Biomedical subjects

T J Smith

Publications and source records attributed to T J Smith.

At least 37 records · Page 2Linked to original sources

PubMed2003

Biokinetics and assessment of intake of thorium dioxide.

The aim of this work was to investigate the biokinetics of thorium dioxide in animals for the purpose of assessing intakes of the compound by workers and the resulting doses. The results imply that measurements of the decay products in the chest or extrapolations from urine analysis data are unlikely to be of value for doses below 20 mSv. Even higher doses should be interpreted with caution as a consequence of uncertainties in particle size distribution and variations in dietary excretion.

Absorption↗

PubMed2003

Infant doses from the transfer of radionuclides in mothers' milk.

Assessments of potential internal exposures of the child following radionuclide intakes by the mother require consideration of transfers during lactation as well as during pregnancy. Current ICRP work on internal dosimetry includes the estimation of radiation doses to newborn infants from radionuclides ingested in mothers' milk. Infant doses will be calculated for maternal intakes by ingestion or inhalation of the radionuclides, radioisotopes of 31 elements, for which fetal dose coefficients have been published. In this paper, modelling approaches are examined, concentrating on models developed for iodine, caesium, polonium, alkaline earth elements and the actinides. Comparisons of model predictions show maximum overall transfer to milk following maternal ingestion during lactation of about 30% of ingested activity for 131I, 20% for 45Ca and 137Cs, 10% for 90Sr, 1% for 210Po and low values of less than 0.01% for 239Pu and 241Am. The corresponding infant doses from milk consumption are estimated in preliminary calculations to be about two to three times the adult dose for 45Ca and 131I, 70-80% of the adult dose for 90Sr, about 40% for 137Cs, 20% for 210Po, and <0.1% for 239Pu and 241Am. Infant doses from radionuclides in breast milk are compared with doses to the offspring resulting from in utero exposures during pregnancy.

Administration, Oral↗

PubMed2003

Dose coefficients for the embryo and fetus following intakes of radionuclides by the mother.

The International Commission on Radiological Protection has recently issued Publication 88, giving dose coefficients for the embryo, fetus and newborn child from intakes of selected radionuclides of 31 elements by the mother, either before or during pregnancy. The biokinetic models used for calculating these doses were based upon the available human data and the results of animal experiments. This paper summarises the approach used for the development of biokinetic and dosimetric models. It also compares the estimates of dose received by the offspring with those received by the reference adult. The main findings are that, in general, doses to the offspring are similar to or lower than those to the reference adult. For a few radionuclides, however, the dose to the offspring can exceed that to the adult. The reasons for these variations in comparative doses are examined.

Administration, Inhalation↗

PubMed2003

Transfer of alkaline earth elements in mothers' milk and doses from 45Ca, 90Sr and 226Ra.

An international programme of work is currently under way to develop methods for calculating doses to infants from ingestion of radionuclides present in mothers' milk. This paper considers the special case of the alkaline earth elements. Models have been developed for 45Ca, 90Sr and 226Ra and the sensitivity of results to various changes in parameter values is discussed. A complication when calculating doses from intakes of radium is that the International Commission on Radiological Protection has previously recommended that doses from decay products of radium should be calculated using element-specific biokinetic models (so-called independent biokinetics). An extension of this method to the models for breastfeeding is proposed. Preliminary estimates of the doses received by the infant for a number of maternal intake scenarios show that doses to the infant can exceed the corresponding adult dose, such as for 45Ca (ratio = 3.1) while, in other cases such as 90Sr, the infant dose can be a significant fraction of the adult dose.

Administration, Oral↗

PubMed2003

Are the material properties and matrix composition of equine flexor and extensor tendons determined by their functions?

