon deposit can be expected to build up with time on the target surface to reduce the characteristic x-ray intensity from the target. In the comparison between the energy dependent yields of CK and AlK x-rays, we find a slightly smaller dependence on energy than that predicted by the empirical cross section formula of Paul (1984) although the latter is not expected to be valid down to Z = 6.

Protons↗
PubMed1987

Physiologically based pharmacokinetics and the risk assessment process for methylene chloride.

Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation by mixed function oxidases (MFO) and the other dependent on glutathione S-transferases (GST). A physiologically based pharmacokinetic (PB-PK) model based on knowledge of these pathways was used to describe the metabolism of DCM in four mammalian species (mouse, rat, hamster, and humans). Kinetic constants for the model were derived from in vivo experiments or the literature. The model was constructed to distinguish contributions from the two pathways of metabolism in lung and liver tissue, and to permit extrapolation from rodents to humans. Model validation was conducted by comparing predicted blood concentration time-course data in rats, mice, and humans with experimental data from these species. The tumor incidence in two chronic studies of DCM toxicity in mice was correlated with various measures of target tissue dose calculated with the PB-PK model. Tumor incidence correlated well with tissue AUC (area under the concentration/time curve) and amount of DCM metabolized by the GST pathway. However, tumor incidence did not correlate with the amount of DCM metabolized by the MFO pathway. Because of its low chemical reactivity, DCM is unlikely to be directly involved in carcinogenesis. Consequently, metabolism of DCM by GST appears to be important in carcinogenesis. The PB-PK model was used to estimate target doses of presumed toxic chemical species in humans exposed to DCM by inhalation or by drinking water. Target tissue doses in humans exposed to low concentrations of DCM are 140- to 170-fold lower (inhalation) or 50- to 210-fold lower (drinking water) than would be expected from the linear extrapolation and body surface area factors which have been used in conventional risk assessment methods (D. V. Singh, H. L. Spitzer, and P. D. White (1985). Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). EPA/600/8-82/004F). The PB-BK analysis thus suggests that conventional risk analyses greatly overestimate the risk in humans exposed to low concentrations of DCM. PB-PK considerations provide a scientific basis for risk assessment, improve experimental design in chronic studies, and structure collection of quantitative metabolic constants required for risk assessment.

Animals↗
PubMed1987

Acute, pharmacokinetic, and subchronic toxicological studies of 2,4-dichlorophenoxyacetic acid.

The single-dose oral LD50 values in Fischer 344 rats for technical-grade, 2,4-dichlorophenoxyacetic acid (2,4-D), esters, and salts ranged from 553 mg/kg (isobutyl ester in females) to 1090 mg/kg (dimethylamine salt in males). The LD50 values for the acid, esters, or salts, when expressed as acid equivalents, were consistent which suggests that the acute toxicity was due to 2,4-D per se. Acute dermal LD50 values in rabbits for the acid, esters, and salts were greater than 2000 mg/kg. Overall, these results indicate that the acute oral and dermal toxicity of 2,4-D are low. Pharmacokinetics were evaluated in male Fischer 344 rats given single oral doses of 10, 25, 50, 100, or 150 mg 2,4-[14C]D/kg. The amount of 2,4-D in the plasma, kidney, and urine 6 hr postdosing indicated that the urinary elimination of 2,4-D was saturated in male rats given oral doses in excess of 50 mg/kg. Subchronic dietary studies in male and female Fischer 344 rats used dose levels of 0, 15, 60, 100, or 150 mg/kg/day of purified or technical-grade 2,4-D acid for 13 weeks. Body weight gains were decreased for both sexes at the higher dose levels of purified and technical-grade 2,4-D acid. Kidney weights were increased in all treated male rats and in females given the higher three dose levels of purified 2,4-D. Treatment-related cytoplasmic alterations were present in the renal proximal tubules of most rats given 60 mg/kg/day and higher of purified or technical-grade 2,4-D; a few females given 15 mg/kg/day also had slight alterations in the cytoplasm of the proximal tubules. A dose-related degenerative change was identified in the descending proximal renal tubules of all male rats given the highest three dose levels of either test material and some given 15 mg/kg/day. Dose levels of 100 or 150 mg/kg/day of either compound for both sexes produced minimal swelling and increased staining homogeneity in the liver cells and were associated with a slight elevation of liver weight and serum glutamic pyruvic transaminase activity. Higher dose levels of technical-grade and purified 2,4-D decreased total serum tetraiodothyronine levels in female rats, however, the morphology of the thyroid gland was normal. The no-observed-effect level (NOEL) was less than 15 mg/kg/day for both purified and technical-grade 2,4-D acid.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1985

The dissociation of some 111In chelates in the presence of transferrin and haemoglobin studied by PAC.

