A major focus in the study of metabolism and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metabolism and to identify those metabolites that are causally associated with toxic responses. Another important issue involves delineation of sex- and species-dependent differences in biotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metabolism of the cysteine conjugate of TCE by the cysteine conjugate ss-lyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. A synthesis of this information is then presented to assess how experimental data, from either animals or from (italic)in vitro (/italic)studies, can be extrapolated to humans for risk assessment. (italic)Key words(/italic): conjugate beta-lyase, cysteine glutathione, cytochrome P450, glutathione (italic)S(/italic)-transferases, metabolism, sex dependence, species dependence, tissue dependence, trichloroethylene. (+info)
Causality and temporality in the study of short-term effects of air pollution on health.
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BACKGROUND: The relationship between air pollution and health is usually analysed by time series analysis. However, temporality (i.e. looking to see whether the cause precedes the effect) is rarely examined in detail. METHODS: Models were fitted to daily levels of black smoke, nitrogen dioxide, sulphur dioxide, ozone and mortality from Barcelona 1986-1995 to account for seasonality, environmental temperature, days of the week and influenza epidemics. Cross-correlations of the residuals were plotted for different lags. RESULTS: Clear evidence of a temporal relationship between mortality and air pollution found for all four pollutants in that changes in the pollutant preceded changes in mortality, implying causality. However the pattern of dependence was different for each pollutant. CONCLUSION: The cross-correlation plot is a useful tool in the analysis of air pollution time series. (+info)
Methodologic issues in measuring physical activity and physical fitness when evaluating the role of dietary supplements for physically active people.
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Physical activity and physical fitness are complex entities comprising numerous diverse components that present a challenge in terms of accurate, reliable measurement. Physical activity can be classified by its mechanical (static or dynamic) or metabolic (aerobic or anaerobic) characteristics and its intensity (absolute or relative to the person's capacity). Habitual physical activity can be assessed by using a variety of questionnaires, diaries, or logs and by monitoring body movement or physiologic responses. Selection of a measurement method depends on the purpose of the evaluation, the nature of the study population, and the resources available. The various components of physical fitness can be assessed accurately in the laboratory and, in many cases, in the field by using a composite of performance tests. Most coaches and high-level athletes would accept as very beneficial a dietary supplement that would increase performance in a competitive event by even 3%; for example, lowering a runner's time of 3 min, 43 s in the 1500 m by 6.7 s. To establish that such small changes are caused by the dietary supplement requires carefully conducted research that involves randomized, placebo-controlled, double-blind studies designed to maximize statistical power. Statistical power can be increased by enlarging sample size, selecting tests with high reliability, selecting a potent but safe supplement, and maximizing adherence. Failure to design studies with adequate statistical power will produce results that are unreliable and will increase the likelihood that a true effect will be missed. (+info)
Commercial predictive testing: the desirability of one overseeing body.
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In Europe a process of harmonisation of standards and regulations on genetic testing has started. Public discussion and consultation are recommended, but it is not clear in every European country how the decision making process as regards the further introduction of genetic testing services should be formed. In this paper the usefulness and importance of an overseeing body for genetic screening and testing is founded on four lines of reasoning: (1) analysis of the role of value judgments in the use of the concept of (genetic) abnormality; (2) a balancing of potential benefits for all parties involved; (3) a balancing of potential disadvantages, and (4) the greater availability of commercial genetic tests in the future. It is further argued that such an overseeing body has advantages for all the interested parties. (+info)
Multicolor FISH analysis of chromosomal breaks, duplications, deletions, and numerical abnormalities in the sperm of healthy men.
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Transmitted de novo structural chromosomal abnormalities, the majority of which are paternally derived, can lead to abnormal reproductive outcomes as well as genetic diseases in offspring. We developed and validated a new multicolor FISH procedure (sperm ACM, which utilizes DNA probes specific for the alpha [1cen], classical, [1q12], and midi [1p36.3] satellites of chromosome 1) which utilizes DNA probes specific for three regions of chromosome 1 to detect human sperm that carry numerical abnormalities plus two categories of structural aberrations: (1) duplications and deletions of 1pter and 1cen, and (2) chromosomal breaks within the 1cen-1q12 region. In healthy men, the average frequencies of sperm with duplications and deletions were (a) 4.5 +/- 0.5 and 4.1 +/- 1.3 per 10(4) involving 1pter and (b) 0.9 +/- 0.4 and 0.8 +/- 0.3 per 10(4) involving 1cen, respectively. The frequency of sperm exhibiting breaks within the 1cen-1q12 region was 14.1 +/- 1.2 per 10(4). Structural aberrations accounted for 71% of the abnormalities detected by sperm ACM, which was significantly higher than numerical abnormalities (P=2x10-8). Our findings also suggest that, for healthy men, (a) sperm carrying postmeiotic chromosomal breaks appear to be more prevalent than those carrying products of premeiotic or meiotic breakage or rearrangements, (b) the high frequency of chromosome breaks measured after "fertilization" by the hamster-egg cytogenetic method already appear to be present and detectable within human sperm by FISH, and (c) there are nonrandom and donor-specific distributions of breakpoint locations within 1q12 in sperm. FISH facilitates the analysis of much larger numbers of sperm than was possible when the hamster-egg method was used. Therefore, FISH-based procedures for simultaneously detecting chromosomal breaks, rearrangements, and numerical abnormalities in sperm may have widespread applications in human genetics, genetic toxicology, and reproductive medicine. (+info)
Changing concepts in lipid nutrition in health and disease.