REASONS FOR PERFORMING STUDY: Injury to the superficial digital flexor tendon (SDFT) is common in competition horses. The SDFT contributes to locomotory efficiency by storing energy; such tendons have low safety margins. Tendons which merely position the limb, including the opposing common digital extensor tendon (CDET), are rarely injured. The current failure of strategies to prevent or effectively treat injury to the SDFT indicates the importance of understanding how it differs from tendons which are not injury-prone. HYPOTHESIS: That the structural and material properties and matrix composition of the SDFT and CDET differ, reflecting their specific functional requirements in vivo. METHODS: Forelimb tendons were harvested from 26 mature horses and loaded to failure prior to matrix composition analysis of specimens. RESULTS: The SDFT had a significantly higher cross-sectional area, structural stiffness, failure load and failure strain and a lower elastic modulus than the CDET (P < 0.0001). CONCLUSIONS: The SDFT has conflicting requirements for strength and elasticity; although as a whole it is a stiffer structure than the CDET, differences in the matrix molecular composition including water and total sulphated glycosaminoglycan contents allow it to remain more elastic as a material. POTENTIAL RELEVANCE: Further information on how the two tendons attain these different properties may be of use in the development of prevention and treatment strategies for SDFT rupture.

Animals↗

PubMed2003

Unique properties of orbital connective tissue underlie its involvement in Graves' disease.

Orbital connective tissue manifests Graves' disease through unknown pathogenic mechanisms. Currently there exists little insight into the identity of factors initiating and sustaining the inflammatory response and tissue remodeling associated with ophthalmopathy. We hypothesize that orbital fibroblasts represent cells with unusual phenotypes. They exhibit exaggerated responses to pro-inflammatory cytokines. Among these are inductions of prostaglandin E(2) and hyaluronan synthesis. Activation of fibroblasts occurs through the trafficking of lymphocytes and mast cells to the orbit and the local production of cytokines. In this brief article, we review some of the attributes of orbital fibroblasts and their interactions with immune cells that are currently believed to contribute to their role in the pathogenesis of Graves' disease.

CD40 Antigens↗

PubMed2002

Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody.

The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT/A) in vivo. Although no single mAb significantly neutralized toxin, a combination of three mAbs (oligoclonal Ab) neutralized 450,000 50% lethal doses of BoNT/A, a potency 90 times greater than human hyperimmune globulin. The potency of oligoclonal Ab was primarily due to a large increase in functional Ab binding affinity. The results indicate that the potency of the polyclonal humoral immune response can be deconvoluted to a few mAbs binding nonoverlapping epitopes, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents.

Animals↗

PubMed2002

Dose coefficients for the embryo and foetus following intakes of radionuclides by the mother.

Committee 2 of the International Commission on Radiological Protection (ICRP) has the responsibility for calculating radiation doses from intakes of radionuclides for all age groups in the population. Publication 88 of the ICRP, which has recently been published, describes the development of models used for calculating radiation doses to the embryo and foetus following intakes of radionuclides by the mother. It also gives radiation doses to the offspring for intakes of radionuclides by the mother either before or during pregnancy. The approaches used in the development of the biokinetic and dosimetric models are summarised here together with a comparison of the doses to the offspring with those to the reference adult.

Adult↗

PubMed2002

Doses to organs and tissues from radon and its decay products.

This paper discusses the doses from radon and from its short-lived decay products to a number of organs and tissues and to the foetus. The aim is to put all these doses into context rather than concentrating only on the largest contributions. There is also a brief discussion of the evidence from epidemiology on the risks of exposure to radon and its decay products. As is well known, under normal circumstances the greatest hazard is to the respiratory tract from inhalation of radon decay products. Radon decay products may also give substantial doses to skin. Under some circumstances it seems likely that ingested radon could give significant doses to the stomach. Other risks appear to be smaller; the results given here allow them to be compared.

Air Pollutants, Radioactive↗

PubMed2002

Expression of mRNA transcripts for ATP-sensitive potassium channels in human myometrium.

The molecular mechanisms regulating human uterine quiescence and parturition are poorly understood. Potassium channels are central to regulation of cell membrane potential and contractility of smooth muscle. The aim of this study was to examine the expression of ATP-sensitive potassium channel (K(ATP) channel) subunits in human myometrium, and to investigate for possible differential expression of these subunits in myometrium obtained from three different functional states: (i) non-pregnant (NP); (ii) late pregnant not in labour (PNL); and (iii) late pregnant in labour (PL). RT-PCR detected the presence of mRNA for four subunits of K(ATP) channels (Kir6.1, Kir6.2, SUR1 and SUR2B) in the three tissue types. Quantitative analysis of these subunits was achieved with real-time RT-PCR using Lightcycler(TM) technology. This analysis showed that there were significantly higher levels of Kir6.1 and SUR2B transcripts in NP myometrium compared with those measured in myometrium obtained during pregnancy (P < 0.001). Lower levels of Kir6.2 and SUR1 mRNA expression were found, although higher transcript levels in NP myometrium (P < 0.05) were still observed. Our results indicate that the major K(ATP) channel expressed in human myometrium is composed of Kir6.1 and SUR2B, and that down-regulation of this channel may facilitate myometrial function during late pregnancy.

