Biomedical subjects

J F Young

Publications and source records attributed to J F Young.

At least 19 recordsLinked to original sources

PubMed2006

Hierarchical models for probabilistic dose-response assessment.

Probabilistic risk assessment is gaining acceptance as the most appropriate way to characterize and communicate uncertainties in estimates of human health risk and/or reference levels of exposure such as benchmark doses. Although probabilistic techniques are well established in the exposure-assessment component of the National Research Council's risk-assessment paradigm, they are less well developed in the dose-response-assessment component. This paper proposes the use of hierarchical statistical models as tools for implementing probabilistic dose-response assessments, in that such models provide a natural connection between the pharmacokinetic (PK) and pharmacodynamic (PD) components of dose-response models. The results show that incorporating internal dose information into dose-response assessments via the coupling of PK and PD models in a hierarchical structure can reduce the uncertainty in the dose-response assessment of risk. However, information on the mean of the internal dose distribution is sufficient; having information on the variance of internal dose does not affect the uncertainty in the resulting estimates of excess risks or benchmark doses. In addition, the complexity of a PK model of internal dose does not affect how the variability in risk is measured via the ultimate endpoint.

Dose-Response Relationship, Drug↗

PubMed2006

Creatine monohydrate and glucose supplementation to slow- and fast-growing chickens changes the postmortem pH in pectoralis major.

The energy status of the chicken at slaughter has a large impact on the development of pH postmortem and thus on color and water-holding capacity (WHC). Supplementation of creatine monohydrate and glucose (CMH+GLU) may increase the creatine content in the muscles before slaughter, thereby delaying the formation of lactic acid and postponing the pH decline. The objective of this study was to examine the impact of supplementing CMH+GLU in the drinking water within the last 48 h before slaughter on the pH decline, meat color, and WHC in the pectoralis major from 2 strains of Ross chickens. Forty Ross 308 (fast-growing) female chickens and 40 Ross 1972 (slow-growing) female chickens had free access to drinking water either supplemented with CMH (15 g/ L) and glucose (50 g/L) within the last 48 h before slaughter or without supplementation. All chickens were slaughtered at 42 or 43 d of age irrespective of weight. Temperature and pH were measured at 1 and 30 min and at 1, 3, 8, and 24 h postmortem. Also, WHC measured as drip loss and color were determined postmortem. The CMH+GLU supplementation decreased pH (P < 0.05) at all time points between 1 min and 8 h postmortem in both strains, whereas at 24 h postmortem only pH in Ross 308 chickens were decreased significantly upon supplementation. Lightness was significantly increased in the meat from Ross 308 but not from Ross 1972 chickens upon supplementation. This interaction was significant (P < 0.05). The redness of the meat was decreased upon supplementation (P < 0.05), although only significantly in Ross 1972. The pH was lower for Ross 1972 chickens at the early time points (P < 0.01) and also a higher drip loss (P < 0.05), lightness (P < 0.01), and redness (P < 0.001) were observed. Thus, there seems to be no beneficial effect of CMH+GLU supplementation on chicken meat quality on the basis of results from this experiment.

Animals↗

PubMed2005

Classification ensembles for unbalanced class sizes in predictive toxicology.

This paper investigates the effects of the ratio of positive-to-negative samples on the sensitivity, specificity, and concordance. When the class sizes in the training samples are not equal, the classification rule derived will favor the majority class and result in a low sensitivity on the minority class prediction. We propose an ensemble classification approach to adjust for differential class sizes in a binary classifier system. An ensemble classifier consists of a set of base classifiers; its prediction rule is based on a summary measure of individual classifications by the base classifiers. Two re-sampling methods, augmentation and abatement, are proposed to generate different bootstrap samples of equal class size to build the base classifiers. The augmentation method balances the two class sizes by bootstrapping additional samples from the minority class, whereas the abatement method balances the two class sizes by sampling only a subset of samples from the majority class. The proposed procedure is applied to a data set to predict estrogen receptor binding activity and to a data set to predict animal liver carcinogenicity using SAR (structure-activity relationship) models as base classifiers. The abatement method appears to perform well in balancing sensitivity and specificity.