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Fat remains a hot topic because of concerns over associations between consumption of fats and the incidence of some chronic conditions including coronary artery disease, diabetes, cancer and obesity. Dietary fats serve multiple purposes. The effects of dietary fats generally reflect the collective influences of multiple fatty acids in the diet or food. This presentation highlights some recent developments on the role of dietary fats and oils in health and disease. Debate continues over the role of dietary modification in coronary prevention by lipid lowering. The degree to which a recommended diet will result in health benefits for an individual is difficult to predict, because the outcome will depend on the influence of other factors such as a person's genetic constitution, level of physical activity and total diet composition. There can now be little doubt about the importance of genetic factors in the etiology of cardiovascular disease, diabetes, obesity and cancer. The importance of antioxidant status in the prevention of cardiovascular disease as well as many cancers is being increasingly recognised. It is now evident that not all saturated fatty acids are equally cholesterolemic. Recent accounts evaluating palm oil's effects on blood lipids and lipoproteins suggest that diets incorporating palm oil as the major dietary fat do not raise plasma total and LDL cholesterol levels to the extent expected from its fatty acid composition. Palm oil is endowed with a good mixture of natural antioxidants and together with its balanced composition of the different classes of fatty acids, makes it a safe, stable and versatile edible oil with many positive health and nutritional attributes. In recent times, adverse health concerns from the consumption of trans fatty acids arising from hydrogenation of oils and fats have been the subject of much discussion and controversy. Trans fatty acids when compared with cis fatty acids or unhydrogenated fats have been shown to lower serum HDL cholesterol, raise serum LDL cholesterol and when substituted for saturated fatty acids, increase lipoprotein Lp (a) level, an independent risk factor for the development of coronary heart disease. The idea of which foods, nutrients and supplements are "healthy" is often being amended as new scientific data is presented and then simplified for the consumers. What was once perceived as a healthy diet is often no longer considered as such and vice versa. Dietary recommendations have to change with time and the evidence available. Nutritional recommendations should encourage eating a great variety of nutrient sources within our food supply in moderation. Various lifestyle options to improve health should also be promoted. (+info)
A randomized controlled trial of concept based indexing of Web page content.
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OBJECTIVE: Medical information is increasingly being presented in a web-enabled format. Medical journals, guidelines, and textbooks are all accessible in a web-based format. It would be desirable to link these reference sources to the electronic medical record to provide education, to facilitate guideline implementation and usage and for decision support. In order for these rich information sources to be accessed via the medical record they will need to be indexed by a single comparable underlying reference terminology. METHODS: We took a random sample of 100 web pages out of the 6,000 web pages on the Mayo Clinic's Health Oasis web site. The web pages were divided into four datasets each containing 25 pages. These were humanly reviewed by four clinicians to identify all of the health concepts present (R1DA, R2DB, R3DC, R4DD). The web pages were simultaneously indexed using the SNOMED-RT beta release. The indexing engine has been previously described and validated. A new clinician reviewed the indexed web pages to determine the accuracy of the automated mappings as compared with the human identified concepts (R4DA, R3DB, R2DC, R1DD). RESULTS: This review found 13,220 health concepts. Of these 10,383 concepts were identified by the initial human review (78.5% +/- 3.6%). The automated process identified 10,083 concepts correctly (76.3% +/- 4.0%) from within this corpus. The computer identified 2,420 concepts, which were not identified by the clinician's review but were upon further consideration important to include as health concepts. There was on average a 17.1% +/- 3.5% variability in the human reviewers ability to identify the important health concepts within web page content. Concept Based Indexing provided a positive predictive value (PPV) of finding a health concept of 79.3% as compared with keyword indexing which only has a PPV of 33.7% (p < 0.001). CONCLUSION: SNOMED-RT is a reasonable ontology for web page indexing. Concept based indexing provides a significantly greater accuracy in identifying health concepts when compared with keyword indexing. (+info)
MedCERTAIN: quality management, certification and rating of health information on the Net.
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MedCERTAIN (MedPICS Certification and Rating of Trustworthy Health Information on the Net, http://www.medcertain.org/) is a recently launched international project funded under the European Union's (EU) "Action Plan for safer use of the Internet. It provides a technical infrastructure and a conceptual basis for an international system of "quality seals", ratings and self-labelling of Internet health information, with the final aim to establish a "trustmark" for networked health information. Digital "quality seals" are evaluative metadata (using standards such as PICS = Platform for Internet Content Selection, now being replaced by RDF/XML) assigned by trusted third-party raters. The project also enables and encourages self-labelling with descriptive meta-information by web authors. Together these measures will help consumers as well as professionals to identify high-quality information on the Internet. MedCERTAIN establishes a fully functional demonstrator for a self- and third-party rating system enabling consumers and professionals to filter harmful health information and to positively identify and select high quality information. We aim to provide a system which allows citizens to place greater trust in networked information, exemplified in the domain of health information, whilst also making a significant contribution for similar projects with different target domains. The project will demonstrate how PICS-based content rating and filtering technologies can automate and exploit value-adding resource description services. It further proposes standards for interoperability of rating services. (+info)