ATP-Binding Cassette Transporters↗

PubMed2002

Expression and modulation of Rho kinase in human pregnant myometrium.

There is little information outlining the role of Rho kinase, RhoA, and calcium sensitization in regulation of human uterine contractility during pregnancy. The aims of this study were to investigate the expression of RhoA, and the Rho kinases ROCK I and ROCK II in human pregnant myometrium, to evaluate the effects of Rho kinase inhibition on pregnant human myometrial contractility in vitro, and to compare these effects with those of the calcium channel blocker nifedipine. RT-PCR using primers for RhoA, ROCK I and ROCK II was performed on mRNA isolated from human pregnant myometrium. Isometric recording was performed in isolated myometrial strips obtained at Caesarean section. The effects of the Rho kinase inhibitor Y-27632 (1 nmol/l to 10 mmol/l), and nifedipine (1 nmol/l to 10 mmol/l), on oxytocin (0.5 nmol/l) induced contractions were measured and compared. Expression of RhoA, ROCK I and ROCK II mRNA was identified in human pregnant myometrium (n = 3). Y-27632 exerted a potent relaxant effect on myometrial contractility with a pD(2) value (+/- SEM) of 7.63 +/- 0.38 (n = 6). The maximum net relaxant effect (+/- SEM) was 72.3 +/- 6.1% (n = 6). Corresponding values for nifedipine were 7.24 +/- 0.48 (n = 6; P = 0.469) and 93.40 +/- 3.1% (n = 6; P = 0.028). Rho A/Rho kinase-mediated calcium sensitization may play role in the physiology of human parturition, and pharmacological inhibition of this pathway may therefore provide a novel approach to tocolysis for pre-term labour.

Adult↗

PubMed2002

Do regional variations in flexor tendons predispose to site-specific injuries?

Partial rupture occurs most often to the superficial digital flexor tendon (SDFT) of the forelimb at the mid-metacarpal level. In this study, we tested the hypothesis that the mid-metacarpal region of the SDFT has the smallest cross sectional area (CSA) and a similar collagen content to other regions and, therefore, represents a weak point in the tendon. The SDFT was collected from the forelimbs of 9 horses. Each tendon was marked at 7 different levels from the origin of the accessory ligament to the phalangeal region. The CSA, water content and collagen content was measured at each level. The mid-metacarpal level had a significantly smaller CSA than the most proximal and distal levels measured and a significantly higher dry matter content than proximal levels. However, the total amount of collagen present in the mid-metacarpal section was not significantly less than other regions except for the most distal sections. The results of this study suggest that the mid-metacarpal region of the SDFT, although smaller in CSA, is not significantly weaker than the proximal end and manica flexoria region of the tendon. Therefore, other factors such as hypoxia and/or hyperthermia may be responsible for site-specific tendon lesions in the SDFT.

Animals↗

PubMed2001

Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues.

The effects of green and black tea polyphenols on cyclooxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonic acid metabolism in normal human colon mucosa and colon cancers were investigated. At a concentration of 30 microg/mL, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin-3-gallate (ECG) from green tea and theaflavins from black tea inhibited LOX-dependent activity by 30-75%. The formation of 5-, 12-, and 15-LOX metabolites was inhibited to a similar extent. Tea polyphenols also inhibited COX-dependent arachidonic acid metabolism in microsomes from normal colon mucosa, with ECG showing the strongest inhibition. The formation of thromboxane (TBX) and 12-hydroxyheptadecatrienoic acid (HHT) was decreased to a greater extent than other metabolites. The inhibitory effects of tea polyphenols on COX activity, however, were less pronounced in tumor microsomes than in normal colon mucosal microsomes. Theaflavins strongly inhibited the formation of TBX and HHT, but increased the production of prostaglandin E(2) (PGE(2)) in tumor microsomes. The enhancing effect of theaflavins on PGE(2) production was related to the COX-2 level in the microsomes. Although theaflavin inhibited ovine COX-2, its activity in the formation of PGE(2) was stimulated by theaflavin when ovine COX-2 was mixed with microsomes, suggesting that theaflavin affects the interaction of COX-2 with other microsomal factors (e.g. PGE synthase). The present results indicate that tea polyphenols can affect arachidonic acid metabolism in human colon mucosa and colon tumors, and this action may alter the risk for colon cancer in humans.