Discriminant Analysis↗

PubMed2004

Water-holding capacity in chicken breast muscle is enhanced by pyruvate and reduced by creatine supplements.

In commercial production, chickens are subjected to feed withdrawal prior to slaughter and exposed to stress during transport and handling of the animals at the slaughterhouse; this causes plasma glucose and glycogen stores in liver and muscle to decrease, which has a negative impact on meat quality. The aim of the present study was to investigate how supplementation of the energy complements creatine and pyruvate during the fasting period would affect postmortem pH decrease, water-holding capacity, and color of the meat. Female Ross 208 broilers were supplemented with glucose combined with either pyruvate or creatine via the drinking water for 18 or 42 h prior to slaughter, i.e., before and throughout the fasting period. Chickens were slaughtered at 42 or 43 d of age. Temperature and pH were measured at 1, 10, 30, and 45 min and 1, 2, 4, 8, and 12 h postmortem. The results showed that the pyruvate and glucose supplementation increased the pH at 45 min postmortem by 0.25 units and decreased drip loss of musculus pectoralis major (PM) by 50 to 65% in chickens supplemented for 42 h. The creatine and glucose supplementation reduced pH at 3 and 4 h postmortem by 0.32 to 0.42 units, increased the lightness (L*) by 2.3 to 5.6 units, and increased drip loss by 51 to 137% in the PM of chickens supplemented for 18 and 42 h. Pyruvate and glucose supplementation thus appear beneficial but whether this is concomitant with an overall improvement in meat quality remains to be determined.

Animals↗

PubMed2003

Feed and strain effects on the use of outdoor areas by broilers.

1. The use of outdoor areas by two broiler strains, known to have different growth rates and with access to either moderate (M) or low (L) energy feeds, was examined to assess the consequences for production, meat quality, health and welfare. 2. Sixteen groups of either Ross 208 (ROSS) or a Labresse cross (LAB) were fed either feed M or L. They were raised indoors until 42 d of age when groups of 102 birds were moved to outdoor houses with free access to an outdoor area. 3. The number of chickens standing and lying, respectively, in each of 5 zones in the outdoor area were recorded at intervals throughout the outdoor growth period until slaughter at 84 d of age. Production variables were measured, and gait, feather condition, litter quality, and dermal lesions on foot-pads and hocks were scored together with objective meat quality measures. 4. Both strains showed a diurnal rhythm with most birds observed outside around sunrise and before sunset. Feed and strain both affected the distribution of the birds on the outdoor area, with more birds on feed M than L observed outside, and with more LAB birds outside and using more of the outdoor area than ROSS. This was reflected in some of the carcase and meat quality measures. Feather pecking and cannibalism only occurred in LAB. 5. ROSS was found to have a faster growth rate, poorer litter quality, more dermal lesions and impaired mobility, reflected in low usage of outdoor area and poor gait score compared with LAB. 6. This together with the presence of pectoral myopathies make ROSS unsuitable for 12 week growth in free range production systems. The occurrence of feather pecking and cannibalism in LAB make this particular Labresse cross questionable for meat-type poultry production.

Aggression↗

PubMed2003

Ascorbic acid, alpha-tocopherol, and oregano supplements reduce stress-induced deterioration of chicken meat quality.

In order to ameliorate a negative effect of stress on meat quality characteristics, chickens were fed a diet supplemented with a combination of ascorbic acid (1,000 ppm) and alpha-tocopherol (200 ppm) or oregano (3%), which has a high content of antioxidants. Chickens were slaughtered by cervical dislocation in the stable (no stress) or after transport and electrical stunning at the slaughter plant (stress). Activities of antioxidative enzymes (catalase, superoxide dismutase, and glutathion peroxidase) in pectoralis major (PM), iliotibialis (IL), and liver were unaffected by supplementation. However, erythrocyte stability, which is a more complex model system for determining oxidative status, increased with ascorbic acid-alpha-tocopherol supplementation and tended to increase after oregano supplementation. In nonstressed birds, this improved antioxidative status was reflected in decreased TBA-reactive substances (TBARS) in PM and liver of ascorbic acid-alpha-tocopherol-supplemented chickens and likewise in liver from oregano-supplemented chickens compared to that of nonstressed control birds. However, postmortem temperature, pH, and water-holding capacity were not affected by supplementation. Drip loss from oregano-supplemented chickens showed increased protein oxidation in specific bands, but this did not relate to water-holding capacity or antioxidative status. When exposed to stress, the concentration of TBARS in the control animals increased in PM and IL. Ascorbic acid-alpha-tocopherol supplementation protected IL, and oregano supplementation protected PM from stress-induced increases in TBARS. This differential effect between muscles may indicate differences in protection mechanisms. In conclusion, ascorbic acid-alpha-tocopherol and oregano supplements to chickens protect against stress-induced increase in TBARS, in different muscles.