The interaction of [111In]Tris-chelates with protein molecules in aqueous solution at room temperature has been studied using time-integral and time-differential PAC. Increasing amounts of apo-transferrin were added to solutions of [111In]tropolonate, -acetylacetonate, -oxinate and -oxine sulphate, and of haemoglobin to [111In]tropolonate. The transfer of 111In from chelate to protein was monitored by time-integral PAC measurements. Analysis of these data in erms of stability constants showed that with added transferrin complete dissociation of each 111In chelate occurred with increasing protein concentration, the radiolabel being sequestered by the protein molecules. Confirmation of this was provided by time-differential PAC measurements at four tropolone:transferrin relative concentrations, and in the pure systems. A value for the first stability constant of transferrin is presented. Analysis of time-integral PAC data showed that added haemoglobin did not cause complete dissociation of [111In]tropolonate, a [111In]tropolone-haemoglobin complex being formed. Time-differential PAC studies of the [111In]tropolonate:haemoglobin and [111In]haemoglobin systems at 77 K and 295 K supported this conclusion, revealing quadrupole frequencies of 14.0 +/- 0.6 MHz in [111In]haemoglobin and 9.1 +/- 1.1 MHz in the mixed system.

Drug Stability↗
PubMed1984

PAC studies of 111In binding to transferrin, tropolone and acetylacetone in aqueous solutions.

Time integral and time-differential PAC measurements have been made over a wide temperature range in aqueous solutions of [111In]tropolonate and [111In]acetylacetonate. The quadrupole frequency in the latter is approximately 30% higher than that in the former and the molecular volumes derived from rotational correlation times show the expected differences. Apo-transferrin was separately added to the two 111In-chelates and the transfer of activity from chelate to transferrin followed as a function of relative molar concentrations. Very much larger molar ratios of transferrin to tropolone than of transferrin to acetylacetone were required before substantial transfer of 111In from chelate to transferrin took place. This difference in affinity for transferrin could be one significant factor in explaining the enhanced ability of [111In]tropolonate to label blood cells in the presence of plasma. The determination of PAC parameters in [111In]transferrin over a range of temperatures showed that the values of quadrupole frequency obtained depended on the number of binding sites assumed. For only one 111In site per molecule, the quadrupole frequency increases by over 50% as the temperature is reduced below the freezing point of the solution. If two 111In sites are assumed there appears to be a change in the percentage occupancy of the two sites on either side of the transition.

Cycloheptanes↗
PubMed1984

Teratologic evaluation of 3,6-Dichloropicolinic acid in rats and rabbits.

3,6-Dichloropicolinic acid (clopyralid), a new herbicide, was evaluated for teratogenic potential in Fischer 344 rats and New Zealand White rabbits. Rats were given 0, 15, 75, or 250 mg clopyralid/kg/day by gavage on Days 6-15 of gestation while rabbits were given 0, 110, or 250 mg clopyralid/kg/day on Days 6-18 of gestation. Maternal toxicity, as evidenced by decreased body weight gain, was observed among pregnant rats in the 250-mg/kg/day group. No evidence of maternal toxicity was observed among treated rabbits. A teratogenic effect was not detected in either species.

Abnormalities, Drug-Induced↗
PubMed1984

A two-year follow-up of a comparative trial of the cost-effectiveness of home and hospital psychiatric treatment.

The manpower and operating cost of home-based treatment was compared with the manpower and operating cost of hospital-based treatment during the second year and at the end of two years of treatment. Of the 155 patients destined to receive inpatient treatment, 76 were randomly assigned to home treatment, 79 to hospital treatment. The two groups were similar as to important social, demographic, and clinical characteristics, including psychiatric diagnosis. The manpower and operating cost of treatment, measured in two ways, was similar in the two groups during the second year. However, over the 2-year period hospital-based treatment of patients in each of the three diagnostic groups was more expensive than home-based treatment. Also, regardless of which treatment was given, the cost of treating schizophrenics was higher than the cost of treating manic-depressives which, in turn, was higher than the cost of treating individuals with depressive neurosis. Treatment failures were discussed. Over the 2-year period, failures in home-based treatment accounted for 39.1% of the total manpower and operating cost of home-based treatment, calculated according to Cost Model 1, and for 67.1% of the cost calculated according to Cost Model 2. The concept of failure in hospital-based treatment is also discussed.

Bipolar Disorder↗
PubMed1983

Identification of two forms of fluorine in tissues of rats inhaling hydrogen fluoride.

Nonionizable fluorine has been detected in the plasma of several species including the human, however, the exact nature and source of this fluorocompound(s) remain unknown. In the current investigation, the fluoride ion sensitive electrode was employed to determine the fluoride content of ashed (total F) and unashed (ionic F-) tissues of rats exposed to hydrogen fluoride (HF). Total fluorine concentration consistently exceeded ionic fluoride concentration in tissues of HF-exposed rats, suggesting the presence of fluorine in unashed tissue which did not respond to the F- ion sensitive electrode. The concentration of this nonresponding fluorine fraction, termed the delta F fraction, was estimated by subtracting the ionic F- from the total F concentration of each sample. Pulmonary and plasma delta F concentrations increased with time following whole body inhalation exposure to HF. It was possible to separate delta F from ionic F- by calcium phosphate adsorption, indicating that the delta F fraction consists of nonionizable fluorine. Upon Sephadex G-25 gel chromatography, plasma delta F migrated near the bed volume, providing evidence that it is of low molecular weight. Finally, a strong correlation (r = 0.99, p less than 0.01) between plasma delta F concentration and airborne HF concentration was observed, indicating that inorganic fluoride (as HF) is the ultimate source of the low-molecular-weight, nonionizable fluorine species present in tissues of HF-exposed rats.

Animals↗