Antioxidants↗

PubMed2001

Gene structure and promoter function of a teleost ribosomal protein: a tilapia (Oreochromis mossambicus) L18 gene.

We have cloned and characterized a tilapia (Oreochromis mossambicus) L18 ribosomal protein gene, including the complete transcribed region and 488 bp of upstream regulatory sequences. We have also isolated two L18 cDNAs from another tilapia (Oreochromis niloticus) with a few conservative nucleotide differences. Our results suggest the presence of two genes in both species. Reporter constructs were tested for transient expression in CV1 cells and in microinjected zebrafish and tilapia embryos. The tilapia L18 promoter was able to drive expression of the reporter gene in all three experiments, with no apparent preference for a particular tissue. The tilapia L18 promoter is therefore likely to be a powerful tool to drive tissue-independent gene expression in fish.

Amino Acid Sequence↗

PubMed2001

Association of heart rate variability with occupational and environmental exposure to particulate air pollution.

BACKGROUND: Airborne particulate matter has been linked to excess morbidity and mortality. Recent attention has focused on the effects of particulate exposure on cardiac autonomic control. Inhaled particulates may affect the autonomic nervous system either directly, by eliciting a sympathetic stress response, or indirectly, through inflammatory cytokines produced in the lungs and released into the circulation. METHODS AND RESULTS: This longitudinal study examined the association of particulates </=2.5 microm in diameter (PM(2.5)) with heart rate variability (HRV) in an occupational cohort (N=40). Continuous monitoring of exposure and HR was performed during and away from work. PM(2.5) levels were higher than ambient levels typically reported in Boston, 0.167+/-3.205 mg/m(3) (geometric mean+/-geometric SD). We found a 2.66% decrease (95% CI, -3.75% to -1.58%) in the 5-minute SD of normal RR intervals (SDNN) for every 1 mg/m(3) increase in the 4-hour moving PM(2.5) average and a 1.02% increase (95% CI, 0.59% to 1.46%) in HR after adjusting for potential confounding factors. The decrease in SDNN became larger as the averaging interval increased. CONCLUSIONS: Workers experienced altered cardiac autonomic control after exposure to occupational and environmental PM(2.5). There appears to be either a long-acting (several hours) and a short-acting (several minutes) component to the mechanism of action that may be related to the production of cytokines and the sympathetic stress response, respectively, or a cumulative effect that begins shortly after exposure begins. The clinical significance of these effects in a healthy working population is unclear.

Adult↗

PubMed2001

Genetic and dietary factors affecting human metabolism of 1,3-butadiene.

The objective of this project was to determine the factors associated with differences in butadiene (BD) inhalation uptake and the rate of metabolism for BD to epoxy butene by monitoring exhaled breath during and after a brief exposure to BD in human volunteers. A total of 133 subjects (equal males and females; four racial groups) provided final data. Volunteers gave informed consent and completed a questionnaire including diet and alcohol use. A venous blood sample was collected for genotyping CYP2E1. Subjects received a 20 min exposure to 2.0 ppm of BD, followed by a 40 min washout period. The total administered dose was 0.6 ppm*h, which is in the range of everyday exposures. Ten, 1 or 2 min exhaled breath samples (five during and five after exposure) were collected using an optimized strategy. BD was determined by GC-FID analysis. Breathing activity (minute ventilation, breath frequency and tidal volume) was measured to estimate alveolar ventilation. After the washout period, 250 mg of chlorzoxazone were administered and urine samples collected for 6 h to measure 2E1 phenotype. The total BD uptake during exposure (inhaled BD minus exhaled) was estimated. A three-compartment PBPK model was fitted to each subject's breath measurements to estimate personal and population model parameters, including in-vivo BD metabolic rate. A hierarchical Bayesian PBPK model was fit by Monte Carlo simulations to estimate model parameters. Regression and ANOVA analyses were performed. Earlier data analysis showed wide ranges for both total uptake BD and metabolic rate. Both varied significantly by sex and age, and showed suggestive differences by race, with Asians having the highest rates. The analyses reported here found no correlation between total BD uptake and metabolic rate. No significant differences were found for oxidation rates by 2E1 genotype or phenotype, but the rates showed trends consistent with reported differences by genotype and phenotype for chlorzoxazone metabolism. No effects on metabolic rate were observed for long-term alcohol consumption, or consumption in the past 24 h. Overall, neither dietary factors nor genetic differences explained much of the wide variability in metabolic rates. Population characteristics, age, sex, and race, were the most important explanatory variables, but a large fraction of the total variability in metabolism remains to be explained.