Animal Feed↗

PubMed2002

Green tea extract only affects markers of oxidative status postprandially: lasting antioxidant effect of flavonoid-free diet.

Epidemiological studies suggest that foods rich in flavonoids might reduce the risk of cardiovascular disease and cancer. The objective of the present study was to investigate the effect of green tea extract (GTE) used as a food antioxidant on markers of oxidative status after dietary depletion of flavonoids and catechins. The study was designed as a 2 x 3 weeks blinded human cross-over intervention study (eight smokers, eight non-smokers) with GTE corresponding to a daily intake of 18.6 mg catechins/d. The GTE was incorporated into meat patties and consumed with a strictly controlled diet otherwise low in flavonoids. GTE intervention increased plasma antioxidant capacity from 1.35 to 1.56 (P<0.02) in postprandially collected plasma, most prominently in smokers. The intervention did not significantly affect markers in fasting blood samples, including plasma or haemoglobin protein oxidation, plasma oxidation lagtime, or activities of the erythrocyte superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase. Neither were fasting plasma triacylglycerol, cholesterol, alpha-tocopherol, retinol, beta-carotene, or ascorbic acid affected by intervention. Urinary 8-oxo-deoxyguanosine excretion was also unaffected. Catechins from the extract were excreted into urine with a half-life of less than 2 h in accordance with the short-term effects on plasma antioxidant capacity. Since no long-term effects of GTE were observed, the study essentially served as a fruit and vegetables depletion study. The overall effect of the 10-week period without dietary fruits and vegetables was a decrease in oxidative damage to DNA, blood proteins, and plasma lipids, concomitantly with marked changes in antioxidative defence.

Adult↗

PubMed2001

Analysis of methylmercury disposition in humans utilizing a PBPK model and animal pharmacokinetic data.

Physiologically based pharmacokinetic (PBPK) models are excellent tools to aid in the extrapolation of animal data to humans. When the fate of the chemical is the same among species being compared, animal data can appropriately be considered as a model for human exposure. For methylmercury exposure, sufficient data exist to allow comparison of numerous mammalian species to humans. PBPK model validation entails obtaining blood and tissue concentrations of the parent chemical and metabolite(s) at various times following a known exposure. From ethical and practical considerations, human tissue concentrations following a known exposure to an environmental toxicant are scarce. While animal-to-human extrapolation demands that sufficient human data exist to validate the model, the validation requirements are less stringent if multiple animal models are utilized within a single model template. A versatile PBPK model was used to analyze the distribution and elimination of methylmercury and its metabolite, inorganic mercury. Uniquely, the model is formed in a generic way from a single basic template during the initial program compilation. Basic parameters are defined for diffferent PBPK models for mammalian species that span a relatively large range of sizes. In this article, the analyses include 12 species (mouse, hamster, rat, guinea pig, cat, rabbit, monkey, sheep, pig, goat, cow, and human). Allometric (weight-based) correlations of tissue binding coefficients, metabolism rate constants, and elimination parameters for both methylmercury and inorganic mercury are presented for species for which sufficient data are available. The resulting human model, in accord with the animal models, predicts relatively high inorganic mercury levels in the kidneys long after the disappearance of methylmercury from the blood.

Animals↗

PubMed2001

Correlation of blood cholinesterase levels with toxicity of sarin in rats.

The dose-mortality response curve for sarin when administered to pregnant rats is extremely steep. The pregnant animal either died during the treatment or survived with no observable fetal toxicity. Animals that died displayed many symptoms characteristic of anticholinesterase toxicity. The present study was conducted to determine whether the maternal deaths, clinical observations, and/or weight loss could be correlated with baseline blood cholinesterase levels in individual animals. Cholinesterase levels (plasma and erythrocyte) were obtained prior to, during, and following treatment of nonpregnant rats by gavage with 380 microg/kg/d sarin for 10 d. After the first dose, there was a drop in the plasma cholinesterase levels, which then remained low throughout the dosing period. There was a statistically significant correlation between body weight loss and plasma cholinesterase levels of the sarin dosed animals. The surviving animals also had lower plasma cholinesterase levels and lower body weights, both of which recovered on the cessation of dosing. The erythrocyte cholinesterase levels were not different between treated and nontreated rats. Neither plasma or erythrocyte baseline cholinesterase levels nor relative or absolute cholinesterase decline values could be used as predictors of mortality from sarin administration in rats.

Animals↗

PubMed2001

Decreased in vitro interaction between p53 and nuclear stress proteins in the p53-deficient mouse.

In a previous study, the strength of the interaction between the nuclear stress proteins (sps) 25a, 70i, 72c, and 90 and the tumor suppressor protein p53 was determined by an in vitro fluorescence binding assay. The relative binding of the individual sps with p53, derived from the bone marrow of transgenic mice heterozygous at the p53 locus (p53+/-), was reduced compared to the interaction of sps and p53 derived from wild-type (p53+/+) mice. In order to determine if the genotype of the p53 donor or the genotype of the sp donor determined the binding efficiency, p53 expression was induced by retinoic acid and sp synthesis by bleomycin. P53 derived from either wild-type or heterozygous animals was cross-reacted with nuclear sps obtained from either wild-type or heterozygous animals. Each of the sps, 25a, 70i, 72c, and 90, bound to wild-type p53 with a similar efficiency, irrespective of the genotype of the sp donor mouse (p53+/+ or p53+/-). In contrast, when the sp interaction with p53 obtained from the heterozygous mouse was measured, the relative value of the fluorescence complex was significantly reduced. The data suggest that the strength of the interaction between p53 and nuclear sps is related to the genotype of the p53 donor, and not to the genotype of the animals from which the sps are derived.

Animals↗

PubMed2001

Cement solidification of simulated off-gas condensates from vitrification of low-level nuclear waste solutions.

Solidification in a cementitious matrix is a viable alternative for low-level nuclear waste management; it is therefore important to understand the behavior and properties of such wasteforms. We have examined the cementitious solidification of simulated off-gas waste streams resulting from the vitrification of low-level nuclear waste. Different possible methods for scrubbing the off-gasses from a vitrifier give rise to three possible types of waste compositions: acidic (from aqueous dissolution of volatile NOx and POx carried over from the vitrifier), basic (from neutralizing the former with sodium hydroxide), and fully carbonated (arising from a direct-combustion vitrifier). Six binder compositions were tested in which ordinary Portland cement was replaced at different proportions by fly ash and/or ground granulated blast furnace slag. A high solution to binder ratio of 1l/1 kg was used to minimize the volume of the wasteform and 10% attapulgite clay was added to all mixes to ensure that the fresh mix did not segregate prior to setting. The 28-day compressive strengths decreased when a high proportion of cement was replaced with fly ash, but were increased significantly when the cement was replaced with slag. The heats of hydration at early age for the various solids compositions decreased when cement was replaced with either fly ash or slag; however, for the fly ash mix the low heat was also associated with a significant decrease in compressive strength. High curing temperature (60 degrees C) or the use of extra-fine slag did not significantly affect the compressive strength. Recommendations for choice of binder formulations and treatment of off-gas condensates are discussed.

Environmental Pollution↗

PubMed2001

A mechanistic approach to modelling the risk of liver tumours in mice exposed to fumonisin B1 in the diet.