Administration, Inhalation↗

PubMed2001

Ensuring quality cancer care by the use of clinical practice guidelines and critical pathways.

PURPOSE: We describe the impact of clinical practice guidelines (CPGs) on improvement in oncology treatment processes or outcomes. METHODS: We performed a comprehensive search of the literature from 1966 to the present and a directed review of the literature. RESULTS: Improvements have been demonstrated in compliance with evidence-based guidelines or evidence-based medicine, and in short-term length of stay, complication rates, and financial outcomes. The data suggest that patient satisfaction can be maintained despite a shorter length of stay. There has been one example of province-wide improvement in disease-free and overall survival of breast cancer patients coincident with the adoption of CPGS: The components of successful guidelines can be summarized as follows: (1) development is based on evidence, with the guideline formulated by key physicians in the group; (2) the guidelines are disseminated to all affected health care professionals for critique; (3) implementation includes direct feedback on performance to physicians or general feedback on system performance; and (4) there is accountability for performance according to the guidelines. This accountability can consist of voluntary peer pressure to conform to evidence-based medicine, and it does not require a financial reward or penalty. CONCLUSION: Some attempts to improve practice have been moderately successful in achievement of reduced health care costs, reduced hospital length of stay, and possibly improved outcomes. Other methods that are still in use have been demonstrated to have little effect. Programs that have not succeeded have relied on voluntary change in practice behavior without incentives to change or have had no accountability component. Further research is needed to assess how guidelines are enacted in organizations other than those demonstrably committed to improvement, ways to improve compliance of health care providers who are not committed to change, and methods to improve accountability.

Critical Pathways↗

PubMed2001

Structures of bovine glutamate dehydrogenase complexes elucidate the mechanism of purine regulation.

Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. However, only animal GDH utilizes both NAD(H) or NADP(H) with comparable efficacy and exhibits a complex pattern of allosteric inhibition by a wide variety of small molecules. The major allosteric inhibitors are GTP and NADH and the two main allosteric activators are ADP and NAD(+). The structures presented here have refined and modified the previous structural model of allosteric regulation inferred from the original boGDH.NADH.GLU.GTP complex. The boGDH.NAD(+).alpha-KG complex structure clearly demonstrates that the second coenzyme-binding site lies directly under the "pivot helix" of the NAD(+) binding domain. In this complex, phosphates are observed to occupy the inhibitory GTP site and may be responsible for the previously observed structural stabilization by polyanions. The boGDH.NADPH.GLU.GTP complex shows the location of the additional phosphate on the active site coenzyme molecule and the GTP molecule bound to the GTP inhibitory site. As expected, since NADPH does not bind well to the second coenzyme site, no evidence of a bound molecule is observed at the second coenzyme site under the pivot helix. Therefore, these results suggest that the inhibitory GTP site is as previously identified. However, ADP, NAD(+), and NADH all bind under the pivot helix, but a second GTP molecule does not. Kinetic analysis of a hyperinsulinism/hyperammonemia mutant strongly suggests that ATP can inhibit the reaction by binding to the GTP site. Finally, the fact that NADH, NAD(+), and ADP all bind to the same site requires a re-analysis of the previous models for NADH inhibition.

Adenosine Diphosphate↗