Data from the National Toxicology Program's carcinogenesis study of fumonisin B1 in B6C3F1 mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from the conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary target organs. The model was used to predict 2-year liver tumour rates in female and male mice based on differences among dose groups in the effect of fumonisin B1 on the growth of normal tissue and on the proliferation of preneoplastic cells as a compensatory response to sphinganine-induced cell death. Fumonisin B1 was assumed to be non-genotoxic, i.e. the model did not include any effect of fumonisin B1 on either of the two mutation rates of the MVK model. The model was able to reproduce reasonably well the observed tumour rates in both female and male mice, predicting substantially increased rates above background only at the highest doses of fumonisin B1 in females.

Animals↗

PubMed2001

Tissue sphinganine as a biomarker of fumonisin-induced apoptosis.

NCTR measured sphinganine concentrations in the livers of mice and in the livers and kidneys of rats in conjunction with a tumour bioassay. In our model of the tumour incidence, target-tissue levels of sphinganine serve as a biomarker for a dose response of fumonisin B1 on cell death. Initially we questioned the utility of sphinganine levels in this role because they were highly variable when compared across time points. In spite of this concern, a conceptual framework and data are presented that support the use of sphinganine as a biomarker for a dose response of fumonisin B1 on cell death. This framework is reasonably consistent with observed sphinganine concentrations in the examined tissues, the literature on fumonisin's effects on sphingolipid synthesis, and our hypothesized mechanism through which fumonisin B1 increases age-specific tumour incidence.

Animals↗

PubMed2001

Resonant scattering and mode coupling in two-dimensional textured planar waveguides.

A heuristic formalism is developed for efficiently determining the specular reflectivity spectrum of two-dimensionally textured planar waveguides. The formalism is based on a Green's function approach wherein the electric fields are assumed to vary little over the thickness of the textured part of the waveguide. Its accuracy, when the thickness of the textured region is much smaller than the wavelength of relevant radiation, is verified by comparison with a much less efficient, exact finite difference solution of Maxwell's equations. In addition to its numerical efficiency, the formalism provides an intuitive explanation of Fano-like features evident in the specular reflectivity spectrum when the incident radiation is phase matched to excite leaky electromagnetic modes attached to the waveguide. By associating various Fourier components of the scattered field with bare slab modes, the dispersion, unique polarization properties, and lifetimes of these Fano-like features are explained in terms of photonic eigenmodes that reveal the renormalization of the slab modes due to interaction with the two-dimensional grating. An application of the formalism, in the analysis of polarization-insensitive notch filters, is also discussed.

Journal Article↗

PubMed2000

[Polyphenolic antioxidants in fruit juice. Urinary excretion and effects on biological markers for antioxidative status].

This intervention study was designed as cross-over (four women, one man) with three doses of black currant/apple (1:1) juice (750, 1000, and 1500 mL) for one week corresponding to an intake of 4.8, 6.4, and 9.6 mg quercetin per day. Urinary excretion of quercetin increased significantly with dose and with time. The fraction excreted in urine was constant 0.29-0.47%. Plasma quercetin did not change with juice intervention. Plasma ascorbate increased during intervention due to ascorbate from the juice. Total plasma malondialdehyde decreased with time during 1500 mL juice intervention. Plasma protein 2-adipic semialdehyde residues, increased with time and dose, and glutathione peroxidase increased with juice dose, whereas other selected markers of oxidative status did not change. These effects might be related to several components of the juice and cannot be attributed solely to its quercetin content.

Adipates↗

PubMed2000

Ecology of Borrelia burgdorferi in ticks (Acari: Ixodidae), rodents, and birds in the Sierra Nevada foothills, Placer County, California.

This study examined the prevalence of Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner in host-seeking adult and nymphal Ixodes pacificus Cooley & Kohls and estimated the I. pacificus infestation and B. burgdorferi infection of rodent and avian hosts in the western Sierra Nevada foothills of northern California. Additionally, we identified species likely to participate in an enzootic cycle for B. burgdorferi in this yellow pine transition habitat. Evidence of infection with B. burgdorferi was identified in 7.3 and 5.4% of host-seeking I. pacificus adults and nymphs, respectively. Mean numbers of I. pacificus observed on rodents were 1.15 for Neotoma fuscipes Baird and 0.18 for Peromyscus spp. One of 104 ear punch tissues obtained from woodrats and none from 49 Peromyscus spp. yielded B. burgdorferi. A total of 291 collected birds representing 34 species had a mean of 0.27 I. pacificus per bird. The mean I. pacificus infestation of ground-dwelling birds was 2.5 ticks per bird. Forty-nine of 92 (53%) blood smears collected from birds were reactive to a B. burgdorferi specific antibody. This study presents the identification of a B. burgdorferi-like spirochete in birds in western North America. The tick burden and spirochete infection of birds suggests that birds may be involved in a local B. burgdorferi enzootic cycle and likely participate in the transport of ticks and spirochetes to other locations while rodents from this site do not appear to be major contributors.

Animals↗

PubMed2000

The effect of grape-skin extract on oxidative status.

Epidemiological studies indicate that moderate alcohol consumption, particularly wine, reduce the risk of CHD. The present study was designed to investigate the effect of grape-skin extract on markers of oxidative status. The study was designed as a randomised crossover. A diet with a low content of flavonoids was served with strict control of intake in two consecutive 1-week intervention periods to fifteen subjects (nine women, six men) divided randomly into two groups. During one of the weeks the subjects from either group consumed 200 ml grape-skin extract in water (1 mg extract/ml) at each of three daily meals (31.3 mg total phenolics, including 9.0 mg catechin). An increased activity of glutathione reductase and a borderline increase of glutathione peroxidase activity in erythrocytes were observed after grape-skin intervention, while the intervention had no significant effect on superoxide dismutase or catalase. Likewise, no effect was found on 2-aminoadipic semialdehyde (AAS) residues, a plasma protein oxidation product, or on malondialdehyde in plasma or in LDL, which are markers of lipoprotein oxidation. A marginal effect of grape-skin intervention was observed on plasma ascorbate levels. Intake of the experimental diet significantly reduced plasma vitamin C and plasma AAS in both groups. This effect was most pronounced in the particular week with no grape-skin extract addition. We speculate that grape-skin extract may have a sparing effect on vitamin C. The effects of the experimental diet may be partly ascribed to a low content of several fruit- and vegetable-related antioxidants like flavonoids and vitamin C and a relatively high content of carrot-derived antioxidants, such as carotenes.

2-Aminoadipic Acid↗

PubMed1999

Induction of stress proteins by electromagnetic fields in cultured HL-60 cells.

HL-60 cells in culture were exposed for 2 h to a sinusoidal 0.1 or 1 mT (1 or 10 Gauss) magnetic field at 60 Hz and pulse labeled after exposure with radioactive isotopes by incubation by using either [(35)S]methionine, [(3)H]leucine, or [(33)P]phosphate. The radioactive labels were incorporated into cellular proteins through synthesis or phosphorylation. Proteins were extracted from electrostatically sorted nuclei, and the heat shock/stress proteins (sp) were analyzed for synthesis and phosphorylation by two-dimensional polyacrylamide gel electrophoresis. In the control cultures (no exposure to the magnetic field), sp 72c (cognate form) was faintly observed. A 0.1 mT exposure did not show sp metabolism to be different from that of the controls; however, after a 1 mT exposure of the HL-60 cells, sp 70i (inducible form) was synthesized ([(35)S]methionine incorporation). Sp 90 was not synthesized at either field level, but was phosphorylated ([(33)P]phosphate incorporation) in the 1 mT exposure. Sp 27 (isoforms a and b) was induced after a 1 mT exposure as reflected by labeling with [(3)H]leucine. These sps were not detected after a 0.1 mT exposure. After a 1 mT exposure and labeling with [(33)P], sp 27 isoforms b and c were phosphorylated whereas isoform 'a' was not observed. Sps 70i, 72c, and 90 were identified by commercial sp antibodies. Likewise, polypeptides a, b, and c were verified as sp 27 isoforms by Western blotting. Statistical evaluation of sp areas and densities, determined from fluorographs by Western-blot analysis, revealed a significant increase in sps 90 and 27a after a 1 mT magnetic field exposure. The 1 mT magnetic field interacts at the cellular level to induce a variety of sp species. Bioelectromagnetics 20:347-357, 1999. Published 1999 Wiley-Liss, Inc.

Electromagnetic Fields↗